Arthritis Flare Research Articles

Immune Checkpoint Inhibitor Associated Rheumatoid Arthritis.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy over the past decade. Unfortunately, immune related adverse events (irAEs) are common, including rheumatologic adverse events. These rheumatologic irAEs include de novo rheumatoid arthritis-like presentations or flares of pre-existing rheumatoid arthritis, collectively called ICI-associated rheumatoid arthritis. In this article we review the different mechanisms of disease activity and management approaches including use of conventional (cs) DMARDs and biologic (b) DMARDs in this patient population. Other forms of ICI-induced inflammatory arthritis e.g., PMR-like or Spondylarthritis-type IA, are beyond the scope of this review. The heterogeneous presentations of inflammatory arthritis in patients receiving immune checkpoint inhibitors has made this a challenging area to study. Nonetheless, recent studies are providing better understanding on the mechanisms of de novo disease and flares in patients with rheumatoid arthritis. About half of patients with pre-existing rheumatoid arthritis flare after receiving checkpoint inhibitors. Persistent arthritis is often encountered in patients receiving combination immune checkpoint inhibitors. Outcomes on overall survival do not differ in rheumatoid arthritis patients receiving checkpoint inhibitors compared to their non-arthritis counterparts. Rheumatologist play a critical role in the management of active rheumatoid arthritis induced by checkpoint inhibitors. Collaboration with oncology colleagues will continue to be a crucial component in providing quality care to these patients. While the use of glucocorticoids is often the first line therapy for active inflammatory arthritic disease, we recommend earlier consideration of DMARDs just as we inverted the treatment pyramid several decades ago, for rheumatoid arthritis.

OA24 Extended oligoarthritis with proximal muscle weakness and antinuclear antibody positivity associated with a novel genetic variant of uncertain significance in lipopolysaccharide-responsive and beige-like anchor protein (LRBA) gene

Abstract Introduction LRBA deficiency is associated with recurrent infections and immune dysregulation, particularly autoimmune cytopenias, enteropathy and intestitial lung disease, and in a few cases chronic polyarthritis and uveitis. Case description A girl presented at three years old with history of not walking for two months with no history of trauma or fever. Examination revealed arthritis in her ankles and knees. Ultrasound showed synovial thickening in both knees and small effusion to hips. There was no evidence of uveitis at presentation. Her bloods showed raised C-Reactive Protein (CRP) 33 mg/L and Erythrocyte Sedimentation rate (ESR) 45 mm/h. Anti-nuclear and anti-centromere antibodies were positive. Diagnosis was made of oligoarticular JIA and she was treated with intra-articular steroids in both knees and ankles and was started on oral prednisolone, weekly oral methotrexate. On subsequent clinic review, she had started to walk with mild restriction to internal rotation of hips and difficulty in getting up from sitting. She was started on regular hydrotherapy, physiotherapy and occupational therapy. From five to 11 years old, she had four flares of uveitis, treated with prednisolone eye drops; and two flares of arthritis, treated with steroids. Her methotrexate was changed to subcutaneous and at eight years of age she was also started on subcutaneous adalimumab fortnightly. Due to prolonged proximal muscle weakness, abnormal gait and chronic pain in leg joints without clinical or radiological evidence of synovitis during clinic reviews, she underwent thorough neurological work up which was inconclusive for myopathies. Her creatinine kinase levels, thyroid profile, MRI brain and spine were normal. Genetic work up showed two variants in the LRBA gene, one pathogenic and the other was variant of uncertain significance (VUS). Her CTLA4 expression was normal by flow cytometry. Discussion Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Key learning points • There is no single diagnostic investigation for JIA as the aetiology is complex and there are currently no specific clinical guidelines of when to consider genetic testing in patients with JIA. With the mainstreaming of genetic services and improved access to cheaper, advanced next-generation sequencing, we should consider looking into monogenic conditions that mimic JIA. • The case illustrates the challenges of determining whether VUS are pathogenic in causing arthritis, or just incidental findings. Compound heterozygous LRBA may present within a spectrum of clinical features, further analysis with CTLA4 expression by flow cytometry and genetic analysis of siblings and parents will be helpful. • Compound heterozygous LRBA variation has different clinical manifestation which needs personalised treatment. Treatment with abatacept (a soluble CTLA4 immunoglobulin fusion protein) which is reported in a case series of LRBA deficiency. Risks of continuous immunosuppressive treatment need to be balanced with more definitive hematopoietic stem cell transplantation (HSCT) previously used to achieved complete remission in LRBA deficiency.

