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Objectives: To study the characteristics of B-cell non-Hodgkin's lymphoma (NHL) or Hodgkin lymphoma complicating rheumatoid arthritis (RA) and to identify RA-related factors associated with their occurrence., Methods: A multicentre case-control study was performed in France. Cases were patients with RA fulfilling ACR-EULAR 2010 criteria in whom B-cell NHL or Hodgkin lymphoma developed after the diagnosis of RA. For each case, 2 controls were assigned at random from the ESPOIR cohort and were matched on age at lymphoma diagnosis (cases)/age at the 10-year follow-up visit in the cohort (controls). Case and control characteristics were compared to identify parameters associated with the occurrence of lymphoma., Results: 54 cases were included and matched to 108 controls. Lymphomas were mostly diffuse large B-cell lymphoma (DLBCL, n=27, 50.0%). On immunochemistry, 4 of 27 (14.8%) lymphoma cases were positive for Epstein-Barr virus. On univariate analysis, factors associated with the occurrence of lymphoma were male sex (OR 3.3, 95% CI 1.7 to 6.7), positivity for ACPA (OR 5.1, 95% CI 2.0 to 15.7) and rheumatoid factor (OR 3.9, 95% CI 1.6 to 12.2), and erosions on radiographs (OR 3.8, 95% CI 1.7 to 8.3) and DAS28 (OR 2.0, 95% CI 1.5 to 2.7), both at the time of matching. Methotrexate, TNF blockers and a number of previous biologics were not associated with the occurrence of lymphoma. On multivariable analysis, erosions and DAS28 remained significantly associated with increased risk of lymphoma., Conclusion: Lymphomas complicating RA are mostly DLBCL. Risk of lymphoma in patients with RA was increased with markers of disease activity and severity, which supports the paradigm of a continuum between autoimmunity and lymphomagenesis in RA., Competing Interests: Competing interests: PD: participation to clinical trials and punctual interventions for BMS and Roche. CM: reports outside the submitted work personal fees from AbbVie, Amgen, Eli Lilly, Novartis, Pfizer, Sanofi. PG: honoraria from AbbVie, Amgen, Biogaran, Biogen, BMS, Celgene, Chugai, Janssen, Lilly, MEDAC, MSD, Nordic Pharma, Novartis, Pfizer, Sanofi, UCB. BF: research grants from AbbVie, Lilly, MSD and Pfizer, and honoraria from AbbVie, Amgen, Biogen, BMS, Celgene, Janssen, Lilly, Medac, MSD, Mylan, NORDIC Pharma, Novartis, Pfizer, Roche, SanofiAventis, SOBI, UCB. PP: participation in clinical trials and punctual honoraria from MSD Pfizer ABBvie Sanofi Novartis Sandoz. BC: honoraria from AbbVie, BMS, Gilead, Galapagos, Janssen, Lilly, Merck, Novartis, Pfizer, RocheChugai and research grants from Novartis, Pfizer, and Roche. GN: received honorarium from Novartis, Lilly and UCB. RS: received honorarium from Pfizer, BMS and UCB. XM: received honorarium from BMS, Gilead, Pfizer, 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.)

Objective: To evaluate the relevance of salivary gland ultrasound (SGUS) and its place in the diagnostic algorithm in patients referred with dry syndrome (DS) for a suspicion of Sjögren's syndrome (SS)., Methods: We included all patients assessed at our dedicated DS clinic from June 2015 to September 2019 for which a SGUS has been carried out. Images were read blindly and the worst salivary gland was scored according to OMERACT classification. Clinical features, disease activity and treatments were collected., Results: 337 patients were seen from June 2015 to September 2019. 269 patients underwent SGUS. 77 patients were diagnosed with SS and 192 did not meet the ACR/EULAR criteria for SS: non-Sjögren's DS (NSDS). Of these 192 patients, 60 had another possible cause of DS, and 132 patients were diagnosed with SAPS (sicca, asthenia, polyalgia syndrome).SGUS abnormalities were significantly higher in patients with SS versus NSDS: 51% vs 8% for a score ≥2 (p<0.0001), and 43% vs 3% for a score ≥3 (p<0.0001). SGUS score ≥2 had a specificity (Sp) of 91%, sensitivity (Se) of 57%, positive predictive value (PPV) of 72% and negative predictive value (NPV) of 82% for SS diagnosis. SGUS's characteristics in SSA-negative patients were similar to the whole population (Se=42%, Sp=91%, PPV=42%, NPV=92%). The high specificity and NPV in this population could avoid labial salivary gland biopsy (LSGB) in SSA-negative patients with normal SGUS (186 patients, 69%)., Conclusion: SGUS is useful for SS diagnosis. If anti-SSA antibodies are negative and SGUS score <2, the diagnosis of SS is very improbable and LSGB could be avoided., Competing Interests: Competing interests: None declared., (© 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.)

