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Iris publishers-Open access journal of Rheumatology & Arthritis Research|  Atypical Griscelli Syndrome Presenting with Immune Dysregulation, Systemic Granulomatosis and Normal Pigment Secondary to A Structural Variant in RAB27A

Authored by:  Gunderman Lauren M

Introduction

Griscelli Syndrome Type 2 (GS2) is a rare autosomal recessive disease characterized by organ granulomas, central nervous system inflammation, hemophagocytic lymphohistiocytosis (HLH) and partial albinism. Patients have immune dysregulation secondary to dysfunctions in natural killer (NK) cell and T cell cytotoxicity as a result of poor vesicular transport [1-2]. Typically, patients also have abnormal skin and hair pigmentation from accumulation of melanosome clumps in hair shafts and melanocytes. Homozygous or compound heterozygous pathogenic variants in RAB27A are associated with GS2. However, patients with atypical GS2 harbor a structural rearrangement in RAB27A not detected by typical genetic sequencing [3]. We present two cases of atypical GS2 (below and in supplement) characterized by systemic granulomatosis, neuroinflammation and normal skin and hair pigment, secondary to a structural variant (SV) in RAB27A and a second pathogenic sequence variant on the other allele of the gene.

Patient Case

Our patient (patient 1) is a previously healthy Caucasian female of distant Lithuanian descent who presented at age 13 with pneumonia requiring IV antibiotics and supplemental oxygen. Despite antibiotics, her respiratory status worsened. She was unable to wean from oxygen until the addition of high-dose corticosteroids. Extensive infectious workup was negative. Immunology workup revealed mild hypogammaglobulinemia, persistent lymphopenia and mild neutropenia. Biopsy of a skin nodule showed non-specific mild perivascular and interstitial dermatitis. Bone Marrow biopsy showed a hypo-cellular marrow with progressive multi-lineage hematopoiesis, but no evidence of leukemia. Nodular opacities were visualized on Chest CT. Of interest, the lung biopsy portrayed intra-alveolar macrophages and extensive non-necrotizing intraalveolar granulomas, concerning for interstitial lung disease (ILD).

After discharge, she re-presented with dyspnea despite continued steroids. Intravenous Immunoglobulin (IVIG) and mycophenolate (a steroid-sparing agent) were started for suspected GLILD (granulomatous lymphocytic interstitial lung disease) and steroids were decreased. However, attempts to further wean steroids led to reoccurrence of hypoxia and skin nodules. The disease course was further complicated by an episode of aphasia, unilateral loss of peripheral vision and severe headache. Brain MRI revealed numerous subcortical, cerebral white matter and basal ganglia lesions concerning for an inflammatory or demyelinating process. Due to concerns for relapse, Mycophenolate was switched to Azathioprine and Rituximab, standard treatment for GLILD. Around this time, singleton WES resulted in multiple variants of uncertain significance (VUS), including a heterozygous likely pathogenic variant in RAB27A (c.259G>C, p. Ala87Pro). She was not diagnosed with Griscelli Syndrome because of the normal skin pigmentation and lack of a second pathogenic variant in the RAB27A gene. and Mycophenolate was restarted for possible better disease control. Yet after 4 weeks on Mycophenolate, episodes of confusion developed and nodular skin lesions worsened. The confusion was attributed to seizures based on Brain MRI results showing acute diffusion restriction in the left temporal lobe and insula, and she began antiepileptic therapy. In the following 6 months, the patient developed asymptomatic anterior uveitis of the eye, retinal granulomas and vasculitis. Prolonged steroid use caused significant side effects including insulin resistance, short stature, central obesity and mild compression fractures. She switched from Rituximab to Infliximab to Abatacept for immune suppression; all failed to gain disease control. Seizures worsened with attempts to wean steroids. Labs became significant for low CD107a (NK cell degranulation) and elevated serum neopterin (62 nmol/L, Reference range: <10.0 nmol/L), despite the normal soluble IL-2 receptor. Therefore, evaluation for a RAB27A SV was conducted via a multiplex ligation-dependent probe amplification (MLPA) assay using 10 probes in coding and non-coding regions of RAB27A and the nearby PIGB gene (Table 1). A complex duplicationinversion SV was found in the 5’ untranslated region (5’UTR) of RAB27A and confirmed by Sanger sequencing. The SV was classified as pathogenic. This, in conjunction with the likely pathogenic RAB27A variant found on WES, resulted in the diagnosis of atypical GS2. Parental genetic testing revealed the variants were inherited in trans. After diagnosis, she was switched from Mycophenolate to Cyclosporine for immune modulation, and Abatacept was discontinued after a 3-month trial. Despite changes in therapy, the neuroinflammation worsened and neopterin levels (76.3 nmol/L) were found elevated in the CSF. Given this progression, she started anti-interferon gamma therapy (Emapalumab; a cytokine therapy) as a bridge to stem cell transplant to reduce inflammation and control disease progression. While on this medication, the CSF neopterin levels declined and repeat MRI was stable. Stem cell transplant was completed. Unfortunately, the patient (Patient 2) did not survive complications from the post-transplant period (Figure 1).

Discussion

The RAB27A gene encodes the Rab27a protein and is important for vesicle transport and docking in a variety of cell types (platelets, leukocytes and melanocytes). Variants in RAB27A lead to GS2, resulting in an immune dysregulatory phenotype with increased susceptibility to infection, cytopenias, HLH, neurologic involvement and complete to partial albinism [2]. Lack of pigment and immunodeficiency in GS2 are linked as both result from a dysfunction in secretory vesicles, a component essential for the proper functioning of cytotoxic T lymphocytes, natural killer cells and melanocytes.

Unlike the variants in RAB27A associated with typical GS2, RAB27A structural variants associated with atypical GS2 are not easily detected. The SV found in the 5’ untranslated region (5’UTR) of RAB27A in our patients was previously reported by Tesi et al., in 5 children from 5 unrelated families of the Baltic Sea population who had characteristic findings of GS2 (immune dysregulation, including neuroinflammation, skin granulomas, and late-onset HLH) but the atypical finding of normal skin and hair pigment [3]. In these families, heterozygous carriers of the SV were not affected by disease, though those homozygous or compound heterozygous for the SV and a separate pathogenic RAB27A variant were affected by atypical GS2 [4]. Expression studies in a homozygous carrier of the SV, using RNA from peripheral blood mononuclear cells, provided evidence that the inverted duplication interrupts the transcription start site of the longest RAB27A transcript (NM_183235.2) [5]. This transcript is the predominant RAB27A isoform in lymphocytes but is expressed to a lesser extent in melanocytes, according to FANTOM CAGE data and expression studies in melanocytes from control individuals [6].

The custom designed targeted MLPA assay used to detect the SV in RAB27A was key to the diagnosis in these patients (Table 1). Typical next-generation sequencing (NGS) based assays are unable to detect the SV as non-coding regions of the genes are not routinely sequenced in panel testing or WES studies. Without the MLPA analysis, it would have been challenging to recognize that these patients had atypical GS2, due to lack of pigment abnormalities and also differences in age of presentation and variability in HLH as a predominant feature. Patients who present with skin granulomas, neurologic involvement, concern for HLH and ancestry in the Baltic Sea region should be evaluated for structural RAB27A variants, even with the absence of pigment abnormalities. If a RAB27A variant is found on NGS and phenotypic features of GS2 are present, a MLPA assay is necessary to evaluate for this SV. This case outlines the importance of early diagnosis in atypical GS2, reiterates the usefulness of targeted genetic testing for early diagnosis and offers a playbook of therapeutic options, including both the success and failures of targeted therapies.

Table 1:MLPA probes used in this study.

Conflict of Interest

None.

Acknowledgements

None.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research|  A Brief Review of Reverse Shoulder Arthroplasty for Rotator Cuff Arthropathy

Abstract

Reverse total shoulder arthroplasty is an increasingly popular procedure performed by orthopedic surgeons. The indications have expanded over the past two decades with well documented success in the treatment of rotator cuff arthropathy. Patients with loss of rotator cuff function experience altered shoulder biomechanics that lead to superior humeral head migration, acetabulization of the acromion and progressive glenohumeral arthritis. Clinically, patients present with chronic shoulder pain, weakness and loss of range of motion that impacts activities of daily living. To address this, a reverse total shoulder can be performed. The procedure is normally done in the beach chair position utilizing the deltopectoral approach. A humeral stem with liner and glenosphere is implanted into the humerus and scapula, respectively. The procedure has shown consistent improvements in pain, strength, range-of-motion and function. Complications include dislocation, instability, fracture and infection.

Keywords: Rotator cuff arthropathy; Reverse total shoulder arthroplasty; Arthritis, Shoulder; Shoulder replacement; Review

Abbreviations:

TSA – Total shoulder arthroplasty

RTSA - Reverse total shoulder arthroplasty

CTA - Cuff tear arthropathy

RCR - Rotator cuff repair

AHI - Acromiohumeral index

MMI - Maximum medical improvement

ER - External rotation

ROM - Range of motion

Introduction

Shoulder arthroplasty is an increasingly popular procedure, with a rise in volume of 103.7% from 2011 to 2017 [1]. This trend is particularly notable when examining the reverse shoulder arthroplasty (rTSA) rates which increased in volume by 191.3% between 2011 and 2017 and increased in incidence by 178.3% within the same time period [2]. Additionally, 42% of all shoulder arthroplasties (anatomic, reverse, or hemiarthroplasty) were rTSAs in 2011 [3]. Using Poisson regression model, overall volume of rTSA was projected to increase 353% by 20252. The demand for all shoulder arthroplasties is expected to increase over 750% by 2030[4].

The indications for rTSA have steadily grown over recent years and now typically include glenohumeral arthritis due to osteoarthritis or cuff tear arthropathy (CTA), failed hemiarthroplasty, malunion, nonunion, humeral fracture, or proximal humeral tumor [5-7]. Rotator cuff tear arthropathy is an increasingly recognized cause of glenohumeral arthritis [5-10]. Anatomic shoulder arthroplasty was historically the gold standard for rotator cuff pathology, until Grammont designed the initial reverse total shoulder arthroplasty (rTSA) in 1987 which has been continually improved upon and optimized [5,6,11,12]. Approved in the US in 2004, rTSA bypasses the need for an intact rotator cuff and creates stability by lowering the humeral head and medializing the center of rotation [5-9,11-13].

Anatomy and Biomechanics

The rotator cuff consists of the supraspinatus, infraspinatus, teres minor, and subscapularis muscles [8]. The first three are considered external rotators, while the subscapularis functions mainly in internal rotation [5]. The first group inserts at the greater tuberosity of the humerus and the subscapularis inserts at the lesser tuberosity. The supraspinatus consists of an anterior and posterior portion. Initially thought to solely contribute to external rotation, this muscle also functions in forward flexion and abduction. Bearing more mechanical stress, the anterior portion is more susceptible to tearing.

Also relevant to rotator cuff arthropathy and reverse total shoulder arthroplasty is the deltoid. The deltoid muscle has three components, each with separate functions. The anterior deltoid flexes, the middle deltoid abducts, and the posterior deltoid extends the shoulder. Mainly, the rotator cuff functions to stabilize the humeral head within the glenoid fossa and to allow concentric rotation of the humeral head6. Specifically, the supraspinatus and subscapularis are the major stabilizers in mid-range of motion and the subscapularis, infraspinatus and teres minor are the major stabilizers in the end-range of motion [14,15]. Loss of rotator cuff function has been shown to disrupt the glenohumeral stability [16].

Pathophysiology of Rotator Cuff Arthropathy

As described by Neer et al in 1983, a deficient rotator cuff leads to superior migration of the humerus due to loss of downward compressive force within the glenoid fossa [8,12]. Humeral migration can erode the superior surface of the glenoid and anteroinferior aspect of the acromion, as well as wear out articular cartilage in areas of higher glenohumeral compression due to joint instability [8].

Burkhart also provides a description of the pathogenesis of rotator cuff arthropathy. Normally, inferior portion of the rotator cuff balances out the deltoid moment and the subscapularis is inferiorly balanced against the infraspinatus and posteriorly against the teres minor [6-9]. With a deficient rotator cuff, elevation of the shoulder causes anterosuperior translation of the humeral head [8,12]. Contact of the humeral head articular cartilage with the anteroinferior margin of the acromion fragments cartilage and causes synovial thickening, effusion, and calcium phosphate crystal deposition [6-9].

Other causative factors include dispersion of synovial fluid due to loss of water-tight seal upon rotator cuff damage, cytokine effects (from increased production of interleukin-1β, TNF, and MMPs), and fatty infiltration, but mechanical forces have been shown to be the most important factor [ 5-8, 10, 12].

Clinical Presentation

The patient with cuff tear arthropathy is most commonly a female older than 65 with severe shoulder pain of long duration8. The dominant side is most often affected. Pain typically presents in the anterolateral shoulder, interferes with sleep, and worsens with activity. Inspection may reveal shoulder profile deformity due to upward migration of the humeral head as well as atrophy of the infraspinatus and supraspinatus muscles [9]. Physical examination likely reveals marked weakness on external rotation, positive full can test, audible crepitus, and severely limited active and passive range of motion. Most noticeable may be the presence of pseudoparalysis which presents as an inability to actively elevate the shoulder above 90 degrees [15]. A known risk factor for cuff tear arthropathy is prior rotator cuff repair (RCR) [5,8,10,14]. Rotator cuff pathology is exceedingly common and accounts for 250,000 surgical procedures annually in the United States [8,10]. The midterm (3-10 year) rate of developing CTA in one study of patients with arthroscopic RCR was 11.5%, with long-term (20+ year) rates ranging from 19-66% in other studies of the same patient populations [10].

Radiographic Findings

Staging of rotator cuff arthropathy is generally a radiographic endeavor. The Hamada classification describes the plain radiograph changes in the shoulder in the setting of rotator cuff deficiency [17]. The classification highlights the superior migration of the humeral head, following by acetabulization of the acromion and finally progression of glenohumeral arthritis. In Grade 1, there is an acromiohumeral interval (AHI) of >6mm with a normal glenohumeral joint. In Grade 2, there is an AHI of <5mm. In Grade 3, there is acetabulization of the acromion. In Grade 4, there is narrowing of the glenohumeral joint and finally in Grade 5 there is humeral head collapse. Reverse total shoulder arthroplasty is typically reserved for Hamada Grades [4-5].

Evolution of Treatment

Various forms of arthroplasty have been utilized in the management of rotator cuff arthropathy. Initially, constrained and non-constrained anatomic total shoulder arthroplasty were thought to be the answer. However, the deficient rotator cuff resulted in high rates of revision due to implant loosening and instability18,19. Due to poor outcomes with total shoulder arthroplasty, hemiarthroplasty was then utilized in the treatment for rotator cuff arthropathy. Unfortunately, while this form of arthroplasty provided predictable pain relief, they did not demonstrate sufficient improvements in strength, range of motion or function [20,21].

The Grammont prosthesis introduced in the 1980s was the pre-curser to the reverse total shoulder. It addressed the altered biomechanics in rotator cuff arthropathy by bringing the center of rotation of the glenohumeral joint medial and distal. This allowed the deltoid to function to offset the diminished rotator cuff, improved strength, range of motion and decreased risk of component loosening [22,23]. Since the introduction of the Grammont prosthesis, there has been continued improvement in the design and implantation. While the best indication for reverse total shoulder is based on the presence of rotator cuff arthropathy, it is important to recognize that there are contraindications. A deficient deltoid, axillary nerve damage, diminished glenoid bone stock and infection are contraindications to reverse total shoulder arthroplasty [24,25].

Surgical Technique for rTSA

The patient is placed in beach chair positioning under general anesthesia, with or without interscalene block [11,26]. In the United States, a deltopectoral approach is most commonly used [1,7,11,12,26,27,28,29]. The cephalic vein is visualized and lateralized [7]. The subscapularis is tenotomies or peeled from the lesser tuberosity and ~1-2 cm of the pectoralis major tendon may be released for better exposure [1,7, 8,11,28,29]. Release of the subacromial, subdeltoid, and sub conjoint spaces is achieved with blunt dissection and occasional electrocautery [7,28]. The musculocutaneous and axillary nerves should be identified and protected [7,11,28]. A Kolbel retractor is placed under the deltoid and conjoint tendon [31]. The humeral capsule is released with progressive external rotation, and complete osteophyte resection is performed to increase glenoid exposure [7,28]. The humerus is then dislocated and the head cut generously, given that supraspinatus preservation is unnecessary in this reverse procedure [7,28,29]. Glenoid retractors are placed followed by labrum resection and release of the anterior capsule, subscapularis, posterior and inferior capsule, and some of the triceps origin to allow low positioning of glenoid baseplate and reduce notching [7,8,28]. The baseplate and glenosphere are placed and optimal tension set with added polyethylene thickness [5-8,11,28]. Typically, the glenoid baseplate is uncemented and fixed, as inferior as possible, with locking screws while the humeral stem is cemented or press fit [1,5,6,8,11,13,26,28].

Rehabilitation Protocol

Post-op protocols vary but typically involve sling immobilization for 4 weeks with elbow, wrist, and finger AROM encouraged from day [11,12,26,27,30]. At 0-2 weeks post-op, pendulum exercises and passive forward flexion and abduction typically begin and active ROM usually begins around week [4-6,11,12,26,30]. Patients are advised to avoid internal rotation and “push-off” activities for the first 6 weeks due to the risk of instability [30].

Outcomes

Maximum medical improvement (MMI) is achieved at 1-year post-op in patients undergoing rTSA for CTA, with rapid improvement in the first 3 months that tapers throughout the 1st year [4]. A systematic review by Cabarcas et al. found that clinically significant improvements occur in patient-reported outcome measurements, forward flexion, and abduction by 3 months with improvements in external rotation between 3 to 6 months and 6 months to 1 year [4]. The lag in ER gain was attributed to relative internal rotation while in post-op sling [4]. Statistically significant improvements in pain and function remained present at 10-year follow up in a large cohort study by Sheth et al. from 2021 [13]. Jobin et al demonstrated that the benefits of the reverse total shoulder were significantly correlated to the deltoid lengthening provided by the prosthesis [32]. Favard et al demonstrated an implant survivorship of 89% at ten years in a retrospective review [33]. The complication rate for rTSA varies between 4.8% to 68%, though most studies examining outcomes are not recent [4]. Given the highly technical nature of rTSA, complications typically occur at a higher rate than anatomic TSA [4]. Possible complications include dislocation (most common; rate: 1.5-31%), heterotopic ossification, limited external rotation, instability, infection, fracture, or peripheral nerve injury [5,11,12,26,31]. The best outcomes are typically found in patients over 70 years old and those with less pre-op ROM, which reinforces the importance of proper patient selection and counseling [6,9]. Worse outcomes are found in males, workers compensation cases, patients with multiple medical comorbidities including depression [34].