Lupus activity and pregnancy outcomes in systemic lupus erythematosus patients undergoing assisted reproductive therapy: A systematic review and meta-analysis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease primarily impacting women of childbearing age. While pregnancy and hormonal stress can trigger SLE flare-ups, the effects of assisted reproductive therapies (ARTs) on SLE patients are not well defined. We conducted a search of PubMed/Medline, Embase, and CENTRAL until March 20, 2024, to find observational studies assessing the prevalence of SLE flares and pregnancy outcomes following ARTs. Our analysis included random-effects meta-analysis and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for evaluating evidence quality. Five studies involving 237 SLE women who underwent ARTs were eligible. The meta-analysis indicated a prevalence of SLE flares at 17% (95% CI: 10-25%) with moderate-quality evidence. The pooled prevalence of arthritis flares was 7% (95% CI: 0-25%) with low-quality evidence. Successful pregnancy rates were 58% (95% CI: 43-72%), and live birth rates were 96% (95% CI: 83-100%), both with low-quality evidence. Moderate-quality evidence showed pregnancy complications, including preterm premature rupture of membranes (PPROM) at 8% (95% CI: 3-16%), miscarriages at 2% (95% CI: 0-9%), intrauterine fetal demise (IUFD) at 4% (95% CI: 0-11%), and preeclampsia at 7% (95% CI: 1-17%). Low-quality evidence showed preterm labor at 10% (95% CI: 0-32%) and ovarian hyperstimulation syndrome (OHSS) at 2% (95% CI: 0-11%). SLE flares, as well as pregnancy complications such as IUFD, miscarriage, PPROM, and preeclampsia in ART recipients, are equivalent to those in spontaneous conception. This indicates that ART is relatively safe for SLE patients with meticulous pregnancy planning. Key Points •Systemic lupus erythematosus (SLE) is a chronic autoimmune disease primarily impacting women of childbearing age. • Pregnancy in women with SLE poses elevated maternal and fetal risks compared to healthy women. • SLE flares and pregnancy complications while receiving ART are equivalent to those in spontaneous conception and ART is relatively safe for SLE patients.

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement and inflammation modulators

Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined in association with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Sera demonstrated altered complement activation and regulatory gene ontology biologic processes. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat treatment decreased complement activation biologic process proteins in cultured BMDMs. Reduced gout flares are linked with a XOI treatment-emergent serum protein interactome that includes inflammation regulators, associated with altered complement activation and regulatory biologic processes. Serum and leukocyte proteomics could help identify when gouty inflammatory processes begin to subside in response to ULT.Trial Registration: ClinicalTrials.gov Identifier NCT02579096, posted October 19, 2015.

Safety and efficacy of intra-articular triamcinolone acetonide injection versus standard of care in patients with rheumatoid arthritis flare

Triamcinolone acetonide is a commonly used corticosteroid for rheumatoid arthritis (RA) flares, providing extended relief. However, there is limited data from controlled trials comparing the efficacy of intra-articular corticosteroid (IACS) injections to standard care, particularly with non-steroidal anti-inflammatory drugs (NSAIDs). This non-randomized, single-center, open-label study evaluated the safety and efficacy of IACS injections in RA patients experiencing knee joint flare-ups. A total of 64 patients were screened and 44 received IACS (triamcinolone acetonide) and 15 were included in the control group. Significant improvements were observed in the IACS group in pain, swelling, and morning stiffness at week 2, which were sustained through weeks 6 and 12. The swollen joint count significantly reduced by week 12, while the tender joint count showed improvement by week 2. Pain reduction was substantial, as indicated by significant decrease in visual analog scale scores for pain, swelling, and mobility. The disease activity score-28 improved significantly across all time points. In addition, the C-reactive protein level decreased significantly at week 2 and its decreasing trend continued until weeks 6 and 12. By week 2, all patients had ceased NSAID use. The study demonstrated the effectiveness of IACS in reducing RA flare severity, particularly in terms of pain, swelling, and functional impairment, with no major safety concerns reported.

