Background: Therapy with immune check point inhibitors (ICIs) has revolutionized cancer treatment during the last years. Despite their high efficacy, ICIs are associated to a new spectrum of adverse events, the immune-related adverse events (irAEs). Inflammatory arthritis and polymyalgia rheumatica (PMR) are two of the most common rheumatic irAEs. The optimal management of irAEs remains unclear. Treatment guidelines largely support the use of glucocorticoids (GCs) as first line therapy [1]. Preclinical data raise concerns regarding the potential risk of impaired antitumoral effect with use of GCs. The high efficacy and potential synergistic effect (according to recent findings) [2] of targeted immunomodulation, such as interleukin 6 (IL-6) blockade, could support a paradigm shift, where targeted treatments are considered earlier in the treatment sequence.

Objectives: To assess how frequently a disease modifying anti-rheumatic drug (DMARD) treatment in patients with ICI induced arthritis and/or PMR, after inadequate response to GCs, is initiated and to assess its effectiveness.

Methods: We retrospectively identified patients who were diagnosed with inflammatory arthritis and/or PMR at the rheumatology department at Karolinska University Hospital, after referral from the oncology department due to suspicion of a rheumatic irAE, between Jan 2020 and Dec 2021. Treatment response was defined as sustained low disease activity or remission according to the rheumatologist evaluation at 6 months (+/- 1 month) after initiation of DMARD.

Results: A total of 20 patients were identified, who were diagnosed with arthritis (N=11), PMR (N=6) or both (N=3). The median (IQR) age was 70 (46-76) years; 50% of patients were females. The type of cancer was urogenital (N=8), melanoma (N=6), lung cancer (N=2), and other (N=4). 14 patients received a PD-1 inhibitor (9 nivolumab, 4 pembrolizumab, 1 cemiplimab), 3 received a PDL-1 inhibitor (2 atezolizumab, 1 avelumab), 2 received a combination of nivolumab and the CTLA-4 inhibitor ipilimumab and one patient combination of nivolumab and pembrolizumab. The median time from start of ICI treatment to symptom debut was 2 (1.25-3.75) months.

83% of patients with PMR and/or arthritis responded well to GCs without the need for treatment escalation. On the contrary,

11 out of 14 patients (79%) with inflammatory arthritis (with or without PMR) responded inadequately to GC treatment, despite receiving moderate-high doses (median 20mg/day Prednisolone or equivalent), or flared when the dose was reduced below 10mg/day. A conventional synthetic DMARD was initiated in 7 patients (methotrexate N=6, hydroxychloroquine N=1), with a response rate of 71%. 3 patients received a biologic DMARD as first-line DMARD, either because of contraindication for methotrexate and/or high disease activity, and 2 patients after methotrexate failure. All 5 patients tocilizumab, with a response rate of 100%. Subsequently 1 of these patients discontinued tocilizumab due to suspected side effects, and started with a TNF inhibitor. After initiation of tocilizumab all patients were able to reduce the dose of GCs to less than 5mg/day.

Conclusion: The majority of patients developing ICI-induced arthritis are refractory to GCs and need a DMARD treatment, although selection bias cannot be formally excluded, since the most severe forms of arthritis might be referred to the rheumatology department. csDMARDs are effective in a significant proportion of patients. Tocilizumab is highly effective and well tolerated in ICI-induced arthritis. ICI-induced PMR seems to respond adequately to GCs.

REFERENCES:

[1]Kostine M, et al. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Annals of the Rheumatic Diseases 2021;80:36-48.

[2]J.S. Weber, et al. Phase II trial of ipilimumab, nivolumab and tocilizumab for unresectable metastatic melanoma. Annals of Oncology (2021) 32 (suppl_5): S867-S905. 10.1016/annonc/annonc706

Disclosure of Interests: Matina Liapi: None declared, Katerina Chatzidionysiou Consultant of: consultancy fees from Eli Lilly, AbbVie and Pfizer