Risk of Toxicity After Initiating Immune Checkpoint Inhibitor Treatment in Patients With Rheumatoid Arthritis

Elizaveta Efuni, MD; Samuel Cytryn, MD; Patrick Boland, MD; Timothy B. Niewold, MD; Anna Pavlick, DO; Jeffrey Weber, MD, PhD; Sabina Sandigursky, MD


J Clin Rheumatol. 2021;27(7):267-271. 

In This Article


Of 84 patients with preexisting autoimmunity who developed malignancy and were treated with ICIs, 22 patients had RA. Of those, 11 had documented positive rheumatoid factor, and 5 had a positive anticitrullinated protein antibody (Figure). Among RA patients, 16 (73%) were female, and 6 (27%) were male. Median age was 67 years. Seven patients (32%) carried another autoimmune diagnosis in addition to RA, including 3 with Sjögren syndrome (14%), 2 with polymyalgia rheumatica (9%), and 5 others (23%). One patient carried a diagnosis of inflammatory arthritis with a differential of seronegative RA, psoriatic arthritis, sarcoidosis, and sicca syndrome (Table 1). Ten patients (45%) were diagnosed with RA more than 5 years prior to ICI start, and 2 patients (9%) had RA disease duration of less than 5 years, whereas the rest of the patients had no documentation of duration of their RA.

Most RA patients (86%) had no evidence of clinically active disease at the time of ICI initiation, as documented by their treating physician. In the majority of patients (96%), inflammatory markers were not checked at start of ICI therapy. Sixteen patients (73%) were nonetheless receiving RA immunomodulatory therapy at the start of ICI, with 12 patients (55%) receiving systemic corticosteroids and 7 patients (32%) on methotrexate. Of those receiving corticosteroids, only 2 (9%) were on intermediate prednisone equivalent dose of 20 mg daily, 4 patients (18%) received doses of 7.5 to 10 mg daily, and 6 (27%) were on a very low dose of less than 5 mg daily. Three patients were on methotrexate 25 mg weekly, and 1 patient was receiving methotrexate 15 mg weekly and no corticosteroids. Two patients were receiving both methotrexate (10 and 12 mg weekly) and low-dose prednisone (<5 mg daily). In 2 patients who were on methotrexate and low-dose steroids prior to initiation of ICI, methotrexate was discontinued within 8 weeks prior to the start of ICI, and they were continued on their oral corticosteroids only. All patients who were on corticosteroids for RA continued their current dose.

The most common cancer diagnoses were metastatic melanoma in 32% of patients and NSCLC in 32% of patients. At time of ICI initiation, all malignancies were stage IV (86%) or III (14%) with median disease duration of 18 months. Melanoma patients had a median disease duration of 34 months, whereas for lung cancer median disease duration was 14 months. Twelve patients underwent surgical resection, and 8 patients received chemotherapy within 3 months prior to ICI. Only 3 patients received ICI as first-line therapy. Thirteen patients (59%) were treated with pembrolizumab, 9 (41%) with nivolumab, and 4 (18%) with ipilimumab. One patient received combination ICI therapy with ipilimumab and nivolumab, followed by monotherapy with pembrolizumab; 2 patients received sequential therapy of ipilimumab and either nivolimumab or pembrolizumab, and 1 patient received monotherapy with nivolumab and subsequently was switched to pembrolizumab (Table 1).

De novo irAEs occurred in 7 RA patients (32%), with only 2 (9%) developing grade 3 irAEs. The most common toxicities were dermatitis in 4 patients (18%) and colitis in 3 patients (14%). Median time to development of irAEs was 1 month (IQR, 3.5 months); some patients developed irAEs as long as 9 months after ICI initiation. Four patients (57%) were treated for irAEs using oral corticosteroids (at doses between 20 and 60 mg/d) with slow taper. There were no irAE recurrences reported. Immunotherapy was temporarily discontinued because of irAEs in 5 patients (23%). Only 1 patient required permanent ICI discontinuation after irAEs.

Frank RA flares occurred in 12 patients (55%). Median time to flare was 1 month (IQR, 1.75 month). Of those who had an RA flare, 10 patients (83%) received oral corticosteroids for flare (8 received oral corticosteroids only, 2 in combination with methotrexate or sulfasalazine). Two patients were continued on current immunosuppressive regimen with addition of supportive care with NSAIDs for their flare. Median prednisone equivalent dose for flare was 20 mg daily. Four patients (33%) received prednisone equivalent dose of 40 mg daily or higher, 4 patients (33%) received dose of less than 10 mg daily, and 2 patients (17%) were on prednisone equivalent dose of 20 mg daily. In 2 patients, corticosteroids were stopped after resolution of flare; however, most (8 patients) were slowly tapered over weeks to a lower dose or continued on the current dose (2 patients) because of persistent, albeit tolerable arthritis. Three patients had recurrent RA flare after improvement in initial symptoms, necessitating increase in corticosteroids dose or addition of a DMARD (sulfasalazine or methotrexate). All patients had close (weekly/biweekly) follow-up with their oncologist and/or rheumatologist for symptomatic monitoring if active RA flare was present. Immune checkpoint inhibitors were permanently discontinued because of flare in 2 patients (9%); however, the majority continued to receive ICI therapy despite flare (Table 2). Inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) were checked in only 1 patient at time of flare and were significantly elevated at 79 and 66, respectively. Overall, either RA flare, de novo irAE, or both occurred in 16 patients (73%). Median overall survival for patients with RA after start of ICI was 10.5 months.