Conclusion

The reverse total shoulder has proven to be a reliable operation for the treatment of rotator cuff arthropathy over the past few decades. It addresses the arthritic component to provide pain relief and restores shoulder biomechanics to a degree that allows increased strength and range of motion. Overall, patients experience a greater quality of life due to this procedure. The reverse total shoulder is not without its complications, which include dislocation, instability, fracture and infection. However, throughout the years, research has led to the characterization of more appropriate indications for surgery, surgical techniques, implant designs and post-operative rehabilitation protocols. Ultimately, reverse total shoulder arthroplasty is a well-supported treatment for rotator cuff arthropathy.

Acknowledgements

None.

Conflict of Interest

No conflict of interest to report.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| Bilateral Isolated Third Metacarpophalageal Arthritis at Long-Term Follow Up After Bilateral Wrist Fusion

Authored by: Dane Daley MD

Abstract

Total wrist fusion is an established surgical option for the management of severe wrist arthritis. Long-term sequelae of wrist fusion are numerous and incompletely understood. The following case documents a patient who developed third metacarpophalangeal (MCP) joint arthritis following radiocarpal wrist fusion with a plate and screw construct from the radius to the third metacarpal. An MCP arthroplasty was subsequently performed and outcomes reported. This case report outlines the need for further study of the force transmission through and motion of the MCP joint following a radiocarpal wrist arthrodesis.

Introduction

Total wrist fusion or radiocarpal arthrodesis is a mainstay treatment for arthritic wrist pain. Arthrodesis has been utilized for the surgical management of advanced arthritis in the radiocarpal joint and midcarpal joints since the early 1900s [1]. When successfully performed, this procedure provides pain relief and increased strength via wrist stability at the expense of motion [2]. Wrist arthrodesis is the definitive surgical management for symptomatic wrist arthritis where limited motion may already be present. Despite the emergence of total wrist arthroplasty (TWA) in the 1970s, wrist arthrodesis remains a common procedure. TWA and radiocarpal arthrodesis have similar indications and outcomes, including pain relief and return to function [3]. The complications of a radiocarpal arthrodesis are frequently preventable and often temporary. These include surgical site infections, symptomatic hardware, impaction, impingement, intra-operative nerve injuries, post-operative neuritis, as well as the development of adjacent joint arthritis, specifically the distal radioulnar joint (DRUJ) and trapeziometacarpal joints [4]. At long term follow-up, progressive arthritic changes were identified in nearly one third of patients [5]. However, arthritic changes of the MCP joint following total wrist arthrodesis have not been reported in the literature. This case report presents a patient with symptomatic bilateral third MCP osteoarthritis following total wrist arthrodeses performed in the 1990s. The goal of this report is to inform hand surgeons of a potential long-term complication after radiocarpal arthrodesis and to direct future biomechanical studies on MCP force transmission and motion.

Case Report

A 77-year-old right-hand-dominant male presents with bilateral hand cramping and long finger pain. Patient is a non-smoker, retired, and denies a medical history of gout or inflammatory arthropathy. The patient previously sustained bilateral distal radius fractures 20 and 25 years prior to presentation. His fractures were managed surgically and complicated by persistent pain, degenerative changes of the wrist, and instability. Ultimately the patient elected to proceed with bilateral radiocarpal fusions utilizing a plate and screw construct extending from the distal radius to the third metacarpal, both of which went on to successful union. The patient reported resolution of his arthritic wrist symptoms and recalled no perioperative or post-operative complications and satisfactory bilateral upper extremity function for nearly 20 years following his wrist fusions. Prior to his presentation, he experienced cramping and pain isolated to the left third MCP joint exacerbated by prolonged activity and pain that interferes with sleep. He attempted bracing, activity modification, and topical and oral anti-inflammatory medications without significant relief. Intra-articular MCP joint injections provided short term pain relief. However, his symptoms impacted his ability to perform certain activities of daily living and prevented him from engaging in pursuits such woodworking and gardening.

Examination of the left upper extremity revealed a well-healed, midline dorsal wrist incision. The extremity was neurovascularly intact with full range of motion of his digits, including all MCP joints. Strength testing showed 4/5 grip strength, 4/5 APB, and 5/5 interossei muscle strength. Tenderness to palpation at the third MCP joint with associated swelling was noted. The provocative tests for carpal tunnel syndrome were negative. No masses, skin wounds, or other evidence of injury to the hand or wrist was identified. Examination of the right upper extremity revealed similar findings with less severe tenderness to palpation at third MCP joint.

Bilateral PA, lateral, and oblique radiographs (Figure 1) were obtained demonstrating diffuse degenerative changes of bilateral hands with severe osteoarthritic changes at the third MCP joints bilaterally. Long finger MCP joints featured large osteophytes, joint space narrowing, subchondral sclerosis, and cyst formation. Images demonstrated appropriate alignment of the plate and screw fixation from the radius to the third metacarpal and a solid fusion mass without hardware complications, lucency, or fracture.

The patient was diagnosed with bilateral long finger MCP joint osteoarthritis. Following discussion with the patient, the patient elected to proceed with a left middle finger MCP joint arthroplasty using a flexible silicone prosthetic.

Via dorsal midline approach, collateral ligaments were found and preserved. A constrained silicone elastomer joint replacement was inserted. Stability and adequate range of motion were confirmed, incision closed, and the procedure was completed without complication. Patient was splinted post-operatively with instructions to initiate hand therapy at 2 weeks.

At final follow up, examination of the left hand revealed wellhealed incision without instability or loss of motion at this MCP joint. The long finger had recovered full preoperative range of motion. He reported resuming activities including yard work and gardening without pain. Post-operative radiographs were obtained at 2 weeks (Figure 2).

Discussion

MCP arthritis is a potential long-term complication following total wrist arthrodesis. There are many known complications of wrist arthrodesis, the majority of which occur in the immediate post-operative period and are largely avoidable by improving patient selection, surgical technique, or postoperative care [5]. Most common complications include surgical site infections, carpal tunnel syndrome, and pain related to prominent hardware, skin irritation, or extensor tendonitis and even attritional rupture [4]. Considerable data exists cataloguing and describing the long-term outcomes of wrist arthrodesis. Multiple studies have reviewed wrist arthrodesis cases, following patients up to thirty years after operation. Extended follow-up studies report positive patient-reported outcomes with over 90% patient satisfaction. Complications are not uncommon but are largely limited in their effect and duration. However, baseline functionality did not return in many patients, even in the absence of complications. The most common functional limitations included opening doorknobs or opening sealed jars [6, 7]. These difficulties and other complications rarely require surgical correction. Nearly 70% of patients who undergo a wrist arthrodesis do not require a secondary surgery within 20 years of the index operation [7].

Adjacent joint arthritis is not mentioned as a common complication in these studies; however, its occurrence is welldocumented. Two additional studies monitoring the long-term consequences of total wrist arthrodesis estimate the prevalence of adjacent joint arthritis between 19-23% [8, 9]. These reports do not mention MCP joint arthritis. Adjacent joint arthritis most commonly involves the distal radioulnar joint. In limited wrist fusions, the trapeziometacarpal and midcarpal joints are the most effected. MCP joint arthritis remains poorly described in the literature. Overall, arthritic complications appear to be more prevalent in midcarpal wrist fusions versus total wrist fusion [4].

Specific limitations require discussion in regard to the case presented. Due to the isolated nature of this case, determination of causality is presumptive. The bilateral nature of the MCP arthritis following surgery indicates shared pathophysiological process. However, osteoarthritis is a common condition among elderly patients and selective joint involvement could be related to other patient-specific and lifestyle factors. MCP arthritis following wrist arthrodesis could be unreported in the literature. Very few patients have documented long term follow-up, making the prevalence of this complication very difficult to estimate. Additionally, it is possible that physicians managing patients with adjacent MCP arthritis did not connect their findings to a past procedure. The arthritic pattern has not been reported in literature in association with total wrist fusion, so correlation could be overlooked.

Conclusion

Adjacent metacarpophalangeal joint arthritis serves as a potential complication of total wrist arthrodesis using a plate and screw construct. Hand surgeons and physicians following patients who have undergone this procedure shoulder consider the possibility of MCP joint arthritis development. These findings suggest an alteration in the biomechanics, stress, and load across the affected MCP joint that should further be explored with biomechanical testing.

Conflicts of interest

None.

Acknowledgements

None.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| The Relation Between Functional Parameters, C-Reactive Protein and Erythrocyte Sedimentation Rate in Ankylosing Spondylitis: A Cross-Sectional Study

Abstract

Introduction: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease characterised by inflammation of the spine and the sacroiliac joints and stiffness, which leads to a progressive decline in the quality of life of individuals. Bath indices are considered the principal functional outcome measure and Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) are the most widely used biomarkers in AS to assess disease activity.

Objective: To characterise individuals with AS and to examine the association between functional parameters and biomarkers.

Methods: Thirty-one patients were recruited from the National Association of Ankylosing Spondylitis (ANEA) – Centre of northern region of Portugal, between February 2014 and June 2015, to be included in the present study. The Bath indices [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI)], the Neck Disability Index (NDI), the Oswestry Disability Index (ODI) and laboratory parameters such as ESR and CRP were analysed.

Results: The participants’ mean age was 42.77 (±14.37) years, with 18 (58.1%) women and 13 (41.9%) men. The mean scores were 3.55 (BASDAI), 2.78 (BASFI) and 2.58 (BASMI). The final mean scores were 25.81± 18.36 (NDI) and 23.29±15.32 (ODI). We found a negative association between ESR and BASDAI (β=-0.038, p=0.025), and between ESR and BASFI (β=-0.044, p=0.013). As to CRP, there was no statistically significant association between Bath indices.

Conclusion: This cross-sectional study in AS patients demonstrated that, on the one hand, this sample had a high education level, having been diagnosed with AS for more than 15 years, with a moderate disability and, on the other hand, with the adjustment of education level and years since diagnosis, there was an association between ESR and BASDAI and BASFI scores.

Keywords: Ankylosing spondylitis; Functionality; Biomarkers; Inflammation; pain

Introduction

Ankylosing spondylitis (AS) is a chronic rheumatic disease, characterised by inflammation of the spine, the sacroiliac joints and stiffness, which can lead to a progressive decrease in the quality of life [1,2]. Disease activity, functionality and symptoms are great impact areas in AS [3]. Pain, stiffness, fatigue and spinal mobility are symptoms which reflect the disease’s inflammatory effect [3]. As a consequence, the irreversible changes that accompany AS, the decreased functionality in activities of daily living, the direct and indirect costs associated with the disease and its effect on patients’ quality of life are important parameters to take into account in the clinical practice to achieve a good diagnosis and an adequate intervention [2]. The socioeconomic impact of AS is substantial, considering the reduced working hours, occasional work changes/ adaptations, missed professional opportunities and early retirement. On the other hand, it has been reported that a higher educational level is associated with maintenance in the labour force, decreased years since AS diagnosis, a higher socioeconomic level and a better understanding of the disease [4,5].

The most commonly used biomarkers to monitor AS activity are Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) [6]. These parameters are usually high in AS, in association with lumbar and cervical pain, as inflammation and entheses in these regions are the first symptoms of the disease [7]. However, there is some issue as to the sensitivity of these inflammatory biomarkers in AS activity and their correlation with functional parameters [6,8]. The basis for this controversy is the assessment of their specificity regarding AS, as these biomarkers are specific to assess the inflammation in structures affected by the disease, such as tendons, bone, ligaments, cartilage, among others, but are also influenced by non-inflammatory aspects, such as age, gender, anaemia and renal failure, which can influence these laboratory parameters [6,9]. Their correlation with functional parameters has been more evident in the assessment of disease activity (BASDAI) [8]. However, to achieve a deeper and more specific understanding of the disease it is necessary to include functional (BASFI), metric (BASMI) and disease activity (BASDAI) parameters in the assessment of an individual with AS, as these are the preferred methods to evaluate individuals with AS [2,6,10,11].

Equally important, given the complexity of this chronic disease, in particular the ankylosis of some segments of the spine, is to explore the assessment of more specific parameters associated with the impact of spinal mobility (cervical and lumbar regions) on activities of daily living [12]. The characterisation of AS individuals in the literature is still scarce. For this reason, it is important to enhance knowledge regarding functional and biomarker parameters, improving the orientation of health professionals in the management of this disease and in providing patient advice. The aims of this study were: (1) to characterise individuals with AS and (2) to verify the association between functional joint and biomarker parameters.

Methods

Study design and participants

A cross-sectional study with a convenience sample of patients with AS was conducted in the northern region of Portugal. The study received approval from the Ethics Committee of the School of Health Allied Sciences of the Polytechnic Institute of Porto. Potential candidates were identified by physiotherapists from the institution and from the National Association of Ankylosing Spondylitis (ANEA) – Centre of northern region of Portugal, and the recruitment occurred between February 2014 and June 2015.

Subjects were eligible to participate in the study if they: (1) were diagnosed with AS according to the modified New York criteria [10]; (2) were aged 18 years or older and [10]; (3) voluntarily consented to participate. The study excluded all patients presenting any other clinically diagnosed spondyloarthropathy, neurological or cardiorespiratory pathologies [10].

Instruments

All patients completed the Portuguese version of the Bath Spondylitis Functional Index (BASFI) [13], a characterisation questionnaire which measures the functional status of patients with AS through ten questions regarding daily activities, with the mean score (range, 0–10) being obtained from the sum of all values. The Portuguese version of the Bath Spondylitis Metrics Index (BASMI) [13] was used to determine the participants’ physical mobility, with the Shober’s test, lateral spine flexion, tragus to wall distance, cervical rotation and intermalleolar distance, with a final score ranging from 0 to 2 in each one of the five parameters (0 – mild disease involvement, 1 – moderate disease involvement, 2 – severe disease involvement).

The Portuguese version of the Bath Spondylitis Disease Activity Index (BASDAI) [13] was used to measure the disease activity status through six questions with a score ranging from 0 to 10, regarding fatigue, spinal pain, peripheral joint, entheses and morning stiffness, to determine a final mean score. A mean of the two scores relating to morning stiffness was calculated before averaging all the answers [13,14].

The Portuguese version of the Oswestry Disability Index (ODI) was used in each of its ten items, each of them including 6 statements, and patients were requested to select only one, obtaining a score from 0 to 5. The Portuguese version of the Neck Disability Index (NDI) also includes 6 statements and the score 0-5. ODI and NDI total scores were converted into a percentage score with 0-20% indicating minimal disability, 21-40% moderate disability, 41-60% severe disability, 61-80% crippled and 81-100% total incapacitation [15-17]. Disease activity variables used included both C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR).

Data collection procedures

Aspects such as age, gender, level of education and employment situation were identified as sociodemographic and anthropometric. Physical examination of patients by a blind trained observer included the assessment of BASMI. Patients have completed two self-administered questionnaires – the NDI and the ODI.

As laboratory assessments of patients’ ESR and CRP were determined, overnight fasting blood samples from all subjects were collected through standard antecubital forearm venepuncture to 8 ml serum-separator and 3.5 ml K2-EDTA tubes (BD Vacutainer® System, BD Diagnostics, Franklin Lakes, NJ). After room temperature clotting, serum was separated by low-speed centrifugation (4500 rpm, 10 min, 22°C) (Sigma ® 3k15, SIGMA Laborzentrifugen GmbH, Osterode am Harz, Germany), transferred into aliquots, and stored at -80°C until analysis [18] and latex immunoturbidimetry (CRP) [19] techniques.

For ESR estimation, K2-EDTA anticoagulated blood samples were mixed for 10 minutes before the test. Samples were aspirated into a Westergren pipette and the distance that the column of blood fell in 1h was recorded according to the International Council for Standardisation in Haematology (ICSH) standardised method [20].

Data analysis

Sample characteristics are presented as counts and proportions for categorical variables and as mean ± standard deviation (SD) for biomarkers and functional parameters. The association between biomarkers and functional parameters was estimated through crude regression coefficients and years since diagnosis and education level-adjusted regression coefficients (β and adjβ). Since the regression prerequisites were not achieved when analysing the ODI and NDI functional parameters, Spearman’s correlation coefficients were calculated. A p-value ≤ 0,005 was considered statistically significant. All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) software, version 23.0 (Chicago, IL).

Results

Table 1 summarises the characteristics of the 31 participants in this study. The patients’ mean age was 42.77 ±14.37 years. Most subjects were female (58.1%), and 45.2% had between 13 and 16 years of education (45.2). 38.7% were diagnosed with AS for more than 15 years. 38.7% of participants had a salary lower than 500€ and 35.5% had a salary higher than 1000€. All participants were taking non-steroidal anti-inflammatory drugs (NSAID).

Table 1:Sample characteristics: socio-demographic information and history of AS.

Patients’ clinical parameters are shown in Table 2. The mean scores were 3.55 ± 1.94 BASDAI), 2.78 ± 2.12 (BASFI) and 2.58 ± 1.86 (BASMI), with a minimum of zero and a maximum of ten. On average, the NDI score was 25.81 ± 18.36 and the ODI score was 23.29 ± 15.32, which indicates a moderate disability in both cases.

Table 2:Clinical parameters of patients with ankylosing spondylitis.

The correlation values between biomarkers and ODI and NDI scores are shown in Table 3. No statistically significant association between biomarkers and ODI or NDI scores was found.

When considering the crude effect, no statistically significant association was found between biomarkers and functional parameters. After adjustment to years since diagnosis and education level, used here as a proxy of professional group, we found a negative association between ESR and BASDAI (β=-0.038, p=0.025) and between ESR and BASFI (β=-0.044, p=0.013), but not between ESR and BASMI (β=0.010, p=0.615). No statistically significant association was found between CRP and functional parameters in BASDAI, BASFI and BASMI (Table 4).

Table 3:Spearman’s correlations between functional and biomarker parameters.

Table 4:Association between biomarkers and functional parameters.

Discussion

The aims of this study were to characterise individuals with AS and to verify the association between functional and biomarker parameters in these patients. The sample of this cross-sectional study included more female than male subjects (58.1% women versus 41.9% men), contrarily to a recent study conducted in Portugal [10] and to the described in the literature regarding other European populations with AS [21]. This difference can result from women’s increased interest in obtaining health-related information when compared to men, showing more interest in participating in this type of programmes [22,23] and volunteering more than men.

Individuals in this sample have an education level of more than 12 years (45.2%), which suggests that they are more demanding when searching for information regarding the disease, an important factor contributing for recognition and control of the associated symptoms [23]. 38.7% of the individuals included in this study have been diagnosed with AS for more than 15 years, as in another study recently conducted in Portugal, in which most subjects were diagnosed with AS for more than 10 years [10]. The therapeutic strategies existing at that time were clearly different from those that are available today, either due to the insufficient knowledge of the disease or to the individual variation during the disease and to the understanding of pathophysiological and biomechanical principles combined with the pharmacological therapy [10,24].