Objectives: The frequency and consequences of anti-drug antibodies to rituximab (RTX-ADA) are not well known in RA and even less in other systemic auto-immune diseases (sAID). We aimed to evaluate the frequency, consequences and predictive factors of RTX-ADA in RA and sAID., Methods: All patients presenting with RA or other sAID treated with RTX from 2012 to 2017 in our tertiary reference centre for sAID were retrospectively studied. Patients who were tested for RTX-ADA were identified., Results: One hundred and ninety-nine patients were treated with RTX (RA: 124, other sAID: 75). Among 62/199 (31.1%) tested for RTX-ADA, 14 were positive: 3/35 RA (8.6%) and 11/27 (40.7%) other sAID, (P = 0.0047). Among the whole RTX-treated populations, the frequency of RTX-ADA was 2.4% and 14.7% (P = 0.0026) in RA and sAID, respectively. Most of the immunized patients had infusion reactions to second or subsequent RTX cycles (11/14) and loss of efficacy (2/14). Predictive factors of immunization were sAID vs RA (78.6% vs 21.4%, P = 0.026, adjusted odds ratio (OR) = 5.35[1.43-54.75]) and African ethnicity (57.1% vs 4.2%, P < 0.001, adjusted OR = 9.25 [5.08-302.12]). Associated immunosuppressive therapy did not protect against immunization. Three patients with pSS immunized against RTX were treated with ofatumumab with complete remission of their disease., Conclusion: Immunization against RTX is more frequent in other sAID than in RA. Testing for RTX-ADA must be performed in patients with infusion reactions or loss of efficacy especially if they are of African origin. Immunized patients might be treated efficiently and safely with ofatumumab. This alternative should be further evaluated for sAID., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: We investigated the activities of an ImmunoTOX board, an academic, multidisciplinary group of oncologists and organ specialists that adopts a real-life, case-by-case approach in the management of patients with immune-related adverse events (irAEs)., Experimental Design: The ImmunoTOX assessment board was set up in 2016 at Gustave Roussy in France. It meets every 2 weeks to discuss the case-by-case management of patients presenting with irAEs. Here, we describe the ImmunoTOX board's activities between 2016 and 2019., Results: Over study period, 398 requests (concerning 356 patients) were submitted to the ImmunoTOX board. Most of the requests concerned the putative causal link between immunotherapy and the irAE (n = 148, 37%), followed by possible retreatment after temporary withdrawal because of an adverse event (n = 109, 27%), the clinical management of complex situations (n = 100, 25%) and the initiation of immunotherapy in patients with pre-existing comorbidities (n = 41, 10%). The ImmunoTOX board discerned 273 irAEs. The five organ systems most frequently involved by irAEs were lung (n = 58, 21%), gastrointestinal tract (n = 36, 13%), liver or biliary tract (n = 33, 12%), musculoskeletal system (n = 27, 10%), and nervous system (n = 23, 8%). The time to occurrence was shorter for severe irAEs (grade III and VI) than for mild irAEs (grades I and II), with medians of 47 and 91 days, respectively (p = 0.0216)., Conclusion: The main medical needs in the management of irAEs involved the lung organ. Severe irAEs were expected to occur earlier than mild irAEs. This real-life study can help to better estimate medical needs and therefore help to assess the management of irAEs., Competing Interests: Conflict of interest statement Pr Olivier Lambotte: Has received expert testimony and consultancy fees from BMS France, MSD, and Astra Zeneca, consultancy fees from Genzyme, and expert testimony fees from Janssen. Dr Jean-Marie Michot: Principal/sub-Investigator of Clinical Trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor. PERSONAL FEES (Monies paid to you for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.): Roche, Celgene, Bristol-Myers Squibb, AstraZeneca, Janssen. Dr Aurélien Marabelle: Principal/sub-Investigator of Clinical Trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor. PERSONAL FEES (Monies paid to you for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.): Medimmune, Pfizer, Servier, AstraZeneca, Janssen Bristol-Myers Squibb. Pr Christophe Massard: Principal/sub-Investigator of Clinical Trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor. PERSONAL FEES (Monies paid to you for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.): Medimmune, Pfizer, AstraZeneca, Janssen, Bristol-Myers Squibb. Pr Jean-Charles Soria: From September 2017 to the end of 2019, Pr Soria was Senior Vice-President Research & Development Oncology at AstraZeneca in Gaithersburg, Maryland, United States. Pr Benjamin Besse: Sponsored research at Gustave Roussy Cancer CenterAbbvie, Amgen, AstraZeneca, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Eli Lilly, GSK, Ignyta, IPSEN, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE Immunopharmaceutics, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. Dr Stéphane Champiat: Principal/sub-Investigator of