Intra-articular therapy with methotrexate or tumor necrosis factor inhibitors in rheumatoid arthritis: a systematic review.

BACKGROUND: Persistent monoarthritis in otherwise well-controlled rheumatoid arthritis presents a therapeutic challenge. Intra-articular (IA) steroids are a mainstay of treatment, though some have queried whether IA disease modifying anti-rheumatic drugs (DMARD) and biologics can be used in those who fail steroid injections. METHODS: A systematic literature review was conducted using four medical databases to identify randomized, controlled trials assessing IA therapies in RA patients. Included studies underwent Cochrane Risk of Bias 2 assessment for quality. RESULTS: Twelve studies were included, 6 of which examined intra-articular (IA) TNF inhibitors (TNFi), and 6 studies evaluating IA methotrexate. Of those evaluating IA TNFi, one study reported statistical improvement in TNFi therapy when compared with placebo. The remaining 5 studies compared IA TNFi therapy with steroid injections. IA TNFi had statistically improved symptom scores and clinical assessments comparable with IA steroid treatments. In the 6 studies evaluating IA methotrexate, the addition of methotrexate to steroid intra-articular therapy was not found to be beneficial, and singular methotrexate injection was not superior to the control arms (saline or triamcinolone). Risk-of-bias (ROB) assessment with the Revised Cochrane ROB tool indicated that 2 of 6 TNFi studies were at some risk or high risk for bias, compared with 5 out of 6 methotrexate studies. CONCLUSION: For persistent monoarthritis in rheumatoid arthritis, IA methotrexate was not found to have clinical utility. Intra-articular TNFi therapy appears to have equal efficacy to IA steroids, though the optimal dose and frequency of injections is yet unknown.

Ultrasound Doppler and tenosynovial fluid analysis in tenosynovitis.

OBJECTIVE: To assess Doppler ultrasound (US) and tenosynovial fluid (TSF) characteristics in tenosynovitis within common rheumatic conditions, as well as their diagnostic utility. METHODS: Subjects with tenosynovitis underwent Doppler US and US-guided TSF aspiration for white cell count (WCC) and crystal analysis. Tenosynovial Doppler scores (DS) were semiquantitatively graded. TSF WCC and DS were compared using Kruskal-Wallis tests and logistic regression between non-inflammatory conditions (NIC), inflammatory conditions (IC) and crystal-related conditions (CRC). Receiver operating curves, sensitivity and specificity assessed the ability of WCC and DS to discriminate IC from NIC. RESULTS: We analysed 100 subjects from 14 sites. The mean age was 62 years, 65% were female, and the mean TSF volume was 1.2 mL. Doppler signal was present in 93.7% of the IC group and was more frequent in IC than in NIC group (OR 6.82, 95% CI 1.41 to 32.97). The TSF median WCC per 109/L was significantly higher in the IC (2.58, p<0.001) and CRC (1.07, p<0.01) groups versus the NIC group (0.38). A TSF cut-off of ≥0.67 WCC per 109/L optimally discriminated IC versus NIC with a sensitivity and specificity each of 81.3%. In the IC group, 20 of 48 (41.7%) subjects had a TSF WCC <2.00 per 109/L. CONCLUSIONS: A negative DS helps rule out IC in tenosynovitis, but a positive DS is non-specific and merits TSF testing. Unlike synovial fluid, a lower TSF WCC better discriminates IC from NIC. US guidance facilitates aspiration of minute TSF volume, which is critical for diagnosing tenosynovial CRC.

The association of fatigue, comorbidity burden, disease activity, disability and gross domestic product in patients with rheumatoid arthritis. Results from 34 countries participating in the Quest-RA program.