The mean age was 42.77 years, with the younger subject aged 18. This reveals that AS is being diagnosed earlier, which provides for a more adequate monitoring of patients. This is coincident with more modern diagnosis approaches, increased accessibility and availability of assessment instruments and the more comprehensive information available to healthcare professionals and patients [10].

As to monthly income, 58% of the individuals have a salary lower than or equal to 1000€, while 42% earn more than 1000€. These values are in accordance with the sample’s education level and another recent Portuguese study [23].

The sample’s mean BASDAI (3.55±1.94), BASFI (2.78±2.12) and BASMI (2.58±1.86) scores show that these individuals are between percentiles 25 and 50 for the Portuguese population, taking the disease’s evolution in years into account [10]. These values are similar to those obtained in previous cross-sectional studies, with similar values as to the education level, years since diagnosis and medication intake, although with a higher sample [25-27]. It should be noted that NDI mean scores in this sample were higher (25.8 ±18.36) than ODI scores (23.29±15.32), although all of them are in the same interval, revealing an increased mean score of cervical disability compared to lumbar disability, as opposed to the described in the literature, which reports that the latter is the most affected segment [28]. This evidence can be due to the female predominance of the sample, as women are more commonly affected at the cervical segment than at the lumbar segment, as opposed to men [29,30]. On the other hand, our results show that both segments have mean scores situated in the interval 21-40, which means a moderate disability, in accordance with the Bath indices’ scores (BASDAI, BASMI and BASFI), taking into account the percentiles for the Portuguese population with AS [10]. As to ESR and CRP parameters, several studies have been reporting that these biomarkers have no predictive value to determine disease activity in individuals with AS [2,6,7,9]. Our results show low ESR and CRP values, suggesting that individuals in our sample have low disease activity. This can be due to the fact that all individuals take antiinflammatory medication, which can influence these biomarkers [31], or to the fact that most subjects were diagnosed with AS for more than 12 years, having an increased knowledge and control of the disease. Patients who have been diagnosed for more years have an increased need of information than recently diagnosed individuals, which provides a safer management of the disease [22].

It has been verified that when values were adjusted for years since diagnosis and education levels, there was an association between ESR and BASDAI and BASFI scores. As ESR levels increase, BASDAI scores also increase, deteriorating these individuals’ functionality; in the same way, when ESR values increase, BASFI scores also increase, which translates into higher disease activity. This can be explained by disease duration/evolution because of the progressive activation of bone reparative/remodelling pathways that are likely to affect these biomarkers [32,33]. As concerns the education level, it influences functionality and disease activity by the knowledge these individuals have regarding the disease [34], although there is no association between this parameter and BASMI scores. As to CRP, there was no association between Bath indices, possibly because this biomarker is more sensitive in inflammation detection and is not increased by the influence of age, sex or anaemia. As this biomarker values were low in individuals of this sample, no association was found with the Bath indices [35].

Both cervical and lumbar vertebral mobility and the inflammation of these segments are dynamic processes which vary in time and with time. This inflammation is a non-linear process, which improves, deteriorates and even disappears throughout time, which makes that its assessment using biomarker parameters is a point estimation, as they are sensitive to changes [6].

Our results also show that the NDI and ODI present a low association with the biomarker parameters. These findings may be explained by the number of years of disease evolution of patients participating in this study, which has somehow provided for adaptations to perform activities of daily living, decreasing the impact of chronic pain in the cervical and lumbar segments. These results have implications for healthcare professionals dealing directly with patients with AS, as they would allow to better understand and monitor these individuals.

Our study has some limitations, such as the reduced number of individuals who constitute our sample and the fact that it is a convenience sample. A second limitation in result analysis was that it was not possible to adjust the years since diagnosis and the education level for NDI and ODI scores, as these parameters do not meet the requirements for that analysis. For these reasons, additional studies with a bigger sample using these two instruments (NDI and ODI), together with additional objective parameters such as imaging examinations, for their sensitivity to detect active inflammation, are required for correlation with biomarkers.

Conclusion

Individuals with AS included in this study have a high education level, an aspect which is in accordance with their monthly income, a disease evolution of at least 15 years and a moderate functional disability.

Our results show a negative association between ESR and BASDAI and BASFI scores.

Funding information

There was no funding.

Conflicts of interest

The authors declare that they have no conflict of interest.

Acknowledgements

None.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| Defiance In The Body’s Defence System

Abstract

Nature has provided immune system to protect the body from the invasions of Non-self-biological and/or chemicals including toxins. These non-self-items, called as antigens produce immune response in the body which in turn produce antibodies. These antibodies inactivate antigens by making antigen antibody complexes Due to various reasons, both genetic and environmental, the components of the lose the regulatory control and go in wrong assortment and instead of protecting the self they attack on the self itself. Sometimes due to attack of “non- self” immune system overreacts and produces “cytokine storm”.

Keywords: Antigen; Antibody; Inflammation; Infection; Autoimmune diseases; Cytokine storm

Immune System

The immune system is provided by nature to protect the body from any external invasion like army for a nation. It recognizes biological components including the microbiota (living in our body) as “self” and “non self” such as infectious organisms, cancers and their metabolic products (toxins) and other chemicals (acts as antigens) are quickly detected by the immune system and mounts an attack that is strong enough to kick them out, and promptly backs off when the job is done [1]. The immune system is a complex network of cells, tissues, and organs and together they help the body to fight infections and other diseases. The skin mucous membranes white blood cells organs and tissues of the lymph system, such as the thymus, spleen, tonsils, lymph nodes, lymph vessels, and bone marrow, antibodies, the complement system, are the ranks of the defence system. When the immune system recognizes an antigen (biological or/and chemical), it attacks them. This is called an immune response. Due to the antigen action new protein is synthesized named as antibodies which weaken and react with antigen and destroy them by making antigen -antibody complex, which is ultimately removed from the body. The human body also makes other cells to fight the antigen [2].

What goes wrong with the immune system?

Following are the possible causes of causes of Immune system disorder

• Be born with a weak immune system. This is called primary immune deficiency.

• Get a disease that weakens immune system. This is called acquired immune deficiency.

• Have an immune system that is too active, may be due to allergic reaction

• Have an immune system that turns against you. This is called autoimmune disease.

Sometimes a person may have an immune response even though there is no real threat or when system overreacts when there is a threat under such situations system goes astray. Because of this one may suffer allergies, asthma, and autoimmune diseases. The causes of Autoimmunity are yet not clear however with recent finding it is surmised that changes in autologous antigens or alterations in immune regulation Are the modes of action. Autoimmune disease, the pathological consequence of an autoimmune response, depends principally upon the stimulation of helper/inducer T cells reactive with self-antigens In such situations the body’s immune system attacks healthy cells. Because the incidence of autoimmune diseases is rising, researchers suspect environmental factors like infections and exposure to chemicals or solvents might also be involved [3]. Other immune system problems happen when the immune system does not work correctly. These problems include immunodeficiency diseases. Patients with Immunodeficiency disease will get sick more often. Chronic infections are troublesome and harder to treat. They are often genetic disorders [4].

There are other diseases that can affect the immune system. For example, HIV is a virus that harms the immune system by destroying white blood cells. Chronic HIV infection results in AIDS (acquired immunodeficiency syndrome) and due to AIDS immune system is badly damaged [5]. There are more than 80 types of autoimmune diseases. Like many other diseases autoimmune diseases also show gender differences. Autoimmune diseases can affect any part of the human body and one disease leads to another. For instance, to begin with a person suffers with alopecia areata later, he develops autoimmune disease of the skin that causes hair loss, autoimmune hepatitis affects the liver. In type 1 diabetes, the immune system attacks the pancreas. In majority of cases, patient of rheumatoid arthritis also suffers with one or many diseases such as joints pain, pulmonary parenchymal disease in lungs, and dry eye, scleritis, or uveitis in eyes. They are mostly syndromic diseases1 [6]. Autoimmune diseases do tend to run in families, however, viruses, certain chemicals, and other things in the environment may trigger an autoimmune disease if one already has the genes for it.

Autoimmune disease

Autoimmune disease usually develops in middle-aged adults but may also appear during childhood or late in life. Patients who are diagnosed between ages 16 and 65 are considered young onset and after 65, late onset with each of them having different sign s and symptoms. Some autoimmune diseases are more common in certain ethnic groups. Certain autoimmune diseases such as, lupus may not affect Caucasians, but African-American and Hispanic people suffer, it was also found out that every family member will not necessarily have the same disease, but they inherit a susceptibility to an autoimmune condition. According to a 2014 study, women get autoimmune diseases at a rate of about 2 to 1 compared to men — 6.4 percent of women vs. 2.7 percent of men. Often the disease starts during a woman’s childbearing years (ages 15 to 44) [7].

Cytokine Storm

Due to antigenic stimulation sometimes immune response flare up and does not stop after neutralizing antigen such situation it is termed as cytokine storm. On a basic level, one can think of it like setting off a bomb in the house because instead of getting rid of a few infections and inflammations, the system overreacts and can be a cause of death. But the real problem isn’t just that the response is too strong; it is that it keeps going when it shouldn’t. This is not a problem of ‘too good’ an immune response, but rather a subtle defect in the immune system that doesn’t let it ramp back down [8,9]. When everything is working as it should, pro-inflammatory cytokines and anti-inflammatory cytokines work together to kill off an invader and then settle down, so the immune system isn’t perpetually in attack mode. When things go awry, however, the immune system stays on the attack and one can end up with a cytokine storm. It’s important to know that’ s cytokine storm is not the same thing as a disease flare. During a flare there is certainly too much pro-inflammatory immune activity, but it only goes so far in a controlled manner. A cytokine storm, however, is like an outof- control brush fire that picks up more power as it continues to spread.

Some autoimmune patients end up with cytokine storms. This is most apt to occur in children with juvenile idiopathic arthritis (JIA). “About 10 percent of patients with JIA will experience it; in some cases, multiple times,” says Dr. Cron. Adults with lupus, Still disease, and other inflammatory/autoimmune conditions may also develop a cytokine storm (Figure 1).

In autoimmune disease patients, cytokine storms are believed to occur because of a genetic defect, though the presence of an infection often serves as a trigger. When it comes to COVID-19, the coronavirus likely coupled with a previously unknown defect in the immune system is what leads the inflammatory cytokines to go haywire and essentially multiply. They “recruit and activate additional immune cells and amplify the immune response” so much so that the immune response starts killing off healthy cells in the body, says Dr. Cron. “If left untreated, this can result in multiorgan failure and eventual death.

Conflict of interest

None.

Acknowledgements

None.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research|Present And Future of Mesenchymal Stem Cells In Rheumatology

Authored by:  Carlos Landa Solís

Abstract

This review is focused the evolution of mesenchymal stem cells (MSCs) and their clinical applications in rheumatology. MSCs have significant properties immunomodulatory by suppressing T- and B-cell proliferation, dampening the generation of mature myeloid dendritic cells, and inhibiting the proliferation, cytokine production and cytotoxic activity of natural killer cells, and they have the capacity to engulf apoptotic cells. This work addresses the results in vitro and in vivo research on the current clinical applications of MSCs in rheumatology, as well as surface markers, cell culture techniques, regenerative properties, and immunomodulatory mechanisms of MSCs, as well as the practical limitations of the last nineteen years (2002 to 2021). MSCs have many clinical applications as well as isolation sources, and with very varied clinics results. Undoubtedly there is still much to discover about their clinical applications and the management of autoimmune diseases, but MSCs continue to represent valuable source for developing of new therapies for the treatment of rheumatologic diseases.

Keywords: Mesenchymal stem cell, Properties immunomodulatory, Rheumatology

Introduction

At the beginning of present century, the first works were reported that related to mesenchymal stem cells with some possible application in rheumatology. These new strategies began with the isolation and characterization of bone marrow multipotential mesenchymal progenitor cells BM-MSCs, using a positive selection of +CD45 (low) cells. The results in these studies showed that the BM-MSCs could be implications for defining the physiologic roles of MSCs in arthritis, bone diseases, and joint regeneration [1]. Continuing with this trend, the first reports appeared where other sources of MSCs with possible applications in rheumatology with special emphasis on the treatment of osteoarthritis (OA) were evaluated,[2] like membrane and liquid synovial,[3] at the same time are incorporated the use of hyaluronic acid scaffold,[4] and growth factors such as BMP2, to promote the differentiation of MSCs to chondrocytes with the subsequent repair of the surface of the articular cartilage[5]. After, two new sources of MSCs were evaluated, the human placenta and cord blood, in both cases, the aim was continued to experiment with joint repair strategies [6, 7]. The advent of all these new of cellular sources of MSCs in rheumatology considerably changed the evolution and prognosis of chronic inflammatory arthritis [8]. Which led to the study of the immunomodulatory properties of MSCs,[9] For the first time, was showed that MSCs exert immunosuppressive activities by suppressing T- and B-cell proliferation, dampening the generation of mature myeloid dendritic cells, and inhibiting the proliferation, cytokine production and cytotoxic activity of natural killer cells, [10, 11] and it was demonstrate that human MSC migrate upon stimulation with CXCL8 but not CCL2 [12]. To compare whether BM-MSCs are similar in patients with some autoimmune disease and healthy donors, BM-MSCs were isolated from patients with systemic lupus erythematosus (SLE) and normal controls. MSCs from SLE patients and normal controls were infused into ICR mice (Tac: Icr: Ha strain) after high-dose chemotherapy, with no adverse events in either group. Recovery of white blood cells, hemoglobin, and platelets was faster (P <0.05) compared to the group without MSC infusion. It was concluded that MSCs in SLE patients present abnormalities compared to those found in normal control. MSCs in SLE patients may play an important role in the pathogenesis of SLE [13].

At this point, It was determined that MSCs they home to inflamed tissue and exert an anti-inflammatory paracrine effect,[14] and the researchers were in an exploratory phase for the treatment of inflammatory arthritis,[15] and with more focused in acute autoimmune disease including SLE. In a case report about MSCs transplantation for diffuse alveolar hemorrhage in SLE, it was found that after transplanting with MSCs isolated from umbilical cord (UC-MSCs, infusion of 8x107 cells), the patient showed dramatic improvements in her clinical condition, oxygenation level, radiographic and hematological status, the patient was discharged from hospital approximately 5 weeks after undergoing transplantation [16]. Later, the allogeneic MSCs transplantation therapy for SLE was continued using UC-MSCs,[17] plus BM-MSCs, obtaining similar results [18-21]. On the other hand, MSCs in patients diagnosed with myelodysplastic syndromes or multiple myeloma showed abnormalities, which could play a role in the physiopathology of the disease. and patients with immune thrombocytopenic purpura, MSCs have a reduced proliferative capacity and a lower inhibitory effect on T-cell proliferation compared with MSC from normal control [22]. Other applications that were explored up to that point using MSCs were: treatment of therapy resistant graft versus host disease, Crohn’s disease and organ transplantation [20, 23-25]. In 2019 year ,was reported that the human UC-MSCs possessed the ability to engulf apoptotic cells (ACs). The MSC exposed to ACs (AC-MSC) increased MSCmediated suppression of CD4+ T cell proliferation compared to MSCs alone. Mechanistically, ACs stimulated MSCs to express COX2 and consequently produced PGE2 that inhibited T cell responses. NF-κB signalling pathway mediated the activation of COX2/PGE2 in AC-MSCs. Importantly, in patients with SLE, the plasma PGEM levels increased significantly in those with reduced apoptotic mononuclear cells in peripheral blood after MSC transplantation [26].

Ten years ago, the research works reported up to that point focused on the biological properties of MSCs, including their immunoregulatory characteristics, differentiation capacity and trophic potential, as well the relevance of delivery of antiinflammatory factors or immunomodulatory MSC-based therapies for rheumatic diseases like rheumatoid arthritis (RA) [27-29]. In this way, the first results of MSCs therapy for knee osteoarthritis were reported, with encouraging, but not excellent. with the observation that the Improvement of the technique may improve the results [30]. Also, advances in the treatment of SLE were reported, it was demonstrated that single MSCs transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE patients,[31] and the UCMSCs therapy was extensive to SLE patients with diffuse alveolar hemorrhage (DAH), with results that suggest that UC-MSCs therapy results in amelioration of oxygen saturation as well as hematological and serological changes, which revealed that UC-MSCs therapy could be applied as a salvage strategy for DAH patients [32].

After a 4-year follow-up after receiving allogenic therapy with MSCs, it was reported the induction of clinical remission, reverse hematological aberration with refractory cytopenia and improvement in organ dysfunction in drug-resistant SLE patients [33, 34]. in a similar study with lupus nephritis (LN) patient’s refractory to conventional therapy, it was reported no transplantation-related adverse event was observed and the Allogeneic MSC therapy resulted in renal remission for active LN patients within 12-month visit, confirming its use as a potential therapy for refractory LN [35]. One of the mechanisms reported to explain these improvements was that immune microenvironment in SLE patients can significantly stimulate the TGF-β1 expression on allogenic MSCs therapy and plays an important role in the upregulation of regulatory T cells in patients [36]. On the other hand, has been reported that autologous MSCs from lupus patients are not effective in treating disease. Furthermore, standard in vitro assays for MSC licensing are not predictive of in vivo efficacy, whereas inhibiting B cell proliferation appears to differentiate effective MSCs from ineffective MSCs [37]. Three years later it was reported that higher baseline levels of IFN-γ might predict a good response to MSC therapy for active lupus patients, which will help to choose suitable patients for clinical transplantation [38].

For exploring of UC-MSCs therapy in patients with active rheumatoid arthritis has been analyzed the treatment with diseasemodifying anti-rheumatic drugs plus UC-MSCs, this combination showed that may provide safe, significant, and persistent clinical benefits for patients with active RA [39]. It has also been shown that UC-MSCs therapy inhibits the expression of Cadherin-11 (CDH11) by fibroblast-like synoviocytes (FLS) in RA patients, and this mechanism might be targeted to ameliorate arthritis [40].Also, in circulating T follicular helper (cTfh) cells in primary Sjögren’s syndrome patients (pSS) and RA patients, exposed to UC-MSCs therapy, it has been observed an inhibitory effect of UC-MSCs on the differentiation of cTfh cells via the secretion of indoleamine 2,3-dioxygenase (IDO), and soluble factors secreted by activated CD4(+) T cells might contribute to IDO secretion by UC-MSCs,[41] these findings reveal a suppressive function of MSCs in cTfh cells [42]. Therefore, the modulation of MSC homing may allow targeted delivery of systemically administered MSCs to damaged articular cartilage, where they can suppress immune-mediated cartilage destruction and contribute to cartilage repair via a combination of chondrogenic differentiation and paracrine stimulation of intrinsic residual repair [43]. Three years later, the UC-MSC therapy continued to be studied in RA patients in a phase Ia clinical trial, where patients received a single intravenous infusion of 2.5×107, 5×107, or 1×108 cells of UC-MSCs for 30 minutes, three patients in each cluster, with an increment of cell numbers when there was no dose-limited adverse event. There was no major toxicity in all clusters up to 4 weeks after the infusion. Reduced levels of IL-1β, IL- 6, IL-8, and TNF-α at 24 hours were observed in the cluster infused with 1×108 MSCs. This study UC-MSCs infusion trial for established RA patients revealed no short-term safety concerns.[44] at the same time other research group reported similar safety analysis in patients with autoimmune disease that receiving allogeneic UCMSCs therapy a long-term, but in more diseases like: SLE, Sjögren’s syndrome, and systemic sclerosis, with an incidence of adverse events, whether infections or malignancies, are acceptable in these patients [45].

