Ocrelizumab, an anti-CD20 monoclonal antibody, is widely used to treat multiple sclerosis (MS), inducing profound B-cell depletion and disease remission. However, it may rarely lead to opportunistic infections. We report two patients with MS on ocrelizumab who developed unique complications of anti-CD20 antibody therapy. One patient developed fulminant endophthalmitis, a novel complication that has not been previously reported. A 38-year-old female of South Asian descent and a 46-year-old White female, both with MS on ocrelizumab, developed disseminated Ureaplasma urealyticum infection which was initially misdiagnosed as reactive arthritis in both cases. Both patients deteriorated following immunosuppression, with one developing fulminant endophthalmitis. Diagnosis was established via broad-range PCR from synovial and ocular samples. Prolonged antimicrobial and glucocorticoid therapy led to resolution in both cases. Novel B-cell targeting agents can be effective treatments for MS; however, their use may be associated with potentially life-threatening complications. These two cases highlight the diagnostic and therapeutic challenges associated with opportunistic infections in the context of anti-CD20 monoclonal antibody therapy.

OBJECTIVES:This study aims to develop classification criteria for haemochromatosis arthropathy (HA). METHODS:A task force was convened per European Alliance of Associations for Rheumatology standardised operating procedures, including physicians experienced in genetic haemochromatosis and its arthropathy and patient research partners. Candidate classification criteria items were selected via systematic literature review, consensus, and Delphi process. Derivation cohorts of patients with C282Y homozygous HFE gene mutation, joint pain, and iron loading, along with disease mimics (primary generalised osteoarthritis or calcium pyrophosphate deposition disease), were recruited from routine care and assessed against candidate items. Group comparison and diagnostic performance analyses identified variables with the greatest discriminatory capacity. A subset of these variables, agreed upon by consensus (considering both statistical results and the HA disease construct), was modelled using multivariable logistic regression and receiver operating characteristic curve analysis to develop classification criteria models. The final model was agreed upon through discussion, voting, and consensus, taking both statistical performance and disease Gestalt (face validity) into account. RESULTS:A derivation cohort of 154 patients with HA and 120 patients with disease mimics was recruited. A point-based classification model was developed using 8 variables covering age of symptom onset, clinical, and radiographic features at the metacarpophalangeal, distal interphalangeal, and ankle joints, and surgery of hips or ankles. A score ≥5 out of 11 provides 93.3% specificity and 71.4% sensitivity for classifying HA. CONCLUSIONS:An international multicentre task force has developed the first classification criteria for HA from a unique derivation cohort using rigorous methodology. Criteria should be used to include patients in research studies and await external validation in separate cohorts.

Patients with acute swollen joints are often presumed to have septic arthritis, leading to intravenous antibiotics and arthroscopic washout. Previously at our centre, joint fluid aspirates often lacked crystal analysis, resulting in excess culture-negative septic arthritis diagnoses. We developed a ‘Hot Joint Pathway’, hypothesising that since acute crystal arthropathy can be misdiagnosed as ‘culture-negative septic arthritis’, introducing the pathway would improve diagnostic accuracy.This pathway provides a structured approach for investigating acutely swollen joints, distinguishing septic arthritis from crystal arthritis. Key features include a secure messaging app for multidisciplinary discussion and rheumatology-led point-of-care polarised light microscopy (POC PLM) <24 hours 6 days per week. A service evaluation of hospital inpatient data identified patients labelled with septic arthritis admitted between two periods: before (1 January 2019–30 November 2020) and after (27 September 2022–29 February 2024) pathway implementation. Emergency department (ED) patients discussed via the app were also analysed (27 September 2022–25 September 2023).Among ED patients, 92% received rheumatology input, and 100% underwent joint aspiration with rheumatologist-led crystal analysis in <24 hours. 68% avoided hospital admission, receiving same-day discharge. Of these, 53% were diagnosed with crystal arthropathy and were discharged with planned outpatient follow-up.Diagnostic accuracy increased for inpatients following pathway introduction. Joint aspirates increased from 50% to 76% (p=0.034). Culture-negative cases of septic arthritis reduced from 34% to 17% and culture positive cases increased from 41% to 76% (p<0.005). Crystal analysis increased from 19% to 28%. Positive blood cultures increased from 28% to 41%. Mean length of stay decreased from 26 to 23 days.A structured care pathway combining rheumatology-led POC PLM and multidisciplinary discussion increases diagnostic accuracy, facilitates admission avoidance and reduces hospital stay for patients with acute swollen joints. Rheumatology-led PLM is essential for the success of this pathway.

