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Background: Potential associations between targeted therapies and a new cancer in patients with inflammatory arthritis (IA) and a previous malignancy are a frequent concern in daily rheumatology practice., Objectives: To develop points to consider (PTC) to assist rheumatologists when initiating a targeted therapy in the context of a previous malignancy., Methods: Following EULAR standardised operating procedures, a task force met to define the research questions for a systematic literature review and to formulate the overarching principles (OPs) and the PTC., Results: The group formulated five OPs; seven PTC were formulated concerning the initiation of targeted therapies in patients with active IA and a previous malignancy in remission and one PTC concerning patients with active IA who were not in cancer remission. Major themes included (a) the need to assess the individualised risk of cancer recurrence based on the characteristics of the patient, cancer and the underlying disease; (b) the importance of engaging with specialists caring for cancer and defining treatment based on a shared decision between the patient and the rheumatologist; (c) the value of initiating without delay an appropriate targeted therapy for the treatment of the IA in patients in remission of their cancer; (d) the proposal to use Janus kinase inhibitors and abatacept with caution and in the absence of therapeutic alternatives, based on the absence of any data concerning their use in the context of previous malignancy., Conclusion: The 2024 EULAR points to consider provide guidance on the management of targeted therapies in patients with IA and a previous malignancy., Competing Interests: Competing interests: No., (© European Alliance of Associations for Rheumatology, EULAR 2024. Re-use permitted under CC BY-NC-ND. No commercial re-use. No derivatives. See rights and permissions. Published by BMJ Group on behalf of EULAR.)

Background: Targeted therapies have been associated with potential risk of malignancy, which is a common concern in daily rheumatology practice in patients with inflammatory arthritis (IA) and a history of cancer., Objectives: To perform a systematic literature review to inform a Task Force formulating EULAR points to consider on the initiation of targeted therapies in patients with IA and a history of cancer., Methods: Specific research questions were defined within the Task Force before formulating the exact research queries with a librarian. We included studies reporting a relative risk measure of patients with a history of cancer initiating a targeted therapy or a conventional synthetic disease-modifying antirheumatic drug (csDMARD), regardless of the time since diagnosis of cancer. All relevant studies included in PubMed or Embase up to 15 July 2022 were included. Two reviewers independently performed standardised article selection, data extraction, synthesis and risk of bias assessment., Results: 14 published articles and one ACR abstract fulfilled the inclusion criteria. All studies were high-quality observational studies, representing a median follow-up from treatment initiation of 4.52 years among 4428 patients and 15 062 patient-years of follow-up for new or recurrent cancer.All patients had a history of cancer, most frequently solid cancer, most frequently receiving treatment for rheumatoid arthritis and most frequently treated with tumour necrosis factor-alpha inhibitors. Across these studies, the overall HR of cancer recurrence was 0.92 (95% CI 0.74 to 1.15) for patients receiving a targeted therapy versus a csDMARD., Conclusion: Overall, the targeted therapies and clinical contexts covered by the included studies were not associated with an increased risk of cancer recurrence as compared with csDMARDs., Competing Interests: Competing interests: Participants provided declarations of interest; the individual declarations will be attached as an online supplemental file., (© European Alliance of Associations for Rheumatology, EULAR 2024. Re-use permitted under CC BY-NC-ND. No commercial re-use. No derivatives. See rights and permissions. Published by BMJ Group on behalf of EULAR.)

Introduction: Immune checkpoint inhibitors-induced inflammatory arthritis (ICI-IA) affects about 5% of ICI recipients. We aimed (1) to characterize the resolution of ICI-IA during ICI treatment and after ICI discontinuation and (2) to assess how ICI-IA influences ICI management across time., Methods: All ICI-treated patients referred to rheumatology at Bordeaux University Hospital were identified and patients with ICI-IA with a follow-up of≥6months after ICI-IA onset were included. Resolution of ICI-IA was defined by discontinuation of ICI-IA medications without recurrence of ICI-IA symptoms., Results: Resolution of ICI-IA occurred in 13 of 80 patients (16%) while maintaining active ICI treatment, mainly in patients with polymyalgia rheumatica (PMR)-like clinical presentation (P=0.03). Synovitis was more frequent in those whose ICI-IA persisted throughout ICI treatment. In patients with persistent ICI-IA throughout ICI treatment, 34 (50%) and 47 (70%) resolved at 6- and 12-months post-ICI discontinuation, respectively. Reason for terminating ICI was more frequently cancer stable or in remission in those who still had active ICI-IA at 6- and 12-months post-ICI discontinuation. Both progression-free survival and overall survival were longer in the groups with active ICI-IA at 6- and 12-months after ICI discontinuation., Discussion: In this cohort, ICI was safely continued in most patients experiencing ICI-IA. About one sixth of ICI-IA resolved despite maintaining active ICI treatment and allowing ICI-IA treatment discontinuation without recurrence of symptoms, mainly in those with PMR-like presentation. Larger studies are needed to determine predicting factors of resolving ICI-IA to minimize exposure to immunosuppressive treatment., Competing Interests: Disclosure of interest AL: speaker fees for AstraZeneca. TB, APL, MBB, BS, ML, CR, MET, MK declare that they have no competing interest. SP and CD: congress fees and investigator in clinical trials: BMS and MSD. EG: congress fees and investigator for BMS and MSD. MZ: grants from AVAD and grants from FRM. RV: consulting fees and speaker fees: Roche; registration reimbursement: Pfizer and AstraZeneca; speaker and registration reimbursement: BMS and MSD. AD: consulting or advisory role: Merck, MSD, BMS, Merus; travel, accommodations, expenses: BMS, Merck. MGG: consulting or advisory role: AstraZeneca, Merck, Pfizer, MSD, BMS, Roche; travel, accommodations, expenses: MSD, Janssen. FL: congress fees, consulting fees, and sub-investigator in trials: AstraZeneca, BMS, MSD, Roche, Pfizer. TS: clinical research: AbbVie, Abivax, Biogen, Pfizer, Lilly, MSD, Novartis, Sandoz; advisory boards: AbbVie, BMS, Lilly, Novartis, Pfizer, Sanofi; education: AbbVie, Biogen, BMS, Galapagos, Lilly, Janssen, Novartis, Nordic Pharma, Pfizer, Viatris; help for research: Pfizer, Lilly, Abbvie, Biogen., (Copyright © 2024 Sociýtý Franýaise de Rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Immune checkpoint inhibitors (ICIs) present clinicians with the challenge of managing immune-related adverse events (irAEs), which can range from mild to severe due to immune system activation 1 . While guidelines recommend discontinuing ICIs for grade 3 partial and all grade 4 irAEs, there is growing interest in rechallenging patients based on oncological outcomes, particularly for cardiovascular and neurological irAEs where data remains scarce 1,2 . We retrospectively evaluated the safety of ICI rechallenge following grade 3-4 irAEs, specifically focusing on cardiovascular and neurological events, in patients discussed at our multidisciplinary immunotoxicity assessment board between 2019 and 2021. Fifteen patients were included, with a median time to severe irAE onset of 49 days. Among them, five patients experienced neurological adverse events (NAEs): aseptic meningitis (3), inflammatory polyradiculoneuropathy (1), and ophthalmoplegia (1), while one patient presented with myocarditis. Of the 15 patients retreated with ICIs after initial severe irAEs, 11 (73%) remained free of subsequent irAEs, two (13%) experienced recurrence of the initial irAE, and two (13%) developed new irAEs distinct from the initial event. The median time to event recurrence was 69 days, occurring no earlier than the initial severe irAE. In the subset analysis focusing on severe cardiovascular and neurological irAEs, rechallenge with ICIs was generally well tolerated. However, one patient treated with anti-PD1 experienced a relapse of grade 2 aseptic meningitis. Overall, our findings suggest that rechallenging with ICIs after severe irAEs, including those affecting the cardiovascular and neurological systems, may be safe, particularly after irAE regression and corticosteroid withdrawal., Competing Interests: EG: congress fees and investigator for BMS and MSD. RV: speakers’ bureau for BMS. SM-P: consultant on boards for BMS. AP-L: congress fees for BMS. CDu: Clinical investigation in trials, congress fees and member of boards for BMS, MSD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Eldani, Kostine, Faure, Lazaro, Rigothier, Hiriart, Teulières, Poullenot, Haissaguerre, Zysman, Veillon, Vergnenegre, Issa, Domblides, Mary-Prey, Beylot-Barry, Pham-Ledard, Dutriaux, Sole, Duval and Gerard.)

Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) is an immune-related adverse event that can occur as a result of receiving ICIs for cancer treatment. Thus far, ICI-IA has been described variably in the literature, in part due to varying presentations that evolve over time, as well as a lack of standardized definitions and classification. This scoping review aggregates various descriptions of ICI-IA, highlighting the most prominent attributes of ICI-IA from categories such as symptoms, signs, imaging, and laboratory findings as well as discussing potential mimic conditions., Competing Interests: Disclosure The authors have no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Monoclonal gammopathy of undetermined significance (MGUS) is common, but there are scarce data regarding the effect of DMARDs on this premalignant condition. We aimed to evaluate the impact of JAK inhibitors (JAKis) on MGUS when initiated for an active rheumatic disease., Methods: Patients with monoclonal abnormality prior to JAKi initiation for an active rheumatic disease were identified through the MAJIK-SFR Registry, a French multicentre prospective study. Clinical and biological data were collected using a standardized case report form., Results: Twenty patients were identified with a mean age of 65 years and a diagnosis of RA (n = 15), PsA (n = 3), and axial SpA (n = 2). The JAKi prescribed was baricitinib (n = 9), tofacitinib (n = 6) or upadacitinib (n = 5), with a mean duration of 15.5 months. Seventeen patients had individualized serum monoclonal protein (IgG kappa n = 9; IgG lambda n = 4; IgM kappa n = 3; IgA lambda n = 1) ranging from 0.16 to 2.3 g/dl, and three patients did not have an initial measurable spike but they had a positive serum immunofixation. With a follow-up of 4-28 months, the serum monoclonal protein level decreased in 8 of 17 patients (47%), remained stable in 8 patients (47%) and increased in 1 patient (6%). The maximal decrease observed was an initial IgG kappa of 2.3 g/dl, decreasing to 0.2 g/dl at month 14., Conclusion: This study provides reassuring and promising data on MGUS evolution in patients treated with JAKis for rheumatic diseases, which may guide the choice of treatment in patients with both conditions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious complications and their potential risk factors., Methods: Retrospective multicentre study including patients with VEXAS syndrome from the French VEXAS Registry. Episodes of serious infections were described, and their risk factors were analysed using multivariable Cox proportional hazards models., Results: Seventy-four patients with 133 serious infections were included. The most common sites of infection were lung (59%), skin (10%) and urinary tract (9%). Microbiological confirmation was obtained in 76%: 52% bacterial, 30% viral, 15% fungal and 3% mycobacterial. Among the pulmonary infections, the main pathogens were SARS-CoV- 2 (28%), Legionella pneumophila (21%) and Pneumocystis jirovecii (19%). Sixteen per cent of severe infections occurred without any immunosuppressive treatment and with a daily glucocorticoid dose ≤10 mg. In multivariate analysis, age >75 years (HR (95% CI) 1.81 (1.02 to 3.24)), p.Met41Val mutation (2.29 (1.10 to 5.10)) and arthralgia (2.14 (1.18 to 3.52)) were associated with the risk of serious infections. JAK inhibitors were most associated with serious infections (3.84 (1.89 to 7.81)) compared with biologics and azacitidine. After a median follow-up of 4.4 (2.5-7.7) years, 27 (36%) patients died, including 15 (56%) due to serious infections., Conclusion: VEXAS syndrome is associated with a high incidence of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAK inhibitors. The high frequency of atypical infections, especially in patients without treatment, may indicate an intrinsic immunodeficiency., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Tropheryma whipplei infection can manifest as inflammatory joint symptoms, which can lead to misdiagnosis of inflammatory rheumatic disease and the use of disease-modifying antirheumatic drugs. We investigated the impact of diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease., Methods: We initiated a registry including patients with disease-modifying antirheumatic drugs-treated inflammatory rheumatic disease who were subsequently diagnosed with Tropheryma whipplei infection. We collected clinical, biological, treatment data of the inflammatory rheumatic disease, of Tropheryma whipplei infection, and impact of antibiotics on the evolution of inflammatory rheumatic disease., Results: Among 73 inflammatory rheumatic disease patients, disease-modifying antirheumatic drugs initiation triggered extra-articular manifestations in 27% and resulted in stabilisation (51%), worsening (34%), or improvement (15%) of inflammatory rheumatic disease. At the diagnosis of Tropheryma whipplei infection, all patients had rheumatological symptoms (mean age 58 years, median inflammatory rheumatic disease duration 79 months), 84% had extra-rheumatological manifestations, 93% had elevated C-reactive protein, and 86% had hypoalbuminemia. Treatment of Tropheryma whipplei infection consisted mainly of doxycycline plus hydroxychloroquine, leading to remission of Tropheryma whipplei infection in 79% of cases. Antibiotic treatment of Tropheryma whipplei infection was associated with remission of inflammatory rheumatic disease in 93% of cases and enabled disease-modifying antirheumatic drugs and glucocorticoid discontinuation in most cases., Conclusions: Tropheryma whipplei infection should be considered in inflammatory rheumatic disease patients with extra-articular manifestations, elevated C-reactive protein, and/or hypoalbuminemia before disease-modifying antirheumatic drugs initiation or in inflammatory rheumatic disease patients with an inadequate response to one or more disease-modifying antirheumatic drugs. Positive results of screening and diagnostic tests for Tropheryma whipplei infection involve antibiotic treatment, which is associated with complete recovery of Tropheryma whipplei infection and rapid remission of inflammatory rheumatic disease, allowing disease-modifying antirheumatic drugs and glucocorticoid discontinuation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: While several studies reported the influence of co-medications on immune checkpoint therapy and chemotherapy, it remains poorly studied with targeted therapy. Targeted therapies inhibiting BRAF and MEK had significantly improved management of advanced melanoma with BRAFV600 mutation over the last decade, we aimed to investigate the possible influence of co-mediations on the efficacy and toxicity of these targeted therapies (TT)., Methods: We conducted an observational study identifying patients with advanced melanoma treated with BRAF/MEK inhibitors between 2013 and 2020 in the Bordeaux University Hospital. Co-medications given within 1 month before until 3 months after the initiation of targeted therapy were recorded and classified by their mechanism or by their metabolism. Survival data were analyzed with univariable and multivariable cox regression and the combined effect of multiple factors was evaluated using a factor analysis of mixed data (FAMD). The impact of co-medications on toxicity related to TT was also assessed., Results: A total of 192 patients were included. Although several co-medications were associated with significantly shorter overall survival (OS) and/or progression-free survival (PFS), PPIs was the only co-medication with a significant impact in multivariable analysis considering all co-medications and specific prognostic factors. Co-medications did not influence the risk, type, or timing of TT-related toxicity. Additional FAMD revealed the impact of each factor on the oncological outcomes. In a subgroup of patients, residual plasma TT concentration was available and did not differ between PPIs users and non-users., Conclusion: Co-medications, especially PPIs, must be carefully assessed at the time of TT initiation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SP: congress fees and consultant on boards for Novartis et Pierre Fabre Oncology. CD: congress fees and consultant for BMS, MSD. Sanofi, Pierre Fabre, sun pharma, Novartis. EG: congress fees and investigator for Novartis and Pierre Fabre Dermatology., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Another course of immune checkpoint inhibitors (ICIs) is often considered in patients with cancer progression and previous immune-related adverse events, including inflammatory arthritis (ICI-IA), but there are limited data regarding safety of ICI rechallenge in this setting. We aimed to assess the rate and clinical features associated with ICI-IA flare/recurrence on ICI rechallenge., Methods: We conducted a multicentre observational study including cancer patients with ICI-IA who started a second course of ICI more than 3 months after ICI discontinuation in four French university hospitals. Primary outcome was the frequency of ICI flare/recurrence after ICI rechallenge., Results: Twenty-three patients were included. At the time of ICI rechallenge, 18 patients reported no symptoms of ICI-IA (78%) and 5 had grade 1 (22%), 11 patients (48%) were not receiving any ICI-IA treatment, 11 (48%) were still on prednisone, 2 (9%) were on conventional synthetic disease-modifying antirheumatic drugs and 1 (4%) on anti-IL-6. ICI-IA flare/recurrence occurred in 12 patients (52%) with a median time of 1 month after ICI rechallenge. ICI-IA phenotype, disease activity and ICI-IA treatment at the time of ICI rechallenge did not differ according to ICI-IA flare/recurrence status., Conclusion: In this first observational study of ICI-IA patients rechallenged with ICI, about half of the patients experienced ICI-IA flare/recurrence with a similar phenotype but occurring earlier than the initial ICI-IA, warranting close monitoring during the first month of retreatment. Risk of flare did not differ according to baseline immunosuppressive treatment at the time of rechallenge., Competing Interests: Competing interests: AL and TB: No conflict of interest. GM: Research support: Abbvie, BMS, Gilead, Lilly, MSD, Novartis, Roche Chugai, Sanofi; consulting fees: Abbvie, UCB, BMS, Lilly, Gilead, Novartis, Janssen; education: Abbvie, BMS, Gilead, Lilly, Novartis, Roche Chugai. AT: Consulting fees: Galapagos; speaker: Brystol-Myers Squibb; support for attending congress: Sanofi, Abbvie. SB: Co conflict of interest. SP, CD: Congress fees and investigator in clinical trials: BMS and MSD. EG: Congress fees and investigator for BMS and MSD. AP-L and MB-B: No conflict of interest. MZ: Grants from AVAD and grants from FRM. RV: Consulting fees and speaker fees: Roche; registration reimbursement: Pfizer and AstraZeneka; speaker and registration reimbursement: BMS and MSD. AD: Consulting or Advisory Role: Merck, MSD, BMS, Merus; travel, accommodations, expenses: BMS, Merck. MG-G: Consulting or Advisory Role: Astra Zeneca, Merck, Pfizer, MSD, BMS, Roche; travel, accommodations, expenses: MSD, Janssen. BS: no conflict of interest. FL: Congress fees, consulting fees, and sub investigator in trials: Astra Zeneca, BMS, MSD, Roche, Pfizer. ML, CR and M-ET: No conflict of interest. TS: Clinical research: AbbVie, Abivax, Biogen, Pfizer, Lilly, MSD, Novartis, Sandoz; advisory Boards: AbbVie, BMS, Lilly, Novartis, Pfizer, Sanofi; education: AbbVie, Biogen, BMS, Galapagos, Lilly, Janssen, Novartis, Nordic Pharma, Pfizer, Viatris; help for research: Pfizer, Lilly, Abbvie, Biogen. MK: No conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Clinical and immunological features of patients with cancer-associated systemic sclerosis: an observational study., Objective: Several studies have reported an increased incidence of cancer in patients with systemic sclerosis (SSc). The presence of RNA polymerase III antibodies (anti-RNA Pol 3) associates with an increased risk of cancer, but other risk factors need yet to be identified. We aimed to assess clinical and immunological predictive factors of cancer-associated SSc to guide clinicians when setting up selective cancer screening., Methods: We conducted a monocentric, retrospective, observational study of SSc patients with and without associated malignancy. Clinical, laboratory and imaging data were collected, as well as SSc treatment. Subgroup analyses were performed according to the type of cancer and the time of diagnosis., Results: Of 464 SSc patients, 74 (16%) had cancer, with breast (n=26) and lung cancer (n=13) being the most frequent. Diagnosis of cancer was made less than 3 years before or after SSc diagnosis for 23 patients (31%). In a multivariate analysis, anti-RNA Pol 3 and anti-SSA antibodies were significantly associated with an increased overall risk of cancer with an odds ratio (OR) of 4.12 (95% CI [1.6-10.7]; P<0.01) and 2.43 (95% CI [1.1-5.4]; P<0.05), respectively. Age at diagnosis of SSc and delay from the SSc diagnosis were also independent risk factors of cancer. Interstitial lung disease and anti-topoisomerase antibodies were associated with an increased risk of lung cancer and cancer occuring more than three years after SSc diagnosis., Conclusion: In addition to anti-RNA Pol 3 antibodies, anti-SSA antibodies associated with an increased risk of cancer in SSc patients. Interstitial lung disease was a risk factor specifically for lung cancer and cancers diagnosed more than 3 years after SSc diagnosis. For these patients, a systematic and regular cancer screening should be considered., (Copyright © 2023 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Background: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement., Research Question: What are the pleuropulmonary manifestations in VEXAS syndrome?, Study Design and Methods: One hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others., Results: Fifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort., Interpretation: Pulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Immune checkpoint inhibitors (ICI), increasingly used cancer therapeutics, can cause off-target inflammatory effects called immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis (ICI-induced IA) and polymyalgia rheumatica (ICI-induced PMR). There are no validated classification criteria or outcome measures for these conditions, and adaptation of treatment recommendations from corresponding rheumatic diseases may not be appropriate. We summarized clinical descriptors of ICI-induced IA and ICI-induced PMR and aggregated domains used for these conditions in order to inform the development of a core set of outcome domains., Methods: As the initial step of the core domain set generation process, we systemically searched Medline (Pubmed), EMBASE, Cochrane, and CINHL through March 2021 to identify all studies that provide both clinical descriptions and domains relevant to ICI-induced IA and ICI-induced PMR. Domains were mapped to core areas, such as pathophysiological manifestations, life impact, resource use, and longevity/survival, as suggested by the OMERACT 2.1 Filter., Results: We identified 69 publications, over a third of which utilized non-specific diagnoses of "arthritis," "arthralgia," and/or "PMR". Other publications provided the number, the distribution and/or names of specific joints affected, while others labeled the irAE as the corresponding rheumatic disease, such as rheumatoid arthritis or spondyloarthritis. Most distinct domains mapped to the pathophysiology/manifestations core area (24 domains), such as signs/symptoms (13 domains), labs (6 domains), and imaging (5 domains), with harm domains of adverse effects from irAE treatment and fear of irAE treatment decreasing ICI efficacy. Forty-three publications also referenced irAE treatment and 35 subsequent response, as well as 32 tumor response., Conclusion: There is considerable heterogeneity in the domains used to clinically characterize ICI-induced IA and ICI-induced PMR. There were several domains mapped to the pathophysiologic manifestations core area, although several publications highlighted domains evenly distributed among the other core areas of life impact, longevity/survival and resource use., Competing Interests: Declarations of Competing Interest CB - Consulting: AbbVie, BMS, Eli Lilly, Janssen, Moderna, Pfizer, Sanofi; Grant support: BMS. EC - Research grants from Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi and UCB, consultancy from Abbvie, Amgen, Biogen, Biocon, Chugai Pharma, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, RPharm and Sanofi, speakers fee from Abbvie, Amgen, Bristol Myer Squibbs, Chugai Pharma, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, RPharm, Roche, Sanofi, and UCB. JL - grant/research support from: Novartis, Pfizer; Abbvie, BMS, Gilead, Janssen, Sanofi; honoraria for consulting or speaking: Abbvie, BMS, Galapagos Janssen-Cilag, Gilead, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, UCB. LC – Supported by AR075872 from NIAMS, Consulting: Bristol-Myers Squibb, Tremeau Pharmaceuticals, Mallinckrodt Pharmaceuticals. Research Funding: Bristol-Myers Squibb. MK - Consulting/speaker fees: Bristol-Myers Squibb, Janssen-Cilag, MSD, Novartis. KB -Consultancy and/or speaker fees and/or travel reimbursements: Abbvie, Bristol Myers Squibb (BMS), Gilead/Galapagos, Janssen, Merck Sharp & Dohme (MSD), Mundipharma, Novartis, Pfizer, Roche, Viatris, UCB. Scientific support: Medical Faculty of University of Heidelberg, Rheumaliga Baden-Württemberg e.V., AbbVie, Novartis. MH - Advisory boards: Boehringer Ingelheim, Alexion, Mallinckrodt; Research grants: Boehringer Ingelheim, Bristol Myers Squibb. CC - speaker and consulting for Sanofi/Regeneron. MSA- Pfizer, Eli Lilly, Avenue Therapeutics, Chemocentryx, Gilead, Bristol Myers Squibb, AMAG, Agile Therapeutics. SG: Grant from Novartis, Advisory board for UCB, ACR guideline subcommittee chair. MLO - National Cancer Institute and Rheumatology Research Foundation. All other co-authors have no declarations., (Copyright © 2022. Published by Elsevier Inc.)

