A narrative review of the comparative safety of disease-modifying anti-rheumatic drugs used for the treatment of rheumatoid arthritis.

INTRODUCTION: Disease-modifying anti-rheumatic drugs (DMARDs) have improved the outcomes of patients with rheumatoid arthritis (RA). DMARDs are classified into three categories: conventional synthetic DMARDs, biological DMARDs (including biosimilars), and targeted synthetic DMARDs. DMARDs, by way of their effect on the immune system, are associated with increased risk of adverse events, including infections, malignancies, cardiovascular disease, gastrointestinal perforations, and other less common events. AREAS COVERED: In this narrative literature review performed with searches of the PubMed database from 1 January 2010 through 1 January 2023, we compare the risk of safety events between DMARDs using data from both randomized clinical trials and observational studies. EXPERT OPINION: DMARD use in RA is associated with higher rates of serious infections, tuberculosis reactivation, opportunistic infections, and possibly malignancies. Specific biologic DMARDs and higher doses are associated with elevated risks of various adverse events (gastrointestinal perforations, thromboembolism, serious infection). Shared decision-making is paramount when choosing a treatment regimen for patients based on their own comorbidities. JAKi are the newest class of medications used for RA with robust safety data provided in clinical trials. However, more real-world evidence and phase-IV pharmacovigilance data are needed to better understand comparative safety profile of DMARDs in RA.

Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis.

OBJECTIVE: Polymorphisms in the antifungal signalling molecule CARD9 are associated with ankylosing spondylitis (AS). Here, we investigated the cellular mechanism by which CARD9 controls pathogenic Th17 responses and the onset of disease in both experimental murine AS and patients. METHODS: Experiments in SKG, Card9-/-SKG, neutrophil-deplete SKG mice along with in vitro murine, neutrophil and CD4+ T cell cocultures examined Card9 function in neutrophil activation, Th17 induction and arthritis in experimental AS. In AS patients the neutrophil: Bath Ankylosing Spondylitis Functional Index relationship was analysed. In vitro studies with autologous neutrophil: T cell cocultures examined endogenous CARD9 versus the AS-associated variant (rs4075515) of CARD9 in T cellular production of IL-17A. RESULTS: Card9 functioned downstream of Dectin-1 and was essential for induction of Th17 cells, arthritis and spondylitis in SKG mice. Card9 expression within T cells was dispensable for arthritis onset in SKG mice. Rather, Card9 expression controlled neutrophil function; and neutrophils in turn, were responsible for triggering Th17 expansion and disease in SKG mice. Mechanistically, cocultures of zymosan prestimulated neutrophils and SKG T cells revealed a direct cellular function for Card9 within neutrophils in the potentiation of IL-17 production by CD4+ T cells on TCR-ligation. The clinical relevance of the neutrophil-Card9-coupled mechanism in Th17-mediated disease is supported by a similar observation in AS patients. Neutrophils from HLA-B27+ AS patients expanded autologous Th17 cells in vitro, and the AS-associated CARD9S12N variant increased IL-17A. CONCLUSIONS: These data reveal a novel neutrophil-intrinsic role for Card9 in arthritogenic Th17 responses and AS pathogenesis. These data provide valuable utility in our future understanding of CARD9-specific mechanisms in spondyloarthritis .

Cardiovascular disease in spondyloarthritis: a narrative review of risk factors and the effect of treatments.

PURPOSE OF REVIEW: This review summarizes the recent evidence available regarding the epidemiology of cardiovascular disease in spondyloarthritis (SpA), including the effect of disease modifying drugs on cardiovascular risk. RECENT FINDINGS: People with SpA suffer from an increased risk of cardiovascular disease compared to the general population. This elevated risk is explained by the high prevalence of traditional cardiovascular risk factors and inflammation from disease activity leading to endothelial dysfunction and accelerated atherosclerosis. Consequently, the American College of Cardiology/American Heart Association and the European League Against Rheumatism recommend enhanced cardiovascular risk screening in SpA patients. There is evidence from observational studies that methotrexate and tumor necrosis factor inhibitors reduce the risk of cardiovascular events in SpA. Unlike what is observed in the general population, the use of nonsteroidal anti-inflammatory drugs does not appear to increase cardiovascular disease risk in SpA. SUMMARY: Cardiovascular diseases are increasingly recognized in patients suffering from SpA, especially axial SpA and psoriatic arthritis. Cardiovascular diseases can cause significant morbidity, mortality, and add to the overall disease burden. Disease modifying drugs may mitigate some of the cardiovascular risk; however, a multidisciplinary team is needed to monitor patients and improve cardiovascular health status.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Biomarkers in Axial Spondyloarthritis: Observational Studies From the Program to Understand the Longterm Outcomes in Spondyloarthritis Registry.