OBJECTIVES: The aim is to assess the prevalence of comorbidities and to further analyse to which degree fatigue can be explained by comorbidity burden, disease activity, disability and gross domestic product (GDP) in patients with rheumatoid arthritis (RA). METHODS: Nine thousands eight hundred seventy-four patients from 34 countries, 16 with high GDP (>24.000 US dollars [USD] per capita) and 18 low-GDP countries (<24.000 USD) participated in the Quantitative Standard monitoring of Patients with RA (QUEST-RA) study. The prevalence of 31 comorbid conditions, fatigue (0-10 cm visual analogue scale [VAS] [10=worst]), disease activity in 28 joints (DAS28), and physical disability (Health Assessment Questionnaire score [HAQ]) were assessed. Univariate and multivariate linear regression analyses were performed to assess the association between fatigue and comorbidities, disease activity, disability and GDP. RESULTS: Overall, patients reported a median of 2 comorbid conditions of which hypertension (31.5%), osteoporosis (17.6%), osteoarthritis (15.5%) and hyperlipidaemia (14.2%) were the most prevalent. The majority of comorbidities were more common in high-GDP countries. The median fatigue score was 4.4 (4.8 in low-GDP countries and 3.8 in high-GDP countries, p<0.001). In low-GDP countries 25.4% of the patients had a high level of fatigue (>6.6) compared with 23.0% in high-GDP countries (p<0.001). In univariate analysis, fatigue increased with increasing number of comorbidities, disease activity and disability in both high- and low-GDP countries. In multivariate analysis of all countries, these 3 variables explained 29.4% of the variability, whereas GDP was not significant. CONCLUSIONS: Fatigue is a widespread problem associated with high comorbidity burden, disease activity and disability regardless of GDP.

Development of a Musculoskeletal Ultrasound Protocol to Evaluate Hand Pain in Systemic Sclerosis Patients.

Hand impairment is a frequently reported complaint in systemic sclerosis (SSc) patients and a leading cause of disability and diminished quality of life. Managing hand pain can be particularly challenging due to the coexistence of non-inflammatory arthralgias, inflammatory arthritis, acro-osteolysis, tenosynovitis, joint contractures, tendon friction rubs, nerve entrapment, Raynaud's phenomenon (RP), digital ulcers (DU), sclerodactyly, calcinosis, and chronic pain. While physical examination and radiographs are the first line methods for evaluating hand pain, they are limited in scope and miss many underlying etiologies of hand impairment. We propose a joint ultrasound (US) hand protocol to differentiate between various articular, periarticular, ischemic, skin, and nerve pathologies and to assist in targeted treatment strategies.

Non-surgical treatment of aseptic olecranon bursitis: A systematic review.

OBJECTIVE: Olecranon bursitis (OB), characterized by inflammation and fluid collection in the olecranon bursa is a commonly encountered out-patient condition. The data is heterogeneous regarding a stepwise and standardized approach to aseptic OB treatment and the efficacy of intra-bursal corticosteroid injections (CSI). The objective of this review is to systematically evaluate the non-surgical treatment options for aseptic OB. METHODS: This systematic review was conducted in accordance with PRISMA recommendations. The English and non-English literature search was performed in 5 medical databases to identify studies evaluating the treatment of OB. All included studies were evaluated for risk of bias (RoB) using the revised Cochrane RoB tool for randomized control trials (RCTs) and the Newcastle-Ottawa Scale (NOS) for case-control and cohort studies. RESULTS: For the final analyses, 2 RCTs and 2 observational studies were included. The RoB for the RCTs was high and both failed to demonstrate a significant difference in terms of the resolution of OB and bursal tenderness among various invasive and non-invasive treatment options. Corticosteroid injection (CSI) was associated with a significant decline in the duration of symptoms. However, it was associated with a higher number of complications including bursal infection and skin atrophy. CONCLUSION: Based on the available data, it appears that the clinical resolution of aseptic OB can occur with conservative methods if implemented earlier in the disease course. Although CSI is more effective than other treatments, it should be reserved for refractory cases because of a higher complication rate.

ACR Appropriateness Criteria® Chronic Extremity Joint Pain-Suspected Inflammatory Arthritis, Crystalline Arthritis, or Erosive Osteoarthritis: 2022 Update.