Competing Interests: Disclosure JH reports personal fees for advisory board membership from Neogene Therapeutics and Scenic Bio; stocks and shares in Neogene Therapeutics; institutional fees for advisory board membership from Achilles Therapeutics, BioNTech, Bristol Myers Squibb (BMS), Gadeta, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, Merck Serono, Merck Sharpe & Dohme (MSD), Molecular Partners, Novartis, Pfizer, PokeAcel, Roche, Sanofi, T-Knife and Third Rock Venture; institutional funding from Amgen, Asher Bio, BioNTech, BMS, MSD, and Novartis; non-remunerated membership of American Association for Cancer Research (AACR), American Society of Clinical Oncology (ASCO) and Society for Immunotherapy of Cancer (SITC); a non-remunerated role as editor-in-chief of IOTECH and a non-remunerated role for editorial board membership for ESMO Open and Kidney Cancer. LS reports personal fees for advisory board membership from BMS and Ipsen; personal fees as an invited speaker from BMS; stocks and shares from Impedimed and institutional funding as local principal investigator (PI) from AstraZeneca, Pfizer and Roche. FC reports personal fees as an invited speaker from Abbvie, biocodex, Biogen, Ferring, Janssen, MSD, Nestlé, Pileje, Takeda and Tillotts; personal fees for advisory board membership from Amgen, Arena, BMS, Celltrion, Enterome, Ferring, Janssen, MaaT Pharma, Medtronic, Pfizer, Pharmacosmos, Roche and Tillotts and institutional funding from Alpha Wassermann, Mayoly Spindler and Nestlé. YW reports personal fees for advisory board membership from MabQuest and consulting fees from AzurRx Pharma and Sorriso. CR reports consultancy fees for advisory board membership from AstraZeneca, BMS, MSD, Novartis, Pfizer, Pierre Fabre, Roche and Sanofi. ARL reports personal fees for advisory board membership from Akcea Therapeutics, BMS, GSK, Heartfelt Technologies Ltd, iOWNA Health, Myocardial Solutions and Pfizer; personal fees as an invited speaker from AstraZeneca, Ferring Pharmaceuticals, Janssen-Cilag Ltd, Novartis, Servier and Takeda and personal fees for a writing engagement from Eisai Ltd. WW reports institutional funding from Apogenix, Pfizer and Roche; institutional funding as coordinating PI role from Enterome; institutional fees as coordinating PI role from Vaximm; a non-remunerated leadership role from Deutscher Wissenschaftsrat, European Association of Neuro-Oncology (EANO), European Organisation for Research and Treatment of Cancer (EORTC) (terminated in 2021) and NOA (terminated in 2021); non-remunerated membership of Leopoldina/Deutsche Gesellschaft der Wissenschaften. MK reports personal fees for advisory board membership from Biogen and Novartis; personal fees as an invited speaker from BMS and MSD; a non-remunerated role as a project lead for the European Alliance of Associations for Rheumatology (EULAR) and a non-remunerated leadership role and co-chair of the OMERACT irAE working group for OMERACT. SP reports personal fees for an editorial role as an Associate Editor for Annals of Oncology; fees paid to her institution as an invited speaker from AstraZeneca, BMS, Boehringer Ingelheim, ecancer, Eli Lilly, Fishawack, Illumina, Imedex, Medscape, Mirati, MSD, Novartis, OncologyEducation, Physician's Education Resource (PER), Pfizer, Partnerships in International Medical Education (PRIME), RMEI Medical Education, LLC (RMEI), Roche/Genentech, Research To Practice (RTP), Sanofi and Takeda; fees paid to her institution for advisory board membership from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Bio Invent, Biocartis, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, IQVIA, iTeos, Janssen, Merck Serono, Mirati, MSD, Novartis, Novocure, Pfizer, PharmaMar, Phosplatin Therapeutics, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda and Vaccibody; institutional funding as a steering committee member from AstraZeneca, BeiGene, BMS, iTeos, Mirati, MSD, PharmaMar, Phosplatin Therapeutics and Roche/Genentech; institutional funding as a coordinating PI from AstraZeneca; institutional funding as a trial chair from GSK and Roche/Genentech; non-remunerated role as President and Council Member for the Ballet Béjart Lausanne Foundation; non-remunerated leadership roles as President of ESMO (2020-2022), Vice-President of Swiss Academy of Multidisciplinary Oncology (SAMO), Vice-President of Lung Group for Swiss Group for Clinical Cancer Research (SAKK); non-remunerated role as PI involved in academic trials for European Thoracic Oncology Platform (ETOP)/EORTC/SAKK; non-remunerated role as Council Member and Scientific Committee Chair for ETOP/International Breast Cancer Study Group (IBCSG) Partners member of AACR, ASCO, Association Suisse des médecines-assistant(e)s et chef(fe)s de Clinique (ASMAC)/Verband Schweizerischer Assistenz- und Oberärztinnen und- ärzte (VSAO), Fédération des médecins suisses (FMH) and International Association for the Study of Lung Cancer (IASLC). KJ reports personal fees as an invited speaker from Amgen, art tempi, Helsinn, Hexal, med update GmbH, MSD, Mundipharma, onkowissen, Riemser, Roche, Shire (Takeda) and Vifor; personal fees for advisory board membership from Amgen, AstraZeneca, BD Solutions, Hexal, Karyopharm and Voluntis; royalties from Elsevier and Wolters Kluwer; institutional funding as a coordinating PI from Helsinn; non-remunerated membership to ASCO, Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie (DGHO) and Multinational Association of Supportive Care in Cancer (MASCC); a non-remunerated leadership role at Arbeitsgemeinschaft Supportive Massnahmen in der Onkologie (AGSMO), Arbeitsgemeinschaft Internistische Onkologie in der Deutschen Krebsgesellschaft e.V. (AIO) and ESMO and a non-remunerated advisory role at Deutsche Krebshilfe, the Federal Ministry of Education and Research, the Hamburg Cancer Society and Leopoldina. JL reports personal fees as an invited speaker for Agence Unik, Aptitude, AstraZeneca, BMS, Calithera, ecancer, Eisai, EUSA Pharma, Goldman Sachs, GSK, Inselgruppe, Ipsen, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, SeaGen, and Ultimovacs; personal consultancy fees from Apple Tree, BMS, Debipharm, Eisai, Incyte, iOnctura and Merck; honoraria from Cambridge Healthcare Research, RGCP, Royal College of Physicians, touchEXPERTS, touchIME and VJOncology and institutional funding from Achilles, Aveo, BMS, Covance, Immunocore, MSD, Nektar, Novartis, Pfizer, Pharmacyclics and Roche. MO has declared no conflicts of interest.

