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Erosive Deforming Inflammatory Arthritis in a Patient With Cervical Adenocarcinoma

Educational Objective
Based on this clinical scenario and the accompanying image, understand how to arrive at a correct diagnosis.
1 Credit CME

A 58-year-old white woman with history of metastatic human papillomavirus–positive cervical adenocarcinoma presented with multiple joint deformities. Her initial symptoms started 1 month after the initiation of nivolumab, which was 1 year prior to the index visit. Treatment with nonsteroidal anti-inflammatory drugs failed, and the patient had a partial response to intra-articular steroids. She refused systemic therapies owing to concern about diminishing the effectiveness of nivolumab. Despite the joint symptoms, nivolumab treatment was continued for a year. Evaluation showed fixed swan neck deformities in multiple fingers (Figure, A). There was evidence of chronic synovial hypertrophy with no active synovitis on examination. The results of a comprehensive autoantibody blood panel, including antinuclear antibody, rheumatoid factor, and anti-citrullinated peptide antibody, were unremarkable. Plain radiographs of the hands demonstrated diffuse osteopenia, joint space narrowing, and multiple deformities. Magnetic resonance imaging of both hands revealed multifocal osseous erosions (Figure, B), synovitis, and tenosynovitis.

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C. Nivolumab-induced inflammatory arthritis

Nivolumab is a fully human monoclonal antibody that selectively binds to the programmed cell death 1 (PD-1) receptor on T cells and blocks the interaction with programed cell death ligand 1 (PD-L1) and PD-L2, resulting in T-cell activation and proliferation.1 The enhanced immune response associated with nivolumab improves antitumor immunity; however, it is also associated with various immune-related adverse events (irAEs). Based on pooled data from clinical trials of nivolumab, the most common irAE was skin related. Gastrointestinal, hepatic, and endocrine systems were among the other systems that were affected.1

Inflammatory arthritis is a reported irAE associated with nivolumab, with a prevalence of approximately 2%.2 Most patients (65%) present with polyarticular inflammatory arthritis with involvement of small and/or large joints.2 Many of these patients do not develop autoantibodies like rheumatoid factor or anti-citrullinated peptide antibody and are thus seronegative. In a cohort of 9 patients who developed arthritis during nivolumab therapy, 5 patients progressed to polyarticular arthritis resembling rheumatoid arthritis, without any evidence of autoantibodies or notable bone erosions. These patients required a much higher dose of systemic steroids than those without polyarticular arthritis, and the arthritis persisted for several months after stopping nivolumab.3 In another case series, the authors described patients who developed seropositive rheumatoid arthritis shortly after receiving nivolumab, raising the concern that nivolumab may unmask underlying autoimmunity.4 In 1 report, a patient developed deforming arthritis during nivolumab therapy; however, imaging did not reveal erosions or joint damage.5

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Article Information

Published Online: September 26, 2019. doi:10.1001/jamaoncol.2019.3140

Correction: This article was corrected on November 14, 2019, to add arrowheads to the Figure.

Corresponding Author: Sarthak Gupta, MD, National Institutes of Health, 10 Center Dr, Rm 5-5521, Bethesda, MD 20892-1930 (sarthak.gupta@nih.gov).

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Cancer Institute of the National Institutes of Health.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the patient for granting permission to publish this information.

References
1.
Weber  JS, Hodi  FS, Wolchok  JD,  et al.  Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.  J Clin Oncol. 2017;35(7):785-792.PubMedGoogle ScholarCrossref
2.
Richter  MD, Crowson  C, Kottschade  LA, Finnes  HD, Markovic  SN, Thanarajasingam  U.  Rheumatic syndromes associated with immune checkpoint inhibitors: a single-center cohort of sixty-one patients.  Arthritis Rheumatol. 2019;71(3):468-475.PubMedGoogle ScholarCrossref
3.
Cappelli  LC, Gutierrez  AK, Baer  AN,  et al.  Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.  Ann Rheum Dis. 2017;76(1):43-50.PubMedGoogle ScholarCrossref
4.
Belkhir  R, Burel  SL, Dunogeant  L,  et al.  Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment.  Ann Rheum Dis. 2017;76(10):1747-1750.PubMedGoogle ScholarCrossref
5.
de Velasco  G, Bermas  B, Choueiri  TK.  Autoimmune arthropathy and uveitis as complications of programmed death 1 inhibitor treatment.  Arthritis Rheumatol. 2016;68(2):556-557.PubMedGoogle ScholarCrossref
6.
Brahmer  JR, Lacchetti  C, Schneider  BJ,  et al; National Comprehensive Cancer Network.  Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline.  J Clin Oncol. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385PubMedGoogle ScholarCrossref
7.
Scott  SC, Pennell  NA.  Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab.  J Thorac Oncol. 2018;13(11):1771-1775. doi:10.1016/j.jtho.2018.06.004PubMedGoogle ScholarCrossref
8.
Shafqat  H, Gourdin  T, Sion  A.  Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy.  Semin Oncol. 2018;45(3):156-163. doi:10.1053/j.seminoncol.2018.07.003PubMedGoogle ScholarCrossref
9.
Schadendorf  D, Wolchok  JD, Hodi  FS,  et al.  Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials.  J Clin Oncol. 2017;35(34):3807-3814.PubMedGoogle ScholarCrossref
10.
Cappelli  LC, Brahmer  JR, Forde  PM,  et al.  Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen.  Semin Arthritis Rheum. 2018;48(3):553-557.PubMedGoogle ScholarCrossref
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