Current Concepts in Immune Checkpoint Inhibitor-Induced Arthritis

Cancer immunotherapy including immune checkpoint inhibitors (ICI) has revolutionised the field of oncology and has been in use in India since 2015. ICI includes monoclonal antibodies directed against programmed cell death-1(PD-1), programmed cell death ligand 1(PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). They are currently approved in various stages of cancer immunotherapy. By inhibiting the negative co-stimulatory signals, unchecked T-cell stimulation can occur which helps enhance anti-tumour responses but at the same time cause immune-related adverse events (irAE) due to excessive/off-target inflammation. The most common irAE is cutaneous (30%) followed by hypothyroidism (20%). Other irAEs like rash and colitis present early in the treatment course, while inflammatory arthritis (ICI-IA) and pneumonitis have variable times of onset. Musculoskeletal AEs are rarely life-threatening and include arthralgia, inflammatory arthritis, polymyalgia rheumatica (PMR) and myositis. Most patients of ICI-IA have undifferentiated phenotypes at onset and do not satisfy any diagnostic or classification criteria for primary rheumatic diseases. Caucasian origin, female sex, combination therapy (anti-CTLA-4 and anti-PD-1/PD-L1) and body mass index (BMI) >25 kg/m 2 are independently associated risk factors. Phenotypic subtypes include rheumatoid arthritis (RA)-like, reactive arthritis (ReA)-like, spondyloarthritis (SpA)-like, PMR-like, undifferentiated arthritis, isolated tenosynovitis and RS3PE-like syndromes. Pre-treatment autoantibodies like RF, anti-cyclic citrullinated peptide (anti-CCP) and anti-nuclear antibody (ANA) have been detected in some patients receiving ICI who went on to develop ICI-IA later. Management includes early rheumatology referral, continuing ICI therapy in grade 1 irAE, holding ICI, non-steroidal anti-inflammatory drug (NSAID)/intra-articular steroids for grade 2 irAE, while grades 3 and 4 require high-dose glucocorticoids prednisolone 0.5–1 mg/kg and conventional synthetic Disease Modifying Anti-Rheumatic Drug (DMARD)/biological DMARDs if not responding within two weeks.