Tryptophanyl tRNA synthetase is an alternative synovial biomarker for diagnosis of septic arthritis in knee joint

BackgroundTo evaluate the diagnostic characteristics of tryptophanyl tRNA synthetase (WRS) for the diagnosis of septic arthritis of the knee joint and to determine whether it is a reliable and sensitive synovial biomarker for discriminating septic arthritis from other types of arthritis.MethodsPatients joint effusions for which septic arthritis was suspected were prospectively recruited between January 2019 and September 2020. A total of 9 patients had septic arthritis, 6 had acute gout attack, 1 had an acute flare of chronic rheumatic arthritis, and 46 had pseudogout or reactive arthropathy. Traditional inflammatory markers were measured, and their diagnostic abilities were compared. Neutrophil count, C-reactive protein (CRP) level, WRS, and human neutrophil α-defensin levels were assessed in the synovial fluids. Demographic parameters and biomarkers with a P < 0.05 in differentiating septic from nonseptic arthritis were included in a multivariable model. A multivariable logistic regression with a stepwise selection was performed to build the final combined model. Receiver operating characteristic curves were used to establish optimal thresholds for the diagnosis of septic arthritis of the knee joint, and the area under the curve was calculated to determine the overall accuracy of these tests compared with patients with nonseptic inflammatory arthritis.ResultsPatients with septic arthritis were more likely to display higher serum WBC and CRP levels, synovial neutrophil counts, and levels of two synovial biomarkers, including WRS and α-defensin. WRS showed the highest specificity (87.5%) and sensitivity (83.3%) with α-defensin among the three synovial biomarkers.ConclusionsSynovial fluid WRS is a relevant biomarker in discriminating septic arthritis from other inflammatory arthritis and should be tested in an independent cohort.Level of evidence: prospective observational study, III.

Circulating neutrophil extracellular trap-forming neutrophils in rheumatoid arthritis exacerbation are majority dual endothelin-1/signal peptide receptor+ subtype.

Neutrophil extracellular traps (NETs) are associated with rheumatoid arthritis pathogenesis and severity. Since homeostatic NET-forming neutrophils [NET+Ns] have beneficial roles in defense against pathogens, their distinction from pro-injury [NET+N] subtypes is important, especially if they are to be therapeutically targeted. Having identified circulating, pro-injury DEspR+CD11b+[NET+Ns] in patients with neutrophilic secondary tissue injury, we determined whether DEspR+[NET+Ns] are present in rheumatoid arthritis (RA) flares. Whole blood samples of patients with RA flares on maintenance therapy (n = 6) were analyzed by flow cytometry (FCM) and immunofluorescence cytology followed by semi-automated quantitative confocal microscopy (qIFC). We assessed clinical parameters, levels of neutrophils and [NET+Ns], and plasma S100A8/A9. qIFC detected circulating DEspR+CD11b+neutrophils and [NET+Ns] in RA-flare patients but not healthy controls. DEspR+[NET+Ns] were positive for citrullinated histone H3 (citH3+), extruded DNA, decondensed but recognizable polymorphic nuclei, and [NET+N] doublet interactions in mostly non-ruptured NET-forming neutrophils. Circulating DNA+/DEspR+/CD11b+/citH3+microvesicles (netMVs) were observed. FCM detected increased %DEspR+CD11b+neutrophils and DEspR+ cell-cell doublets whose levels trended with DAS28 scores, as did plasma S100A8/A9 levels. This study identifies circulating DEspR+/CD11b+neutrophils and [NET+Ns] in RA-flare patients on maintenance therapy. Detection of circulating DEspR+citH3+[NET+Ns] and netMVs indicate a systemic neutrophilic source of citH3-antigen concordant with multi-joint RA pathogenesis. Increased S100A8/A9 alarmin levels are associated with cell injury and released upon NET-formation. As a ligand for TLR4, S100A8/A9 forms a positive feedback loop for TLR4-induced DEspR+neutrophils. These data identify DEspR+neutrophils and [NET+Ns] in RA pathogenesis as a potential biomarker and/or therapeutic target.