Immune-checkpoint inhibitors (ICIs) have dramatically changed the management of advanced cancers. Designed to enhance the antitumour immune response, they can also cause off-target immune-related adverse events (irAEs), which are sometimes severe. Although the efficacy of ICIs suggests that they could have wide-ranging benefits, clinical trials of the drugs have so far excluded patients with pre-existing autoimmune disease. However, evidence is accumulating with regard to the use of ICIs in this 'at-risk' population, with retrospective data suggesting that they have an acceptable safety profile, but that there is a risk of disease flare or other irAE occurrence. The management of immunosuppressive drugs at ICI initiation in patients with autoimmune disease (or later in instances of disease flare or irAE) remains a question of particular interest in clinical practice, in which there is always a search for the balance between protecting against autoimmunity and ensuring a good tumour response. Although temporary use of immunosuppressants seems safe, prolonged use or use at ICI initiation might hamper the antitumour immune response, prompting clinicians to use the minimal efficient immunosuppressive regimen. However, a new paradigm is emerging, in which inhibitors of TNF or IL-6 could have synergistic effects with ICIs on tumour response, while also preventing severe irAEs. If confirmed, this 'decoupling' effect on toxicity and efficacy could change therapeutic practice in this field. Knowledge of the current use of ICIs in patients with pre-existing autoimmune disease, particularly with regard to the use of immunosuppressive drugs and/or biologic DMARDs, can help to guide clinical practice., (© 2022. Springer Nature Limited.)