New strategies have been proposed for the treatment of refractory lupus nephritis and leukopenia, a case of autologous hematopoietic stem cell (HSC) transplantation combined with MSCs in a 25 year-old SLE patient with multiple life-threatening complications and refractory to conventional was reported cyclophosphamide (CYC) therapy, the findings suggest that the combined transplantation of HSCs and MSCs may reset the adaptive immune system to re-establish self-tolerance in SLE. A 36-month follow-up showed that the clinical symptoms remained in remission, and the combined transplantation of HSCs and MSCs may be a novel and effective therapy for refractory SLE [46]. At the same time by other research team, it was evaluated the osteoblastic potential of infrapatellar fat pad-MSCs (IFP-MSCs) cells from rheumatoid RA and OA patients, they concluded that IFP-MSCs from RA have comparable or slightly stronger osteogenic potential than IFP-MSCs from OA, these findings indicate that IFP-MSCs have the therapeutic potential for the development of new therapeutic strategies in both RA and OA pathologies [47]. At the same time to finish the 2015 year, was reported the evaluation of BM-MSCs therapy for knee osteoarthritis 5 years follow-up in three patients with advanced stage of OA, they observed that for the advanced stage of OA in the patients at 5 years continued its progression toward aggravation to disease. Due to these findings the authors recommended the use of therapy with BM-MSCs in early stages of OA for better long-term outcomes [48].

At the beginning of 2016, it was evaluated in 12 patients with follow-up for one year, the therapy with Autologous adiposederived stromal vascular fraction (ADSVF-MSCs), The results of this research were very promising, characterized mainly by a significant improvement of finger oedema, skin sclerosis, motion, and strength of the hands and of the vascular suppression score was also noted, the reduction in hand pain approached statistical significance (P = 0.052). The questionnaire revealed a benefit in daily activities, housework, and social activities, with the extension of all this benefits in the patients for one year [49]. In the following year, it was reported the effect of combined plasmapheresis (PE) and allogeneic MSC therapy on systemic sclerosis (SSc), obtaining apparent good results owing to feasible treatment associated with possible clinical benefit for SSc patients at one year of follow-up [50]. In a subsequent randomized placebo-controlled doubleblind trial to assess the safety of intramuscular administration of allogeneic MSC for digital ulcers in SSc. The patients received eight intramuscular injections with either placebo or 50x106 MSCs. Follow-up visits will be scheduled at 48 hours and 2-, 4-, 8-, 12-, 24- and 52-weeks post-treatment. If the results confirm safety, feasibility, and potential efficacy of this therapy [51].

In early 2018, repeated-dose adipose-MSCs (haMSCs) were evaluated in patients with a definite diagnosis of knee OA (between ≥2 to ≥4 grade), 18 patients were enrolled and divided into three dose groups: the low-dose, mid- dose and high-dose group (1×107, 2× 107 and 5×107 cells, respectively), provided three injections and followed up for 96 weeks. The results suggested that intraarticular injections of haMSCs improved the pain, the improvement was superior in a dosage of 5×107 cells combined with repeated injections, and the authors were cautiously optimistic regarding the articular injection of haMSCs as a putative treatment for knee OA [52]. In the next year in another study, was evaluated therapy with BM-MSC in refractory juvenile idiopathic arthritis (JIA) patients, using an intravenous infusions of allogeneic BM-MSC (2 million/kg cells), after the therapy no acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in adverse events was found, and it is recommended to continue with the drug immunosuppressant treatment to send the macrophage activation syndrome[53] Recently in 2020, was carried out a phase I pilot study, where the patients with symptomatic, bilateral knee osteoarthritis were randomized to three treatment groups (low dose, 1×107 cells; medium dose, 2×107 cells; high dose, 5×107 haMSC). All patients received two bilateral intra-articular injections: week 0 (baseline) and week 3, the follow-up was carried out by 48 weeks. Adverse events were transient, including mild to moderate pain and swelling of injection site. Improvements from baseline were measured in the secondary end points. MRI assessments showed slight improvements in the low-dose group and, Safety and improvements in pain and function after intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells into arthritic patients was demonstrated [54].

Conclusion

To date there is enough evidence to support the use of MSCs in the autoimmune diseases, like RA, SLE, myelodysplastic syndromes or multiple myeloma, and in other for maintain joint health such as OA.

Undoubtedly one of the fields in which the most progress has been made is the treatment of systemic lupus erythematosus, where UC-MSC have proven to be very useful and have even led patients to enter into remission in cases where patients presenting refractory to conventional therapy.[33, 35, 42] On the other hand, in the treatment of osteoarthritis, it has been observed to obtain better results when therapy with MSCs is applied in early stages of the disease since it has been reported that when therapy with BM-MSC advanced stage of OA is applied, to long term all benefits of treatment are lost [Figure 1] [30, 48].

Therefore, and according to current trends of last reported studies, the community of clinical and basic researchers need together to propose large prospective controlled trials, for the development of new therapies that help to the best application of MSCs in the treatment of rheumatic diseases.

In this review, I show the points that were most important to me in the development of MSC therapies at today and the challenges that still need to be solved in the future.

Conflict of interest

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acknowledgements

None.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| PVNS Of The Knee: A Consecutive Series of 53 Patients Treated Either Arthroscopically or With Open Synovectomy

Authored by: Yazan Kadkoy

Abstract

Pigmented villonodular synovitis (PVNS) is a subtype of tenosynovial giant cell tumor. Such tumors are rare and locally aggressive, though benign, with an average annual incidence between 1.8 and 9.2 cases per million in the U.S. [1] This low incidence of disease makes clinical trials difficult to conduct. Clinically, PVNS is separated into localized (LPVNS) and diffuse (DPVNS) disease. Surgical options include open, arthroscopic and combination arthroscopic/ open approaches for disease involving both anterior and posterior compartments of a joint. Despite surgical resection being the most common treatment modality for PVNS, recent medications have been developed targeting the colony stimulating factor 1 receptor (CSF1R) pathway.[2] In our case series, we selected 53 patients meeting inclusion criteria and treated between 2002-2019,

(29) with DPVNS and (24) with LPVNS. Patients were first categorized by the local or diffuse subtypes of disease, followed by anatomic location anterior, posterior, or both. Surgical treatment method was stratified by the following categories: (1) mini open incision (<4cm) (2) arthroscopy (3) arthroscopy with open incision

(4) open. Mean follow up was 33months ±12months. Open synovectomy was utilized for 23 patients (79%) with DPVNS and 5(21%) patients with LPVNS. Nine patients (38%) with LPVNS and 1(3%) patient with DPVNS underwent arthroscopic synovectomy. Patients treated with open synovectomy had significantly larger tumor volume (196.1+/-311.0 cm3 vs. 42.7+/- 64.6 cm3; p=0.0350). For the diffuse treated group 3/5 treated arthroscopically assisted and 8/23 treated open recurred. The overall rate of recurrence was 37% for DPVNS, and 4% for LPVNS. Further analysis revealed significantly higher rate of recurrence in patients with DPVNS (OR 15.1; p=0.002). Additionally, infection rates were similar for diffuse versus localized disease at 6% versus 5% respectively. The overall complication rate for patients treated with open synovectomy was 38% which was significant (OR 5.2; p=0.019)

Keywords: Pigmented; Villonodular; Synovitis, LPVNS, DPVNS

Abbreviations:

PVNS: Pigmented villonodular synovitis

LPVNS: Localized pigmented villonodular synovitis

DPVNS: Diffuse pigmented villonodular synovitis

CSF1R: Colony stimulating factor 1 receptor

Introduction

Pigmented villonodular synovitis (PVNS) is a subtype of tenosynovial giant cell tumor characterized by the presence of synovial stromal and fibroblast cell proliferation, hemosiderin deposition, and multinucleated giant cells. PVNS most commonly affects the knee, and typically presents with swelling and discomfort of the affected joint. [3] Such tumors are rare and locally aggressive, though benign, with an average annual incidence between 1.8 and 9.2 cases per million in the U.S. [1] This low incidence of disease makes clinical trials difficult to conduct. Clinically, PVNS is separated into localized (LPVNS) and diffuse (DPVNS) subtypes. The localized form is nodular and can be found in and around the joint. [4] The diffuse form affects the entire synovium and invades extraarticular structures such as muscle and tendon. [5-8] This distinction is useful for determining management, with open surgical resection being the gold standard for DPVNS. Synovectomy can be performed arthroscopically, open, or with a combination of both. [9-12] post- operative goals include maximizing knee function through preserving structures, while limiting rate of recurrence with a thorough debridement. Despite surgical resection being the most common treatment modality for PVNS, recent medications have been developed targeting the colony stimulating factor 1 receptor (CSF1R) pathway. Use of these medications as well as tyrosine kinase inhibitors have shown promise in the treatment of recurrent disease or that which is refractory to surgical intervention [2].

The goal of this study was to further elucidate outcomes of operatively treated PVNS with arthroscopy, open surgical resection, or a combination of both. We hypothesize that DPVNS will have a higher incidence of recurrence and complications when compared to LPVNS.

Materials and Methods

After acquiring an IRB approval, a retrospective review of records from a single institution was performed with records dating from 2002-2019. The main inclusion criteria consisted of patients that underwent surgical excision of PVNS or nodular synovitis that was localized to the knee. A cohort of 53 patients that met the criteria was selected, (29) with DPVNS and (24) with LPVNS. Patients were then categorized by the local or diffuse presence of PVNS, followed by anatomic location anterior, posterior, or both. Surgical treatment method was stratified by: (1) mini open incision (<4cm) (2) arthroscopy (3) arthroscopy with open incision (4) open, regarding the anatomical location and diffuse versus local nodular PVNS.

Patient data was collected for age, gender, tumor volume, overall complication rate, recurrence rate, and infection rate. Nonparametric analysis of categorical information was performed using a chi-square test, unless an expected value was less than five, in which case Fischer’s exact test was utilized. Odds ratios were generated with computation of confidence intervals utilizing the Baptista-Pike method. Non-parametric analysis of continuous variables was performed using a Mann-Whitney U test. All analyses were performed using GraphPad Prism version 7.00 (GraphPad Software, La Jolla, California, USA, www.graphpad.com). In all tests, significance was set at p < 0.05.

Results and Discussion

From 2002-2019, we found 53 patients who underwent open, mini-open, arthroscopic, or combination synovectomies for PVNS. Mean follow-up was 33months ±12months. Mean patient age was 42.0 (SD 14.1) years with 39 female and 14 males. Of these, 24 patients were diagnosed with localized disease and 29 with diffuse disease. The mean tumor volume was 18cm3 for localized and 228cm3 for diffuse. Anatomic location also varied, as 28 patients had anterior disease, 9 had posterior disease, and 16 had disease anteriorly and posteriorly. For LPVNS, 9 (38%) were treated with arthroscopy alone, 7 (29%) with mini open, 5 (21%) with arthroscopy and open, and 3 (13%) with open alone. This is in contrast to DPVNS where 23 (79%) were treated open, 1 (3%) with arthroscopy, and 5 (17%) with a combination of anterior arthroscopy, and posterior synovectomy. (Table 1) It should be noted that patients with localized, single compartment disease were treated arthroscopically unless the lesion was too large to be removed as a single piece in which case a mini open incision was made to assist with removal from the joint.

Table 1:Surgical intervention breakup by disease type.

Recurrence, infection, and complication rates were also analyzed. For LPVNS the recurrence rate was 1 (3%), which occurred in the open treated group. For the diffuse treated group 3/5 that were treated arthroscopically assisted and 8/23 that were treated open recurred. The overall rate of recurrence was 37% for DPVNS, and 4% for LPVNS. There were no recurrences seen on the arthroscopy alone, and mini open groups for localized or diffuse disease. It should be noted that no patient with DPVNS was treated with mini open and only one patient with DPVNS was treated with arthroscopy alone. Further analysis revealed significantly higher rate of recurrence in patients with DPVNS (OR 15.1; p=0.002). (Table 2) Patients who suffered recurrence had a higher mean tumor volume than patients without recurrence (57.5±93.9 versus 139.8±166.9; p=0.039). Additionally, infection rates were similar for diffuse versus localized disease at 6% versus 5% respectively. The overall complication rate for patients treated with open synovectomy was 38% which was significant (OR 5.2; p=0.019). The largest complication was related to local disease recurrence

Table 2:Recurrence rate by surgical intervention and disease type.

After a review of the recent literature, recurrence rates of arthroscopic versus open synovectomies were analyzed. A large multicentered cohort study on the surgical treatment of LPVNS found a recurrence rate of 12% and a complication rate of 4% among 941 treated patients. This same group also demonstrated a recurrence rate of 44% and a complication rate of 12% amongst 906 patients with DPVNS. [13,14] These rates are similar to the rates observed in our case series.

As seen in our study and described in prior studies, the variability in presentation of and lack of a standardized approach to PVNS leads to challenges in analyzing outcomes following treatment. Overall, patients with localized disease at the anterior knee did well with both a mini-open incision and with arthroscopy. Frequently in these cases, arthroscopy was first performed with the occasional need to make a mini-open incision to sufficiently remove the entirety of resected synovium as a unit. In cases of diffuse disease both anteriorly and posteriorly, treatment decision-making becomes more complex and diverse.

Caution should be taken with choosing combined treatment of arthroscopic synovectomy anteriorly followed by open treatment of posterior PVNS, due to the high (67%) rate of recurrence. Despite this, a diagnostic arthroscopy may aid in thorough localization and detection of disease prior to synovectomy.

Tumor volume plays a substantial role in evaluating recurrence risk, regardless of treatment performed. However, readers must be cautioned against strict interpretation of this finding, as patients with larger tumor volume are more likely to have diffuse disease, inherently increasing their risk for recurrence. However, within the subgroups of open and arthroscopic treatment, patients with larger tumor volumes had a higher recurrence rate. Unfortunately, this study lacks sufficient power to determine a “cutoff” tumor volume for which patients could be treated successfully with arthroscopy alone.

Conclusion

PVNS remains a difficult condition to manage and treat. The low incidence makes it difficult to perform clinical trials. DVPNS poses a greater challenge for treatment given its higher likelihood to invade locally as well as the higher incidence of recurrence when compared to localized disease.

In our series, diffuse disease, which we defined as tumor in multiple compartments of the knee, had a high correlation with large tumor volume. We treated this either open or with an anterior arthroscopic debridement and posterior open synovectomy. Here, surgical intervention correlated to the overall size of tumor, with large tumors being treated open. The purpose of utilizing arthroscopy was two- fold: (1) decrease the injured structures, and (2) minimize arthropathy. Despite the rationale for choosing a given surgical intervention, the rate of recurrence and complication remained the same for all patients with DPVNS.

There were several limitations to this study. Given the retrospective nature of this case series we were not able to formally assess functional outcomes for patients after surgical intervention. Additionally, our average follow-up time of 33 months may have been too soon to detect disease recurrence.

Given these results, we offer an algorithm for synovectomy. LPVNS should be treated either arthroscopically or with a mini open. DPVNS should be treated open or in a combined approach, which ever minimizes disruption of surrounding structures and allows for faster return to baseline function; however, use of arthroscopy comes with an increased risk of recurrence. This should also come with an understanding that the likelihood of recurrence is high. Future studies will look to assess the impact of novel biologics on the recurrence rate of disease as well as try to further elucidate a more concise protocol for the treatment and management of disease.

Acknowledgements

None.

Conflict of Interest

Non relevant to these works.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| Evaluating Physical Activity And Quality of Life For Older Adults Through Walk With Ease

Authored by: Kimberly A Shaffe 

 Abstract

Background: Prolonged sedentary behavior may have adverse effects on an individual’s physical and psychological well-being, especially among older adult populations. Programs such as Walk With Ease (WWE) have been developed to encourage more physical activity among targeted audiences. However, little research has been done to evaluate the program’s impact on participants’ quality of life in addition to physical activity behavior.

Aims: This study evaluated physical activity and quality of life outcomes among older adults in the WWE program, determined participants with the greatest overall change in behavior, and identified elements within course content that had a significant impact on outcomes.

Methods: Pre- and post-survey assessments (n=86) were administered to participants before and after the six-week program. The assessment included questions from validated tools such as the Physical Activity Scale for the Elderly (PASE) and Brief Inventory of Thriving (BIT) scale. Participant surveys were later matched to provide individual behavior change.

Results: Participants engaged in significantly more walking after completing WWE than they did before beginning the program (g = 0.63; 95% CI [0.33, 0.94]). Attending Session 1 was associated with significant pre-posttest decreases in sitting (b = -2.40, p < .05) and attending Session 3 was associated with significant increases in muscle strength/endurance activities (b = 1.65, p < .01).

Conclusion: WWE provides desirable pre-posttest changes in physical activity and quality of life among a general sample of older adults. A hybrid program in which some activity sessions are provided independently may be a valuable option for future courses.

Keywords: Physical activity, walking, quality of life, Older adults, Health behavior change

Introduction

When public health experts first identified the obesity epidemic in 1999, they issued a call for health professionals to make the development of weight management strategies/programs a public health priority [1]. Despite such efforts to control this epidemic, data from the 2017-2018 wave of the National Health and Nutrition Examination Survey (NHANES) indicate that the obesity epidemic is growing, with the age-adjusted prevalence of obesity (BMI > 30) among American adults reaching 42% [2].

Although obesity threatens the health of Americans consistently across the life course, prevention efforts often overlook the unique needs of older adults. For example, recommendations from the CDC’s Measures Project tend to target children (e.g., policy recommendations for schools and daycares) or adults as a whole (e.g., policy recommendations for access to healthy foods and safe space for exercise) without much attention to differing needs of younger and older adults. This is a noteworthy oversight, as older adults’ perceived barriers to exercise are often unique from those of younger adults, with one of the most consistent barriers being poor health and/or mobility [3].

Poor health and mobility can lead to sedentary behavior, defined as waking behavior characterized by minimal-energy expenditure while in a resting or reclining position [4]. A systematic review of longitudinal studies indicated that longer durations of sedentary behavior can lead to increased risk of obesity, diabetes, site-specific cancers (e.g., ovarian, colon, endometrial), cardiovascular disease, and mortality [5]. Additionally, a recent meta-analysis indicated that sedentary behavior is inversely related to health-related quality of life, defined as self-perception of quality of life [6]. These patterns have serious implications for older adults, as data from the NHANES indicate older Americans spend approximately 60% of their waking hours engaged in sedentary behavior [7].

