Objectives To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). Methods The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. Results 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. Conclusion The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.

Janus kinase inhibitors (JAKi) have enormous appeal as immune-modulating therapies across many chronic inflammatory diseases, but recently this promise has been overshadowed by questions regarding associated cardiovascular and cancer risk emerging from the ORAL Surveillance phase 3b/4 post-marketing requirement randomized controlled trial. In that study of patients with rheumatoid arthritis with existing cardiovascular risk, tofacitinib, the first JAKi registered for chronic inflammatory disease, failed to meet non-inferiority thresholds when compared with tumor necrosis factor inhibitors for both incident major adverse cardiovascular events and incident cancer. While this result was unexpected by many, subsequently published observational data have also supported this finding. Notably, however, such a risk has largely not yet been demonstrated in patients outside the specific clinical situation examined in the trial, even in the face of many studies examining this. Nevertheless, this signal has practically re-aligned approaches to both tofacitinib and other JAKi to varying extents, in other patient populations and contexts: within rheumatoid arthritis, but also in psoriatic arthritis, axial spondyloarthritis, inflammatory bowel disease, atopic dermatitis, and beyond. Application to individual patients can be more challenging but remains important to harness the substantive potential of JAKi to the maximum extent safely possible. This review not only explores the evolution of the regulatory response to the signal, its informing data, biological plausibility, and its impact on guidelines, but also the many factors that clinicians must consider in navigating cardiovascular and cancer risk for their patients considering JAKi as immune-modulating therapy.

Janus kinase inhibitors (JAKi) have dramatically improved the treatment of various autoimmune, and myeloproliferative disorders. Recently concern has arisen regarding their safety in patients with rheumatoid arthritis. Here we provide a comprehensive summary of the major current and emerging JAKi and their indications, address recent studies on comparative safety, and provide insight into their future and use. We emphasize that the application of the research findings on a case-by-case basis should consider a patient's age, comorbidities, disease for which JAKi is being considered, disease activity, the JAKi target(s), alternate treatment options available for the patient, and the planned duration of JAKi. Rheumatologists are used to prescribing therapies in which a risk to benefit assessment is required as well as with screening and monitoring for safety of medications. Thus, rheumatologists are already practiced in applying specific criteria to effectively screen and monitor patients who are candidates for JAKi therapy. Ongoing research will help to clarify any mechanisms underlying differential safety signals between JAK and other therapies, what the balance between risk and efficacy is, who the susceptible subpopulations are, and whether safety signals are shared between different JAKis and across indications.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but can result in toxicities, known as immune-related adverse events (irAEs), due to a hyperactivated immune system. ICI-related inflammatory arthritis has been described in literature, but herewith we introduce and characterize post-ICI-activated osteoarthritis (ICI-aOA). We conducted a multicenter, retrospective, observational study of patients with cancer treated with ICIs and diagnosed with ICI-aOA by a rheumatologist. ICI-aOA was defined by (1) an increase in non-inflammatory joint pain after ICI initiation, (2) in joints characteristically affected by osteoarthritis, and (3) lack of inflammation on exam. Cases were graded using the Common Terminology Criteria for Adverse Events (CTCAE) V.6.0 rubric for arthralgia. Response Evaluation Criteria in Solid Tumors V.1.1 (v.4.03) guidelines determined tumor response. Results were analyzed using χ² tests of association and multivariate logistic regression. Thirty-six patients had ICI-aOA with a mean age at time of rheumatology presentation of 66 years (51–81 years). Most patients had metastatic melanoma (10/36, 28%) and had received a PD-1/PD-L1 inhibitor monotherapy (31/36, 86%) with 5/36 (14%) combination therapy. Large joint involvement (hip/knee) was noted in 53% (19/36), small joints of hand 25% (9/36), and spine 14% (5/36). Two-thirds (24/36) suffered multiple joint involvement. Three of 36 (8%) had CTCAE grade 3, 14 (39%) grade 2 and 19 (53%) grade 1 manifestations. Symptom onset ranged from 6 days to 33.8 months with a median of 5.2 months after ICI initiation; five patients suffered from ICI-aOA after ICI cessation (0.6, 3.5, 4.4, 7.3, and 15.4 months after ICI cessation). The most common form of therapy was intra-articular corticosteroid injections only (15/36, 42%) followed by non-steroidal anti-inflammatory drugs only (7/36, 20%). Twenty patients (56%) experienced other irAEs, with rheumatic and dermatological being the most common. All three patients with high-grade ICI-aOA also had another irAE diagnosis at some point after ICI initiation. ICI-aOA should be recognized as an adverse event of ICI immunotherapy. Early referral to a rheumatologist can facilitate the distinction between ICI induced inflammatory arthritis from post-ICI mechanical arthropathy, the latter of which can be managed with local therapy that will not compromise ICI efficacy.

Research on the relationship between inflammatory myopathy and malignancy has grown considerably within the last century. Now, the burgeoning field of inflammatory myopathy has yet another player in the mix: immune checkpoint inhibitor–associated myositis (ICI myositis). Immune checkpoint inhibitor–associated myositis is indicated by clinical diagnosis of inflammatory myopathy after initiation of immune checkpoint inhibitor for cancer management. Current literature reflects low prevalence but high mortality associated with ICI myositis, especially when involving myasthenia gravis and myocarditis. Immune checkpoint inhibitor–associated myositis tends to have muscle pain along with weakness, infrequent presentation with dermatitis, or interstitial lung disease and is typically seronegative with scattered, endomysial inflammatory infiltrates on biopsy. The differential diagnosis of ICI myositis includes myasthenia gravis and other neurological immune-related adverse events. Therapeutic approach involves high doses of corticosteroids with a choice of steroid-sparing immunomodulating agent(s) that is primarily driven by expert opinion due to lack of robust research to support one agent over another. There is wide variation in the inclusion criteria for ICI myositis used in previous studies. We review previously used inclusion criteria and suggest an expertise-based classification criterion to provide a standardized definition and allow comparability between studies. There is a critical need for prospective translational and clinical studies that elucidate the pathophysiology of ICI myositis in order to improve evaluation and management of these patients.