A 28-year-old female presented with a sixweek history of rapid onset proximal muscle weakness, dysphagia, and inflammatory rash (heliotropic rash, Gottron papules, and livedo reticularis). Of note, three weeks prior to developing symptoms the patient had tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The manual muscle testing score 8 (MMT8) was 72/150. The patient had marked anasarca. Laboratory assessment revealed high creatine kinase (CK) 9270 IU/L. Extended myositis panel revealed a positive antinuclear matrix protein 2 (NXP2) antibody. Full body MRI showed extensive muscle edema in the adductor and flexor muscle groups of the shoulder and hip girdle and erector spiny muscles. Muscle biopsy and skin biopsies were both consistent with dermatomyositis (DM). Computed tomography-positron emission tomography showed evidence of intense muscle uptake, particularly in the proximal muscles of the forearms, without any findings suggestive of an underlying malignancy. The initial treatment consisted of high dose intravenous methylprednisolone (1.5 g in total), followed by oral taper and a course of intravenous immunoglobulin (2 g/kg). The patient was initiated on mycophenolate 500 mg twice daily. The patient’s condition worsened, and two weeks following the initial presentation, the patient was bed-bound with worsening dysphagia, ascites, anasarca, and bilateral pleural effusions in the setting of low albumin (26 g/L). Due to deteriorating peak flow measurements at ward level, the patient was moved to the intensive treatment unit where the patient was intubated for airway protection. Magnetic resonance imaging of the brain and acetylcholine receptor antibodies were normal. Given the severity of symptoms and lack of response to treatment, the combination of intravenous 6-hourly 100 mg hydrocortisone, 500 mg of cyclophosphamide every two weeks (3 g in total), and 1 g of rituximab at days one and 15 was prescribed. Steroids were tapered slowly. The patient received one further course of intravenous immunoglobulin due to evidence of residual disease activity. Symptoms slowly improved with recovery of muscle function (MMT8=147/150) and the resolution of skin rash and dysphagia two months following rituximab treatment. CK peaked at 21,525 IU/L before slowly returning to normal range. The patient remains well six months after discharge, has been switched to mycophenolate 500 mg twice daily maintenance therapy, and prednisone has been discontinued. During the coronavirus disease 2019 (COVID-19) pandemic, evidence suggested that 10% of COVID-19 patients developed myopathic symptoms along with hyperCKemia.[1] Recently, there have been case reports of DM following SARS-CoV-2 infection, specifically cases relating to NXP2 antibodies.[2] NXP2 binds to viral RNA (ribonucleic acid) and is an important mediator of viral transcription.[3] It has been hypothesized that NXP2 antibodies can be induced by both the SARS-CoV-2 virus and messenger RNA vaccines. Presence of anti-NXP2 has also been associated with a more severe SARS-CoV-2 infection course.[4,5] In this report, we describe an atypical case of COVID-19-related DM, marked by several factors associated with an unfavorable prognosis and limited treatment response. While existing case reports featuring these attributes are scarce, they hint at a potential connection between anasarca and bulbar weakness, suggesting the possibility of a rare DM subtype.[6-8] To the best of our knowledge, this case report represents the first documented instance of a severe and refractory COVID-19-related DM patient presenting with such features to be treated successfully.