Background: To investigate the evolution of bone metastases in patients receiving immune checkpoint inhibitors (ICI)., Methods: A single-center retrospective study included cancer patients with bone metastases treated with ICI at our institution between January 2014 and September 2019. Clinical and biological data were collected from medical records and independent expert review of imaging was performed. Target and non-target lesions were identified and followed up to 1 year. Patients were then classified as bone responder or non-responder. Comparisons between groups were performed with Student's t test or Mann-Whitney test., Results: Among 1108 patients screened, 192 patients had bone metastases and 48 patients were included in the final analysis, with lung cancer, renal carcinoma and melanoma as most represented cancer type. Half of the patients experienced stability, condensation or peripheral sclerosis of bone lesions. Initial progression before stabilization with or without sclerosis of bone lesion occurred for 19% of patients (pseudoprogression). There was an association between bone response and global oncological outcomes. Bone responder patients had a significant decrease in morphine and co-analgesic prescription as well as a significant decrease in alkaline phosphatases compared to non-responder patients., Conclusion: Bone response was observed in half of patients with available imaging and follow-up after 3 months of ICI treatment, with sclerosis observed in one-third of bone lesions at month 3, in all tumor types. Up to 20% of patients experienced a pseudoprogression of bone lesions such as previously described in primary tumor and other metastatic sites. Bone response was associated with improvement of pain and survival., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: There is limited experience regarding the use of biological disease-modifying antirheumatic drug (bDMARD) and JAK inhibitor (JAKi) for the management of immune checkpoint inhibitors (ICI)-induced inflammatory arthritis. We aimed to assess their efficacy and safety in this setting., Methods: Using the Club Rhumatismes and Inflammation French network, we conducted a multicentre, retrospective, observational study of patients with cancer diagnosed with inflammatory arthritis under ICI(s) and treated with bDMARD or JAKi. Clinical data were collected using a standardised case report form., Results: Twenty patients (60% men, median age 69.5 years) were included, with rheumatoid arthritis (RA)-like (n=16), polymyalgia rheumatica-like (n=2) or psoriatic arthritis-like (n=2) clinical presentation. Two patients had pre-existing RA. 90% were treated with glucocorticoids as first-line therapy and 60% received methotrexate prior to bDMARD or JAKi. Anti-interleukin-6 receptor (IL-6R) therapy was used in 13/20 patients (65%), leading to clinical improvement in 11/13 patients (85%), but one patient experienced intestinal perforation and cancer progression was noticed in 6/13 patients (46%). Tumour necrosis factor inhibitors were used in 5/20 patients (25%), with improvement in 4/5 patients (80%) and cancer progression was observed in 3/5 patients (60%). Two infections (diverticulitis and pneumonitis) were reported. Anakinra, baricitinib and ustekinumab were each used in one patient. Median duration of the bDMARD or JAKi was 17 weeks., Conclusion: Anti-IL-6R therapy is currently the most common strategy in patients with ICI-induced inflammatory arthritis and insufficient response to glucocorticoids and methotrexate, leading to improvement in &gt;80%. Overall, cancer progression occurred in about half of patients and whether the bDMARD/JAKi impacted the tumour response remains to be determined., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We aimed to analyze rheumatic immune-related (ir) and nonimmune-related adverse events (AEs) due to immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 or its ligand PD-(L)1 in lung cancer patients from the available literature., Methods: We performed a systematic review and meta-analysis of phase III randomized clinical trials (RCTs) assessing PD-(L)1-ICIs in lung cancer patients, from inception until January 12th, 2021. We extracted data of each trial to estimate odds ratio (OR) for rheumatic ir or non-irAE as classified in RCTs safety data. Sensitivity analyses (by ICI, treatment group and histology) were performed., Results: Eighteen RCTs met the inclusion criteria (n=12172 subjects). The OR [95%IC] for rheumatic irAE in ICIs versus controls (either placebo or chemotherapy) was 2.20 [0.85,5.72]. Among rheumatic non-irAEs, both overall and severe (grade≥3) back pain were significantly more frequent in ICIs versus controls, 2.01 [1.09;3.73] and 2.90 [1.18;7.08], respectively. The overall frequency of arthralgia was similar between ICIs and controls; by sensitivity analysis RCTs assessing ICIs in combination with chemotherapy showed a significant association with arthralgia (1.55 [1.15;2.10]). Similarly, the frequency of myalgia was significantly lower in RCTs assessing ICIs alone versus chemotherapy (OR 0.32 [0.24;0.42]). Muscular pain was not significantly increased with ICI., Conclusion: Rheumatic irAEs are not increased in RCTs assessing PD-(L)1 inhibitors, not reflecting the real-life incidence, therefore likely underreported or misclassified. Back pain is significantly associated with them regardless its severity, while arthralgia only when ICIs are added on conventional chemotherapy., (Copyright © 2022 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) is a relatively new disease entity caused by ICI agents during cancer therapy. Reactive arthritis (ReA) is a well-known disease entity caused by urogenital or gastrointestinal bacterial infection or pneumonia. In this sense, ICI-IA and ReA are both defined by a reaction to a well-specified causal event. As a result, comparing these diseases may help to determine therapeutic strategies., Methods: We compared ICI-IA and ReA with special focus on pharmacological management. Specifically regarding treatment, we conducted a literature search of studies published in the PubMed database. Inclusion criteria were studies on treatment with non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GC), or disease modifying antirheumatic drugs (DMARDs) in ICI-IA or ReA. During systematic selection, 21 studies evaluating ICI-IA and 14 studies evaluating ReA were included., Results: In ICI-IA, prospective and retrospective studies have shown effects of non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoid (GC), sulfasalazine (SSZ), methotrexate (MTX), hydroxychloroquine (HCQ) and TNFi. In ReA, retrospective studies evaluated NSAIDs and GC. A randomized controlled trial reported the effect of SSZ, and a retrospective study reported the effect of MTX and SSZ in combination with tumor necrosis factor alpha inhibition (TNFi). For both entities, small case reports show treatment effects of interleukin 6 receptor inhibition (IL-6Ri)., Discussion: This literature review identified both similarities and differences regarding the pathogenesis and clinical features of ReA and ICI-IA. Studies on treatment reported effectiveness of NSAIDs, GC, MTX, SSZ and TNFi in both diseases. Further, small case reports showed effects of IL-6Ri., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome')., Objectives: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome., Methods: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded., Results: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis., Conclusions: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation., (© 2021 British Association of Dermatologists.)