Evaluation for suspected inflammatory arthritis as a cause for chronic extremity joint pain often relies on imaging. It is essential that imaging results are interpreted in the context of clinical and serologic results to add specificity because there is significant overlap of imaging findings among the various types of arthritis. This document provides recommendations for imaging evaluation of specific types of inflammatory arthritis, including rheumatoid arthritis, seronegative spondyloarthropathy, gout, calcium pyrophosphate dihydrate disease (or pseudogout), and erosive osteoarthritis. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Progression from palindromic rheumatism to rheumatoid arthritis after COVID-19 vaccination.

Infections including COVID-19 infection are associated with immune overactivation and hyperinflammation, and cases of incident inflammatory arthritis after COVID-19 and other respiratory viral infections have been reported. Theoretical concerns of autoimmunity due to molecular mimicry exist with vaccines including vaccines for COVID-19, and rare cases of flares of underlying chronic inflammatory disorders such as systemic lupus erythematosus have been reported after COVID-19 vaccination. Here we present the case of a patient with a 7-year history of well-controlled palindromic rheumatism who developed rheumatoid arthritis 2 weeks after vaccination for COVID-19. This is the first such case to our knowledge, and further studies can elaborate on the risk of autoimmunity due to COVID-19 vaccines if one exists. Given the overall safety and efficacy of COVID-19 vaccines, the proven benefits of vaccinating vulnerable patients with autoimmune disorders outweigh this potential theoretical risk of autoimmune disease flare, and vaccinations in this at-risk population shall be strongly encouraged.

Impact of colchicine on mortality and morbidity in COVID-19: a systematic review.

INTRODUCTION: Colchicine, because of its anti-inflammatory and possible anti-viral properties, has been proposed as potential therapeutic option for COVID-19. The role of colchicine to mitigate "cytokine storm" and to decrease the severity and mortality associated with COVID-19 has been evaluated in many studies. OBJECTIVE: To evaluate the role of colchicine on morbidity and mortality in COVID-19 patients. METHODS: This systematic review was conducted in accordance with the PRISMA recommendations. The literature search was conducted in 6 medical databases from inception to February 17, 2021 to identify studies evaluating colchicine as a therapeutic agent in COVID-19. All included studies were evaluated for risk of bias (ROB) using the Revised Cochrane ROB tool for randomised controlled trials (RCTs) and Newcastle-Ottawa Scale (NOS) for case-control and cohort studies. RESULTS: Four RCTs and four observational studies were included in the final analysis. One study evaluated colchicine in outpatients, while all others evaluated inpatient use of colchicine. There was significant variability in treatment protocols for colchicine and standard of care in all studies. A statistically significant decrease in all-cause mortality was observed in three observational studies. The risk of mechanical ventilation was significantly reduced only in one observational study. Length of hospitalisation was significantly reduced in two RCTs. Risk for hospitalisation was not significantly decreased in the study evaluating colchicine in outpatients. Very few studies had low risk of bias. CONCLUSION: Based on the available data, colchicine shall not be recommended to treat COVID-19. Further high-quality and multi-center RCTs are required to assess the meaningful impact of this drug in COVID-19.KEY MESSAGESColchicine, an anti-inflammatory agent has demonstrated anti-viral properties in in-vitro studies by degrading the microtubules, as well as by inhibiting the production of pro-inflammatory cytokines.Colchicine has been studied as a potential therapeutic option for COVID-19, with variable results.Until further research can establish the efficacy of colchicine in COVID-19, the use of colchicine in COVID-19 shall be restricted to clinical trials.

Unilateral diaphragmatic paralysis in a diabetic patient: a case of trepopnea.

Dyspnea is a common presenting complaint. Trepopnea, an under-recognized form of dyspnea, is difficult breathing in only one lateral decubitus position. One cause of trepopnea is unilateral diaphragmatic paralysis, which in itself is an uncommon diagnosis. We report a unique case of a 55-year-old diabetic man who presented with trepopnea and was found to have unilateral diaphragmatic paralysis secondary to isolated diabetic phrenic neuropathy. This case highlights the importance of recognizing trepopnea as an early clinical symptom of diaphragmatic paralysis and discusses diabetic phrenic neuropathy which can occur in the absence of peripheral neuropathy.