OBJECTIVES: This study was conducted to assess the utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting radiographic sacroiliitis and active disease in axial spondyloarthritis (SpA) and to explore the association between use of a tumor necrosis factor inhibitor (TNFi) and these laboratory values compared with traditional inflammatory markers. METHODS: Observational data from the Program to Understand the Longterm Outcomes in Spondyloarthritis (PULSAR) registry were analyzed. We generated receiver operating characteristic curves to calculate laboratory cutoff values; we used these values in multivariable logistic regression models to identify associations with radiographically confirmed sacroiliitis and active disease. We also used logistic regression to determine the likelihood of elevated laboratory values after initiation of TNFi. RESULTS: Most study participants (n = 354) were White, male, and HLA-B27 positive. NLR (odds ratio [OR] 1.459, P = 0.034), PLR (OR 4.842, P < 0.001), erythrocyte sedimentation rate (OR 4.397, P < 0.001), and C-reactive protein (CRP) level (OR 2.911, P = 0.001) were independent predictors of radiographic sacroiliitis. Models that included PLR with traditional biomarkers performed better than those with traditional biomarkers alone. NLR (OR 6.931, P = 0.002) and CRP (OR 2.678, P = 0.004) were predictors of active disease, but the model that included both NLR and CRP performed better than CRP alone. TNFi use reduced the odds of elevated NLR (OR 0.172, P < 0.001), PLR (OR 0.073, P < 0.001), erythrocyte sedimentation rate (OR 0.319, P < 0.001), and CRP (OR 0.407, P < 0.001), but models that included NLR or PLR and traditional biomarkers performed best. CONCLUSIONS: These findings demonstrate an association between NLR and PLR and sacroiliitis and disease activity, with NLR and PLR showing response after TNFi treatment and adding useful clinical information to established biomarkers, thus perhaps assisting in management of axial SpA.

Current treatment and molecular targets for axial spondyloarthritis: Evidence from randomized controlled trials.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the axial skeleton and is characterized by inflammatory back pain. While much has been published regarding non-steroidal anti-inflammatory drugs and tumor necrosis factor inhibitors, other classes of medications which leverage alternate molecular mechanisms receive less attention. In this review, we summarize a few of the novel targets in axSpA, review the putative mechanism of action of therapies that focus on these targets, and reference the germane recently completed, ongoing, or proposed randomized controlled clinical trials. The agents addressed include inhibitors of interleukin-23, interleukin-17, janus kinases, granulocyte-macrophage colony-stimulating factor, macrophage migration inhibitory factor, antibodies recognizing T cell receptor beta variable 9 gene positive clones, as well as inhibitors of mitogen-activated protein kinase-activated protein kinase-2.

Hydroxychloroquine and Fabry Disease: Three Case Reports Examining an Unexpected Pathologic Link and a Review of the Literature.

Background: Hydroxychloroquine is an effective and widely used treatment in multiple autoimmune connective tissue diseases that gained a lot of publicity in the coronavirus disease 2019 (COVID-19) pandemic. Our case reports are unique in that they explore the rare and sometimes overlooked effects of this drug on multiple organ systems, specifically the kidney, cardiac muscle, and skeletal muscle. We include key histologic features in images which aid in identifying and distinguishing hydroxychloroquine toxicity from mimickers. Lastly, we report the very interesting similarity in the intracellular action of hydroxychloroquine to the pathology of Fabry disease (and its associated lysosomal enzyme, α-galactosidase A). Case Presentation. We will examine the case presentations of three female Caucasian patients: a 22-year-old with lupus nephritis class V, a 72-year-old with long-standing systemic lupus erythematosus, and a 74-year-old with undifferentiated connective tissue disease. All three patients were on hydroxychloroquine therapy for varying amounts of time with histologic evidence of hydroxychloroquine toxicity that is three is present in histological samples of the kidney, the heart, and the skeletal muscle. Conclusions: Hydroxychloroquine is a very important and beneficial medication used for various autoimmune connective tissue diseases. Clinicians should be aware of the rare but sometimes serious side effects that can result from the medication, which at times can mimic manifestations of the connective tissue disease itself or Fabry disease. A thorough investigation should be performed in these cases to properly elucidate the cause followed by the appropriate targeted therapy.

Cerebral Sinus Venous Thrombosis in a Patient Using Etonogestrel/Ethinyl Estradiol Vaginal Ring.

A case of 43-year-old female presented to the emergency department (ED) with a new onset grand mal tonic-clonic seizure lasting at least two minutes with post-ictal confusion. Imaging was consistent with cerebral sinus venous thrombosis (CSVT) associated with intracranial hemorrhage. After ruling out most common causes of thrombosis, the etiology was attributed to estrogen vaginal ring. The patient was treated with anticoagulation therapy and had increasing hemorrhagic changes in the first few days, which eventually improved. The estimated annual incidence of cerebral sinus vein thromboses is approximately 3-4 cases per 1 million adults, mostly occurring in females. More than 80% of patients have favorable neurologic outcomes due to increased awareness of the condition as well as availability of advanced imagining and treatment options. The treatment is still controversial due to the high risk of intracranial hemorrhage with sinus thrombosis, especially for patients on anticoagulation. Still, most guidelines support starting anticoagulation. In this report, we highlight the association of CSVT with estrogen vaginal ring and discuss recent management recommendations per different society guidelines.