Objectives Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. Methods We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. Results We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. Conclusions As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.

Background Immune checkpoint inhibitors (ICI) are improving prognosis in advanced stage cancers, but also lead to immune-related adverse events (IRAE). IRAEs targeting many organ systems have been reported, but musculoskeletal and rheumatic IRAE have not been well characterized. We systematically reviewed published literature on musculoskeletal and rheumatic IRAE to better understand prevalence and clinical characteristics. Methods Medline and CENTRAL databases were searched for articles reporting rheumatic and musculoskeletal IRAEs secondary to ICI treatment. After screening abstracts and full texts in duplicate, clinical features, prevalence and treatment data were extracted and summarized. Results 1725 unique abstracts were screened; 231 contained original data and were about ICIs and went to full text screening. Fifty-two of these contained information about musculoskeletal or rheumatic IRAEs or about treatment with ICIs in pre-existing autoimmune disease. Of these, 33 were clinical trials, 3 were observational studies, and 16 were case reports or series. Arthralgia prevalence in clinical trials ranged from 1–43%, and myalgia was reported in 2–20%. Arthritis was reported in 5/33 clinical trials, and vasculitis was reported in only 2. One observational study and 3 case reports described patients with pre-existing autoimmune disease treated with ICIs. Case reports included development of inflammatory arthritis, vasculitis, myositis, and lupus nephritis. Conclusions Arthralgia and myalgia have been reported commonly in patients treated with ICIs. The prevalence of rheumatic IRAEs like inflammatory arthritis, vasculitis, and sicca syndrome is less clear from current evidence. There is limited observational and case-level evidence describing ICI use in patients with pre-existing autoimmune disease.

Background Fatigue is prevalent and impactful in rheumatoid arthritis (RA). There is no standardized measure for its assessment nor data concerning the performance of PROMIS-Fatigue short forms (SFs) in people with RA. We evaluated the construct validity of 4-, 7-, and 8-item PROMIS-Fatigue SFs in RA patients across the range of disease activity. Methods Adult RA patients were recruited from an online patient community and an observational cohort from three academic medical centers. Measures included PROMIS-Fatigue SFs, other PROMIS measures, and other patient reported outcomes including RAND-36 Vitality, Fatigue NRS, and patient global assessment of disease activity. Other measures from the observational cohort included 28-joint swollen and tender joints, physician global assessment, and the composite RA clinical disease activity index (CDAI). Results Two-hundred online participants and 348 participants from the observational cohort were included. PROMIS Fatigue SF scores spanned the measurement continuum and correlated highly with each other (r’s ≥ 0.91) and other fatigue measures (r’s ≥ 0.85). PROMIS-Fatigue SF scores were highly and inversely associated with Physical Function and Participation (r’s − 0.77 to − 0.78), and moderately-highly and positively correlated with pain, sleep disturbance, anxiety, and depression (r’s 0.60 to 0.75). PROMIS-Fatigue SF scores showed dose-response relationships across fatigue severity descriptors and CDAI categories. Conclusions These results provide robust evidence supporting the construct validity of the 4, 7, and 8-item PROMIS-Fatigue SFs. They capture fatigue across the spectrum of RA disease activity in diverse groups of individuals and should be considered for use as patient-centered assessments of disease control and treatment efficacy.

This commentary summarizes current knowledge on the clinical presentation, management, and outcomes of the inflammatory arthritis which may occur as an immune‐related adverse evet of immune checkpoint inhibitor therapy. Herein, we propose a new algorithm aimed at assisting oncologists in the diagnosis and management of this immune‐related adverse event.

Objective Rheumatoid arthritis (RA) is chronic, painful, disabling condition resulting in significant impairments in physical, emotional, and social health. Our objective was to use different methods and perspectives to evaluate the responsiveness of Patient‐Reported Outcomes Measurement Information System (PROMIS) short forms (SFs) and to identify minimal and meaningful score changes. Methods Adults with RA who were enrolled in a multisite prospective observational cohort completed PROMIS physical function, pain interference, fatigue, and participation in social roles/activities SFs, the PROMIS 29‐item form (PROMIS‐29), and pain and patient global assessment, and rated change in specific symptoms and RA (a little versus lot better or worse) at the second visit. Physicians recorded joint counts, physician global assessment, and change in RA at visit 2. We compared mean score differences for minimal and meaningful improvement/worsening using patient and physician change ratings and distribution‐based methods, and we visually inspected empirical cumulative distribution function curves by change categories. Results The 348 adults were mostly female (81%) with longstanding RA. Using patient ratings, generally 1–3‐point differences were observed for minimal change and 3–7 points for meaningful change. Larger differences were observed with patient versus physician ratings and for symptom‐specific versus RA change. Mean differences were similar among SF versions. Prespecified hypotheses about change in PROMIS physical function, pain interference, fatigue, and participation and legacy scales were supported. Conclusion PROMIS SFs and the PROMIS‐29 profiles are responsive to change and generally distinguish between minimal and meaningful improvement and worsening in key RA domains. These data add to a growing body of evidence demonstrating the robust psychometric properties of PROMIS and supporting its use in RA care, research, and decision‐making.

Results suggest that items in the single-score PROMIS Fatigue SFs demonstrate content validity and can adequately capture the wide range of fatigue experiences of people with RA.