This article aims to review the challenges to diagnosis and management of calcium crystal deposition diseases and evaluate the literature published over the past 3 years. The awaited development of classification criteria is an essential step in the progression of calcium crystal deposition disease clinical research. There have been recent improvements in the accuracy of imaging for the diagnosis of crystal deposition diseases with published definitions of characteristic features. Factors associated with acute flares of disease have been identified and an association with increased cardiovascular risk has been demonstrated. Targeted treatment options for calcium crystal diseases remain elusive. However, there have been advances in understanding the molecular mechanisms of disease revealing potential targets for future drug development. Calcium-crystal deposition diseases are increasing in incidence and prevalence as populations age and continue to associate with a high burden of disability. Despite this, calcium crystal deposition disease remains under-studied with a paucity of evidence-based treatment guidelines.

Objective Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. Methods Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. Results Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). Conclusion The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

The purpose of this study was to explore whether patients with Inflammatory Arthritis (IA) (Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) or Ankylosing Spondylitis (AS)) would remain in remission following a reduction in biologic dosing frequency and to calculate the cost savings associated with dose reduction. This prospective non-blinded non-randomised study commenced in 2010. Patients with Inflammatory Arthritis being treated with a biologic agent were screened for disease activity. A cohort of those in remission according to standardized disease activity indices (DAS28 < 2.6, BASDAI < 4) was offered a reduction in dosing frequency of two commonly used biologic therapies (etanercept 50 mg once per fortnight instead of weekly, adalimumab 40 mg once per month instead of fortnightly). Patients were assessed for disease activity at 3, 6, 12, 18 and 24 months following reduction in dosing frequency. Cost saving was calculated. 79 patients with inflammatory arthritis in remission were recruited. 57% had rheumatoid arthritis (n = 45), 13% psoriatic arthritis (n = 10) and 30% ankylosing spondylitis (n = 24). 57% (n = 45) were taking etanercept and 43% (n = 34) adalimumab. The percentage of patients in remission at 24 months was 56% (n = 44). This resulted in an actual saving to the state of approximately 600,000 euro over two years. This study demonstrates the reduction in biologic dosing frequency is feasible in Inflammatory Arthritis. There was a considerable cost saving at two years. The potential for major cost savings in biologic usage should be pursued further.

We investigated endogenous levels of a novel peptide, pituitary adenylate cyclase activating polypeptide (PACAP), in the rat central nervous system. The amount of PACAP was measured by means of highly specific and sensitive sandwich-enzyme immunoassay. This assay system following HPLC analysis revealed that PACAP38 was a major portion of the total PACAP immunoreactivity and PACAP27 levels were negligibly low in the brain. Therefore, we measured the amount of PACAP38 in 62 regions punched out from frozen tissue sections. High amounts of PACAP38 were found in the lateral septal nucleus (intermediate part), diagonal band, central amygdaloid nucleus, several parts of the hypothalamus (suprachiasmatic, supraoptic, periventricular and arcuate nuclei), central gray, interpeduncular nucleus and dorsal raphe. The suprachiasmatic, paraventricular and periventricular hypothalamic nuclei showed the highest levels. A moderate amount of the peptide was observed in the lateral septal nucleus (dorsal part), medial septal nucleus, medial amygdaloid nucleus, thalamus (paraventricular, paratenial, central medial, ventromedial, reuniens and rhomboid nuclei), hypothalamus (lateral hypothalamic area and mammillary body), ventral tegmental area, interfascicular nucleus and in the locus coeruleus. Such a distribution of endogenous PACAP38 did not parallel the localization of PACAP binding sites which we had demonstrated recently. Moreover, the topographical distribution of PACAP38 observed in the present study differed from that of VIP which had been previously reported. The present results suggest that PACAP38 may have a neurotransmitter/neuromodulator role which is different from that of VIP in the central nervous system.