Clinical Trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor. PERSONAL FEES (Monies paid to you for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.): Amgen. All other authors: no conflicts of interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Understanding the neural mechanisms that support spontaneous recovery of cognitive abilities can place important constraints on mechanistic theories of brain organization and function, and holds potential to inform clinical interventions. Connectivity-based MRI measures have emerged as a way to study how recovery from brain injury is modulated by changes in intra- and inter-hemispheric connectivity. Here we report a detailed and multi-modal case study of a 26 year-old male who presented with a left inferior parietal glioma infiltrating the left arcuate fasciculus. The patient underwent pre- and post-operative functional MRI and Diffusion Tensor Imaging, as well as behavioral assessments of language, motor, vision and praxis. The surgery for removal of the tumor was carried out with the patient awake, and direct electrical stimulation mapping was used to evaluate cortical language centers. The patient developed a specific difficulty with repeating sentences toward the end of the surgery, after resection of the tumor and partial transection of the arcuate fasciculus. The patient recovered from the sentence repetition impairments over several months after the operation. Coincident with the patient's cognitive recovery, we document a pattern whereby intra-hemispheric functional connectivity was reduced in the left hemisphere, while inter-hemispheric connectivity increased between classic left hemisphere language regions and their right hemisphere homologues. These findings suggest that increased synchrony between the two hemispheres, in the setting of focal transection of the left arcuate fasciculus, can facilitate functional recovery., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Competing interests: RS received consulting fees from Roche (<10.000€). Other authors declared any competing interest in link with the present study.

The Translational Brain Mapping Program at the University of Rochester is an interdisciplinary effort that integrates cognitive science, neurophysiology, neuroanesthesia, and neurosurgery. Patients who have tumors or epileptogenic tissue in eloquent brain areas are studied preoperatively with functional and structural MRI, and intraoperatively with direct electrical stimulation mapping. Post-operative neural and cognitive outcome measures fuel basic science studies about the factors that mediate good versus poor outcome after surgery, and how brain mapping can be further optimized to ensure the best outcome for future patients. In this article, we describe the interdisciplinary workflow that allows our team to meet the synergistic goals of optimizing patient outcome and advancing scientific understanding of the human brain.

Objective: The usefulness of positron emission tomography-computed tomography (PET-CT) with 18 F-labeled fluorodeoxyglucose ( 18 F-FDG) for the diagnosis of lymphoma in patients with primary Sjögren's syndrome (SS) is unclear, since the abnormalities it reveals may be due to systemic manifestations of SS. This study was undertaken to compare 18 F-FDG-PET-CT in patients with primary SS with lymphoma and those without lymphoma in order to identify patterns associated with lymphoma., Methods: A retrospective study was conducted in 2 centers and included patients who met the American College of Rheumatology/European League Against Rheumatism 2016 criteria for primary SS and had undergone PET-CT. Two independent readers who were blinded with regard to lymphoma diagnosis analyzed PET-CT scans. Abnormalities were compared between patients with and those without lymphoma., Results: Of the 45 patients included, 15 had lymphoma. Compared to patients without lymphoma, the mean size (P = 0.048) and maximum standardized uptake value (SUVmax) (P = 0.001) of the parotid glands were higher in patients with lymphoma. FDG uptake in the lymph nodes was observed in 53.3% of the patients with lymphoma and 43.3% of the patients without lymphoma, with no difference in the number of sites, uptake pattern, or mean SUVmax. Focal pulmonary uptake (nodules or condensations) was observed in 5 of the patients with lymphoma (33.3%) but only 1 patient without lymphoma (3.3%) (P = 0.01). Having an SUVmax in the parotid gland of ≥4.7 and/or the presence of focal pulmonary lesions was highly suggestive of lymphoma (sensitivity 80%, specificity 83.3%)., Conclusion: Some systemic manifestations of primary SS (lymphadenopathy, pulmonary involvement, and salivary gland involvement) can be visualized by PET-CT. Involvement of the lymph nodes and parotid glands is commonly observed with a similar frequency in SS patients with and those without lymphoma. An SUVmax in the parotid glands of ≥4.7 and/or the presence of focal lung lesions are associated with the diagnosis of lymphoma., (© 2019, American College of Rheumatology.)

