Reports of patients with cancer treated with checkpoint inhibitors who developed immune-related adverse events continue to accumulate, with the largest cohort thus far now being reported from the Mayo Clinic.
And now, through March 1, 2018, a total of 61 cases of rheumatic adverse events in patients given any immune-checkpoint inhibitor have been seen at the Mayo Clinic in Rochester, Minnesota, as reported by Uma Thanarajasingam, MD, PhD, and colleagues in
Arthritis & Rheumatology.
The latest series includes patients with inflammatory arthritis, myopathy, vasculitis, polymyalgia-like syndrome, and other connective tissue diseases, and most required extensive courses of immunosuppression.
Since the introduction of ipilimumab (Yervoy) for metastatic melanoma in 2011, immune checkpoint inhibitors have transformed cancer treatment, and currently at least 1,000 clinical trials of these agents are underway.
Estimates of the prevalence of rheumatic adverse events with this treatment have ranged from 1% to 10%. Standard treatment has relied on glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) — sometimes with discontinuation of immune checkpoint inhibitor therapy. Management has been based primarily on the experience of experts and findings from retrospective studies.
“This study aims to add granularity to the existing literature by describing the prevalence, clinical characteristics, and treatment outcomes of a large, single-institution cohort of patients with rheumatic immune-related adverse events,” the investigators wrote.
The analysis included 1,293 patients who had received treatment with ipilimumab, nivolumab (Opdivo), pembrolizumab (Keytruda), avelumab (Bavencio), or atezolizumab (Tecentriq) at the Mayo Clinic, as well as patients who had been given the cancer treatment elsewhere but who were seen at the Rochester clinic for their immune-related adverse events.
There were 43 cases of these adverse events from the Mayo cohort and 18 who had been treated with checkpoint inhibitors at other centers. Patients’ mean age was 62.6, half were women, and the mean follow-up from the time of adverse event onset was 86 weeks.
The most common types of malignancy were melanoma, pulmonary cancers, and lymphoma, and the most frequently used checkpoint inhibitors were pembrolizumab, nivolumab, and ipilimumab. Pre-existing autoimmune diseases were present in 13 patients, and included rheumatoid arthritis, inflammatory bowel disease, and psoriasis. A total of 21% of patients with immune-related events discontinued their cancer treatment.
Among the 34 patients who developed new-onset inflammatory arthritis — the most common form of immune adverse event — mean age was 59.2, and the disease was polyarticular in two-thirds. Treatment consisted of prednisone alone in 62%, with a mean starting dose of 30.6 mg/day and mean time on steroid treatment of 18 weeks.
An additional 15% were treated with prednisone plus a DMARD, while 24% received nonsteroidal anti-inflammatory drugs or intra-articular steroids.
One recent small studysuggested that interleukin 6 inhibition with tocilizumab (Actemra) might be a potential treatment for arthritic symptoms in these patients.
Complete resolution after treatment was seen in 47% of patients and partial resolution in 53%. Only five of the patients who had complete resolution were still on the checkpoint inhibitor treatment, and all five had required immune suppression during the cancer treatment.
Ten patients, median age of 67.7, developed myopathies, which represented the most severe rheumatic adverse events.
Manifestations included bulbar myopathy in 50% and myocarditis in 40%. Treatments consisted of prednisone alone in 50%, with mean starting doses of 74 mg/day and time on steroid treatment of 15 weeks. Intravenous methylprednisolone was required in 50%, and 30% also had plasma exchange. Complete resolution of the myopathy was observed in 70%. Two died from complications associated with myocarditis and bulbar myopathy.
Other rheumatic events included four cases of vasculitis, manifesting as granulomatosis with polyangiitis, giant cell arteritis, or necrotizing vasculitis, as well as four cases of polymyalgia rheumatica. Among connective tissue diseases were six cases of diffuse systemic sclerosis or sicca syndromes, and three patients had flares of pre-existing rheumatoid arthritis or Sjogren’s syndrome.
Most of those patients were treated with steroids, and six also received DMARDs. One patient with necrotizing vasculitis discontinued the checkpoint inhibitor treatment, as did one of granulomatosis with polyangiitis and one with systemic sclerosis. The only cases in this subgroup with complete resolution of their rheumatic adverse events were two patients with necrotizing vasculitis, one patient with a flare of previously inactive rheumatoid arthritis, and one with a polymyalgia rheumatica-like syndrome.
“It remains unclear why some patients develop rheumatic immune-related adverse events, and so far no genomic risk factors have been identified, although the varied clinical phenotypes … certainly suggest multiple underlying immunopathogenic mechanisms,” Thanarajasingam and co-authors observed.
A limitation of the study, they said, was its use of retrospective data.
The authors reported having no financial disclosures.
Primary Source
Arthritis & Rheumatology
