Efeitos adversos reumatológicos associados a Pembrolizumab: revisão sistemática

Abstract

Objectives: The primary goal is to describe the rheumatic adverse events in patients who use Pembrolizumab, and the secondary one is to analyze the frequency of rheumatic adverse events in this patient population. Background: Rheumatic diseases are a mixed group of entities that commonly has musculoskeletal pain among their symptoms. The etiologies are diverse, with autoimmunity playing a key role. Both hereditary and acquired factors can make autotolerance mechanisms fail, leading to autoimmune diseases, localized or systemic injuries caused by the immune system’s failure to recognize self-elements as non-threatening. PD1 is a immune cell membrane receptor that when activated by the PD-L1 and PD-L2 ligands has a global immunossupressant effect. These ligands can be also found in neoplastic clones, which makes them able to evade the immune response. Pembrolizumab is an antibody against the PD-1 receptor designed to inhibit this mechanism. However, that could interfere with autotolerance mechanisms, generating rheumatic adverse events. Thus, it’s fundamental to describe, based on the current literature, the frequency and spectrum of rheumatic diseases in patients who use these antibodies. Methods: a systematic review of articles from 2000 to 2017, in the MEDLINE, SCIELO, LILACS, and Portal Capes electronic databases, using “Pembrolizumab”, “clinical trials” and “case reports” as keywords, as well as their counterparts in Portuguese, French and Spanish. Findings: Forty-five articles were found in total, with 27 being clinical trials and 18 case reports. In the clinical trials, 3494 patients were included, 2116 men and 1378 women. The most common adverse events were arthralgia, with 276 cases, and myalgia, with 96, and most symptoms were of mild to moderate intensity. Less common events such as arthritis, myositis, vasculitis and Sjogren Syndrome were also found. In the case reports, scleroderma, sarcoidosis, polymyalgia rheumatica and inflammatory myopathies were the main disorders, but rheumatoid arthritis, seronegative polyarthritis with tenosynovitis, eosinofilic fasciitis, temporal arteritis, monoarthritis, inflammatory polyarthritis and vasculitic neuropathy were also reported. Conclusion: Rheumatic adverse events are diverse in patients using Pembrolizumab with arthralgia and myalgia as the most common ones, found respectively in 272 and 96 patients. The symptoms are mostly milt to moderate. Rheumatic syndromes like polymyalgia rheumatica, scleroderma, sarcoidosis, rheumatoid arthritis, eosinofilic fasciitis, Sjögren Syndrome, seronegative polyarthritis with tenosynovitis, inflammatory myopathies, poly and monoarthritis were also found, albeit in much lower frequencies than arthralgia and myalgia.