Objective: To investigate maintenance of rituximab (RTX) in RA patients re-treated with reduced doses compared with standard dose in a real life setting., Methods: The Autoimmunity and Rituximab (AIR) registry is a nationwide prospective observational cohort investigating the long-term safety and efficacy of RTX in RA. The present study included patients from the AIR registry that have been re-treated with RTX after a first course of RTX standard dose (1000 mg × 2). Two groups were defined according to dose of RTX of the first retreatment course (i.e. second course): standard dose group and reduced dose group. Five years' maintenance and rate of serious infections of the retreatment period were compared between standard dose and reduced dose groups. Analyses used the inverse probability of treatment weighting propensity score adjusted method., Results: Among the 1986 patients from the AIR registry, 1278 were included, 1093 (85.5%) treated with standard dose and 185 (14.5%) with reduced doses. Maintenance of RTX at 5 years in the standard and reduced groups was 55.5 and 53.8%, respectively, and did not significantly differ between groups in adjusted analyses (hazard ratio = 1.03; 95% CI: 0.81, 1.30), but the cumulative RTX dose received for retreatment [1.4 (0.6) vs 2.3 (1.0) g/year, P < 0.001] and the rate of serious infections were significantly lower in the reduced dose group (adjusted hazard ratio = 0.50; 95% CI: 0.27, 0.92; P = 0.02)., Conclusion: Use of reduced doses of RTX for retreatment did not alter the maintenance of RTX at 5 years in RA patients, but allowed a 39% total dose reduction and a lower rate of serious infections., (© The Author 2017. 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: Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have demonstrated improved survival for multiple cancers. However, these new drug classes have led to increased immune-related adverse events (IrAE). Rheumatic IrAEs have not been well described in clinical trials. We report here cases of rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI treatment., Methods: This was a retrospective study of patients receiving an ICI in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of RA or PMR., Results: In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression., Conclusions: This is the first description of RA occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients., Competing Interests: Competing interests: AM reports being one of the principal investigator for clinical trials from Roche/Genentech, BMS, Merck (MSD), Pfizer, Lytix pharma, Eisai, Astra Zeneca/Medimmune, Bayer, Celgene. AH reports advisory boards for Amgen and Lilly. OL reports consulting for MSD, BMS and Genzyme and received travel support from LFB and CSL Behring. 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) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Prior research using functional magnetic resonance imaging (fMRI) [1-4] and behavioral studies of patients with acquired or congenital amusia [5-8] suggest that the right posterior superior temporal gyrus (STG) in the human brain is specialized for aspects of music processing (for review, see [9-12]). Intracranial electrical brain stimulation in awake neurosurgery patients is a powerful means to determine the computations supported by specific brain regions and networks [13-21] because it provides reversible causal evidence with high spatial resolution (for review, see [22, 23]). Prior intracranial stimulation or cortical cooling studies have investigated musical abilities related to reading music scores [13, 14] and singing familiar songs [24, 25]. However, individuals with amusia (congenitally, or from a brain injury) have difficulty humming melodies but can be spared for singing familiar songs with familiar lyrics [26]. Here we report a detailed study of a musician with a low-grade tumor in the right temporal lobe. Functional MRI was used pre-operatively to localize music processing to the right STG, and the patient subsequently underwent awake intraoperative mapping using direct electrical stimulation during a melody repetition task. Stimulation of the right STG induced "music arrest" and errors in pitch but did not affect language processing. These findings provide causal evidence for the functional segregation of music and language processing in the human brain and confirm a specific role of the right STG in melody processing. VIDEO ABSTRACT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: The growing use of immune checkpoint inhibitors (ICIs) is associated with the occurrence of immune-related adverse events (irAEs). Few data are published