Publications by authors named "Patrice Cacoub"

392 Publications

Apremilast in Refractory Behçet's Syndrome: A Multicenter Observational Study.

Front Immunol 2020 4;11:626792. Epub 2021 Feb 4.

Sorbonne Universités AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, Paris, France.

Objective: Mucocutaneous and joint disorders are the most common manifestations in Behçet's syndrome (BS) and are frequently clustered in the so-called minor forms of BS. There remains a need for safe and effective treatment for joint lesions in BS. We report the long-term safety and effectiveness of apremilast in refractory joint and mucocutaneous manifestations of BS.

Methods: French nationwide multicenter study including 50 BS patients with either active joint and/or mucocutaneous manifestations resistant to colchicine and/or DMARDs. Patients received apremilast 30 mg twice a day. Primary effectiveness endpoint was the proportion of patients with complete response (CR) of articular symptoms at month 6 (M6), defined as resolution of inflammatory arthralgia and arthritis, with joint count equal to zero.

Results: At inclusion, the median tender and swollen joint count was of 4 [2-6] and 2 [1-2], respectively. The proportion of CR in joint disease at M6 was 65% (n = 15/23), and 17% (n = 4/23) were partial responders. CR of oral and genital ulcers, and pseudofolliculitis at M6 was 73% (n = 24/33), 94% (n = 16/17) and 71% (n = 10/14), respectively. The overall response at M6 was 74% for the entire cohort and 70% for the mucocutaneous-articular cluster (n = 27). The median Behçet's syndrome activity score significantly decreased during study period [50 (40-60) 20 (0-40); 0.0001]. After a median follow-up of 11 [6-13] months, 27 (54%) patients were still on apremilast. Reasons for apremilast withdrawal included adverse events (n = 15, 30%) and treatment failure (n = 8, 16%). Thirty-three (66%) patients experienced adverse events, mostly diarrhea (n = 19, 38%), nausea (n = 17, 34%) and headache (n = 16, 32%).

Conclusion: Apremilast seems effective in BS-related articular disease refractory to colchicine and DMARDs. Discontinuation rates were significantly higher than that reported in clinical trials.
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http://dx.doi.org/10.3389/fimmu.2020.626792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889954PMC
February 2021

Direct oral anticoagulant for venous thrombosis in Behçet's syndrome.

Autoimmun Rev 2021 Feb 17:102783. Epub 2021 Feb 17.

Sorbonne Universités, Hopital universitaire Pitié-Salpêtrière, Paris, France; Département de médecine interne et d'immunologie clinique, France; AP-HP, Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013 Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013 Paris, France; CNRS, FRE3632, RHU IMAP, F-75005 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2021.102783DOI Listing
February 2021

Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19.

Therapie 2021 Jan 28. Epub 2021 Jan 28.

AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France.

Background: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients.

Methods: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2.

Results: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs).

Conclusion: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.
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http://dx.doi.org/10.1016/j.therap.2021.01.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842207PMC
January 2021

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

Ann Rheum Dis 2021 Jan 27. Epub 2021 Jan 27.

National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, University College London Hospitals National Health Service (NHS) Trust, London, UK

Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases.

Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category.

Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death.

Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.
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http://dx.doi.org/10.1136/annrheumdis-2020-219498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843211PMC
January 2021

Medium- and Large-Vessel Vasculitis.

Circulation 2021 Jan 19;143(3):267-282. Epub 2021 Jan 19.

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité mixte de recherche (UMR) S 959, and Recherche Hospitalo-Universitaire en santé (RHU) Interleukin-2 Therapy for autoimmune and inflammatory diseases, Paris, France (D.S., P.C.).

Systemic vasculitides are multisystem blood vessel disorders, which are defined by the size of the vessel predominantly affected, namely small, medium, or large vessels. The term "large vessel" relates to the aorta and its major branches; "medium vessel" refers to the main visceral arteries and veins and their initial branches. The most common causes of large-vessel vasculitis are giant cell arteritis and Takayasu arteritis, and those of medium-vessel arteritis are polyarteritis nodosa and Kawasaki disease. However, there is some overlap, and arteries of any size can potentially be involved in any of the 3 main categories of dominant vessel involvement. In addition to multisystem vasculitides, other forms of vasculitis have been defined, including single-organ vasculitis (eg, isolated aortitis). Prompt identification of vasculitides is important because they are associated with an increased risk of mortality. Left undiagnosed or mismanaged, these conditions may result in serious adverse outcomes that might otherwise have been avoided or minimized. The ethnic and regional differences in the incidence, prevalence, and clinical characteristics of patients with vasculitis should be recognized. Because the clinical presentation of vasculitis is highly variable, the cardiovascular clinician must have a high index of suspicion to establish a reliable and prompt diagnosis. This article reviews the pathophysiology, epidemiology, diagnostic strategies, and management of vasculitis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046657DOI Listing
January 2021

Women and Pregnancy in Thromboangiitis Obliterans.

J Vasc Res 2021 Jan 12:1-3. Epub 2021 Jan 12.

