Objective To determine incidence rate and predictors of venous thromboembolism (VTE) in a population-based cohort with ANCA-associated vasculitis (AAV). Design The study comprised 325 patients diagnosed with AAV from 1997–2016. All cases of VTE from prior to vasculitis diagnosis to the end of the study period were identified. The Birmingham Vasculitis Activity Score (BVAS) was used to assess disease activity at diagnosis. Venous thromboembolisms occurring in a period beginning three months prior to AAV diagnosis were considered to be AAV-related. The standardized incidence ratio (SIR) and 95% confidence intervals (CI) of VTE were calculated using the incidence rate in the general population. Results Fifty-nine patients (18%) suffered 69 VTE events. Of these, 48 (81%) suffered AAV-related VTE [deep vein thrombosis (DVT, n = 23), pulmonary embolism (PE, n = 18), and other (n = 9)]. The incidence rate of AAV-related VTE was 2.4/100 person-years (95% CI 1.7–3.0) during 2039 person-years of follow-up. The incidence during the first three months post–AAV diagnosis was 20.4/100 person-years (95% CI 11.5–29.4), decreasing to 8.9 (95% CI 0.2–17.6) and 1.5 (95% CI 0.0–3.5) in months 4–6 and months 7–12 post–AAV diagnosis, respectively. The SIR was 34.2 (95% CI 20.2–48.1) for DVT and 10.4 (95% CI 5.6–15.1) for PE. In multivariate Cox-regression analyses, only age and BVAS were predictive of VTE. Conclusions The incidence rate and SIR of AAV-related VTE is high, and higher early in the course of the disease. Vasculitis activity and age are positively associated with VTE.

Immunotherapy has revolutionized cancer treatment during the last years. Several monoclonal antibodies that are specific for regulatory checkpoint molecules, that is, immune checkpoint inhibitors (ICIs), have been approved and are currently in use for various types of cancer in different lines of treatment. Cancer immunotherapy aims for enhancing the immune response against cancer cells. Despite their high efficacy, ICIs are associated to a new spectrum of adverse events of autoimmune origin, often referred to as immune-related adverse events (irAEs), which limit the utility of these drugs. These irAEs are quite common and can affect almost every organ. The grade of toxicity varies from very mild to life-threatening. The pathophysiological mechanisms behind these events are not fully understood. In this review, we will summarize current evidence specifically regarding the rheumatic irAEs and we will focus on current and future treatment strategies. Treatment guidelines largely support the use of glucocorticoids as first-line therapy, when symptomatic therapy is not efficient, and for more persistent and/or moderate/severe degree of inflammation. Targeted therapies are higher up in the treatment pyramid, after inadequate response to glucocorticoids and conventional, broad immunosuppressive agents, and for severe forms of irAEs. However, preclinical data provide evidence that raise concerns regarding the potential risk of impaired antitumoral effect. This potential risk of glucocorticoids, together with the high efficacy and potential synergistic effect of newer, targeted immunomodulation, such as tumor necrosis factor and interleukin-6 blockade, could support a paradigm shift, where more targeted treatments are considered earlier in the treatment sequence.

BackgroundTherapy 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.ObjectivesTo 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.MethodsWe 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.ResultsA 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.ConclusionThe 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/annonc706Disclosure of InterestsMatina Liapi: None declared, Katerina Chatzidionysiou Consultant of: consultancy fees from Eli Lilly, AbbVie and Pfizer