on systemic, immunohaematological and rheumatic irAEs. In a pharmacovigilance database analysis, we screened for these irAEs and calculated their prevalence., Patients and Methods: Participants were recruited via Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) 1  a French registry of grade ≥2 irAEs occurring in ICI-treated patients. The pathologies of interest were systemic autoimmune and inflammatory diseases, rheumatic diseases and immune cytopenia., Results: Out of 908 patients treated with anti-Programmed cell Death 1 (PD1)/anti-Programmed cell Death-Ligand 1 (PD-L1) agents (together with an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent in 40 cases) between December 2012 and December 2016 at a single centre, 21 patients experienced systemic irAEs. The types and the prevalence of irAEs were as follows: immune thrombocytopenia (0.2%), Sjögren syndrome (0.3%), rheumatoid arthritis (0.2%), polymyalgia rheumatica (0.2%), psoriatic arthritis (0.2%), seronegative polyarthritis (0.7%) and sarcoidosis (0.2%). Patients with Sjögren syndrome or seronegative polyarthritis were more likely to have received combination therapy with ipilimumab (2.5% for both). We described these 21 cases, together with nine additional cases from five other centres. Most irAE were moderately severe (grade 2, 63%). The median time to onset was 57°days (interquartile range (IQR) 24-117). The ICI was withdrawn in 12 cases, 25 patients (83%) received corticosteroids, and five patients (17%) received immunosuppressant/immunomodulatory agents. The irAEs resolved fully or partially in 28 cases (93%)., Conclusion: Although systemic, immunohaematological and rheumatic diseases are rarely associated with ICI use, the prevalence is higher when two ICIs are combined. Corticosteroids are often effective and may enable the continued administration of ICIs. Studies designed to identify at-risk patients are warranted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We present a rare case of a large infarcted submucous fibroid removed manually after a normal vaginal delivery. This patient was known to have a large postero-fundal hybrid predominantly intramural uterine fibroid, measuring 11 x 10 cm in diameter and diagnosed 2 years prior to last conception. Thirty-five days postpartum, she presented with severe lower abdominal pain and foul smell per vaginum. Abdominal examination revealed a very tender bulky uterus at 24 weeks size, and vaginal examination revealed a big fleshy smelly mass with friable surface just bulging from a dilated cervix. Examination under anaesthesia revealed a very foul smelly large pedunculated submucous fibroid that was felt through a dilated cervix. It was deliverable vaginally, so the submucous leiomyoma was removed manually, a procedure similar to manual removal of placenta. Histopathology examination confirmed an infarcted massive fibroid., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Spondyloarthritis (SpA) and Takayasu arteritis (TA) are 2 chronic inflammatory diseases; their coexistence in a single patient is uncommon. The aims of our study were to describe clinical features of patients having SpA associated with TA and to identify some characteristics of the types of patients with SpA associated with TA. We also analyzed treatments used in this context., Methods: This French multicenter retrospective survey called for observations on behalf of the Club Rhumatismes et Inflammations, with a standardized questionnaire established by the investigators., Results: We included 14 patients (women: 10/14; median age at SpA diagnosis: 43.5 yrs, ranging from 19 to 63). Subtypes of SpA were ankylosing spondylitis (n = 11), psoriatic arthritis (n = 2), and synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (n = 1). HLA-B27 was positive in 3 cases, negative in 9, and unknown in 2. SpA was diagnosed before TA in 13 cases. Imaging findings compatible with the diagnosis of TA were found with computed tomography (11/14) and/or Doppler ultrasound (10/14). Laboratory tests showed increased acute-phase reactants in all cases (C-reactive protein ≥ 25 mg/l in 71% of the cases). All patients except 1 received corticosteroids and 7 were treated with anti-tumor necrosis factor (anti-TNF)., Conclusion: Association of SpA and TA is rare but probably not coincidental. Peripheral pulse palpation and vascular auscultation should be systematic and are the first indicators of TA in patients with SpA. Moreover, increased acute-phase reactants during SpA followup should lead to search for TA. Finally, there are therapeutic implications because anti-TNF are efficient in SpA and might be efficient in TA.