Thus, programs that encourage older adults to engage in lowimpact physical activities, such as those that can be performed by individuals with health/mobility concerns, have great potential to prevent the adverse health outcomes of sedentary behavior and promote quality of life. One such program that has shown some empirical evidence of health benefits among older Americans is Walk With Ease (WWE).

Walk With Ease

Walking is a low-impact activity that is inexpensive, safe, convenient, and acceptable for adults with limited mobility. Thus, to promote walking as an accessible form of physical activity, the Arthritis Foundation developed WWE, a 6-week community-based program for adults with low mobility. The overarching goals of WWE are to educate arthritis patients about physical activity/ arthritis management and to provide ongoing opportunities to engage in physical activity [8]. The program follows a 6-chapter manual, with participants completing one chapter during each weekly session [9] (Arthritis Foundation, 2010).

Session 1 introduces participants to the health benefits of walking. Session 2 provides participants with facts about arthritis and exercise, defines moderate activity, provides “dos” and don’ts” of exercise, and discusses exercise safety. During Session 3 participants learn to select the right shoes and socks for walking, develop an exercise plan, select an exercise location, and complete a walking diary. Session 4 addresses barriers to exercise (e.g., pain, discomfort) that participants may experience while implementing their exercise plan. Session 5 provides tips for comfortable walking and teaches participants to measure exercise intensity and personal fitness level. Finally, in Session 6 participants receive resources on how to maintain physical activity.

WWE has accumulated a growing body of research evaluating its health benefits. These studies show promising results, but they tend to be limited in scope in a couple of important ways. First, existing studies largely focus on pain, fatigue, flexibility, and mobility outcomes among older adults living with arthritis [10-13]. To date, there are no studies examining the effects of WWE among general populations of older adults and only one study as evaluated quality of life outcomes. Specifically, Bruno et al. (2006) examined pre- and posttest changes in depression among older adults with arthritis who participated in WWE, but they found no effect on this outcome.

Second, the existing research has either (1) compared the selfguided WWE format to the community-based WWE, (2) compared WWE to another active treatment condition, or (3) compared preand posttest measures among a single group of WWE participants without attention to variation in participant characteristics or in treatment exposure. As a result, there is little evidence to indicate which participants benefit most from WWE and which specific WWE components/sessions are effective at promoting health and quality of life among older adults.

The present study attempts to fill some of these voids in the empirical evidence base for WWE. Its specific purpose is to (1) evaluate physical activity and quality of life outcomes of WWE when implemented with a general sample of older adults and (2) determine which participants benefit most from WWE as well as identify the WWE sessions that have a significant effect on outcomes. The study specifically addresses the following research questions:

• RQ1: Do WWE participants demonstrate changes in quality of life after completing a community-based WWE program?

• RQ2: Are there any differences in changes in physical activity and quality of life among WWE participants based on age, sex, and race?

• RQ3: Which of the six WWE sessions are associated with significant changes in physical activity and quality of life after participating in a community-based WWE program?

Method

The present study is a single-group pre-posttest evaluation of WWE. It uses data from12 senior centers, community centers, and faith-based organizations that implemented WWE throughout Upstate South Carolina in 2019. This program evaluation relies on a pre-existing de-identified dataset of survey measures that were collected by these agencies for routine administrative purposes. Since the study authors could not identify participants in the pre-existing dataset, our institutional review board deemed the research to be exempt from review.

Participants

The funding mechanism that supported implementation of WWE in the 12 centers providing data for the study necessitates that at least half of participants in each WWE class are eligible to receive Supplemental Nutrition Assistance Program (SNAP) benefits. However, there are no other criteria for participation in WWE. Participants who attended Session 1 of WWE were asked to complete a pretest survey prior to any discussion of the curriculum, using a unique identifier so that pre- and posttest surveys could be linked. Participants were asked to complete a posttest immediately after completion of the 6-week program. Of the 159 WWE participants who completed the pretest, 95 also completed the posttest, yielding a response rate of 59.75%. In order to draw conclusions about experiences of older adults, we limited the analytic sample to those participants who were 60 years of age or older. This provided an analytic sample of 86 WWE participants. The mean age of the analytic sample was 74.48 (SD = 7.50), with the majority (77.91%) of participants identifying as female, 20.93% identifying as male, and 1.16% not indicating their sex. The analytic sample was 53.49% White, 41.86% African American, 1.16% Native American, 0% Hispanic, and 3.49% (n = 3) race/ethnicity not reported.

Program Implementation

All WWE classes were conducted by trained facilitators who adhered to the WWE manual. Facilitators directed participants in creating exercise goals, discussed the significance of staying physically active, and demonstrated additional stretching exercises to warm-up and cool-down after each group walking exercise. Each of the six sessions typically lasted two hours and began with a review of the previous week’s session. Participants then logged the number of days they walked since the last session and record their thoughts regarding their physical activity experiences thus far. The facilitator then demonstrated 3-5 chair exercises to engage participants and get them moving prior to walking.

Session 1 included a five-minute walk. However, in order to make progress toward the final goal of a thirty-minute walk, each subsequent session entailed participants walking the duration of the previous week’s walk plus an additional five minutes. Facilitators understood that some participants faced more physical limitations than others and, thus, did not force participants. Rather, they encouraged them to do the best that they felt they could do until the time was completed. Chairs, benches, or alternative seating was provided around each walking track for rest, if needed. Facilitators walked and talked with participants while monitoring time. Once the weekly walking exercise was completed, facilitators instructed participants to return to their seats and perform 3-5 cool-down stretches, led a conversation about the session’s activities, and dismissed participants for the week.

Measures

Participants completed pre- and posttest surveys measuring self-reported physical activity and quality of life. Pre- and posttests were identical except that the pretest included demographic items that were not included on the posttest. Physical activity was assessed using the Physical Activity Scale for the Elderly (PASE) and quality of life was measured using the Brief Inventory of Thriving (BIT) scale.

The PASE asks participants to report how often they engaged in specific physical activities over the past 7 days. Physical activities include sitting behaviors (e.g., reading, watching tv, doing handicrafts), walking (e.g., for fun/exercise, walking the dog, walking to work), light sport/recreational activities (e.g., bowling, golf with a cart, shuffleboard, fishing from a boat/pier), moderate sport/recreational activities (e.g., tennis, ballroom dancing, hunting, ice skating, golf without a cart, softball), strenuous sport activities (e.g., jogging, swimming, cycling, aerobic dance, skiing), and exercise to increase muscle strength/endurance (e.g., lifting weights, pushups). Responses are recorded on a 4-point Likert scale (i.e., Never, Seldom/1-2 days, Sometimes/3-4 days, and Often/5-7 days).

The PASE has shown good reliability and validity in measuring physical activity among older adults, as scale items are highly correlated with each other when administered in written format (r = 0.84) and scores correlate with measures of health status and physiologic measures [14,15]. In the present study, we do not calculate PASE scores for analysis. Rather, in order to evaluate pre-posttest changes in specific physical activities, we recoded each of the use each of the aforementioned items onto a numeric scale (1 to 4, with higher values representing greater frequency of the behavior) and examined pre-posttest differences in each as a discrete outcome.

The BIT asks participants to indicate their level of agreement with ten statements that measure quality of life and psychological wellbeing. Examples include “My life has a clear sense of purpose,” “I feel good most of the time,” “What I do in life is valuable and worthwhile,” and “I feel a sense of belonging in my community.” Responses are recorded on a 5-point Likert scale (i.e., Strongly disagree, Disagree, Neither agree nor disagree, Agree, Strongly agree). The BIT has shown good reliability and validity, as scale items are highly correlated with each other (alpha coefficients are over .90 across samples) and scores correlate with other existing measures of wellbeing [16]. In the present study, we calculated BIT scores by recoding the items onto a numeric scale (1 to 5, with higher values representing greater agreement with the item), summing all items, and dividing the total by 10. We examined preposttest score differences as the outcome of interest. The alpha for the BIT in present study was .93 for both the pretest and posttest.

Data Analysis

We conducted all data analysis in R 3.5.0 [17]. Rates of missing data for the analytic sample were low, ranging from 0% to 6.98% for each variable. Thus, we did not impute missing values and, instead, used pairwise deletion. As a result, the observed sample sizes vary between analyses.

To determine the magnitude and significance of pre-posttest changes in physical activity and quality of life, we calculated standardized mean difference scores with a small sample correction (Hedges g). We report these with their 95% confidence intervals. Then, to determine whether these pre-posttest changes varied significantly based on age, sex, and race/ethnicity of participants, we ran a series of multivariate OLS regression models in which we regressed these demographic variables, net of each other, on preposttest changes in each of the main outcomes. Finally, to evaluate the significance of each WWE session on pre-posttest changes in physical activity and quality of life, we ran a series of multivariate OLS regression models in which we regressed attendance for each of the six sessions (0 = No; 1 = Yes), net of each other, on preposttest changes in the main outcomes. This specific analysis was limited to data provided by the three sites that reported attendance for participants (n = 38).

Results

RQ1: Research Question 1 asked whether WWE participants exhibit pre-posttest changes in measures quality of life. Findings pertinent to these to questions are reported in Table 1, which summarizes Hedges g statistics and corresponding 95% confidence intervals for pre-posttest differences in each of the physical activity outcomes and BIT scores. Results indicate participants’ BIT scores were approximately half a standard deviation higher at posttest than they were at pretest (g = 0.46, 95% CI [0.14, 0.78]). Pre-posttest effects were non-significant for sitting and engaging in light sport/recreational activities, moderate sport/recreational activities, strenuous sport/recreational activities, and exercise to increase muscle strength/endurance.

Table 1:Pre-Posttest Effect Sizes for Physical Activity and Brief Inventory of Thriving Outcomes (N = 86).

RQ2: Research Question 2 asked whether there are any differences in changes in physical activity and quality of life among WWE participants based on age, sex, and race. Table 2 summarizes results from multivariate OLS regression models predicting preposttest changes in physical activity outcomes and BIT from these demographic variables. Findings indicate that the only significant demographic predictor of pre-posttest outcomes was whether or not a participant identified as African American. Compared to White participants, African American participants exhibited larger pre-posttest increases in sitting activities and smaller increases in walking, moderate sport/recreation, and muscle strengthening/ endurance activities. Additionally, compared to White participants, African American participants exhibited significantly smaller increases in BIT scores. Age, sex, and identifying as Native American were not significant predictors of pre-posttest physical activity and BIT outcomes.

Table 2:Unstandardized coefficients from OLS Models Predicting Pre-Posttest Differences in Physical Activity and Brief Inventory of Thriving Outcomes from Age, Sex, and Race (N = 86).

RQ3: Research Question 4 asked which of the six WWE sessions are associated with significant changes in physical activity and quality of life after participating in a community-based WWE program. This specific analysis was limited to data obtained from the three WWE sites that reported attendance data (n = 38). Table 3 summarizes results from multivariate OLS regression models predicting pre-posttest changes in physical activity outcomes and BIT scores from attendance of Sessions 1 through 5. There was no variation in attendance of Session 6 (all participants attended this session); thus, it was dropped from the analysis. Findings indicate that attending Session 1 was associated with significant pre-posttest decreases in sitting (b = -2.40, p < .05) and attending Session 3 was associated with significant increases in muscle strength/endurance activities (b = 1.65, p < .01). Attending Sessions 2, 4, and 5 was not significantly associated with pre-posttest changes in any of the outcomes.

Table 3:Unstandardized coefficients from OLS Models Predicting Pre-Posttest Differences in Physical Activity and Brief Inventory of Thriving Outcomes from WWE Session Attendance (N = 38).

Conclusion

In the present study we sought to evaluate pre-posttest changes in quality of life among a sample of older adults participating in WWE. We also sought to identify any differences in pre-posttest changes based on age, sex, and race of participants as well as determine which program sessions are significant predictors of outcome changes. Findings indicate that older adults who participate in WWE demonstrate increases in quality of life (measured with the Brief Inventor of Thriving) relative to measures reported before participating in the program.

Perhaps one of the most important findings of this study is that African American participants experienced significantly fewer preposttest improvements compared to White participants. This has practical implications, considering that African American adults are at greater risk of obesity than White adults [18]. Thus, the program has fewer benefits for those who may need it most. Future research should seek to determine the source of this disparity by evaluating the influence of racial composition of WWE groups, racial match between facilitators and participants, and culturally-specific program content in predicting disparities in program effects among participants.

In terms of identifying program sessions with the greatest influence on pre-posttest changes in outcomes, our findings indicate that, net of the influence of all sessions as a whole, attending Session 1 is associated with greater pre-posttest decreases in sedentary behavior (i.e., sitting) and attending Session 3 is associated with greater pre-posttest increases in muscle strength/endurance activities. Session 1 serves as an introduction to WWE and emphasizes the benefits of walking; thus, it is intuitive that attending this session may encourage participants to become active and engage in fewer sedentary behaviors. Interestingly, past studies have sought to determine whether community-based or selfdirected versions of WWE have the most benefits [11]. However, the fact that we only found attendance of two program sessions to be significant predictors of outcomes suggest a hybrid version in which participants attend Session 1 and then complete some or all of the remaining sessions independently, may be sufficient for fostering desirable change. Future research should examine this possibility under better controlled conditions, by randomizing participants to a hybrid or full community-based version of WWE. Allowing participants to complete parts of the program independently seems consistent with the logic that walking is an easily accessible physical activity (e.g., no need for special equipment or access to fitness spaces).

Overall, this study makes a couple important contributions to the empirical evidence base for WWE. First, it demonstrates desirable pre-posttest changes in quality of life among a general sample of older adults. Past research has tended to focus on pain, fatigue, flexibility, and mobility outcomes among older adults living with arthritis. A notable dearth of studies has focused on psychosocial wellbeing outcomes and/or more general samples of older adults. Second, this study adds to the extant literature by identifying racial disparities in program outcomes that should be addressed in order for all participants to receive optimal benefit from participating in WWE.

Despite these contributions, findings of this study must be interpreted within the confines of a couple important limitations. First, this study relied on a pre-existing dataset of pre-posttest measures collected from adults who participated in WWE. Thus, there was no control or comparison group. Additionally, the study sample exhibited a high level of attrition, as approximately 40% of participants failed to complete the posttest, potentially introducing bias into the results. These issues mostly result from the fact that this study was an analysis of pre-existing data that were not collected for research purposes.

Conflict of Interest

None.

Acknowledgements

None.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| Behind the Scenes Of Cns Vasculitis: A Rare Case of Cns Vasculitis with Two Primary Malignancies

Abstract

To highlight the importance of a broad differential diagnosis, including malignancy, in patients with central nervous system vasculitis (CNSV) presenting as multiple, recurrent cryptogenic strokes.

Recent Findings

We describe a rare entity, CNSV in the setting of two underlying neoplastic disorders and a chorioretinal inflammatory disease. The clinical presentation, imaging study results, histopathologic features, and response to treatment are reported.

Summary

Cancer-associated CNSV is a rare cause of recurrent cryptogenic strokes. This case highlights the importance of clinical suspicion of and comprehensive work-up for neoplasms in a patient presenting with brain lesions consistent with CNSV.

Keywords: Vasculitis; Infarction; Visual loss; Retina; Paraneoplastic syndrome

Abbreviations:

APMPPE- Acute posterior multifocal placoid pigment epitheliopathy

CNSV- Central Nervous system Vasculitis

MRI- magnetic resonance imaging

MRA- magnetic resonance angiography

ANA- anti-nuclear antibody

CSF- Cerebrospinal fluid

PET- positron emission tomography

CT - computerized tomography

CYC- cyclophosphamide

Introduction

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a rare, self-limiting chorioretinal inflammatory disorder that is often characterized by a flu-like prodrome and usually presents in young adults [1]. Neurological complications are rare but potentially fatal manifestations of APMPPE that have been previously reported in 56 cases, with the most common being CNSV (50% of the cases) [2]. CNSV is a diagnostically challenging disease and has been rarely associated with malignancies, especially with Hodgkin lymphoma [3].

We report one patient with APMPPE and neurological symptoms consistent with CNSV, who was diagnosed with two primary malignancies during the medical work-up for CNSV.

Case Presentation

A 59-year-old female presented to the hospital with bilateral blurry vision, floaters and light flashes that persisted over a twoweek period. These symptoms were preceded by holocephalic aching headaches associated with temporal tenderness two weeks prior to the vision symptoms. The patient has a medical history of recurrent herpes zoster, hyperlipidemia, and type 2 diabetes mellitus. Review of systems was notable for fatigue, fever, chills, night sweats, dry mouth, and weight loss of 64 pounds in the past year. Physical exam revealed normal vital signs, a palpable left submandibular lymph node, impaired visual acuity to counting fingers at 3 feet in the left eye and 20/200 in the right eye, and fundus exam revealed yellow-white placoid lesions with areas of chorioretinal atrophy (Figures 1-4) The remainder of the eye exam was unremarkable. Neurological examination revealed impaired range of central visual field and decreased sensation to pinprick in the right cranial nerve V3 (mandibular) distribution and right upper extremity. Brain magnetic resonance imaging (MRI) showed a subacute lacunar infarct in the dorsal left putamen/capsular junction and minimal white matter chronic microvascular ischemic disease (Figure 5). Cranial magnetic resonance angiography (MRA) demonstrated no evidence of flow-limiting stenosis or occlusion. The patient was treated with atorvastatin 40 mg and aspirin 325 mg for secondary stroke prevention.

Ophthalmologic findings triggered a concern for cerebral vasculitis, thus immunologic workup was done which was unremarkable except for a weakly positive anti-nuclear antibody (ANA) (titer of 1:160). The results of the tests for anti-dsDNA and anti-extractable nuclear antigen antibodies, viral hepatitis B and C, and HIV screening were all negative.

Laboratory studies at presentation demonstrated mildly elevated inflammatory markers (Table 1). Cerebrospinal fluid (CSF) demonstrated lymphocytic pleocytosis and elevated protein levels (Table 2). CSF studies for varicella zoster virus PCR, IgG, and IgM were negative. Transthoracic echocardiogram and cardiac MRI did not demonstrate any findings to suggest acute or chronic cardiopulmonary abnormality. The patient was started on methylprednisolone 1000 mg intravenously daily for 3 days followed by prednisone 60 mg by mouth daily with a slow taper to manage her suspected CNSV.

Table 1:Relevant lab studies.

Table 2:CSF Findings.