Missing data in randomised controlled trials of rheumatoid arthritis drug therapy are substantial and handled inappropriately.

OBJECTIVES: To analyse the amount, reporting and handling of missing data, approach to intention-to-treat (ITT) principle application and sensitivity analysis utilisation in randomised clinical trials (RCTs) of rheumatoid arthritis (RA). To assess the trend in such reporting 10 years apart (2006 and 2016). METHODS: Parallel group drug therapy RA RCTs with a clinical primary endpoint. RESULTS: 176 studies enrolling a median of 160 (IQR 62-339) patients were eligible. In terms of actual analysis: 81 (46%) RCTs conducted ITT, 42 (23.9%) conducted modified ITT while 53 (30.1%) conducted non-ITT analysis. Only 58 of 97 (59.8%) RCTs reporting an ITT analysis actually performed it. The median (IQR) numbers of participants completing the trial and included in analysis for primary outcome were 86% (74%-91%) and 100% (97.1%-100%), respectively. 53 (32.7%) and 65 (40.1%) RCTs had >20% and 10%-20% missing primary outcome data, respectively. Missing data handling was unreported by 58 of 171 (33.9%) RCTs. When reported, vast majority used simple imputation methods. No significant trend towards improved reporting was seen between 2006 and 2016. Sensitivity analysis numerically improved from 2006 to 2016 (14.7% vs 21.4%). CONCLUSIONS: There is significant discrepancy in the reported and the actual performed analysis in RA drug therapy RCTs. Nearly one-third of RCTs had >20% missing data. The reporting and methods of missing data handling remain inadequate with high usage of non-preferred simple imputation methods. Sensitivity analysis utilisation was low. No trend towards better missing data reporting and handling was seen.

Clinical implications of synovial fluid specimen handling for crystal associated arthritides: A systematic review.

AIM: To identify the appropriate methods of synovial fluid (SF) specimen storage, manipulation and handling for crystal associated arthritides (CAA) diagnosis. METHOD: A systematic literature review was conducted using 5 medical databases to identify diagnostic studies assessing SF specimen handling for calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals identification. All included studies were rated for quality using the Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: Fifteen studies, including 2 non-English language manuscripts, were included. Eight studies examined both types of crystals, while 3 studies examined CPP and 4 studies examined MSU crystals only. Overall, MSU crystals were more stable over time compared to CPP crystals. MSU stability was generally independent of time, preservative and temperature. CPP crystals deteriorated with time and were more stable if refrigerated. Ethylenediaminetetraacetic acid (EDTA) was a suitable preservative. Re-examining an initially negative SF sample at 24 hours facilitated detection of additional cases. Very few studies had an overall low risk of bias and applicability. CONCLUSION: Monosodium urate crystals remain stable over time independent of storage time, temperature and preservative. CPP crystals are mostly stable for 24-48 hours but can deteriorate with time. Overall, SF crystal examination should ideally be done within 24-48 hours. They may be stored at room temperature without any preservative. Otherwise, refrigeration (4°C/39°F) and EDTA preservation is reasonable. Stored SF re-examination, at 24 hours, helps identify a small number of additional MSU and CPP cases. Centrifugation techniques allow better and easier crystal identification, particularly CPP. Most studies were of unclear or low quality.

Vasculitis Presenting as Autonomic Failure.