Objective The objective of this study was to assess the safety and efficacy of abatacept in patients with SLE refractory to conventional treatment in routine clinical practice. Methods This retrospective study included 11 SLE patients treated with abatacept for an active and refractory disease. The primary endpoint was the change in SLE Disease Activity Index (SLEDAI) score at six months. Response was defined as a decrease of SLEDAI ≥4 in a patient continuing abatacept. Results Indications of abatacept treatment were articular ( n=8), renal ( n=1) and cutaneous ( n=1) involvement and autoimmune thrombocytopenia ( n=1). Abatacept was discontinued before six months in two patients, because of adverse event ( n=1) and/or lupus flare ( n=2). The median SLEDAI decreased from 6 (2-20) to 4 (0-20) ( p=0.031). Decrease of SLEDAI ≥4 was observed in 6/11 patients (55%) and response to treatment according to the physician's judgement in 8/11 (73%) patients. Improvement of articular involvement was observed in 7/8 (87.5%) patients. Four adverse events were observed in three patients, but no severe infection occurred. Conclusion This study suggests some efficacy of abatacept in patients with refractory disease in routine clinical practice, particularly in the case of articular manifestations, with an acceptable safety profile. These data support conducting new controlled trials of abatacept in SLE patients.

Background: Beyond genetics, epigenetics alterations and especially those related to DNA methylation, play key roles in the pathogenesis of autoimmune diseases such as primary Sjögren's syndrome (pSS) and systemic lupus erythematosus. This study aimed to assess the role of methylation deregulation in pSS pathogeny through a genome-wide methylation approach., Patients and Methods: 26 female patients with pSS and 22 age-matched controls were included in this study. CD4+ T cells and CD19+ B cells were isolated from peripheral blood mononuclear cells by magnetic microbeads and their genome-wide DNA methylation profiles were analysed using Infinium Human Methylation 450 K BeadChips. Probes with a median DNA methylation difference of at least 7% and p<0.01 between patients and controls were considered significantly differentially methylated., Results: Methylation alterations were mainly present in B cells compared with T cells. In B cells, an enrichment of genes with differentially methylated probes in genetic at-risk loci was observed, suggesting involvement of both genetic and epigenetic abnormalities in the same genes. Methylation alterations in B cells were more frequent in some specific pathways including Interferon Regulated Genes, mainly among patients who were autoantibody positive. Moreover, genes with differentially methylated probes were over-represented in B cells from patients with active disease., Conclusions: This study demonstrated more important deregulation of DNA methylation patterns in B cells compared with T cells, emphasising the importance of B cells in the pathogenesis of the disease. Overlap between genes with differentially methylated probes in B lymphocytes and genetic at-risk loci is a new finding highlighting their importance in pSS., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To assess the link between monoclonal gammopathy (MG), disease activity, and incidence of malignant hematologic disorders (MHDs), including lymphoma and multiple myeloma (MM), in patients with primary Sjögren's syndrome (SS)., Methods: Screening for the presence of MG was performed in 352 primary SS patients. Each patient with MG was paired with 2 age- and sex-matched primary SS controls without MG. Their characteristics were compared for the presence of risk factors for MG and for the relationship between MG and MHD., Results: Twenty-six of the 352 primary SS patients (7.4%) had MG; 88% were women, with a median age of 62.7 years (interquartile range [IQR] 50.3-69.1 years) and a median disease duration of 7.8 years (IQR 3.6-12.8 years). The parameters associated with MG on multivariate analysis were higher disease activity, as measured by either the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI; adjusted odds ratio [OR] 9.7, P = 0.0002) or the Clinical ESSDAI (adjusted OR 6.7, P = 0.001), and low C4 level (adjusted OR 3.4, P = 0.04). After a median follow-up of 6.3 years (IQR 3.1-9.5 years), 10 patients with MG had developed an MHD (38.5%; 4 had lymphomas and 6 had MM), as compared with 4 patients in the control group (7.7%; all had lymphomas) (OR 7.5, P = 0.002). The only factor associated with the risk of MHDs was the presence of MG (adjusted OR 5.5, P = 0.02), which was principally associated with an increased risk of MM (23% versus 0%; P = 0.0009), but not lymphoma (15% versus 8%; P = 0.3)., Conclusion: The presence of MG was associated with higher disease activity and an increased risk of MHD in primary SS. In the presence of MG, the risk of MM was even higher than the risk of lymphoma. These results suggest that regular monitoring of primary SS patients with MG for the emergence of both lymphoma and MM is necessary., (© 2016, American College of Rheumatology.)