A man in his 40s was referred to our centre with rapidly progressive interstitial lung disease for lung transplant evaluation. Three months prior to his presentation he had developed periorbital oedema and discolouration, papules over the dorsal aspect of his metacarpophalangeal (MCP) joints and mucocutaneous ulcerations over the dorsum and palmar aspects of his MCPs. He had also been experiencing progressive shortness of breath. Based on the characteristic appearance of the cutaneous lesions, lack of muscle weakness on clinical examination, rapid progression of the interstitial lung disease together with presence of melanoma differentiation-associated gene 5 (MDA5) antibodies a diagnosis of anti-MDA5 dermatomyositis was made. Prompt treatment was initiated with aggressive combined immunomodulatory therapy that resulted in significant improvement in symptoms.

Background Patients with inflammatory arthritis die prematurely of cardiovascular disease. Inflammation activates platelets. Since treatment of inflammatory arthritis is associated with reduced mortality, and decreased platelet reactivity reduces cardiovascular events, we hypothesised that platelet reactivity as measured by dynamic platelet function (DPF) would be increased in patients with inflammatory arthritis and that reactivity could be reduced with therapeutic intervention. Objectives To characterise platelet function using a validated physiological assay in patients with inflammatory arthritis before and after disease improvement. Methods 22 patients were recruited and treated as per local protocol. DPF was measured at baseline and after clinical improvement. Video microscopy was utilised to measure dynamic platelet behaviour in microliters of blood perfused over von Willebrand factor (VWF) at arterial shear rates (1500 s-1). Motion-analysis software measured the number of platelets interacting with VWF, translocating across VWF, the speed and distance platelets travelled across VWF, and stably adhering to the surface. Platelet parameters at baseline and following improvement were compared using Wilcoxon signed rank test and paired student t-test. Changes in platelet function were correlated to inflammatory disease markers by Pearson Correlation. Results 18 patients completed the study. Platelet adhesion decreased and platelet motion increased following treatment. Tender joint count correlated with platelet adhesion (Pearson r = 0.616, p≤0.01) while CRP correlated with velocity of platelet movement (Pearson r = 0.563, p≤0.01). Conclusions Improvement in clinical markers of inflammation is associated with a corresponding change in platelet function. Given the association between reduced mortality and decreased platelet reactivity our results suggest that an appropriate assay of platelet function could guide future therapy of patients with inflammatory arthritis.

An increasing array of drugs can induce vasculitis, a process which causes necrotizing inflammation of vessels and, in turn, tissue ischaemia and inflammation. While most cases will be mild, presenting with arthralgia, malaise and cutaneous leucocytoclastic vasculitis, some cases can be severe and cause major organ involvement, critical illness and rarely death. Clinicians therefore need to be vigilant for systemic disease involvement, stop the offending agent promptly and initiate immunomodulatory therapy when necessary. Novel cancer immunotherapeutic agents such as checkpoint inhibitors (CPIs) are associated with a growing spectrum of rheumatic side effects, including vasculitis. Collectively, these are termed immune related adverse events (irAEs). In this chapter, the drugs most frequently associated with drug-induced vasculitis are discussed, known pathogenic mechanisms are explored, and a clinical approach to diagnosis and management is outlined.

We describe two young cases of reactive haemophagocytic lymphohistiocytosis (HLH) with the resultant stress cardiomyopathy in the setting of underlying autoimmune diseases, systemic lupus erythematosus (SLE) and Still's disease. The initial presentation was similar in both cases with fever, hyperinflammatory response, hypotension (vasoplegia), bicytopenia and hyperferritinemia. Despite standard of care and multiple broad-spectrum antibiotics, both cases remained pyrexic and were ultimately admitted to the intensive therapy unit to treat cardiogenic shock. Echocardiogram of both cases showed low ejection fraction, the cause for which was not found until the final diagnosis of HLH was made. Both cases made a complete clinical and cardiac recovery following the initiation of high-dose glucocorticoids and anakinra.