Comparison of Gout Flares With the Initiation of Treat-to-Target Allopurinol and Febuxostat: A Post-Hoc Analysis of a Randomized Multicenter Trial.

Initiating urate-lowering therapy (ULT) in gout can precipitate arthritis flares. There have been limited comparisons of flare risk during the initiation and escalation of allopurinol and febuxostat, administered as a treat-to-target strategy with optimal anti-inflammatory prophylaxis. This was a post-hoc analysis of a 72-week randomized, double-blind, placebo-controlled, noninferiority trial comparing the efficacy of allopurinol and febuxostat. For this analysis, the occurrence of flares was examined during weeks 0 to 24 when ULT was initiated and titrated to a serum urate (sUA) goal of less than 6 mg/dl (<5 mg/dl if tophi). Flares were assessed at regular intervals through structured participant interviews. Predictors of flare, including treatment assignment, were examined using multivariable Cox proportional hazards regression. Study participants (n = 940) were predominantly male (98.4%) and had a mean age of 62.1 years with approximately equal proportions receiving allopurinol or febuxostat. Mean baseline sUA was 8.5 mg/dl and all participants received anti-inflammatory prophylaxis (90% colchicine). In a multivariable model, there were no significant associations of ULT treatment (hazard ratio [HR] 1.17; febuxostat vs allopurinol), ULT-dose escalation (HR 1.18 vs no escalation), prophylaxis type, or individual comorbidity with flare and no evidence of ULT-dose escalation interaction. Factors independently associated with flare risk during ULT initiation/escalation included younger age, higher baseline sUA, and absence of tophi. These results demonstrate that gout flare risk during the initiation and titration of allopurinol is similar to febuxostat when these agents are administered according to a treat-to-target strategy using gradual ULT-dose titration and best practice gout flare prophylaxis.

Deciding to Attend the Emergency Department: Experiences of Patients With Inflammatory Arthritis.

Patients may use emergency departments (EDs) to meet their health needs when ambulatory care systems are not sufficient. We aim to describe contributing factors to the decision made by persons with inflammatory arthritis (IA) to present to the ED, as well as their experiences of ED care and postdischarge follow-up. An embedded mixed-methods approach was taken to contextualize quantitative data with associated free-text responses from an online survey distributed to residents of Alberta with a known IA condition and an ED visit. Eighty-two persons (63% aged 16-55 years, 48% female, 50% urban residents) with rheumatoid arthritis (48%), psoriatic arthritis (12%), spondyloarthritis (6%), or gout (34%) completed the survey. Presenting concerns were arthritis flare (37%), chest pain (15%), injury (12%), and infection (11%). Of all visits, 29% proceeded directly to the ED, 35% attempted accessing ambulatory care first, and 32% arrived for a return visit. In presentations for arthritis flare, patients were aware of the rheumatology service being contacted by the ED provider for advice in just 9% of events. Challenges in healthcare system coordination and system pressures resulted in patients requiring ED attendance to assess their concern. The quality of communication and relationality developed between patients with IA and healthcare providers informed experiences of ED care. Modifying rheumatology ambulatory care models could better meet patient needs and ultimately reduce avoidable ED use by patients with IA.