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Non-Hodgkin's lymphoma (NHL) is a severe complication of primary Sjögren's syndrome (SS). Ectopic germinal centers (GCs) in the salivary glands are predictors of the occurrence of NHL. Given the association between CCL11 and CXCL13 and ectopic GCs, we assessed the link between these chemokines and NHL, as well as the association between these chemokines and disease activity, in patients with primary SS., Methods: Serum levels of CCL11 and CXCL13 were evaluated by multiplex assay in 385 patients included in the Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. The association between chemokine levels, B cell biomarkers, and patient subsets was assessed using Spearman's test for continuous data and the nonparametric Mann-Whitney U test for categorical data. Multivariate analyses were performed to identify parameters associated with lymphoma and disease activity., Results: Seventeen patients had a history of lymphoma, and 5 of them had developed NHL during followup. The median serum levels of CCL11 and CXCL13 in the total cohort were 106.48 pg/ml (interquartile range 69.33-149.85) and 108.31 pg/ml (interquartile range 58.88-200.13), respectively. Patients with lymphoma had higher levels of CXCL13 than did patients without lymphoma (P = 0.006) and a trend toward a higher level of CCL11 (P = 0.056). Low C4 and high BAFF levels were associated with NHL on multivariate analysis (P = 0.01 and P = 0.0002, respectively). CCL11 and CXCL13 levels correlated positively with the rheumatoid factor titer, the κ-to-λ free light chain ratio, and the β2 -microglubulin level. CXCL13 was the only parameter associated with disease activity on multivariate analysis., Conclusion: These findings demonstrate a link between CXCL13 and CCL11 and disease activity and lymphoma. This highlights the continuum between chronic B cell activation, disease activity, and lymphomagenesis in patients with primary SS., (© 2015, American College of Rheumatology.)

Introduction: In this study, we sought to address changes in blood lymphocyte subpopulations and labial salivary gland (LSG) inflammation after belimumab treatment in patients with primary Sjögren's syndrome (pSS) and to identify predictors of response to treatment., Methods: Sequential blood lymphocyte subsets and LSG biopsies were analysed between week 0 (W0) and W28 in 15 patients with pSS treated with belimumab. Systemic response to treatment was defined as a decrease in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index score of ≥3 points at W28., Results: After belimumab, we observed a decrease in blood B lymphocytes primarily involving CD27-negative/immunoglobulin D-positive naïve B cells (p=0.008). Lymphocytic sialadenitis (focus score >1) that was present in 12 patients (80.0 %) before belimumab treatment became negative in 5 of them after treatment (p=0.03). The median (interquartile range) LSG B-cell/T-cell ratio decreased from 0.58 (0.5-0.67) to 0.50 (0.5-0.5) (p=0.06). B-cell activating factor (BAFF) staining was detected in 11 (78.6 %) of 14 patients before belimumab treatment compared with 7 (50.0 %) of 14 after belimumab therapy (p=0.10). The median percentage of BAFF-positive cells in foci significantly decreased from 27.5 % (10-40) to 5 % (0-20) (p=0.03). A systemic response was achieved in six patients (40 %). The only predictor of response was the presence of a low number of natural killer (NK) cells, both in blood (8.5 % [7-10] vs 11 % [9-21]; p=0.04) and in LSG (20.6/mm(3) [20.0-21.4] vs 30.0/mm(3) [25.0-100.0], p=0.003). Serum BAFF levels did not influence response to treatment., Conclusions: Low blood and salivary NK cell numbers are associated with a better response to belimumab. This suggests that two distinct subsets of pSS may exist: one with a predominant type I interferon (IFN)-BAFF-B-cell axis, representing good responders to belimumab; and one with a predominant type II IFN-NK cell axis, representing non-responders., Trial Registration: ClinicalTrials.gov identifier: NCT01160666 . Registered 9 July 2010.