Background : COVID-19 confers an increased risk of thrombosis however the mechanisms underlying this coagulopathy and the optimal approach to thromboprophylaxis are unknown. Thrombotic risk is likely greatest among patients with severe COVID-19 requiring critical organ support however patients with moderate disease may be at risk and might also benefit from intensified thromboprophylaxis. Aims : To characterise plasma thrombin generation (TG) in patients with COVID-19 of moderate severity, treated with pharmacological thromboprophylaxis. Methods : Blood was collected from individuals admitted to hospital with COVID-19 of moderate severity (not requiring critical care support) and a group of age-matched patients admitted with infective/ inflammatory illness (negative for COVID-19). All subjects received standard dose low molecular weight heparin (LMWH) thromboprophylaxis with samples taken at time of predicted trough levels (confirmed by measuring anti-FXa activity). TG in platelet-poor plasma was determined by calibrated automated thrombography in the presence/absence of tissue factor (TF) (ppp-LOW reagent, 1 pM TF & 4 μM phospholipid;MP-reagent, 4 μM phospholipid;Thrombinoscope BV™). Results : Fourteen COVID-19 positive subjects and 11 hospitalised COVID-19 negative controls were recruited. Mean trough plasma anti-Xa activity was similar in both groups (0.06 vs 0.04 IU/mL;P = 0.2). In the presence of TF, mean endogenous thrombin potential was significantly higher in the COVID group in comparison to controls (1929 ± 119.7 vs 1528 ± 138.9 nM∗min;P = 0.02). Peak thrombin was also higher in COVID-19 (267.3 ± 22.2 vs 208.6 ± 17.8 nM;P = 0.06). Despite increased TG overall, lagtime to TG was significantly prolonged in COVID-19 (8.1 ± 0.5 vs 6.2 ± 0.5 mins;P = 0.02). No difference in any parameter of TG was observed between groups in the absence of TF. Conclusions : Despite pharmacological thromboprophylaxis plasma TG is enhanced in COVID-19. The underlying mechanisms remain to be elucidated. Specific clinical implications of increased TG despite pharmacological thromboprophylaxis have yet to be determined although clinical trials evaluating intensified anticoagulant regimens in a similar population are ongoing.

In contrast to gout, no disease-modifying therapies currently exist that reduce articular crystal deposition of calcium pyrophosphate crystals (CPPs). Treatment is aimed at ameliorating the inflammatory response and reducing the frequency and severity of clinical symptoms due to CPP deposition (CPPD). Despite being one of the most common forms of inflammatory arthritis, CPPD remains under-studied and evidence-based treatment guidelines remain lacking. Commonly used treatments for clinical manifestations of CPPD (non-steroidal anti-inflammatory drugs [NSAIDs], colchicine and corticosteroids [CSs]) are extrapolated from use in gout. Anakinra and tocilizumab can be used in refractory cases. Though no current crystal-targeted treatments exist, studies suggest that nucleoside analogues and phosphocitrate can attenuate calcification of human cartilage ex-vivo. Hindering research, is the lack of a well-defined description of CPPD. However, international working groups have convened to establish classification criteria and validated outcome domains for CPPD. This should help facilitate the setting up of large multicentre studies, with well-defined cohorts, which can evaluate suitable therapies, providing high levels of evidence to guide clinicians. Here, we summarise and discuss the currently available anti-inflammatory treatment options for CPPD and discuss potential future crystal-targeted approaches.