Objective: To compare the effect of the biological reference agents (infliximab, etanercept, adalimumab) in RA in pivotal superiority placebo-controlled trials (reference agent vs placebo) vs their effect in equivalence active comparator-controlled trials (reference agent vs biosimilar)., Methods: The PubMed, EMBASE and Cochrane databases were searched for randomized, double-blind, controlled trials up to March 2020 comparing a biological reference agent vs placebo or biosimilar. The study assessed the ACR 20/50/70 responses of the reference agent in these groups (Reference-pbo and Reference-bs, respectively). The effect of the reference agent in both groups was estimated with 95% CI, pooled using random-effects models and then compared using a meta-regression model., Results: We included 31 trials. The main characteristics of the population (disease duration and activity, % seropositivity and methotrexate dose) of the population in both groups were similar. The meta-analysis found a better ACR20 response to the biological originator in the Reference-bs group with a global rate of 70% (95% CI, 66, 74) compared with 59% (95% CI, 55, 62) in the reference-pbo group (P =0.001). A significant difference was also found for ACR 50 [44% (95% CI, 39, 50) vs 35% (95% CI, 31, 39), respectively, P <0.01]., Conclusion: The effect of the reference biologic agent was better when compared with an active drug to a placebo. This could be linked to an increased placebo effect in active comparator-controlled studies or a nocebo effect in placebo-controlled studies. This effect can be called the lessebo effect., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Cancer patients with pre-existing autoimmune disease, such as systemic sclerosis (SSc), are excluded from clinical trials, so the data on tolerability and efficacy of immune checkpoint inhibitors in these patients are limited. This study investigated the tolerability and efficacy of anti-programmed death ligand 1 (PD (L)1) immunotherapies in patients with pre-existing SSc., Methods: Scleronco-01 was a multicentre, nationwide, open-label, phase IV observational study, from 2019 to 2021., Results: Seventeen SSc patients receiving treatment for lung carcinoma (n = 13, 77%), head and neck cancer (n = 2, 12%), melanoma (n = 1, 6%), and colorectal carcinoma (n = 1, 6%) were included. The median (interquartile range) patient age was 60 (34-82) years. Fifteen (88%) patients received anti-PD1 (nivolumab and pembrolizumab) and two (12%) anti-PD-L1 (durvalumab). The median follow-up duration was 12 (range, 2-38) months. Four patients (24%) experienced flare-up of SSc symptoms. Ten patients (59%) developed an immune-related adverse event (grade I-II in 11 patients [65%], grade III-IV in one [6%]) without grade V. The overall response rate was 41% (7/17 patients). The median overall survival was 15.8 (95% confidence interval: 7.3 to not reached) months., Conclusion: Anti-PD1 or PD-L1 immunotherapies are suitable options for cancer patients with pre-existing SSc. Longer follow-up periods are required for long-term safety analyses., Competing Interests: Conflict of interest statement None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: As gut microbiota composition is an important determinant of response to immune checkpoint inhibitors (ICIs), we examined the effect of various co-medications known for their interaction with microbiota, when given at ICI initiation., Patients and Methods: We identified patients with advanced cancer treated with ICI between May 2015 and September 2017 in our institution. Co-medications given within 1 month before or 1 month after the first administration of ICI were reviewed from medical records. Survival data were analysed with univariable Cox regression, and the combined effect of multiple factors was assessed with factor analysis of mixed data (FAMD). The impact of co-medications on immune-related adverse events (irAEs) occurrence was also assessed., Results: A total of 635 patients were included. Psychotropic drugs (41%), proton pump inhibitors (PPIs; 38%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs; 32%), glucocorticoids (26%), antibiotics (24%), statins (21%) and morphine (20%) were the most prescribed co-medications. Baseline use of antibiotics, glucocorticoids >10 mg/day, PPIs, psychotropic drugs, morphine and insulin was associated with significantly shortened overall survival and decreased tumour response, whereas coadministration of statins, ACEs and/or ARBs, non-steroidal anti-inflammatory drugs, aspirin and oral antidiabetic drugs did not impact patient outcomes. Treatments that altered the response to ICI were also associated with a decreased incidence of irAEs. FAMD revealed the respective weight of each factor or co-medication on the oncological outcomes., Conclusion: Co-medications must be carefully assessed at the time of ICI initiation and clinicians aware of their possible deleterious effect, notably for PPIs, glucocorticoids, antibiotics and psychotropic drugs., Competing Interests: Conflict of interest statement M.B.B. reports consulting and advisory boards for BMS and MSD France. A.R. reports being a member of Global, European and/or French Advisory Board in genitourinary tumours and/or immunotherapy for Pfizer, Novartis, BMS, Roche, Astra Zeneca and MSD and received travel support from Pfizer, BMS, Roche, Astra Zeneca and MSD. S.P. reports consulting for BMS and travel support from MSD. R.V. reports being one of the investigators for a clinical trial from BMS, consulting and advisory boards for BMS and MSD and travel support from BMS and MSD. All the others authors declared no conflict of interest for this work., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Clinical factors associated with vitiligo in patients receiving anti-programmed cell death-1 (PD-1) remain unknown., Objective: To better characterize the occurrence of vitiligo in patients receiving anti-PD-1., Methods: The present single-center ambispective cohort study included patients with melanoma treated with anti-PD-1. Progression-free survival, overall survival, and objective tumor response were compared between patients with and those without vitiligo using Kaplan-Meier curves and the log-rank test. Demographic and clinical factors associated with vitiligo were evaluated using multivariate logistic regression., Results: Of the 457 patients included in the study, vitiligo developed in 85 patients. The clinical presentation of vitiligo consisted of the presence of ovalar and multiple flecked white macules, mainly located on chronic sun-exposed areas. The presence of vitiligo was associated with a significant improvement in overall survival and progression-free survival ( P  < .001). A Cox proportional hazards model estimation demonstrated markedly improved survival in patients with vitiligo compared with those without vitiligo (aHR [overall survival], 0.20; 95% CI, 0.12-0.33;  P  < .001; and aHR [progression-free survival], 0.33; 95% CI, 0.23-0.47;  P  < .001). In the multivariate logistic regression analyses, men showed an independent increased risk of the development of vitiligo (odds ratio, 1.66). In contrast, the presence of pulmonary metastases was found to be an independent factor associated with a reduced risk of the development of vitiligo (odds ratio, 0.50)., Limitations: Single-center ambispective cohort., Conclusion: Vitiligo in patients receiving anti-PD-1 for advanced melanoma is associated with a better outcome. A gender effect associated with the development of vitiligo will need further investigation., Competing Interests: Dr Dousset received fees from MSD, BMS, Novartis, AbbVie, and Pierre Fabre, outside the submitted work. Dr Kostine received fees from AbbVie, BMS, Lilly, Novartis, and Pfizer, outside the submitted work. Dr Beylot-Barry received fees from MSD, outside the submitted work. Drs Pacaud, Barnetche, Dutriaux, Pham-Ledard, Gérard, Prey, Boniface, and Seneschal and Author Andreu have no conflicts of interest to declare., (© 2021 Published by Elsevier Inc on behalf of the American Academy of Dermatology, Inc.)

Introduction: There has been an increased demand for mismatch repair (MMR) status testing in sarcoma patients after the success of immune checkpoint inhibition (ICI) in MMR deficient tumors. However, data on MMR deficiency in bone and soft tissue tumors is sparse, rendering it unclear if routine screening should be applied. Hence, we aimed to study the frequency of MMR deficiency in bone and soft tissue tumors after we were prompted by two (potential) Lynch syndrome patients developing sarcomas., Methods: Immunohistochemical expression of MLH1, PMS2, MSH2 and MSH6 was assessed on tissue micro arrays (TMAs), and included 353 bone and 539 soft tissue tumors. Molecular data was either retrieved from reports or microsatellite instability (MSI) analysis was performed. In MLH1 negative cases, additional MLH1 promoter hypermethylation analysis followed. Furthermore, a systematic literature review on MMR deficiency in bone and soft tissue tumors was conducted., Results: Eight MMR deficient tumors were identified (1%), which included four leiomyosarcoma, two rhabdomyosarcoma, one malignant peripheral nerve sheath tumor and one radiation-associated sarcoma. Three patients were suspected for Lynch syndrome. Literature review revealed 30 MMR deficient sarcomas, of which 33% were undifferentiated/unclassifiable sarcomas. 57% of the patients were genetically predisposed., Conclusion: MMR deficiency is rare in bone and soft tissue tumors. Screening focusing on tumors with myogenic differentiation, undifferentiated/unclassifiable sarcomas and in patients with a genetic predisposition / co-occurrence of other malignancies can be helpful in identifying patients potentially eligible for ICI., (© 2021 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management., Methods: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed., Results: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies., Conclusion: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations., Competing Interests: Competing interests: MK: honoraria from Abbvie, BMS, Lilly, Novartis, Pfizer; TRDJR: grants from AbbVie, Takeda, UCB, Janssen, GSK and honoraria from Abbvie, Pfizer, Takeda, Lilly, Medimmune, Novartis, GSK, BMS, AstraZeneca, Janssen; XM: honoraria from BMS; COB: grants and honoraria from BMS and honoraria from Genetech/Roche, Sanofi/Regeneron; OL: grant from Gilead and honoraria from BMS, MSD, AstraZeneca, Janssen; JLe: grants from Novartis, Pfizer and honoraria from Abbvie, AstraZeneca, BMS, Celgene, Hospira, Janssen-Cilag, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB; AM: grants from BMS, Merus and honoraria from Merck Serono, Lytix, BMS, Symphogen, Amgen, AZ/Medimmune, Servier, Gritstone, Pierre Fabre, EISAI, Sanofi; TS: honoraria from Pfizer, Lilly, Novartis, BMS, Abbvie, Sanofi; EHC: grants from Biogen, grants and honoraria from Amgen, Bio-Cancer, Roche, UCB, Pfizer, honoraria from Chugai Pharma, Abbvie, BMS, Celgene, Eli Lilly, Janssen, ObsEva, Regeneron, Sanofi, SynAct Pharma, Tonix, Gilead; LT: honoraria from Novartis; KB: grants from Abbvie, Novartis, Rheumaliga Baden-Württemberg and honoraria from MSD, Abbvie, BMS, Janssen, Lilly, Mundipharma, Novartis, Pfizer, Roche, UCB; KV: speaker fees from BMS; JLa: grants from Aveo and Pharmacyclics, grants and honoraria from Achilles Therapeutics, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Roche/Genetech and Immunocore, honoraria from AstraZeneca, Boston Biomedical, BMS, Eisai, EUSA Pharma, GSK, Ipsen, Imugen, Incyte, iOnctura, Kymab, Merck Serono, Secarna, Vitaccess and Covance; JBAGH: grants from BMS, Novartis and advisory boards and/or lectures for MSD, BMS, Roche, Novartis; J-EG: grants from BMS, UCB, Pfizer, Sanofi and honoraria from BMS, Lilly, Pfizer, Sanofi-Genzyme, UCB., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Multidisciplinary collaboration is defined as a collective work involving multiple disciplines and is common in clinical care and research. Our aim was to describe current clinical and research collaboration among young specialists and to identify unmet needs in this area., Methods: An online survey was disseminated by email and social media to members of the EMerging EUlar NETwork, the Young Nephrologists' Platform, the Paediatric Rheumatology European Society Emerging Rheumatologists and Researchers and the European Academy of Allergy and Clinical Immunology Junior Members., Results: Of 303 respondents from 36 countries, 61% were female, 21% were aged below 30 years and 67% were aged 31-40 years. Young rheumatologists were the most represented (39%), followed by young nephrologists (24%), young paediatricians (20%), young allergologists (11%) then young internists (3%) and 3% other specialities. Collaborations were reported frequently by phone and email, also by various combined clinics while common local multidisciplinary meetings were uncommon. 96% would like to develop clinical research collaborations and 69% basic research collaborations. The majority of young specialists would be interested in online (84%) and/or 1-2 days (85%) common courses including case discussion (81%) and training workshops (85%), as well as webinars recorded with several specialists on a specific disease (96%)., Conclusions: This collaborative initiative highlighted wishes from young specialists for developing (1) regular local multidisciplinary meetings to discuss complex patients, (2) clinical research collaboration with combined grants and (3) multidisciplinary online projects such as common courses, webinars and apps., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy., Methods: We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively., Findings: Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1., Interpretation: Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