Objectives: Anticyclic citrullinated protein antibodies (ACPA) are highly specific of rheumatoid arthritis (RA). However, they have also been detected in 5-10% of primary Sjögren's syndrome (pSS). We compared ACPA-positive and negative patients with pSS and assessed the risk of evolution to RA., Patients and Methods: ACPA-positive and negative patients with pSS were included in this study. For ACPA-positive patients, clinical and radiological re-evaluation was systematically performed after at least 5 years of follow-up. Diagnosis was reassessed at the end of the follow-up to identify patients that developed RA according to the American College of Rheumatology 1987 classification criteria., Results: At inclusion in the cohort 16 patients with pSS were ACPA positive and 278 were ACPA negative. ACPA-positive patients, had more frequently arthritis (43.7% vs 12.2%; p=0.003) but not arthralgias. They also had more frequent lung involvement (25% vs 8.1%; p=0.05). After median follow-up of 8 (5-10) years, 7/16 (43.8%) patients developed RA including 5 (31.25%) with typical RA erosions. Elevation of acute phase reactants at inclusion was the only parameter associated with progression to erosive RA., Conclusions: Median term follow-up of ACPA-positive patients with pSS showed that almost half of them developed RA, particularly in the presence of elevation of acute phase reactants. These results support the usefulness of a close radiological monitoring of these patients for early detection of erosive change not to delay initiation of effective treatment. Indeed, number of these patients with ACPA-positive pSS may actually have RA and associated SS.

Epigenetic deregulation of genes encoded on the X chromosome as reported for CD40L in lupus could explain the female predominance of autoimmune diseases. We compared CD40L expression on CD4(+) T cells from primary Sjögren's syndrome (pSS) women and healthy controls and investigated DNA methylation patterns of the promoter and enhancer regions of CD40L. The expression of CD40L on activated CD4(+) T cells was higher in patients with pSS than controls after phorbolmyristate acetate and ionomycin activation (P = 0.02). CD40L mRNA level in CD4(+) T cells did not differ between patients with pSS and controls and was similar in both groups in cultures treated with the demethylating agent 5-azacytidine C. Pyrosequencing analysis revealed no significant differences in methylation profiles between patients and controls. Inducible membrane-bound CD40L on CD4(+) T cells is increased in patients with pSS but was not related to epigenetic deregulation by demethylation patterns of the regulatory regions of CD40L., (© 2013 John Wiley & Sons Ltd.)

The transcription factor interferon regulatory factor 5 (IRF5), in the type I interferon pathway is involved in the genetic susceptibility to various autoimmune diseases. A 5-bp insertion/deletion (CGGGG indel) polymorphism in the promoter region of IRF5 associated with primary Sjögren's syndrome (pSS) could be epigenetically deregulated in this condition. Therefore, we investigated DNA methylation patterns of the promoter region of IRF5 to determine whether its epigenetic deregulation could explain the increased expression of IRF5 mRNA in pSS patients, along with the risk of pSS induced by the genetic polymorphism. DNA extracted from total peripheral blood mononuclear cells, isolated CD4(+) T cells, B lymphocytes and monocytes from 19 pSS patients and 24 healthy controls underwent methylation analysis by pyrosequencing. Salivary gland epithelial cells (SGECs) were cultured from minor salivary glands. Regions of interest in the CGGGG repeat and ATG initiation codon region were amplified by PCR and analysed by pyrosequencing. The effect of the demethylating agent 5-AzaC on IRF5 mRNA expression in controls was quantified by RT-PCR. Among the healthy controls, the mean methylation of the nine CpG pairs of the CGGGG repeat region and the 18 CpG pairs of the ATG region was < 15% in CD4(+) T cells, B lymphocytes, monocytes and SGECs. Patients and controls did not differ in methylation profiles as regards CD4(+) T cells and B lymphocytes. IRF5 mRNA expression did not differ with or without 5-AzaC in controls. The absence of aberrant DNA methylation profiles for the putative regulatory regions of IRF5 in CD4(+) T cells, B lymphocytes, and monocytes from patients with pSS, does not support the hypothesis that epigenetic deregulation in combination with the genetic polymorphism explains the increase in IRF5 mRNA levels in pSS patients.

We present the results of a preliminary study (the first of this kind in Algeria) in which 4 families presenting with congenital deficiency of the C1-esterase inhibitor (C1-INH) responsible for hereditary angioneurotic oedema were biologically explored. The complement fractions C1-INH, C4 and C3d were assayed in 38 subjects of the 4 families. Extending this biological evaluation to all members of theses families enabled us to identify all asymptomatic subjects (46 percent in our series). In 2 patients the congenital disease was associated with systemic lupus erythematosus. Some clinico-biological discordances are reported and discussed in the light of data from the literature.