Catheter-based angiogram of the brain was negative for vasculitic changes. Given the lack of definite diagnosis, a brain biopsy was ordered. However, a pre-operative head CT scan showed multiple interval lacunar infarcts within the right periventricular corona radiata, right cerebellum, mesial left temporal lobe, and left occipital lobe, and an evolving subacute infarct within the left basal ganglia. Additionally, whole body PET CT imaging showed a region with increased uptake in the right breast with associated hypermetabolic right axillary lymphadenopathy and left submandibular lymph node, but no evidence of large-vessel vasculitis (Figure 6). At that time the brain biopsy was aborted pending work up for these lesions, prednisone was titrated to 100 mg by mouth daily, and the patient was discharged to facilitate necessary outpatient oncologic workup, including breast biopsy.

Four days later, immediately following her breast biopsy, the patient presented again with an episode of numbness and paresthesia on the left side of her body, speech difficulty, and facial droop. A repeat MRI confirmed the presence of multiple new acute infarcts in the superior frontal gyrus and bilaterally in the occipital lobe (Figure 7).

The breast biopsy revealed invasive ductal carcinoma. A needle core biopsy of the patient’s submandibular lymph node was consistent with follicular lymphoma; however the sample was too scant for grading. An open brain biopsy (right occipital craniotomy and biopsy of dura and brain with neuro navigation) was performed, which showed no evidence of neoplastic process or definite features of vasculitis. Repeat catheter angiography of the brain demonstrated multifocal regions of vessel wall narrowing leading to occlusion, most pronounced in distal bilateral middle cerebral arteries and distal left posterior cerebral artery territories concerning for vasculitis or other cause of vasospasm. No verapamil was administered due to recent stroke and risk of reperfusion hemorrhage.

Based on discussion with oncology, both breast malignancy and follicular lymphoma were thought to be indolent and thus a decision was made to start induction immunosuppression for CNSV.

The patient was started on cyclophosphamide (CYC) 600 mg/ m2 IV every 4 weeks along with tapering the prednisone, which was well-tolerated for 3 doses of CYC. However, one week after her third dose she had an episode of right leg weakness and numbness and presented to the emergency room, where brain MRI showed new subacute/acute infarcts in both cerebral hemispheres and the left genu of the corpus callosum. CT angiogram showed new multifocal areas of moderate to severe narrowing of the bilateral pericallosal arteries and posterior cerebral arteries. Transthoracic echocardiogram was again negative for acute or chronic abnormalities and repeat CSF studies showed normal leukocyte count and protein level.

At this point, the decision was made to add rituximab 375 mg/ m2 IV weekly to her CYC therapy and increase the prednisone dose to 60 mg. At the time of submission of this case report, the patient had received a total of 5 doses of CYC and 6 doses of rituximab. Clinically, the patient did well with no recurrence of neurologic deficits.

Discussion

CNSV was found in some studies to be associated with APMPPE. The mechanism that leads to this association is unknown but is often attributed to an underlying vasculitis process [2]. Our experience here demonstrates the difficulty of diagnosing CNSV, a rare disease that is sometimes associated with other pathologies. Ambiguous clinical presentation and radiographic imaging can often mimic other disease processes and can present diagnostic and therapeutic challenges. Angiography has a sensitivity for diagnosing CNSV between 50% and 90% while some report the sensitivity of brain biopsy to be less than 50%, although the latter might be helpful in excluding the presence of other syndromes [4]. In our case, the diagnostic interventions were further complicated by the discovery of two primary malignancies as associated and potentially causative pathologies.

To our knowledge there is only one other report in the literature of a case of APMPPE associated with a malignancy. However, in that case the patient presented differently. He was diagnosed with and treated for metastatic clear cell renal carcinoma before the APMPPE was diagnosed. The development of APMPPE was proposed to be a result of the spreading of tumor-originated circulating immune complexes [5]. CNSV has been rarely associated with malignancy. CNSV has been previously reported in a patient who presented with intractable seizures and was later diagnosed with invasive lobular carcinoma of the breast [6]. Two additional patients presenting with CNSV after receiving treatment for malignant vaginal squamous cell carcinoma and invasive breast ductal carcinoma responded to methylprednisolone/plasmapheresis and to prednisone, respectively [7].

A study looking at patients diagnosed with any type of vasculitis and lymphoma over a 32-year period found the incidence of lymphoma presenting together with CNSV to be 10/168, or 5.9%. All of the patients in that study were treated with prednisone and two patients also received cyclophosphamide. Overall, 6/10 patients responded to therapy and showed almost no residual deficits [3]. Significant in our case is the simultaneous presence of two primary malignancies in addition to APMPPE and a CNSV process. Cyclophosphamide may be an appropriate firstline treatment in a patient with CNSV. However, in the setting of underlying malignancy, our patient did not respond well to cyclophosphamide despite adequate dosing for 12 weeks. The addition of rituximab to cyclophosphamide was possibly beneficial due to the underlying follicular lymphoma, pointing to the possibility of a paraneoplastic etiology of the CNSV. The relationship between systemic malignancies and CNSV continues to be difficult to assess. A cell-mediated immune process triggered by abnormal serum proteins or tumor antigens has been suggested as a possible etiopathogenetic mechanism [6,7]. Treatment recommendations and patient outcomes vary in the literature. Additionally, these clinical entities are often difficult to diagnose which leads to further problems in determining the optimal treatment plan. Our case demonstrates the importance of considering a broad differential in a patient presenting with APMPPE and atypical persistent neurologic symptoms. Further studies are needed to help guide treatment for CNSV when associated with malignancy Appendix 1.

Conflict of Interest

The authors report no financial disclosures

Acknowledgement

None

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| Chronic Synovitis of Wrist: A Diagnostic Dilemma & Role of Arthroscopy

Authored by: Jawed Akram

Abstract

Chronic Synovitis presents a diagnostic dilemma for clinicians and surgeons. In our study we investigated patients presenting with chronic synovitis of wrist joint with wrist arthroscopy. 8 out of 34 (23.53%) of cases were histologically positive for granulomas suggestive of tuberculosis. We were able to predict the etiology of the disease based on the arthroscopy findings.

Introduction

Chronic synovitis of wrist joint is a common manifestation seen in a majority of cases of inflammatory arthritis especially rheumatoid arthritis, the involvement in these cases is usually poly-articular, but occasionally oligo- articular and mono articular involvement may be seen. In the Indian population tuberculosis of wrist joint is an important differential diagnosis to be kept when a patient presents with Mon-articular wrist swelling.

Methods

We investigated 34 patients presenting to our clinic with symptoms of chronic synovitis of wrist joint in the time duration between January 2014 to June 2021. We included the patients with a single joint involvement excluding those with oligo articular or poly articular involvement. All of these patients have been treated initially with non-steroidal anti-inflammatory drugs. We excluded patients with symptoms less than three months duration. The patients were investigated and scheduled for diagnostic arthroscopy with synovial biopsy. None of the patients complained of fever as the presenting complaint. Family history positive for tuberculosis was present in two of the patients. Chest X-rays were normal in all but one patient which showed right upper lobe infiltrates [Table 1]. The mean ESR was recorded to be 38.7 [Table 2]. All of the patients had a past history of BCG vaccination. Past history of tuberculosis was present in one patient ten years back which was treated with directly observed treatment for a period of six months. The rheumatoid factor was positive in eleven of the cases. The mean duration of involvement in these cases was 5.5 months. X-rays of wrist joint were taken and found to be normal in 22 out of 24 cases whereas the rest 12 there were features like juxta-articular osteopenia, periarticular erosion etc. Wrist arthroscopy was performed in these patients with a diagnostic intent and synovial biopsy was taken from the involved synovium which was sent for histopathological examination.

Table 1:clinical detail.

Table 2:Arthroscopic findings in the 2 groups.

Literature Review

Reports tuberculosis infections of wrist have been scarce, especially during past 30 years. Role of arthroscopy of wrist joint for tuberculosis infection has not been reported as yet. Arthroscopy has now been a standard therapy for rheumatoid arthritis of wrist allowing effective pain relief and high patient satisfaction [1]. Most of the report of tuberculosis within literature concentrate around atypical mycobacterial infection. Tuberculosis infection in wrist joint can come of variety of pathology including tuberculous arthritis, synovitis, tenosynovitis, soft tissue tuberculosis. Most striking feature of previous studies was delay between the onset of symptoms and the correct diagnosis. Most of earlier studies revealed an absence of pulmonary symptoms [2]. [Figure 1] Formation of rice like bodies has been explained in an earlier case report [3]. Earlier series express open synovectomy of wrist both as a diagnostic and therapeutic tool [4].

Surgical technique: The 3-4 and 4-5 portals were used as standard entry portals for radio-carpal joint. Additional 1-2 and 6U portals were also used occasionally to view dorsal side of radiocarpal joint. Adequate synovial biopsy specimen was taken from the region of synovium which visibly seemed to be maximally involved [Figure 2]. We noticed some peculiar findings in a subgroup of patients which didn’t comply with the characteristically described synovium in inflammatory diseases like rheumatoid arthritis. The peculiar features which were observed in these patients were absence of hypertrophic synovium (12 out of 34), absence of pannus formation (18 out of 34), atrophic villi (12 out of 34). 4 of the patients revealed small rice like bodies from the synovium [Figure 3].

Assessment: We tried to correlate our arthroscopic findings with the histopathological diagnosis. Absence of pannus and atrophic villi like architecture was strongly associated (66% 8 out of 12) with visibility of granulomas on histopathology. Both of the two patients whose synovium revealed rice like bodies showed features suggestive of granulomatous inflammation on histopathology. Overall, 8 out of the 34 patients were diagnosed as having tuberculosis on histopathological grounds [Figure 4,5]. Ziel Nielson staining failed to reveal acid fast bacilli in any of the case. A single patient developed growth of Mycobacterium tuberculosis on culture in LJ medium.

Conclusion

Tuberculosis must be kept as a differential diagnosis in cases presenting as chronic synovitis of wrist especially in tuberculosis endemic zones of southeast Asia. An early arthroscopy and arthroscopic synovial biopsy must be considered in these cases in order to establish a diagnosis. Arthroscopic examination can serve as a good predictor of etiology, but histopathology and culture remain the gold standard.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| A New Ache in The World of Joints

Authored by: Teresa A Simon

The State of the Joint

Patients with rheumatic diseases are afflicted with many different symptoms depending on the disease, however the one symptom that is common among all the rheumatic diseases is pain. In an explorative effort to combat this pain since currently available treatments frequently provide insufficient relief, this patient population has been increasing use of cannabis and hemp products for symptom management.

This increase is documented in a recent study that evaluated the prevalence of cannabis use in a rheumatic disease population from the FORWARD registry, a registry of rheumatic disease patients [1]. This study documented an increase in cannabis use nationwide (from 6.3% to 18.4%) and at the state level regardless of rheumatic disease diagnosis or cannabis legality status between 2014 and 2019 [2]. Results are consistent with the increased prevalence of cannabis use in patients with rheumatic diseases in Canada, (4.3% in 2016 and 12.6% in 2020) [3]. Therefore, the prevalence of cannabis use among individuals with rheumatic diseases has tripled in both the Canadian and US population in similar timeframes.

Given this increase, there remains a dearth of evidence on the long-term use and impact of cannabis and/or hemp-based products in the rheumatic disease community. Health care providers consistently hear how patients are reluctant to accept recommendations and prescriptions for proton pump inhibitors, statins, biologic anti-rheumatic therapies because of perceived dangers and toxicities, yet some patients will accept a cannabis or hemp-product as a treatment (e.g., for cancer) as if both its efficacy and safety is more solidly proven [4]. A recent study from the National Survey on Drug Use and Health showed an 18% relative decrease in perceived risk of cannabis [5].

Simultaneously, there has been an increase in public support for the federal legalization of cannabis in the United States (US) [6]. Presently, most of the United States population lives in a State where an adult can purchase a cannabis product as easily as a beer from a licensed dispensary. There are also several ways to access hemp-products outside of State licensed stores. Hemp products are defined as any cannabis-product with less than 0.3% Δ9- tetrahydrocannabinol (THC) by weight. These hemp products are often rich in cannabidiol (CBD) and other plant compounds with significant pharmacological activity, but often skirt much regulatory oversight (e.g., labeling accuracy) beyond the THC limit [7].

Despite the increased availability and consumption of cannabis and hemp products, there is mounting evidence that consumers, the public, and healthcare professionals are confused about how to read the labels of these products, what exactly are in these products, and what potential benefits and side effects they might have [7–10]. An example is from a recent pilot study of consumers and their knowledge and attitudes [11]. The data demonstrate a lack in understanding of cannabis while supporting legalization. There seems to be a disconnect between support in the legalization of cannabis and the understanding of its risks, benefits, and potential adverse effects. Admittedly there is evidence of potential benefit, such as with spasticity, nausea and vomiting associated with chemotherapy, seizures, and pain to mention a few [12]. However, and often overlooked, is the evolving literature documenting potential side effects of cannabis on reproductive health, cardiovascular health, mental health, and sensorimotor skills/reaction times impacting ability to drive safely. Despite the availability of adverse effects data, the balance between risks and benefits of cannabis and hemp does not appear to have slowed down public support of cannabis.

Consumers have been going through a trial-and-error process with the use of cannabis products in different states [13]. Pain is among the most common indications associated with the use of medical cannabis [14]. There is some evidence that cannabis is associated with reductions in opioid use across pain disorders [15- 19]. In addition, cannabis has become increasingly popular as a go to treatment for patients with rheumatic diseases [20].

Education is The Biggest Challenge Facing Patients

Patients who are considering using these products should be able to receive sound education and speak with qualified individuals that have a certain level of education regarding cannabis and hemp. Who should be responsible for this education on cannabis, hemp, and related products? In lieu of a national consensus on the issue, we can only speculate. Several states have made this the responsibility of a pharmacist, which is required to be available for patient consultations. This approach may work for a niche patient group but cannabinoid containing products can be purchased outside of dispensaries, in places such as gas stations. Are we planning to put pharmacists in every retail outlet that sells cannabis-derived products?

Another viewpoint is that we should rely on the companies making the products. If a company is going to make even an indirect claim about its product, then the company should provide evidence of such a claim which includes the safety data, product standards and labelling. Others suggest it is society’s responsibility. Or the government’s? Or organized medicine’s? Or is it buyer beware? Society has created the incentives for cannabis companies to do what they are setting out to do – make a profit. Whose responsibility is it to ensure education remains unclear. In the end, the education of health care professionals and patients should be one of the most important aspects of national legalization [21]. Is it possible that the members of the cannabis and hemp industry are taking advantage of the public’s lack of knowledge? There are many examples of the issues that can arise from a few bad apples in these industries [22]. Most recently the commercial availability of delta-8 THC synthesized from hemp CBD has led to an increased number of cases presenting at poison control centers and reported adverse events to the FDA related to the products containing this compound [11].

Conclusion

There is a well-recognized public perception that these substances are safe, leading to a possible underappreciation of potential adverse effects. This situation may exist, at least in part, because cannabis is not treated as a “drug” from a regulatory perspective. The public may believe it is safe because they perceive that the regulatory agencies have “signed off” or “passed” on it [9].

A summary from a recent paper: Sarzi-Puttini et al. states “it’s necessary to have educational programs that modify the concerns and widespread preconceptions related to cannabis and rheumatic diseases in the medical community by increasing confidence. More extensive basic and clinical research on the mechanisms and clinical utility of cannabis and derivatives in various diseases and their long-term side effects is necessary” [23].

In summary, little is known about the efficacy and safety of medical cannabis or hemp products in the treatment of patients with rheumatic diseases. Despite this dearth of knowledge, or perhaps because of it, education is urgently needed for both patients and health professionals to help them navigate the use of these products while minimizing risks. Presently we must strive to do the best that we can with an incomplete knowledge base, while we wait for desperately needed data from industry and academia to help understand the benefits and mitigate the risks.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| An Atypical Presentation of Dermatomyositis Sine Dermatitis in A Child with Autism

Authored by: Laurel G Wolf

Abstract

Background: Juvenile Dermatomyositis (JDM) is a rare inflammatory myopathy that classically presents with proximal muscle weakness and classic rashes, however there is a form without rash, “sine dermatitis.” There are also relatively recently described myositis-specific autoantibodies, such as NXP-2 antibody, that can be present in JDM. Variations in clinical presentation and associations of this myositis-specific autoantibody have not been extensively described.

Case Presentation: A 5-year-old female with a history of autism spectrum disorder (ASD) and recent travel to Jamaica presented with 2.5 months of left lower extremity weakness and more recent onset of left upper extremity weakness. Her physical exam was significant for left upper and lower extremity pain and decreased range of motion, absence of skin rash, as well as communication deficits secondary to ASD. She underwent an extensive workup including evaluation for infectious, neurologic, and rheumatologic etiologies of her weakness. Initial laboratory evaluation revealed elevated inflammatory markers, mildly elevated creatine kinase, and positive antinuclear antibody. Magnetic resonance imaging showed evidence of bilateral diffuse myositis with subsequent muscle biopsy of left lower extremity showing signs of an inflammatory myopathy. Further laboratory evaluation was positive for NXP-2 autoantibody associated with JDM. Her clinical picture is most consistent with JDM sine dermatitis. She was treated with steroid taper and methotrexate with improvement in symptoms.

Conclusion: JDM can present in various ways, and clinical suspicion should be high even in patients with misleading historical and physical exam findings. Because JDM is such a rare disease, this case provides important insight into the atypical way that it can present, particularly with a challenging physical exam, and it provides information on clinical manifestations appreciated with the NXP-2 autoantibody.

Keywords: Juvenile dermatomyositis; Dermatomyositis sine dermatitis; Juvenile idiopathic inflammatory myopathy; NXP-2 antibody.

Abbreviations: ASD Autism Spectrum Disorder; ANA Antinuclear Antibody; CK Creatine Kinase; ESR Erythrocyte Sedimentation Rate; LDH Lactate Dehydrogenase; JIIM Juvenile Idiopathic Inflammatory Myopathy; JDM Juvenile Dermatomyositis; JPM Juvenile Polymyositis; AST Aspartate Aminotransferase; ALT Alanine Aminotransferase; EULAR European League Against Rheumatism; ACR American College of Rheumatology

Introduction

Juvenile idiopathic inflammatory myopathies (JIIMs) are rare childhood chronic autoimmune rheumatic diseases. Juvenile dermatomyositis (JDM) is the most common of the JIIMs with an incidence of 3.2 per million children per year. Other subtypes of IIMs include focal myositis, polymyositis, inclusion body myositis, immune-mediated necrotizing myopathy, anti-synthetase syndrome, and overlap syndromes [1-3].