INTRODUCTION: Granulomatosis with polyangiitis (GPA) is a vasculitic process that can cause neurological dysfunction in addition to characteristic sinus and pulmonary manifestations. This case report highlights the spectrum of nervous system manifestations and includes rarely reported autonomic and pituitary involvement. CASE REPORT: A 62-year-old woman presented with orthostatic intolerance, tachycardia, dry mouth, and temperature sensitivity; subsequent autonomic reflex study demonstrated widespread postganglionic sympathetic sudomotor, cardiovagal, and cardiovascular adrenergic impairment reflective of autonomic neuropathy and overall autonomic failure. Additional progressive symptoms included dysarthria, dysphagia, bilateral hearing loss, voice hoarseness, and right-sided facial numbness with multiple cranial neuropathies identified on neurological examination. The diagnosis of central diabetes insipidus was also confirmed. Pachymeningitis was present on brain magnetic resonance imaging. Pathologic review of the dural biopsy specimen revealed necrotizing granulomatous vasculitis consistent with GPA. She was treated with intravenous methylprednisolone and rituximab. Over the next 2 months, she had near-complete resolution of her symptoms with normalization on repeat autonomic testing. CONCLUSIONS: This is a unique GPA case presenting with autonomic failure and pituitary dysfunction with conclusive objective findings of autonomic dysfunction. Autonomic dysfunction and other disease manifestations were responsive to immunosuppressive therapy.

Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019.

Hydroxychloroquine, initially used as an antimalarial, is used as an immunomodulatory and anti-inflammatory agent for the management of autoimmune and rheumatic diseases such as systemic lupus erythematosus. Lately, there has been interest in its potential efficacy against severe acute respiratory syndrome coronavirus 2, with several speculated mechanisms. The purpose of this review is to elaborate on the mechanisms surrounding hydroxychloroquine. The review is an in-depth analysis of the antimalarial, immunomodulatory, and antiviral mechanisms of hydroxychloroquine, with detailed and novel pictorial explanations. The mechanisms of hydroxychloroquine are related to potential cardiotoxic manifestations and demonstrate potential adverse effects when used for coronavirus disease 2019 (COVID-19). Finally, current literature associated with hydroxychloroquine and COVID-19 has been analyzed to interrelate the mechanisms, adverse effects, and use of hydroxychloroquine in the current pandemic. Currently, there is insufficient evidence about the efficacy and safety of hydroxychloroquine in COVID-19. KEY MESSAGES HCQ, initially an antimalarial agent, is used as an immunomodulatory agent for managing several autoimmune diseases, for which its efficacy is linked to inhibiting lysosomal antigen processing, MHC-II antigen presentation, and TLR functions. HCQ is generally well-tolerated although severe life-threatening adverse effects including cardiomyopathy and conduction defects have been reported. HCQ use in COVID-19 should be discouraged outside clinical trials under strict medical supervision.

Rheumatoid Meningitis: Clinical Characteristics, Diagnostic Evaluation, and Treatment.

BACKGROUND AND PURPOSE: Due to the potential for high mortality and neurologic complications of rheumatoid meningitis (RM), awaiting biopsy confirmation may delay vital treatment intervention. Our aim was to describe the clinical presentations of RM in our population and determine whether meningeal biopsy impacted diagnosis, treatment, and outcomes. METHODS: A retrospective chart review was completed for patients at Mayo Clinic with a diagnosis of RM within the last 28 years. Those with identified alternative inflammatory, infectious, or neoplastic causes of pachymeningitis or leptomeningitis were excluded. RESULTS: Fourteen patients meeting inclusion/exclusion criteria were identified. All patients were positive for rheumatoid factor or cyclic citrullinated peptide. All patients had magnetic resonance imaging abnormalities characterized by pachymeningeal and/or leptomeningeal enhancement. Of the 10 patients who underwent biopsy, nonspecific findings were seen in 74%. All patients except one were treated with corticosteroids with subsequent symptomatic improvement. Radiographic improvement or resolution was seen in 10 (83%) of 12. Patients improved with corticosteroid treatment, including those who were diagnosed with RM on clinical basis without undergoing a biopsy as well. CONCLUSIONS: This retrospective review displays the myriad of clinical presentations of RM. It also suggests that with appropriate exclusion of infectious, neoplastic, and other autoimmune etiologies, biopsy may not be necessary to initiate treatment.

Myalgia with Elevated Inflammatory Markers in an Obese Young Female: Fibromyalgia or Polymyalgia Rheumatica?