Investigating protease-mediated peptides of inflammation and tissue remodeling as biomarkers associated with flares in psoriatic arthritis.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. PsA disease involves flares, which are associated with increased joint inflammation and tissue remodeling. There is a need for identifying biomarkers related to PsA disease activity and flares to improve the management of PsA patients and decrease flares. The tissue turnover imbalance that occurs during the inflammatory and fibro-proliferative processes during flares leads to an increased degradation and/or reorganization of the extracellular matrix (ECM), where increased proteolysis plays a key role. Hence, protease-mediated fragments of inflammatory and tissue-remodeling components could be used as markers reflecting flares in PsA patients. A broad panel of protease-mediated biomarkers reflecting inflammation and tissue remodeling was measured in serum and synovial fluid (SF) obtained from PsA patients experiencing flares (acutely swollen joint[s], PsA-flare). In serum, biomarker levels assessed in PsA-flare patients were compared to controls and in early-diagnosed PsA patients not experiencing flares (referred to as PsA without flare). Furthermore, the biomarker levels assessed in SF from PsA-flare patients were compared to the levels in SF of osteoarthritis (OA) patients. In serum, levels of the PRO-C3 and C3M, reflecting formation and degradation of the interstitial matrix, were found significantly elevated in PsA-flare compared to controls and PsA without flare. The remodeling marker of the basement membrane, PRO-C4, was significantly elevated in PsA-flare compared to PsA without flare. The inflammation and immune cell activity related markers, CRPM, VICM, and CPa9-HNE were significantly elevated in PsA-flare patients compared to controls and PsA without flare. In addition, VICM (AUC = 0.71), CPa9-HNE (AUC = 0.89), CRPM (AUC = 0.76), and PRO-C3 (AUC = 0.86) showed good discriminatory performance for separating PsA-flare from PsA without flare. In SF, the macrophage activity marker, VICM, was significantly elevated whereas the type II collagen formation marker, PRO-C2, was significantly reduced in the PsA-flare compared to OA. The combination of five serum markers reflecting type III and IV collagen degradation (C3M and C4M, respectively), type III and VI collagen formation (PRO-C3 and PRO-C6, respectively), and neutrophil activity (CPa9-HNE) showed an excellent discriminatory performance (AUC = 0.98) for separating PsA-flare from PsA without flares. The serum biomarker panel of C3M, C4M, PRO-C3, PRO-C6, and CPa9-HNE reflecting synovitis, enthesitis, and neutrophil activity may serve as novel tool for quantitatively monitoring flares in PsA patients.

Classifying Self-Reported Rheumatoid Arthritis Flares Using Daily Patient-Generated Data From a Smartphone App: Exploratory Analysis Applying Machine Learning Approaches.

The ability to predict rheumatoid arthritis (RA) flares between clinic visits based on real-time, longitudinal patient-generated data could potentially allow for timely interventions to avoid disease worsening. This exploratory study aims to investigate the feasibility of using machine learning methods to classify self-reported RA flares based on a small data set of daily symptom data collected on a smartphone app. Daily symptoms and weekly flares reported on the Remote Monitoring of Rheumatoid Arthritis (REMORA) smartphone app from 20 patients with RA over 3 months were used. Predictors were several summary features of the daily symptom scores (eg, pain and fatigue) collected in the week leading up to the flare question. We fitted 3 binary classifiers: logistic regression with and without elastic net regularization, a random forest, and naive Bayes. Performance was evaluated according to the area under the curve (AUC) of the receiver operating characteristic curve. For the best-performing model, we considered sensitivity and specificity for different thresholds in order to illustrate different ways in which the predictive model could behave in a clinical setting. The data comprised an average of 60.6 daily reports and 10.5 weekly reports per participant. Participants reported a median of 2 (IQR 0.75-4.25) flares each over a median follow-up time of 81 (IQR 79-82) days. AUCs were broadly similar between models, but logistic regression with elastic net regularization had the highest AUC of 0.82. At a cutoff requiring specificity to be 0.80, the corresponding sensitivity to detect flares was 0.60 for this model. The positive predictive value (PPV) in this population was 53%, and the negative predictive value (NPV) was 85%. Given the prevalence of flares, the best PPV achieved meant only around 2 of every 3 positive predictions were correct (PPV 0.65). By prioritizing a higher NPV, the model correctly predicted over 9 in every 10 non-flare weeks, but the accuracy of predicted flares fell to only 1 in 2 being correct (NPV and PPV of 0.92 and 0.51, respectively). Predicting self-reported flares based on daily symptom scorings in the preceding week using machine learning methods was feasible. The observed predictive accuracy might improve as we obtain more data, and these exploratory results need to be validated in an external cohort. In the future, analysis of frequently collected patient-generated data may allow us to predict flares before they unfold, opening opportunities for just-in-time adaptative interventions. Depending on the nature and implication of an intervention, different cutoff values for an intervention decision need to be considered, as well as the level of predictive certainty required.