Objective: Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer., Methods: A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response., Results: The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation., Conclusion: Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes., (© 2019, American College of Rheumatology.)

Compared with conventional cancer therapies, the spectrum of toxicities observed with checkpoint inhibitors is unique and can affect any organ system. Arthralgia and myalgia were by far the most commonly reported rheumatic immune-related adverse events in clinical trials, and there is now a growing number of case series and reports describing clinical features of de novo rheumatic immune-related adverse events, which will be the focus of this review. Some patients develop genuine classic rheumatic and musculoskeletal diseases, but a number of rheumatic immune-related adverse events mimic rheumatic and musculoskeletal diseases with atypical features, mainly polymyalgia rheumatica, rheumatoid arthritis and myositis, as well as several systemic conditions, including sicca syndrome, vasculitis, sarcoidosis, systemic sclerosis and lupus., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Mobile health applications (apps) are available to enable people with rheumatic and musculoskeletal diseases (RMDs) to better self-manage their health. However, guidance on the development and evaluation of such apps is lacking., Objectives: The objective of this EULAR task force was to establish points to consider (PtC) for the development, evaluation and implementation of apps for self-management of RMDs., Methods: A systematic literature review of app content and development strategies was conducted, followed by patient focus group and an online survey. Based on this information and along with task force expert opinion, PtC were formulated in a face-to-face meeting by a multidisciplinary task force panel of experts, including two patient research partners. The level of agreement among the panel in regard to each PtC was established by anonymous online voting., Results: Three overarching principles and 10 PtC were formulated. Three PtC are related to patient safety, considered as a critical issue by the panel. Three are related to relevance of the content and functionalities. The requirement for transparency around app development and funding sources, along with involvement of relevant health professionals, were also raised. Ease of app access across ages and abilities was highlighted, in addition to considering the cost benefit of apps from the outset. The level of agreement was from 8.8 to 9.9 out of 10., Conclusion: These EULAR PtC provide guidance on important aspects that should be considered for the development, evaluation and implementation of existing and new apps., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To analyse the worldwide occurrence of sicca/Sjögren's (SS) syndrome associated with the use of immune checkpoint inhibitors (ICI) in patients with cancer., Methods: The ImmunoCancer International Registry (ICIR) is a Big Data-Sharing multidisciplinary network composed by 40 specialists in Rheumatology, Internal Medicine, Immunology and Oncology from 18 countries focused on the clinical and basic research of the immune-related adverse events (irAEs) related to cancer immunotherapies. For this study, patients who were investigated for a clinical suspicion of SS after being exposed to ICI were included., Results: We identified 26 patients (11 women and 15 men, with a mean age at diagnosis of 63.57 years). Underlying cancer included lung (n=12), renal (n=7), melanoma (n=4), and other (n=3) neoplasia. Cancer immunotherapies consisted of monotherapy (77%) and combined regimens (23%). In those patients receiving monotherapy, all patients were treated with PD-1/PD-L1 inhibitors (nivolumab in 9, pembrolizumab in 7 and durvalumab in 4); no cases associated with CTLA-4 inhibitors were identified. The main SS-related features consisted of dry mouth in 25 (96%) patients, dry eye in 17 (65%), abnormal ocular tests in 10/16 (62%) and abnormal oral diagnostic tests in 12/14 (86%) patients. Minor salivary gland biopsy was carried out in 15 patients: histopathological findings consisted of mild chronic sialadenitis in 8 (53%) patients and focal lymphocytic sialadenitis in the remaining 7 (47%); a focus score was measured in 5 of the 6 patients (mean of 1.8, range 1-4). Immunological markers included positive ANA in 13/25 (52%), anti-Ro/ SS-A in 5/25 (20%), RF in 2/22 (9%), anti-La/SS-B in 2/25 (8%), low C3/C4 levels in 1/17 (6%) and positive cryoglobulins in 1/10 (10%). Classification criteria for SS were fulfilled by 10 (62%) out of 16 patients in whom the two key classificatory features were carried out. Among the 26 patients, there were only 3 (11%) who presented exclusively with sicca syndrome without organ-specific autoimmune manifestations. Therapeutic management included measures directed to treat sicca symptoms and therapies against autoimmune-mediated manifestations (glucocorticoids in 42%, second/third-line therapies in 31%); therapeutic response for systemic features was observed in 8/11 (73%). No patient died due to autoimmune involvement., Conclusions: Patients with Sjögren's syndrome triggered by ICI display a very specific profile different from that reported in idiopathic primary SS, including more frequent occurrence in men, a higher mean age, a predominant immunonegative serological profile, and a notable development of organ-specific autoimmune involvement in spite of the poor immunological profile. The close association found between sicca/Sjögren's syndrome and primarily PD-1 blockade requires further specific investigation.

Objective: To assess whether the polymyalgia rheumatica (PMR)-like syndrome reported as an immune related adverse event (irAE) from checkpoint inhibitor therapy is consistent with the 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) provisional criteria for PMR., Methods: The cases were derived from two sources. Group 1 represents reported cases from three contributing centres. Group 2 was derived from a systematic review of the literature searching for all cases reported as PMR or PMR-like illness associated with checkpoint inhibitor therapy. Cases were assessed for the quality of reporting and then analysed to determine whether they fulfilled the 2012 EULAR/ACR provisional criteria for PMR., Results: A total of 49 patients were included for analysis. Among the entire group, 37 (75%) were designated 'complete' indicating that they had sufficient data to reliably apply the 2012 EULAR/ACR criteria. 28 (75%) cases fulfilled complete criteria for PMR. A number of cases also demonstrated some clinical features unusual for idiopathic PMR., Conclusion: This study suggests a high proportion of reported cases of checkpoint inhibitor-related PMR fulfil preliminary criteria for PMR, yet in one quarter clinical details were incomplete making verification problematic. Furthermore, in the absence of a gold standard for the diagnosis of PMR, the relationship of checkpoint inhibitor-related PMR to the idiopathic form remains unclear., Competing Interests: Competing interests: CC speaks for Regeneron/Sanofi. LCC received a research grant from Bristol-Myers Squibb and consults for Regeneron/Sanofi. MK consults for Bristol-Myers-Squibb. TB is a fellow supported by T32 grant. EK consults for Celgene, Horizon, Novartis, Regeneron and speaks for Merck and Sanofi. LC consults for Bristol-Myers-Squibb, Genentech and Astra-Zeneca.