JDM is clinically characterized by symmetric proximal muscle weakness, classic rashes (including malar, heliotrope, Gottron’s sign, and Gottron’s papules), and nailfold capillaropathy, although disease can include musculoskeletal, pulmonary, and gastrointestinal manifestations. However, JDM can have variable presentations that include an amyopathic form or sine dermatitis. Laboratory findings consistent with muscle breakdown include elevations in serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and aldolase. EULAR/ACR criteria have been used to diagnose inflammatory myopathy, however these criteria only denote risk of disease and do not rule out disease if negative. More recently, presence of myositis-specific autoantibodies has been used to attempt to distinguish phenotypes of JIIMs. In particular, NXP-2 antibody is a novel autoantibody that has previously been associated with calcinosis, joint contractures, and polyarthritis in JIIM [1-3]. In this report, we describe a patient with an atypical presentation of JDM sine dermatitis and the presence of the novel myositis specific autoantibody NXP-2 without the previously described associations.

Case Presentation

A 5-year-old female with a past medical history of autism spectrum disorder (ASD) and recent travel history to Jamaica presented with limp and left-sided weakness for 2.5 months. The patient’s symptoms started with limp when she was in Jamaica visiting family and progressed to weakness, stiffness, refusal to bear weight on the left lower extremity, then requiring use of a wall to assist with standing from a seated position. She also had more recent decreased use of her left upper extremity and kept her arm flexed at the elbow. She had no associated joint swelling, erythema, tenderness, rash, or fever. She was up-to-date on vaccinations. When she returned from Jamaica, she was evaluated by an orthopedic surgeon in clinic who recommended physical therapy, but she had no clinical improvement. Her primary care doctor obtained lab work which was significant for positive antinuclear antibody (ANA) 1:2560 titer (speckled pattern), CK 238 U/L, and erythrocyte sedimentation rate (ESR) 82 mm/hour, prompting presentation to the Emergency Department.

On admission, she was afebrile and hemodynamically stable. Physical exam was extremely limited by her poor communication secondary to ASD; however, pain and decreased range of motion in the left lower and upper extremities were observed. Physical exam was also significant for toe walking, which was present at baseline due to her ASD, and a left-sided antalgic gait. Radiograph of left knee and elbow were unrevealing. The differential diagnosis at this time was quite broad and included rheumatologic, infectious, neurologic, metabolic (heavy metals, vitamin deficiency), and malignant causes.

Rheumatology was consulted and recommended laboratory evaluation to look for autoimmune processes as a potential cause of her symptoms. These were significant for elevated CK (239 U/L), elevated LDH (467 U/L), elevated aldolase (10.8 U/L), slightly elevated complement levels (C3 154.7 mg/dL, C4 43.4 mg/dL), hypoalbuminemia (3.2 g/dL), and normocytic anemia (hemoglobin 10.5 g/dL). Jo-1, Sm, RNP, dsDNA, SSA, and SSB antibodies were all negative. Serum transaminases and urinalysis were normal. MRI with and without contrast of the left lower extremity was obtained to evaluate for osteomyelitis, arthritis, and myositis and showed extensive hyperintensity and enhancement in gluteal, hip abductors, and upper leg musculature representing myositis or myopathy. Included portions of the right lower extremity showed the same signal abnormalities.

With this new information and due to her recent travel history, infectious workup, including testing for Echovirus, Coxsackie virus, human immunodeficiency virus, human t-cell lymphotropic virus type 1, Dengue virus, Zika virus, and Chikungunya virus, was performed, and tests were all negative. Simultaneously, a muscle biopsy of the left thigh was pursued and significant for interstitial perivascular mononuclear inflammatory infiltrates consistent with an inflammatory myopathy. There were no myotubes, myophagocytosis, perifascicular atrophy, cytoplasmic inclusions by trichrome stain, or target fibers. The DPAS and PAS stains showed a normal glycogen content. Neuropathic changes such as group atrophy were not found. Electromyography was not pursued because of patient’s difficulty cooperating with exam due to ASD. She was started on scheduled naproxen 10 mg/kg twice daily and daily oral prednisolone 0.6 mg/kg daily due to concern for JIIM. Pain and range of motion improved, and the patient was able to discharge home with rheumatology follow up.

After discharge, myositis-specific autoantibody panel resulted positive for NXP-2 antibody, which is associated with juvenile polymyositis (JPM) and JDM. Given that the muscle biopsy pathology was more consistent with DM, and that the patient never had a rash (malar, heliotrope, or Gottron’s rash) throughout her disease course, her clinical picture is most consistent with JDM sine dermatitis. She has also been treated with injectable methotrexate ~15 mg/m2 weekly as an immunosuppressant agent along with physical therapy. These have led to improvement in symptoms, serum muscle enzymes, and allowed for prednisolone taper.

Discussion

JDM classically presents with signs and symptoms of proximal muscle weakness based on history and physical exam. This patient’s presentation was unique because her physical exam and laboratory findings were not typical for inflammatory myopathy. In particular, her muscle weakness appeared to be unilateral instead of the typical symmetric pattern that is seen in JDM, and she seemed to have pain with passive and active range of motion. It is possible that the interpretation of her exam was altered by behavioral concerns with her history of ASD. Additionally, she did not have any skin findings that would point to the much more common classic presentation of JDM. Her labs did show slightly elevated CK, elevated aldolase, and elevated LDH, but she did not have elevated AST/ALT and CK elevations tend to be much higher in polymyositis. Jo-1 antibody, associated with DM, was negative, however this is rare in childhood-onset dermatomyositis.

In 2017, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) published classification criteria for adult and juvenile idiopathic inflammatory myopathy [4]. The criteria include physical exam findings, such as muscle weakness and skin manifestations, as well as laboratory measurements and other clinical manifestations like dysphagia (Table 1). Because some providers are pursuing muscle biopsy less frequently than in the past, the EULAR/ACR criteria can be scored with or without a muscle biopsy.

Utilizing the EULAR/ACR criteria for this patient (Table 1), her objective findings do not suggest increased risk of idiopathic inflammatory myopathy either with or without using the results of her muscle biopsy. Even though her muscle biopsy was consistent with an idiopathic inflammatory myopathy – showing interstitial perivascular mononuclear inflammatory infiltrates – her apparent unilateral physical exam findings and lack of skin manifestations kept her score from being above the cutoff for increased risk of idiopathic inflammatory myopathy. It is unclear how communication and behavior could have played a role in the objective exam for assessing symmetric muscle weakness, and it is important to note that the MRI did show symmetric proximal muscle involvement consistent with JIIM.

Table 1:EULAR/ACR Criteria for this Specific Patient Prior to muscle biopsy her score was 2.2, which correlates with a <50% chance of having the disease. A score of ≥ 5.5 would correlate with increased risk of having inflammatory myopathy. After muscle biopsy, her score was 3.8, which similarly denotes a low chance of having the disease. A score of ≥ 6.7 is associated with increased risk of disease. (CK creatine kinase, LDH lactate dehydrogenase, AST aspartate aminotransferase, ALT alanine aminotransferase).

The positive NXP-2 antibody and lack of rash in the setting of abnormal MRI and muscle biopsy helped to confirm the diagnosis of JDM sine dermatitis in this patient, even though EULAR/ACR criteria denoted low risk of disease. NXP-2 antibody is specific for idiopathic inflammatory myopathies and is diagnostic in the right clinical scenario. NXP-2 antibody is a relatively recently described myositis-specific autoantibody and is not currently included in the EULAR/ACR criteria [5]. The antibody was first described in a cohort of patients with JDM in 1997 [6] and was associated with severe calcinosis, polyarthritis, joint contractures, and intestinal vasculitis. Since then, NXP-2 antibody has been documented in various other cohorts in both pediatric and adult patients [5]. Because of the relative novelty of this antibody, its disease associations have not been well described. Positive NXP-2 antibodies were more commonly identified in JDM in case series but were also seen in few patients with JPM [7,8]. Additionally, 86% of patients with DM sine dermatitis were positive for NXP-2 antibody in a small cohort of 14 patients [9]. Patients with NXP-2 antibodies had more severe disease at follow up, including severe atrophy with contractures, large joint arthritis, and dysphagia, although the study did not distinguish these characteristics between patients with JDM and JPM [10]. The patient presented in this report did not have any calcinosis, severe atrophy, or other stigmata of severe disease, however she did have decreased range of motion in her upper and lower extremities which denotes contractures. This supports the notions that these manifestations take time to develop, there is a broad spectrum of associated disease manifestations, and there is still much unknown about this particular autoantibody.

There were multiple confounding factors in this case that made this patient’s diagnosis a difficult one. The most significant factor was her diagnosis of ASD that limited the physical exam and the patient’s ability to communicate about her symptoms. Her primary symptom of weakness was difficult to parse out and could have easily been mistaken for solely pain. Additionally, she was assessed as having unilateral symptoms, however bilateral MRI findings would suggest that symptoms were in fact bilateral and limited by communication and participation in exam. During her workup, there was significant thought given to the idea of a genetic disorder that may have been misdiagnosed as ASD. On further research, the patient had received formal neurodevelopmental testing to confirm ASD and had been tested for appropriate genetic causes of ASD. Although there are no case reports of ASD and JDM, there is much research into the role of the immune system and inflammation in ASD [11].

Another confounding factor to her presentation was her recent international travel history. The patient’s symptoms started while she was visiting family in Jamaica, therefore there was concern for an infectious etiology. Her infectious workup was negative; however, the possibility remains that there was some infectious agent that prompted the onset of her myositis.

In conclusion, this patient presented with atypical signs and symptoms of JIIM including unilateral weakness, pain, and no dermatologic signs. Based on EULAR/ACR criteria, she was at low risk for JIIM. Her clinical picture was confounded by her recent travel history and her perceived unilateral muscle weakness likely affected by her diagnosis of ASD. Ultimately, diagnosis was confirmed as JDM sine dermatitis based on MRI, muscle biopsy, and serum antibody testing. This relatively novel autoantibody has not been well-described, and this case report offers insight into an atypical presentation of JDM associated with positive NXP-2 antibody.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| Time To Conversion of Hemi/Total Shoulder Arthroplasty To Reverse Total Shoulder Arthroplasty: A Systematic Review of Longevity and Factors Influencing Conversion

Authored by: David S Constantinescu

Abstract

Background: The purposes of this study were to determine the average time from hemiarthroplasty (HA) or total shoulder arthroplasty (TSA) to conversion to reverse total shoulder arthroplasty (RTSA) and to determine the factors leading to conversion to RTSA.

Methods: A review of the literature regarding the existing evidence for conversion of HA/TSA to RTSA was performed. Inclusion criteria were as follows: reporting of conversion of a HA or TSA to RTSA with a follow up of greater than 24 months, English language, and human studies. Excluded were articles that did not mention a time to conversion surgery.

Results: One hundred studies were initially retrieved with 3 meeting the inclusion criteria. The weighted mean time to conversion of HA/TSA to RTSA was 36.8 months. Rotator cuff failure was the indication for conversion in 66% of cases (65/99), while component loosening (glenoid or humeral stem) was the indication in 14% (14/99) of cases.

Conclusions: Among patients that undergo conversion of HA/TSA to RTSA the reported time to conversion was 36.8 months on average. The most common indication for conversion to RTSA was rotator cuff failure, highlighting the importance of rotator cuff integrity when performing a primary HA or TSA.

Keywords: Shoulder, arthroplasty, total shoulder arthroplasty, reverse shoulder arthroplasty, rotator cuff tear, revision shoulder arthroplasty, conversion shoulder arthroplasty.

Abbreviations:

1.Hemiarthroplasty (HA).

2.Total shoulder arthroplasty (TSA).

3.Reverse total shoulder arthroplasty (RTSA).

Introduction

The number of primary total shoulder arthroplasty (TSA) procedures performed is increasing [1-3]. The need for conversion to reverse total shoulder arthroplasty (RTSA) can also expected to follow given the number of primary TSAs performed among an increasingly active population. In instances of TSA or hemiarthroplasty (HA) where anatomic revision is not possible, a RTSA may be indicated to provide biomechanical stability to the shoulder [4-7]. No registrar data or aggregate literature analysis currently exists on the time from HA or TSA to conversion to RTSA.

There were two purposes of this study. The primary purpose of this study was to determine the average time from HA/TSA to conversion RTSA. The secondary purpose of this study was to determine the factors leading to conversion to RTSA. The outcomes of a revised TSA can be predicted on whether the indication for revision a component-related problem or soft tissue deficiency is [8] Therefore, surgeons must be aware of the most common reasons for HA/TSA revision and take this into account into their planning and prognostic discussions with patients. Our hypothesis was that the most common indication for conversion to RTSA was rotator cuff insufficiency.

Materials and Methods

Article Identification and Selection

This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. A systematic review of the literature regarding the existing evidence for conversion to RTSA was performed using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (1980-present), and MEDLINE (1980-present). The queries were performed in August 2019.

The literature search strategy included the following search: “(((total shoulder arthroplasty) OR total shoulder replacement) AND conversion”. Inclusion criteria were as follows: reporting of conversion of a HA or TSA to RTSA with a follow up of greater than 24 months, English language, and human studies. The exclusion criteria included: non-English articles, case reports, technique papers, and articles that did not mention a time to conversion surgery. All references within included studies were crossreferenced for inclusion if missed by the initial search. If a duplicate study population was encountered, the manuscript with the longer mean follow-up was included to avoid overlap.

Two investigators independently reviewed the abstracts from all identified articles. Full-text articles were obtained for review if necessary to allow further assessment of inclusion and exclusion criteria. Additionally, all references from the included studies were reviewed and reconciled to verify that no relevant articles were missing from the systematic review.

Bias

Studies classified as level of evidence 3 or 4 can potentially be affected by selection and performance bias because of the lack of randomization and prospective comparative control groups (level 4), especially in populations characterized by heterogeneity of injuries. Selected studies were reviewed to ensure that authors minimized bias while recognizing the constraints present with such studies.

Data Collection

The level of evidence of the studies was assigned according to the classification as specified by Wright et al. [9] The information was collected from the included studies. Patient demographics, follow-up, outcome scoring methods, primary surgery, time to conversion surgery and implant system used were extracted and recorded. For continuous variables (eg, age, timing, follow-up, outcome scores), the mean and range were collected if reported. Data were recorded into a custom Microsoft Excel spreadsheet (Microsoft Corp) using a modified information extraction table.

Results

Study Selection

The systematic search performed using the above-mentioned keywords and phrases identified three studies, after removing duplicates and applying exclusion criteria [10-12]. One hundred articles were initially identified from the MEDLINE database. There were no additional articles from the Cochrane database. Each article was first screened by title leaving 21 articles. Excluded articles based on title screen were those that did not report on conversion surgeries from HA/TSA. The remaining articles were then screened by abstract yielding 15 articles. Excluded articles based on abstract screen were those that did not report outcomes following conversion surgery. After full text review, three studies met criteria and were included in the review. Studies that were excluded after full text screen were those that did not report a time to conversion surgery from primary surgery. Two studies that were included were of Level III evidence and one study was of Level IV evidence. Figure 1 is a PRISMA flowchart that demonstrates selection criteria of the systematic review. Following review of all references from the included studies, no additional studies met inclusion criteria.

Demographics

In this review a total of 99 patients were included. Study sizes ranging from 17 patients to 56 patients. The review included 99 patients (31 male, 68 female) with a mean age 69 (range: 67 – 73). The average follow up was 35.8 months (range: 32.3 – 37.4). Demographics of each included study are reported in Table 1.

Table 1:Study design, patient demographics and outcome scores of included conversion RTSA studies. VAS = Visual analog scale.

Table 2:Primary surgery implant, indication for conversion, time to conversion, implant system, retention of primary humeral stem and complication rates for included conversion RTSA studies. HA = hemiarthroplasty. TSA = total shoulder arthroplasty.

Time to conversion RTSA

The weighted mean time to conversion of HA/TSA to RTSA was 36.8 months (31.9 – 40). Individual times reported by each study are detailed in Table 2. All three studies contained patients whose primary surgery was a HA or TSA. Castagne et al. was the only of the three who compared the time to surgery between HA and TSA [10].

Indications for Conversion

Rotator cuff failure occurred in 66% of cases (65/99), while component loosening occurred in 14% (14/99) of cases. Among the component loosening, glenoid occurred in 6% (6/99) of cases and humeral stem occurred in 8% (8/99) of cases. Castagne et al. reported that 100% (26/26) patients who underwent conversion did so due to rotator cuff insufficiency [10]. None of the studies reported evaluation of rotator cuff integrity prior to primary TSA.

Primary surgery hardware retention and complication rates

Retaining the humeral stem when performing RTSA conversion surgery occurred in 57% (56/99) of patients. Humeral stem exchange was performed in 43% (43/99) of patients. All three studies reported on complications. Overall, there was a 26.2% (26/99) complication rate among conversion RTSA’s. Reoperation rate was 10% (10/99) and all reoperations occurred within Wieser et al. [11].

Discussion

This review found that the reported time to conversion of HA/ TSA to RTSA was 36.8 months on average with the most common indication for conversion being rotator cuff insufficiency. This highlights the importance of rotator cuff integrity when performing a primary HA or TSA.

TSA has historically been indicated in patients with pain due to isolated glenohumeral arthritis while RTSA has been indicated in cases of rotator cuff arthropathy [13]. Survivorship studies have demonstrated that 85% of primary TSA’s will survive 20 years, with the most common need for revision being component loosening. [14] However, restoring range of motion and activity in previously arthritic shoulder may predispose the rotator cuff to damage. The resultant loss of function in the shoulder may be addressed through conversion of a TSA to RTSA, which recovers shoulder function through restoring the deltoid muscle and altering the functional fulcrum in a rotator cuff deficient shoulder [15]. In fact, a recent study has suggested that RTSA’s may have a role over TSAs in select populations with glenohumeral arthritis even in the presence of an intact rotator cuff [16]. Our study corroborates this idea given the high incidence of rotator cuff insufficiency that necessitated conversion to RTSA.

Due to anticipated rotator cuff insufficiency that may follow TSA, modular components of the humeral stem and glenoid have been designed to facilitate conversion to RTSA [17-20]. Retaining the humeral stem when performing conversion RTSA has been demonstrated to result in lower complication rates [21-24] Of the three studies included in our review, Wieser et al was the only one to include a cohort of patients undergoing humeral stem exchange and also found that stem exchange was associated with a higher complication rate than stem retention [11].

Complication rates for RTSA have been reported to be approximately 15% in the primary surgery and become higher (40%) when RTSA in the revision setting [25]. The complication rate in our studies was 26.2% (26/99) rate among conversion RTSA’s, with the majority of complications being from a cohort of patients that included humeral stem exchange. This finding emphasizes the importance of proper component alignment in the primary surgery to minimize complications if a revision surgery is required.

An important limitation of this study was the level of evidence of the included studies. All were Level III or IV of retrospective cohorts of patients. Subsequently, it is difficult to give definitive quantification of arthroplasty longevity and predisposing factors to revision surgery. Being that not all primary HA’s TSA’s were included and followed for an extended period, this was not a survivorship study suited to answer how long HA/TSA last. Rather, we were able to provide insight as to when primary HA/TSA’s are typically converted to RTSA and the underlying etiology necessitating revision. Based upon available literature, this manuscript is able to provide reasonable analysis to aid the physician in prognostic factors in conversion RTSA.