E044 The role of patient education in a joint injection clinic. The most ‘cost effective’ approach for the management of your arthritis

Abstract Background/Aims GGH operates a self-referral joint injection clinic where patients suffering from an acute arthritis flare, can call and book an appointment for review and possible joint injection. The self referral service applies to all the patients attending the GGH rheumatology service and are under the care of a rheumatologist. A screening questionnaire was originally designed to triage those requesting appointments last year. We have amplified this work further this year by raising awareness and educating patients about their rheumatological condition and specifically about steroid intra-articular joint injections. Their benefits, risks and their indications. Aims-1. Providing education and awareness of joint injections in the community aiding patients to participate in their joint care. 2. Help patient understand the indications, side effects and risks involved with repeated injection . 3. To know the difference between osteoarthritis and inflammatory arthritis. Methods Retrospective study of patients who self-referred for joint injection between 07/07/2022 and 22/05/2023. Total of 138 self referred via phone calls, emails or letters. All the self referral data was compiled, assessed by screening questions and reviewed. An education and awareness campaign was made possible through an improved waiting room, educational pamphlets, leaflets and 1:1 consultations. Results Two pools of patients who received joint injections were analysed. Group A (07/07/2022 - 08/12/2022) where 102 patients self-referred and 43 received a joint injection. Group B (04/01/2023 - 22/05/2023) 36 self-referred and 15 received injection. The table below shows the different demographics of the two groups. Conclusion Patient Education remains one of the most important cornerstones in management of arthritis patients. After an ongoing campaign of education/awareness, self referrals were reduced by 66 %.This audit demonstrates that patient education about joint injections allows for more effective management, allowing better informed shared care. It also reduces the waiting times for patients to be seen in the injection clinic - from 3 months to 2 weeks. A cost effective approach in service improvement. Population who still availed joined injection in the re- audit were more elderly, obese, female, and had more metabolic diseases however the self referral to injection ratio is almost the same both groups. Disclosure S. Maunick: None. C. Mullet: None. T. Mccoll: None. M. Reed: None. M. Gupta: None. M. Hafeez: None. S. Bawa: None.

Chronic back pain in untreated gout

A 41-year-old man with a 10-year history of untreated chronic tophaceous gout presented with acute flare of gouty arthritis. He has chronic low back pain which has become more severe for the past 1 year. Clinically he has tenderness at lower lumbar spine although there was no neurological deficit. Laboratory test revealed raised inflammatory markers (ESR 70mm/hour) and C-reactive protein 287.1 mg/L, reactive thrombocytosis and leucocytosis, renal impairment and elevated serum uric acid (780 μmol/L). He had microscopic hematuria and ultrasound showed right mild hydronephrosis without any calculi identified. Computerized Tomography Urogram (CTU) confirmed the findings of an obstructive right hydronephrosis and hydroureter due to a right ureteric calculus. Incidentally, CTU revealed a lobulated, heterogenous hyperdense soft tissue ossified mass measuring (4.6x7.3x8.1 cm) at lumbar vertebral bodies (L2-L4) with overhanging edge erosions of adjacent vertebra mainly involving the facet joints, pedicles and lamina (Figure 1).

The Effect of Crystal Arthropathy on the Diagnostic Criteria of Native Septic Arthritis.