Based on morphology it is often challenging to distinguish between the many different soft tissue sarcoma subtypes. Moreover, outcome of disease is highly variable even between patients with the same disease. Machine learning on transcriptome sequencing data could be a valuable new tool to understand differences between and within entities. Here we used machine learning analysis to identify novel diagnostic and prognostic markers and therapeutic targets for soft tissue sarcomas. Gene expression data was used from the Cancer Genome Atlas, the Genotype-Tissue Expression project and the French Sarcoma Group. We identified three groups of tumors that overlap in their molecular profiles as seen with unsupervised t-Distributed Stochastic Neighbor Embedding clustering and a deep neural network. The three groups corresponded to subtypes that are morphologically overlapping. Using a random forest algorithm, we identified novel diagnostic markers for soft tissue sarcoma that distinguished between synovial sarcoma and MPNST, and that we validated using qRT-PCR in an independent series. Next, we identified prognostic genes that are strong predictors of disease outcome when used in a k-nearest neighbor algorithm. The prognostic genes were further validated in expression data from the French Sarcoma Group. One of these, HMMR, was validated in an independent series of leiomyosarcomas using immunohistochemistry on tissue micro array as a prognostic gene for disease-free interval. Furthermore, reconstruction of regulatory networks combined with data from the Connectivity Map showed, amongst others, that HDAC inhibitors could be a potential effective therapy for multiple soft tissue sarcoma subtypes. A viability assay with two HDAC inhibitors confirmed that both leiomyosarcoma and synovial sarcoma are sensitive to HDAC inhibition. In this study we identified novel diagnostic markers, prognostic markers and therapeutic leads from multiple soft tissue sarcoma gene expression datasets. Thus, machine learning algorithms are powerful new tools to improve our understanding of rare tumor entities., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response., Methods: This was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management., Results: From September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti-CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non-steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; P<0.0001)., Conclusion: Since ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs., Competing Interests: Competing interests: MB-B reports consulting and advisory boards for BMS and MSD France. AR reports being a member of Global, European and/or French Advisory Board in GU tumours and/or immunotherapy for Pfizer, Novartis, BMS, Roche, Astra Zeneca and MSD and received travel support from Pfizer, BMS, Roche, Astra Zeneca and MSD. SP reports consulting for BMS and travel support from MSD. AP-L has received honoraria and travel support from BMS and MSD. RV reports being one of the investigators for a clinical trial from BMS, consulting and advisory boards for BMS and MSD and travel support from BMS and MSD. All the others authors declared no conflict of interest for this work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Sarcomas are a rare group of tumors of mesenchymal origin. Metastatic sarcomas are often difficult to treat and unresponsive to standard radio- and chemotherapy, resulting in a poor survival rate for patients. Novel treatments with immune checkpoint inhibitors have been proven to prolong survival of patients with a variety of cancers, including metastatic melanoma, lung, and renal cell carcinoma. Since immune checkpoint inhibitors could provide a novel treatment option for patients with sarcomas, clinical trials investigating their efficacy in these group of tumors are ongoing. However, the discrimination of patients that are the most likely to respond to these treatments is still an obstacle in the design of clinical trials. In this review, we provide a brief overview of the mechanisms of action of immune checkpoint inhibitors and discuss the proposed biomarkers of therapy response, such as lymphocytic infiltration, intratumoral PD-L1 expression, and mutational load in sarcomas.

Background: Immunotherapy may be a rational strategy in leiomyosarcoma (LMS), a tumor known for its genomic complexity. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in LMS, as well as its prognostic value. Methods: CD163 + macrophages, CD3 + T-cells, PD-L1/PD-L2 and HLA class I expression (HCA2, HC10 and β2m) were evaluated using immunohistochemistry in primary tumors (n = 75), local relapses (n = 6) and metastases (n = 19) of 87 LMS patients, as well as in benign leiomyomas (n = 7). Correlation with clinicopathological parameters and survival analyses were assessed. Effect of LMS cells on macrophage differentiation was investigated using coculture of CD14 + monocytes with LMS cell lines or their conditioned media (CM). Results: 58% and 52% of the tumors were highly infiltrated with CD163 + macrophages and T-cells, respectively, with HLA class I expression observed in almost all tumors and PD-L1 expression in 30%. PD-L2 expression was also detected in some PD-L1 + tumors. All these immune markers correlated with high tumor grade but only CD163 associated with overall survival ( p = 0.003) and disease-specific survival ( p = 0.041). In vitro , CD163 was upregulated in the presence of LMS cells producing M-CSF, suggesting that this tumor drives macrophages towards the M2 phenotype. Conclusion: The clinical significance of M2 macrophages, possibly induced by LMS cell-secreted factors, suggests that 2/3 of high-grade LMS patients might benefit from macrophage-targeting agents. Furthermore, PD-L1 expression together with high T-cell infiltrate and HLA class I expression in around 30% of high grade LMS reflects an active immune microenvironment potentially responsive to immune checkpoint inhibitors.

Introduction: although the outcome for patients with rheumatoid arthritis (ra) has improved in the past decades, adequate disease control cannot be achieved in a substantial proportion of patients. new drugs with a novel mechanism of action, may represent a valuable addition to the current armamentarium. Areas covered: This review focuses on the pharmacodynamics and pharmacokinetics of baricitinib. Furthermore, the article summarizes and comments the drug's efficacy and safety profile in RA patients. Expert opinion: Baricitinib is an oral targeted synthetic (ts) disease-modifying antirheumatic drug (DMARD) that mainly inhibits JAK1 and JAK2. Baricitinib monotherapy, or in combination with conventional synthetic (cs) DMARDs, has demonstrated its efficacy while having an acceptable safety profile in early active RA naive to DMARDs, and active RA with an inadequate response to csDMARDs and/or biologic (b)DMARDs. The future place of baricitinib in the management of RA patients will depend on several factors. However, baricitinib offer few advantages: oral administration, rapidity of action, efficacy in monotherapy and over adalimumab in one study and non-immunization. However, pending further safety data, current practice would be to start a bDMARD when the treatment target is not achieved with csDMARDs. Availability of additional long-term safety data may influence prescribing decisions.

Although there is an unmet need for pain medications that are both effective and safe, virtually no novel analgesics have been approved over the past two decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, the clinical development of humanised anti-nerve growth factor monoclonal antibodies (anti-NGF mAbs) aroused particular interest. However, the US Food and Drug Administration (FDA) placed a clinical hold on anti-NGF mAb clinical studies in late 2010, first because of reports of serious joint-related adverse events, and afterwards because of sympathetic nervous system safety concerns. The development programmes of tanezumab and fasinumab resumed after the FDA lifted its hold in March 2015, whereas other anti-NGF mAbs were dropped by their sponsors. This article provides an updated review on the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies and public information from websites, and discusses the possible future role of these agents in managing chronic pain. The efficacy of anti-NGF mAbs was highly variable depending on the chronic pain condition studied. The most consistent and convincing results were obtained in patients with symptomatic osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain and peripheral neuropathic pain generated mixed results. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in cancer pain and urological chronic pelvic pain syndromes. Treatment-emergent adverse events were similar across anti-NGF mAbs, thus being suggestive of 'class-specific effects'. Although most patients tolerated anti-NGF agents well, neurosensory symptoms occurred frequently, and some patients developed new or worsened peripheral neuropathies. However, the most problematic safety issue was rapidly destructive arthropathies, leading to joint replacement surgery. To date, the aetiologies of joint-related side effects and their pathophysiology have not been clearly elucidated. However, some risk factors have been identified, such as higher doses of anti-NGF mAbs and longer drug exposure, concurrent nonsteroidal anti-inflammatory drug use and pre-existing subchondral insufficiency fractures. Taken together, the present data suggest that low-dose anti-NGF mABs may exhibit a favourable risk-benefit ratio in selected patients with certain chronic pain conditions, especially symptomatic osteoarthritis.