Abstract Background Hospitalised patients with severe COVID-19 (requiring critical care level support) appear to be at increased risk of thrombosis despite standard pharmacological thromboprophylaxis. The magnitude of thrombotic risk in patients with COVID-19 of moderate severity (not requiring critical care) is less clear. The optimal approach to thromboprophylaxis (and the role of intensified thromboprophylaxis) remains to be determined. Evidence of endothelial dysfunction has been widely reported in COVID-19 (particularly in severe COVID) and this may contribute to hypercoagulability. Aim To assess differences in patterns of hypercoagulability and endothelial dysfunction between a group of patients with moderate COVID-19 and a group of age-matched hospitalized patients (SARS-CoV-2 PCR negative) receiving low molecular weight heparin (LMWH) thromboprophylaxis. Methods Blood was collected from individuals admitted to hospital with COVID-19 of moderate severity (not requiring critical care level support) and a group of age-matched patients admitted with infective/inflammatory illness (SARS-CoV-2 PCR negative). All subjects received standard-dose LMWH thromboprophylaxis, with blood drawn at 12 hours post-dose (and with measurement of anti-FXa activity levels). Circulating levels of endothelial & fibrinolytic markers including ICAM, PAI-1, VCAM, soluble thrombomodulin (sTM), and tissue plasminogen activator (tPA) were determined by ELISA. Thrombin generation (TG) in platelet-poor plasma was assessed by calibrated automated thrombography in the presence of tissue factor (Final concentration, 1pM & 5pM), thrombomodulin (TM) (Final concentration, 6.25nM), and an inhibitory anti-tissue factor pathway inhibitor antibody (anti-TFPI; Final concentration 100μg/mL). Results 14 COVID-19 positive subjects and 11 hospitalized controls were recruited. There were no differences in mean age (69.7±4.5 vs 61.6±4.7 years; p= 0.2) or mean Body mass index (25.7±1.1 vs 22.7±1.2 Kg/m2; p=0.1) between groups. No COVID-19 patient or control required critical care support. In the COVID group, radiological evidence of pneumonitis [diffuse (n=3) or peripheral infiltrates (n=7)] was present in the majority of cases. None of the COVID-19 cases were requiring supplemental oxygen at the time of recruitment. All controls were admitted with either respiratory or urinary infection [radiological evidence of pneumonia in 4/11; supplemental oxygen requirement in 2/11, (28-36% FiO2 via nasal cannula)]. Plasma levels of sTM, ICAM, PAI-1 & VCAM were similar in both groups. Levels of t-PA were significantly higher in the COVID group (8.31±4.35 vs 4.91±2.37 ng/mL; p= 0.005). Despite similar plasma anti-Xa activity in both groups (0.06 vs 0.04 IU/mL; p=0.2), mean endogenous thrombin potential (ETP) was significantly higher in the COVID group (1929±119.7 vs 1528±138.9 nM*min; p=0.02), although peak thrombin was similar (173.6±26 vs 161.5±31nM). ETP-TM ratio was similar between groups (0.3±0.1 vs 0.2±0.1; p=0.3). Despite increased ETP, the lag time to thrombin generation was significantly prolonged in the COVID group (8.3±0.6 vs 5.8±0.5 mins, p= 0.006). This pattern has previously been observed in vascular diseases associated with altered plasma tissue factor pathway inhibitor (TFPI) activity. In the presence of an anti-TFPI antibody, the difference in lagtime between groups was attenuated (4.7±0.2 vs 3.5±0.1 mins; p= 0.002) and the difference in overall thrombin generation (delta TG) between both groups became significantly increased (Fig.1). Conclusion Plasma thrombin generation is enhanced in patients with non-severe COVID-19 despite pharmacological thromboprophylaxis. Endothelial dysfunction is also observed in this group and appears to modulate parameters of plasma thrombin generation. The clinical implications of these observations are not known although clinical studies of intensified thromboprophylaxis in attenuating thrombotic risk and other complications are ongoing. Fig 1. Inhibition of TFPI activity enhances thrombin generation in COVID-19. In the presence of an inhibitory anti-TFPI antibody, peak plasma thrombin generation was enhanced in COVID-19 in contrast to that observed among SARS-CoV-2 PCR negative hospitalised patients (339.6+25.2 vs 247.4+10.1, p=0.01). Figure 1 Figure 1. Disclosures Maguire: Actelion: Research Funding; Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding; Actelion: Research Funding; Leo Pharma: Research Funding; Bayer Pharma: Research Funding. Kevane: Leo Pharma: Research Funding.