Background Immune checkpoint inhibitors are a new promising class of antitumor drugs that have been associated with a number of immune-related Adverse Events (AEs), including musculoskeletal and rheumatic disease. Methods We searched Medline reviewing reports of musculoskeletal and rheumatic AEs induced by immune checkpoint inhibitors. Results Several musculoskeletal and rheumatic AEs associated with immune checkpoint inhibitors treatment are reported in the literature. In particular, arthralgia and myalgia were the most common reported AEs, whereas the prevalence of arthritis, myositis and vasculitis is less characterized and mainly reported in case series and case reports. Other occasionally described AEs are sicca syndrome, polymyalgia rheumatica, systemic lupus erythematosus and sarcoidosis. Conclusion Newly induced musculoskeletal and rheumatic diseases are a frequent adverse event associated with immune checkpoint inhibitors treatment.

Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors: A Review of the Literature.

Immune checkpoint inhibitors (ICPIs) have emerged as a frontline treatment for a growing list of malignancies. Disruption of the negative regulatory immune checkpoints by ICPIs has been associated with many immune-related adverse events. Granulomatous reactions, such as sarcoidosis-like reactions, granulomatous panniculitis, granuloma annulare, and granulomatous dermatitis, are uncommon but increasingly recognized immune-related adverse events seen in patients treated with ICPIs. The frequency and significance of these eruptions, including whether they portend responsiveness to treatment, remain unclear. Additionally, understanding the role of immune checkpoint blockade in these reactions may provide mechanistic insight into the relevant signaling pathways involved in sarcoidosis and other granulomatous disorders.

Immune checkpoint inhibitors and the development of granulomatous reactions.

Immune checkpoint inhibitors have advanced the treatment paradigm of various cancers, achieving remarkable survival benefits. However, a myriad of immune-related adverse events (irAE) has been recognized in almost every organ system, presumably because of persistent immune system activation. Rheumatic symptoms such as arthralgia or myalgia are very common. More specific irAE are increasingly being reported. The most frequent ones are inflammatory arthritis, polymyalgia-like syndromes, myositis and sicca manifestations. These rheumatic irAE can develop in ∼5-10% of patients treated with immune checkpoint inhibitors, although true incidence rates cannot be estimated given the lack of prospective cohort studies, and likely underreporting of rheumatic irAE in oncology trials. In this review, we will provide a summary of the epidemiologic data reported for these rheumatic irAE, until more robust prospective longitudinal studies become available to further define the true incidence rate of rheumatic irAE in patients receiving these novel cancer therapies.

Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy.

Immune checkpoint inhibitors targeting the cytotoxic T lymphocyte-associated antigen-4 and programmed cell death-1 receptors have transformed the treatment of melanoma and other cancers. These therapies are associated with a number of side effects, including immune-related adverse events. Sarcoidosis-like granulomas (SLGs) are important immune checkpoint inhibitor-related reactions to recognize as SLGs can mimic disease progression and accordingly impact treatment decisions. We systematically review reports of immune checkpoint inhibitor-induced SLGs in cancer patients and discuss potential underlying pathophysiological mechanisms.

Immune checkpoint inhibitor-induced sarcoidosis-like granulomas

Background:We report a case of nivolumab-related sarcoidosis-like syndrome that initially presented with erythema nodosum. Sarcoidosis development has been described in single and combination immun...

Erythema Nodosum as the Initial Presentation of Nivolumab-Induced Sarcoidosis-Like Reaction:

Novel treatments of metastatic melanoma include the usage of checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated antigen (CTLA-4) or anti-programmed death-1 (PD-1) antibodies, which are immunomodulatory antibodies that enhance the immune response against tumors. While they have substantially improved the prognosis for patients, these therapies are associated with a large spectrum of immune-related adverse effects (irAEs). We report a patient developing pulmonary and cutaneous sarcoidosis after pembrolizumab therapy while complete regression of stage IV melanoma was perceived. Coincident development of sarcoidosis and metastatic melanoma as illustrated by this case report poses a diagnostic challenge because, in contrast to other irAEs, both diseases share common features such as pulmonary lesions, hilar adenopathies and skin nodules. Considering sarcoidosis as a potential side-effect of pembrolizumab treatment is crucial to avoid misdiagnosis with malignant lesions, hence careful description and reporting of such cases is primordial for patient care and may also provide us with insightful knowledge on the pathogenesis of immune-related diseases.

N. Yatim

Papers

Sarcoidosis post-anti-PD-1 therapy, mimicking relapse of metastatic melanoma in a patient undergoing complete remission