Conclusions

Among patients that undergo conversion of HA/TSA to RTSA the reported time to conversion was 36.8 months on average. The most common indication for conversion to RTSA was rotator cuff failure, highlighting the importance of rotator cuff integrity when performing a primary HA or TSA.

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| Atypical Initial Presentations of SLE – Our Experience From A Tertiary Centre In Eastern India

Authored by: Rajesh Kumar

Introduction

Systemic Lupus Erythematosus (SLE) is the prototypical multisystem connective tissue disorder affecting persons of all age and both sexes although it is more common in women with childbearing age [1]. The disease was first described by Italian physician Rogerius in 12th century in patients presenting with malar rash, but the systemic nature of the disease was established much later in 1872 by Moric Kaposi [2]. Currently the prevalence of SLE worldwide is reported between 17 to 48 per 100000 individuals [3]. The hallmark characteristics of the disease is production of large amount of different kinds of autoantibodies detectible in blood and other body fluids. Because of its wide variety of manifestations SLE has been previously dubbed as the “great mimicker” [1]. The Systemic Lupus Collaborating Clinics (SLICC) criteria and more recently the ACR-EULAR criteria is used to make a diagnosis of SLE compiling both clinical and immunological features [4]. In terms of presenting features of SLE, the usual symptoms which we encounter in our clinical life are polyarthralgia/arthritis (58%), fever (33%), alopecia (32%), discoid rash (29%), weight loss (28%), buccal ulcer (22%), fatigue (18%), pleuritic chest pain (17%), malar rash, headache, seizures, recurrent abortion, photosensitivity, cognitive impairment etc [3]. However, time and again SLE presents with certain unusual symptoms which baffles us making it difficult and time-consuming to diagnose. There are sporadic case reports of some such presentations in the various public domains.

In this article we have put together 5 cases showcasing our experience in dealing with unusual initial presentations of SLE in our tertiary centre.

Cases

Case 1: 62 year old male patient presented to us with history of fever, knee pain for 2 months and altered sensorium for 10 days. Clinical examination showed widespread purpura and ecchymosis in trunk and extremities. Routine investigations showed anemia, thrombocytopenia, raised urea and creatinine. Peripheral blood smear showed 14-20 schistocytes per HPF. Autoantibody panel showed positivity for ANA Hep2 with homogenous pattern along with dsDNA and anti-Sm positivity. Diagnosis was made of SLE with Thrombotic thrombocytopenic purpura (TTP). Patient responded to 5 cycles of plasmapheresis along with steroids, Mycophenolate mofetil and other supportive management.

Case 2: 20 year old male patient presented to us with history of irregular fever for 2 months and right sided chest pain with difficulty in breathing for 2 days. Clinical examination showed evidence of right sided hydropneumothorax with positive shifting dullness and succussion splash on that side. CT scan of chest showed hydropneumothorax with features of pneumonitis on right side. Autoantibody panel showed positivity for ANA Hep2 with homogenous pattern along with dsDNA positivity. Diagnosis of SLE was confirmed and management started with steroids, cyclophosphamide, intercostal tube drainage and other supportive measures.

Case 3: 15 year old female patient presented with fever, multiple joint pain, rash over face and back of neck, and bleeding from nose and gums. Clinical examination detected malar rash, alopecia and palatal ulcers. Routine investigations showed anemia, hyperferritinemia, hypertriglyceridemia and low fibrinogen levels. Autoantibody panel was positive for ANA Hep2 with coarse speckled pattern with positive anti-Sm fraction. Complement 3 and 4 levels were subnormal and direct Coomb’s test was strongly positive. Infectious etiology was ruled out. Bone marrow biopsy revealed increased histiocytes with hemophagocytosis. Diagnosis of SLE with hemophagocytic lymphohistiocytosis (HLH) was clinched. Management was started with steroids, cyclosporine and hydroxychloroquine

Case 4: 20 year old female patient presented with history of fatigue, ankle and knee joint pain and swelling along with blackish discoloration of right great toe proceeded by burning pain. On clinical examination right great toe dry gangrene was detected. Autoantibody panel was positive for ANA Hep2 with coarse speckled pattern with positive anti-Sm fraction. Complement 3 and 4 levels were low. Antiphospholipid profile done in this patient was negative. MR angiography of the lower limb ruled out any obstructive cause. Treatment was started with steroid and cyclophosphamide following which progression of gangrene halted.

Case 5: 31 year old female patient presented with history of Raynaud’s phenomenon, joint pain and fatigue and was on evaluation in OPD basis. She was admitted to psychiatry ward when she developed catatonic posturing. Investigations showed ANA Hep2 positivity with coarse speckled pattern with positive anti- Sm fraction, SSa and Ro52. ANCA was negative. MRI Brain revealed multiple small infarcts in bilateral brain suggestive of CNS vasculitis. CSF study was normal. Thyroid profile and anti TPO was normal. Patient was started on steroids and cyclophosphamide. Henceforth, there was gradual improvement of catatonia in 2 months.

Discussion

In all our cases, SLE was suspected based on clinical features and confirmed with autoantibody assay. Response to treatment was assessed with monthly follow ups in outpatient department where most of our patients showed marked improvement in symptoms and quality of life.

Although this article showcases rare manifestations of SLE, these initial presentations are not unprecedented.

There is very sparse literature regarding TTP in SLE patients. However, several studies put the incidence of TTP in SLE patients to be as low as 0.5% [5]. It is difficult to detect both conditions simultaneously as many of the features overlap [6]. In our patient increased number of schistocytes in peripheral smear, low platelet count in presence of autoantibodies related to SLE and response to plasmapheresis clinched the diagnosis.

Lupus can present with any number of lung manifestations including pruritus, pneumonia, pulmonary hemorrhage or effusion, interstitial lung disease, pulmonary hypertension; but spontaneous pneumothorax in a young patient is not a common finding. Although aetiology is uncertain, but it has been postulated that rupture of small blebs secondary to underlying pneumonitis or infarction can cause spontaneous pneumothorax [7]. There are 11 reported cases of SLE presenting with pneumothorax in adults of which 10 patients had underlying parenchymal lesion. In our young patient with chest pain, hydropneumothorax was detected on clinical examination and radiography which resolved on chest tube drainage and steroids.

SLE as an autoimmune disorder can predispose to hemophagocytic lymphohistiocytosis (HLH). Multiple studies put the worldwide incidence to be somewhere around 0.9 to 4.6% [8]. It poses a diagnostic challenge as features of HLH can often be confused with sepsis which is very common in a SLE patient on immunosuppressants. In our patient HLH was diagnosed in consensus to HLH-2004 criteria and treatment given with high dose steroids following which patient improved.

Digital gangrene is a relatively rare presentation of SLE which may be attributed to vasospasm, vasculitis or thromboembolism usually in long standing disease or in association with antiphospholipid antibody syndrome (APLA) or Raynaud’s phenomenon. There are few case reports of gangrene in SLE patients with secondary APLA [9,10] but in absence of APLA digital gangrene in SLE is very rare. In our patient APLA profile was negative and patient improved on steroids and cyclophosphamide therapy.

Neuropsychiatric SLE includes a constellation of symptoms – both neurological and psychiatric secondary to central nervous system involvement [11]. Catatonia as a presenting feature of NPSLE is uncommon. Usual treatment in our patient with SLE caused remission without any relapse of symptoms.

The objective of our case series is to put forward the unusual initial presentations of SLE and emphasis the need of awareness so that early detection and timely institution of appropriate treatment of this deadly disease can be achieved.

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Iris Publishers - Open Access Journal of Archives of Archives of Rheumatology & Arthritis Research| Wishing you a Happy Thanksgiving Day

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Iris publishers-Open access journal of Rheumatology & Arthritis Research| Circadian Rhythms and the Treatment of Rheumatoid Arthritis

Authored by: Yool Lee

Abstract

Circadian clocks are ubiquitous biological timing systems that drive roughly 24 rhythms of our behavior (e.g., sleep/wake, feeding/fasting cycles) and physiology (e.g., metabolism, hormonal system, immune functions) through daily adjustments to environmental day and night cycles. Besides the rhythmic regulation of physiological processes, the circadian clockwork has been increasingly recognized to determine the daily variation in pathological symptoms and severity, particularly in autoimmune diseases including Rheumatoid Arthritis (RA). RA is a chronic inflammatory disease caused by the body’s immune system attacking its own tissues and joints, resulting in major symptoms such as joint pain and stiffness. In most RA patients, the autoimmune symptoms are pronounced in the morning and are mediated by circadian rhythms of leukocyte recruitment to inflamed tissues, release of pro-inflammatory cytokines (e.g., IL-6, TNF-α), and immune-modulatory hormone levels (e.g., glucocorticoid, melatonin). With the growing knowledge of the circadian etiology of RA clinical symptoms, here, we will briefly discuss recently established chronotherapeutic concepts as well as approaches to improve outcomes of RA treatment.

Keywords: Circadian clock; Rheumatoid arthritis; Autoimmune diseases; Glucocorticoid, Melatonin; Chronotherapeutic treatment

Introduction

Circadian clocks are cell-autonomous timing systems that generate roughly 24-hour periodic rhythms that are conserved in nearly all life from unicellular organisms to humans. These internal timing systems integrate with diverse environmental (e.g., light) and metabolic (e.g., food intake) stimuli to regulate biological activities, including sleep/wake, feeding times, energy metabolism, and hormonal and immune functions [1]. Disturbances of these rhythms caused by sleep deprivation, mistimed eating, or chronic jet lag are closely associated with the development of obesity, diabetes, and cancer, as well as allergic and immunological diseases [2-4]. Beyond the circadian regulation of physiology, clinical studies indicate that multiple diseases exhibit time of day variations in symptoms and severity [5]. In particular, autoimmune diseases, such as Rheumatoid Arthritis (RA), exhibit higher severity in the morning than at night in most patients [6,7]. According to animal and human model studies, hyper-morning inflammatory symptoms are associated with night (inactive phase) synthesis and the release of pro-inflammatory cytokines and chemokines, as well as the nocturnal rise of immune cell trafficking, proliferation, and phagocytosis at the site of inflammation [7]. Such chronic inflammatory conditions in RA severely compromise the nighttime availability of endogenous anti-inflammatory glucocorticoid, and, conversely, increase the pro-inflammatory melatonin hormone level, which contributes to disease severity [8]. Thus far, experimental and clinical evidence has shown that daily administration of exogenous glucocorticoids or anti-inflammatory drugs (e.g., NSAIDs, methotrexate) at bedtime is more effective than in the morning for the prevention and treatment of morning RA clinical symptoms [7,9]. In this short review, we will briefly discuss further details regarding the link between circadian rhythms and RA, highlighting treatment strategies that exploit chrono pathophysiologic mechanisms.

The Circadian Clock and the Immune System

In all living organisms, the basic biological timing unit is the cell. In mammals, including humans, circadian rhythms are primarily driven by a cell-autonomous molecular feedback mechanism in which the circadian transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (BMAL1) and circadian locomotor output cycles kaput (CLOCK) cyclically activate the expression of their own repressors Period (PER)/Cryptochrome (CRY) [10]. The core clock machinery is mobilized to reset cellular rhythms upon intrinsic and extrinsic stimuli, involving multiple post-translational (e.g., phosphorylation, sumoylation) and metabolic (e.g., Ca2+, cAMP) signaling pathways [11-14]. Systemically, multi-stimuli responsive oscillators in neurons and fibroblasts are tightly coupled to form the brain and peripheral organ clock systems, which, in turn, constitute a body-wide circadian network with adaptive synchronous capacity for environmental entrainment of rhythmic behaviors (e.g., sleep/ wake and feed/fast cycles) and physiology (e.g., temperature, blood pressure, metabolism, immune functions [1]. In particular, the hypothalamic suprachiasmatic nucleus (SCN), a central circadian pacemaker in the brain, communicates retinal light input to peripheral clock systems, thus mediating periodic synchronization of internal body rhythms with external day and night cycles. For example, the SCN coordinates the rhythmic peak secretion of melatonin sleep hormone in the pineal gland at night as well as glucocorticoid (cortisol in humans) stress hormone in the adrenal glands in the morning via sympathetic innervations, thus ensuring sleep/wake cycles [15]. Similarly, the SCN also conveys external timing information to the immune system through endocrine and autonomic pathways, such as local adrenergic innervation of β2-adrenergic receptors (β2ARs) expressed on lymphocytes [16]. Interactions between the circadian and immune systems are bidirectional in that most immune cells contain the molecular clocks that drive the rhythmic synthesis and release of immune factors, which, in turn modulate the circadian phases of body clock systems [17,18]. Mirroring the circadian-immune connection, circadian disruptions, such as environmental desynchronization (e.g., sleep deprivation, jet lag, mistimed feeding) and/or molecular clock dysfunctions (e.g., host or immune cell-specific mutations of core clock genes), lead to the dysregulation of immune responses and inflammation that can further disrupt circadian rhythms [2,19]. Consistent with these findings, increasing numbers of epidemiological studies have reported that night shift workers, transatlantic air travelers, and people with sleep disorders are at greater risk of developing RA than controls [20-25].

Circadian Rhythms in Rheumatoid Arthritis

Accumulating evidence has shown that circadian clocks control the timing of symptoms and severity of chronic inflammatory diseases, including RA [2,26]. RA is a chronic, progressive inflammatory disease with massive infiltration of inflammatory cells into the synovium of multiple joints, causing major symptoms, such as pain, inflammation, and stiffness. It has been welldocumented that RA symptoms exhibit a nearly 24-hour circadian rhythm, with maximum pain and stiffness in the early morning [2,7]. These symptoms are associated with increased release of pro-inflammatory cytokines (including TNF-α and IL-6) from hyper-activated immune cells, such as macrophages, at night and in the early morning, favoring edema and the accumulation of synovial fluid that results in morning stiffness and swelling [6]. In this regard, the daily anti-phasic fluctuation of circadian hormones, such as the lowest level of anti-inflammatory cortisol and the highest level of pro-inflammatory melatonin at night, contributes to the morning RA symptoms. The elevated melatonin level at night stimulates the secretion of pro-inflammatory cytokines, including IFN-g, IL-1, IL-6, and TNF-α, from immune-modulatory cells [7]. This increase in cytokines promotes hepatic expression of 11β-hydroxysteroid dehydrogenase, which converts cortisol, the most potent endogenous anti-inflammatory hormone, into inactive cortisone [6]. This conversion results in abnormal hyposecretion of cortisol during the night, contributing to the presence of early morning clinical joint symptoms in patients with RA [7]. Notably, this vicious cycle appears to be further potentiated by a higher level and earlier increase (at least 2 hours earlier than its normal peak at 2 am) of melatonin in RA patients compared to control subjects, probably due, in part, to the altered chronophysiology caused by the chronic nature of RA [17,27,28]. Considering these findings, the use of melatonin intended to induce sleep is not recommended for people with RA or other inflammatory or autoimmune diseases [23].

Circadian Treatment of Rheumatoid Arthritis

Based on the circadian pathophysiology of RA symptoms, timed administration of an exogenous glucocorticoid has been widely implemented as the main treatment strategy for RA patients to replenish the insufficient availability of the endogenous antiinflammatory hormone at night [2,7,9]. Indeed, several clinical studies have shown that treatment with glucocorticoids late at night is more effective at relieving or preventing morning symptoms in RA patients because it inhibits nocturnal increases in the proinflammatory cytokines IL-6 and TNF-α [6,8]. Earlier studies also showed that a dose of prednisolone, a synthetic glucocorticoid, at night (10pm-11 pm or 2 am) resulted in a significantly shorter duration of morning stiffness than the same dose provided in the morning (6 am-7 am) [29,30]. Furthermore, in subsequent CAPRA (Circadian Administration of Prednisone in RA) clinical studies, Modified-Release (MR) prednisone taken at night (administration at 10 pm and release from the capsule after 4 h at 3-4 am) was shown to be highly effective in abolishing the IL-6 morning peak, with improvement in morning stiffness that was substantially greater than what was observed with conventional immediaterelease prednisolone [31-33]. Similar to the glucocorticoid chronotherapy results, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) taken at night have been reported to be more effective in controlling morning signs and symptoms of RA than either morning Based on the circadian pathophysiology of RA symptoms, timed administration of an exogenous glucocorticoid has been widely implemented as the main treatment strategy for RA patients to replenish the insufficient availability of the endogenous antiinflammatory hormone at night [2,7,9]. Indeed, several clinical studies have shown that treatment with glucocorticoids late at night is more effective at relieving or preventing morning symptoms in RA patients because it inhibits nocturnal increases in the proinflammatory cytokines IL-6 and TNF-α [6,8]. Earlier studies also showed that a dose of prednisolone, a synthetic glucocorticoid, at night (10pm-11 pm or 2 am) resulted in a significantly shorter duration of morning stiffness than the same dose provided in the morning (6 am-7 am) [29,30]. Furthermore, in subsequent CAPRA (Circadian Administration of Prednisone in RA) clinical studies, Modified-Release (MR) prednisone taken at night (administration at 10 pm and release from the capsule after 4 h at 3-4 am) was shown to be highly effective in abolishing the IL-6 morning peak, with improvement in morning stiffness that was substantially greater than what was observed with conventional immediaterelease prednisolone [31-33]. Similar to the glucocorticoid chronotherapy results, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) taken at night have been reported to be more effective in controlling morning signs and symptoms of RA than either morning

Conclusion

In recent decades, extensive chronobiological studies have increased our understanding of the circadian nature of the physiology and pathology of immune systems. This has allowed for the establishment of mechanism-based chronotherapeutic interventions for autoimmune diseases, including RA. Along with the progressive development of manipulatable drug-release technologies, current anti-rheumatic treatment protocols with glucocorticoids, NSAIDs, and DMARDs at bedtime have proven to be more efficacious at improving morning RA symptoms, relative to daytime dosing schemes, via preemptive prevention of the nocturnal rise in pro-inflammatory immune activity (e.g., nightly surge of cytokines). Beyond RA therapies, circadian mechanisms of immunopathogenesis can be applied to the treatment of other inflammatory diseases. For example, a recent clinical trial study reported that dexamethasone (dex), a synthetic glucocorticoid, reduced the death rate of critically ill Covid-19 patients by about one-third, perhaps by suppressing hyperactive immune responses in the lung, such as acute respiratory distress syndrome (ARDS), caused by the viral infection [44]. Considering the success of treating chronic autoimmune diseases with steroid chronotherapy, it is reasonable to assume that nighttime glucocorticoid delivery would likely be helpful in reducing the severe immunopathological consequences (ex., cytokine storm) observed in patients with Covid-19 infection. Moreover, in future clinical studies, it would be beneficial and important to take chronobiology into account for improving the safety and efficacy of existing or novel therapeutic interventions used for the management of RA and/or other immune-related diseases.

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