Distinguishing between septic arthritis and crystal arthropathy flares can be challenging. The purpose of this study was to determine how the presence of synovial crystals affects the diagnostic criteria of septic arthritis. A retrospective review identified patients undergoing joint aspirations to rule out native septic arthritis. Differences between septic arthritis presenting with and without synovial crystals were analyzed. A receiver-operating characteristic curve was plotted for laboratory markers to determine the area under the curve, or diagnostic accuracy, for septic arthritis and to evaluate thresholds that maximized sensitivity and specificity. There were 302 joint aspirations in 267 patients. Septic arthritis was diagnosed in 17.9% (54/302). Patients with synovial crystals were less likely to have septic arthritis (4.2% [5/119] vs. 26.8% [49/183], P < 0.0001). Septic arthritis in patients with no synovial crystals was associated with fever and a higher synovial white blood cell (WBC) count, synovial polymorphonuclear cell percentage (PMN%), serum WBC, and C-reactive protein (CRP) ( P < 0.05). Septic arthritis in patients with synovial crystals was only associated with inability to bear weight and a higher synovial WBC and CRP ( P < 0.05). Synovial PMN% was considered nondiagnostic of septic arthritis (area under the curve 0.56) in patients with crystals while synovial WBC and CRP had acceptable (0.76) and excellent (0.83) diagnostic utility, respectively. The WBC and CRP value thresholds that maximized sensitivity and specificity for septic arthritis were greater in patients with crystals (21,600 vs. 17,954 cells/μL and 125 vs. 69 mg/L, respectively). The presence of synovial crystals reduced the likelihood of septic arthritis and altered the laboratory diagnostic criteria. PMN% was nondiagnostic in the setting of synovial crystals.

Spatiotemporal Observation of Monosodium Urate Crystals Deposition in Synovial Organoids Using Label-Free Stimulated Raman Scattering.

Gout, a common form of arthritis, is characterized by the deposition of monosodium urate (MSU) crystals in joints. MSU deposition in synovial tissues would initiate arthritis flares and recurrence, causing irreversible joint damage. However, the dynamic deposition of MSU crystals in tissues lacks experimental observation. In this study, we used chemical-specific, label-free stimulated Raman scattering (SRS) microscopy to investigate the spatiotemporal deposition and morphological characteristics of MSU crystals in human synovial organoids. Our findings revealed a critical 12-h window for MSU deposition in the lining layer of gouty synovium. Moreover, distinctive inflammatory reactions of the lining and sublining synovial layers in gout using SRS microscopy were further verified by immunofluorescence. Importantly, we identified a crucial proinflammatory role of sublining fibroblast-like synoviocytes, indicating a need for targeted medication treatment on these cells. Our work contributes to the fundamental understanding of MSU-based diseases and offers valuable insights for the future development of targeted gout therapies.

The good, the bad and the ugly of pain in haemophilia: Recent evidence on the epidemiology, molecular mechanisms and knowledge gaps preventing optimal treatment.

Haemophilia is an inherited, X-linked blood clotting disorder caused by the deficiency of coagulation factors VIII (FVIII, haemophilia A) or IX (FIX, haemophilia B). Spontaneous bleeds are common in severe forms of haemophilia and can also occur in moderate and mild haemophilia. Severe or repeated bleeding at a joint can evolve into chronic haemophilic arthropathy, with functional damage of the joint, disability, and intense chronic articular pain. Nonetheless, acute and chronic pain may emerge due to secondary conditions related to bleedings. This narrative review aims to critically discuss the most recent evidence about pain in haemophilia to give healthcare professionals a clear picture of current knowledge hence favouring the optimisation of clinical management of pain. Extensive literature search with the terms 'hemophilia' AND 'pain', focusing on the time window 2021-2023. Acute and chronic pain is a critical aspect of haemophilia at all ages. It should be considered a multifaceted phenomenon, with a positive role as an early emergency signal of a clinical event (haemarthrosis), and numerous detrimental aspects linked to its burden that heavily affects the health-related quality of life, with psychological and social consequences. Despite its prevalence and frequency in people with haemophilia, pain is often underestimated by healthcare professionals, leading to insufficient and inadequate treatment, also due to uncertainty linked to the presence of the coagulation disorder or arthritic flares.

Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis.