BACKGROUND Fibromyalgia (FM) is a common disorder of diffuse musculoskeletal pain. It is distinctly different from polymyalgia rheumatica (PMR), a disease seen in people over the age of 50 years. Hallmark features of PMR are the presence of elevated erythrocytes sedimentation rate (ESR) and/or C-reactive protein (CRP). These markers are normal in FM. Obesity in itself can be associated with elevated CRP and ESR, and when obese patients present with myalgia and elevated inflammatory markers, diagnostic confusion can ensue. CASE REPORT We describe a case of 38-year-old female with diffuse musculoskeletal pain and elevated ESR and CRP who was initially misdiagnosed with PMR and responded partially to steroids. She developed severe adverse effects from chronic steroid use. She was ultimately diagnosed with FM. CONCLUSIONS We highlight features to help clinicians avoid the pitfall of diagnosing PMR in young obese patients with FM and elevated inflammatory markers. In this case report, we discuss the features of FM, PMR, PMR-like symptoms presentation, and the association of obesity with elevated inflammatory markers.

Vasculitis on brain angiography is not always vasculitis: intravascular large B-cell lymphoma mimicking central nervous system vasculitis.

A 68-year-old man, with a history of non-Hodgkin's lymphoma in remission, was admitted for homonymous hemianopsia, headaches and subacute progressive cognitive decline. Imaging revealed brain infarcts and angiography suggested vasculitis. A brain biopsy, however, revealed an intravascular large B-cell lymphoma (IVLBL). Central nervous system (CNS) vasculitis and IVLBL of the brain are extremely rare diseases that can have an almost identical clinical presentation. Angiographic findings are very similar but usually are reported as compatible with vasculitis. Brain biopsy or a random skin biopsy are crucial in diagnosing IVLBL as the accuracy of angiographic findings for CNS vasculitis is low.

Positive HLA-B27 and sacroiliitis is not always spondyloarthritis.

A 36-year-old man was treated for several years with multiple agents for ankylosing spondylitis based on positive human leukocyte antigen-B27 and sacroiliitis. He was also diagnosed with osteoporosis and hypophosphatemia. Over these years, from being an avid runner, he became dependent on a walker for ambulation. The lack of treatment response and the low phosphorus were clues that eventually led to a diagnosis of tumor-induced osteomalacia. This case discusses the importance of not solely relying on genetic markers and sacroiliitis for diagnosing ankylosing spondylitis as other conditions can cause similar presentations.

Tools for the Assessment of Comorbidity Burden in Rheumatoid Arthritis.

INTRODUCTION: Comorbidities influence the prognosis, clinical outcomes, disease activity, and treatment response in rheumatoid arthritis (RA). RA patients have a high-comorbidity burden necessitating their study. Comorbidity indices are used to measure comorbidities and to study their impacts on different outcomes. A large number of such indices are used in clinical research. Some indices have been specifically developed in RA patients. AIM: This review aims to provide an overview of generic and specific comorbidity indices commonly used in RA research. METHODS: We performed a critical literature review of comorbidity indices in RA using the PubMed database. RESULTS/DISCUSSION: This non-systematic literature review provides an overview of generic and specific comorbidity indices commonly used in RA studies. Some of the older but commonly used comorbidity indices like the Charlson comorbidity index and the Elixhauser comorbidity measure were primarily developed to estimate mortality risk from comorbid diseases. They were not specifically developed for RA patients but have been widely used in rheumatology comorbidity measurement. Of the many comorbidity indices available, only the rheumatic disease comorbidity index (RDCI) and the multimorbidity index have been specifically developed in RA patients. The functional comorbidity index was developed to look at functional disability and has been used in RA patients considering that morbidity is more important than mortality in such patients. While there is limited data comparing these indices, available evidence seems to favor the use of RDCI as it predicts mortality, hospitalization, disability, and healthcare utilization. The choice of the index, however, depends on several factors such as the population under study, outcome of interest, and sources of data. More research is needed to study the RA-specific comorbidity measures to make evidence-based recommendations for the choice of a comorbidity measure.