Sofia Tsagouli

Nivolumab-Induced Recurrence of Rheumatoid Arthritis in a Patient With Advanced Non–Small Cell Lung Cancer: A Case Report

Background: Nivolumab (Opdivo, Bristol-Myers Squibb) is a human IgG4 monoclonal antibody with high affinity for the programmed death-1 receptor and is the first programmed death-1 immune checkpoint inhibitor approved by the U.S. Food and Drug Administration for second-line treatment of patients with advanced squamous and nonsquamous nonsmall cell lung cancer (1). Because of its unbalancing effect on the immune system, nivolumab may trigger immune-related adverse events (IRAEs), especially among patients with an autoimmune predisposition (2). Objective: To present a case of nivolumab-induced recurrence of rheumatoid arthritis successfully treated with concurrent administration of prednisolone in a patient with advanced nonsmall cell lung cancer. Case Report: A 76-year-old man with previously untreated stage IV lung adenocarcinoma and a history of rheumatoid arthritis that had been in clinical and laboratory remission for 25 years was referred to the oncology clinic of Sotiria Athens General Hospital for oncologic evaluation and treatment. The patient was treated with first-line carboplatinpemetrexed plus bevacizumab, maintenance pemetrexed plus bevacizumab, second-line carboplatinpaclitaxel, and third-line gemcitabinebevacizumab. Following disease progression after third-line therapy was begun, intravenous nivolumab treatment at 3 mg/kg of body weight every 2 weeks was initiated. Fifteen days after the first nivolumab infusion, a rheumatoid arthritis crisis occurred, with symmetrical polyarthritis of the upper extremities (particularly in the interphalangeal and metacarpophalangeal joints) and lower-extremity weakness accompanied by marked elevation of rheumatoid factor levels (251 IU/mL [reference range,<30 IU/mL]) and citrullinated peptide antibodies (104.3 U/mL [reference range,<5.0 U/mL]). Oral prednisolone therapy was begun at 20 mg/d and gradually tapered over 10 weeks; symptoms remitted within 5 days after treatment. Nivolumab therapy was continued during prednisolone treatment and after its completion without any modification of the initial protocol. Follow-up chest computed tomography 3 months after initiation of nivolumab therapy showed a partial response. Discussion: Patients with a history of autoimmunity are at increased theoretical risk for IRAEs (2, 3). In support of this hypothesis, serologic aggravation of autoimmune thyroiditis and induction of autoimmune hemolytic anemia in patients receiving nivolumab have been reported (4, 5). However, adequate clinical evidence to substantiate this concern is lacking, mainly because clinical trials of immune checkpoint inhibitors typically exclude patients with autoimmune disorders (2, 3). Therapeutic management of immune checkpoint blockadeinduced IRAEs generally includes interruption of the offending agent and suppression of lymphocyte activation with moderate to high doses of corticosteroids or other immunomodulatory drugs, such as azathioprine or tumor necrosis factor- antagonists, in the presence of steroid-refractory symptoms (2). Cautious use of immunosuppressive agents has nevertheless been advised in this setting because of concerns over a potential compromise of antitumor immunity (2). To our knowledge, this is the first reported case of a patient with cancer who had a nivolumab-induced clinical recurrence of a previously diagnosed autoimmune disorder that was successfully treated with corticosteroids without discontinuation of the culprit drug. It provides much-needed, real-world clinical evidence that nivolumab may induce clinical exacerbation of an underlying autoimmune condition even decades after its last manifestation. Furthermore, prednisolone successfully controlled the arthritis recurrence without the need to discontinue nivolumab therapy and, most important, without affecting antitumor response. Further studies are warranted to provide additional data on the efficacy and toxicity of nivolumab in patients with a history of autoimmune conditions, as well as to confirm the feasibility of its concurrent administration with corticosteroids in the presence of nivolumab-induced IRAEs.