Anti-IL-6 receptor antibodies are clinically efficacious in the management of RA with an associated increase in Tregs; however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyse the relationship between these Treg subsets and the clinical outcome of RA. We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. Blocking the IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favourable treatment course and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

Cytokine and T cell responses in post-chikungunya viral arthritis: A cross-sectional study.

To define the relationship between chronic chikungunya post-viral arthritis disease severity, cytokine response and T cell subsets in order to identify potential targets for therapy. Participants with chikungunya arthritis were recruited from Colombia from 2019-2021. Arthritis disease severity was quantified using the Disease Activity Score-28 and an Arthritis-Flare Questionnaire adapted for chikungunya arthritis. Plasma cytokine concentrations (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ and tumor necrosis factor (TNF)) were measured using a Meso Scale Diagnostics assay. Peripheral blood T cell subsets were measured using flow cytometry. Among participants with chikungunya arthritis (N = 158), IL-2 levels and frequency of regulatory T cells (Tregs) were low. Increased arthritis disease activity was associated with higher levels of inflammatory cytokines (IL-6, TNF and CRP) and immunoregulatory cytokine IL-10 (p<0.05). Increased arthritis flare activity was associated with higher Treg frequencies (p<0.05) without affecting T effector (Teff) frequencies, Treg/Teff ratios and Treg subsets. Finally, elevated levels of IL-2 were correlated with increased Treg frequency, percent Tregs out of CD4+ T cells, and Treg subsets expressing immunosuppressive markers, while also correlating with an increased percent Teff out of live lymphocytes (p<0.05). Chikungunya arthritis is characterized by increased inflammatory cytokines and deficient IL-2 and Treg responses. Greater levels of IL-2 were associated with improved Treg numbers and immunosuppressive markers. Future research may consider targeting these pathways for therapy.

An Environmental Scan and Appraisal of Patient Online Resources for Managing Rheumatoid Arthritis Flares.

To conduct an environmental scan and appraisal of online patient resources to support rheumatoid arthritis (RA) flare self-management. We used the Google search engine (last search March 2023) using the terms "rheumatoid arthritis" and "flare management." Additional searches targeted major arthritis organizations, as well as regional, national, and international resources. Appraisal of the resources was conducted by 2 research team members and 1 patient partner to assess the understandability and actionability of the resource using the Patient Education Materials Assessment Tool (PEMAT). Resources rating ≥ 60% in both domains by either the research team or the patient partner were further considered for content review. During content review, resources were excluded if they contained product advertisements, inaccurate information, or use of noninclusive language. If content review criteria were met, resources were designated as "highly recommended" if both patient partners and researchers' PEMAT ratings were ≥ 60%. If PEMAT ratings were divergent and had a rating ≥ 60% from only 1 group of reviewers, the resource was designated "acceptable." We identified 44 resources; 12 were excluded as they did not pass the PEMAT assessment. Fourteen resources received ratings ≥ 60% on understandability and actionability from both researchers and patient partners; 10 of these were retained following content review as "highly recommended" flare resources. Of the 18 divergent PEMAT ratings, 8 resources were retained as "acceptable" following content review. There is high variability in the actionability and understandability of online RA flare materials; only 23% of resources were highly recommended by researchers and patient partners.

The clinical benefits of sodium-glucose cotransporter type 2 inhibitors in people with gout.

Gout is the most common form of inflammatory arthritis worldwide and is characterized by painful recurrent flares of inflammatory arthritis that are associated with a transiently increased risk of adverse cardiovascular events. Furthermore, gout is associated with multiple cardiometabolic-renal comorbidities such as type 2 diabetes, chronic kidney disease and cardiovascular disease. These comorbidities, potentially combined with gout flare-related inflammation, contribute to persistent premature mortality in gout, independently of serum urate concentrations and traditional cardiovascular risk factors. Although better implementation of standard gout care could improve gout outcomes, deliberate efforts to address the cardiovascular risk in patients with gout are likely to berequired to reduce mortality. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are approved for multiple indications owing to their ability to lower the risk of all-cause and cardiovascular death, hospitalizations for heart failure and chronic kidney disease progression, making them an attractive treatment option for gout. These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.