Department of Internal Medicine and Clinical Immunology, Centre National de Référence des Maladies Autoimmunes Systémiques Rares, Centre National de Référence des Maladies Autoinflammatoires et de l'Amylose, Hôpital Pitié-Salpêtrière, APHP, Sorbonne Universités, INSERM, UMR_S 959, Paris, France.

Data regarding women and thromboangiitis obliterans (TAO) are conflicted, and a few cases of pregnancy have been described. We aimed to describe the interplay between TAO and pregnancies. Among 224 TAO patients, 22.8% were women. Demographic data, clinical manifestations, and outcomes were similar between men and women. Twenty-one (41.2%) women had 48 pregnancies. Thirty-six (75%) pregnancies with on term and complication free delivery occurred. None of the patients experienced a disease flare of TAO during pregnancy. TAO does not seem to affect pregnancy complications, and pregnancy does not seem to interfere with the course of TAO.
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http://dx.doi.org/10.1159/000512596DOI Listing
January 2021

Impact of aging on phenotype and prognosis in IgA vasculitis.

Rheumatology (Oxford) 2021 Jan 7. Epub 2021 Jan 7.

Université Paris Descartes, Paris, France.

Objectives: Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis most frequently benign in children while the disease is more severe in adults. We aimed to study the impact of age on presentation and outcome of adult IgAV.

Methods: We conducted a nationwide retrospective study including 260 IgAV patients. Patients were divided into four quartiles according to the age at IgAV diagnosis: <36; 36≤age < 52; 52≤age < 63 and ≥63 years. Comparison of presentation and outcome were performed according to age of disease onset.

Results: Mean age at diagnosis was 50.1 ± 18 years and 63% were male. IgAV diagnosed in the lowest quartile of age was associated with more frequent joint (p< 0.0001) and gastrointestinal involvement (p= 0.001). In contrast, the oldest patients had more severe purpura with necrotic lesions (p= 0.001) and more frequent renal involvement (p< 0.0001), with more frequent hematuria, renal failure, higher urine protein excretion and more frequent tubulointerstitial lesions. Patients were treated similarly in all groups of age, and clinical response and relapse rates were similar between groups. In the 127 treated patients with follow-up data for >6 months, clinical response and relapse rates were similar between the four groups. Median follow-up was of 17.2 months (9.1-38.3 months). Renal failure at the end of follow-up was significantly more frequent in the highest quartile of age (p= 0.02), but the occurrence of end-stage renal disease was similar in all groups. Last, overall and IgAV-related deaths were associated with increase age.

Conclusion: Aging negatively impacts the severity and outcome of IgAV in adults. Younger patients have more frequent joint and gastrointestinal involvement, while old patients display more frequent severe purpura and glomerulonephritis.
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http://dx.doi.org/10.1093/rheumatology/keaa921DOI Listing
January 2021

Emerging Molecular Targets for the Treatment of Refractory Sarcoidosis.

Front Med (Lausanne) 2020 24;7:594133. Epub 2020 Nov 24.

AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France.

Sarcoidosis is a multisystem granulomatous disease of unknown origin that has variable clinical course and can affect nearly any organ. It has a chronic course in about 25% of patients. Corticosteroids (CS) are the cornerstone of therapy but their long-term use is associated with cumulative toxicity. Commonly used CS-sparing agents include methotrexate, cyclophosphamide, azathioprine, and mycophenolate mofetil. Twenty to forty percentage of sarcoidosis patients are refractory to these therapies or develop severe adverse events. Therefore, additional and targeted CS-sparing agents are needed for chronic sarcoidosis. Macrophage activation, interferon response, and formation of the granuloma are mainly mediated by T helper-1 responses. Different pro-inflammatory cytokines such as interleukin (IL)-8, IL-12, IL-6, and tumor necrosis factor-alpha (TNF-α) have been shown to be highly expressed in sarcoidosis-affected tissues. As a result of increased production of these cytokines, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is constitutively active in sarcoidosis. Several studies of biological agents that target TNF-α have reported their efficacy and appear today as a second line option in refractory sarcoidosis. Some case series report a positive effect of tocilizumab an anti-IL-6 monoclonal antibody in this setting. More recently, JAK inhibition appears as a new promising strategy. This review highlights key advances on the management of chronic refractory sarcoidosis. Novel therapeutic strategies and treatment agents to manage the disease are described.
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http://dx.doi.org/10.3389/fmed.2020.594133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732552PMC
November 2020

Antiphospholipid antibodies and thrombotic events in COVID-19 patients hospitalized in medicine ward.

Autoimmun Rev 2021 Feb 13;20(2):102729. Epub 2020 Dec 13.

Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Centre National de Référence Maladies AUtoimmunes et systémiques rares Maladies Autoinflammatoires Rares et des Myopathies Inflamatoires, F-75013 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2020.102729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834187PMC
February 2021

Correspondance on 'Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases'.

Ann Rheum Dis 2020 Dec 9. Epub 2020 Dec 9.

AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Hopitaux Universitaires Pitie Salpetriere-Charles Foix, Paris, France.

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http://dx.doi.org/10.1136/annrheumdis-2020-219566DOI Listing
December 2020

Hepatitis C virus-related vasculitis.

Clin Res Hepatol Gastroenterol 2020 Nov 29:101575. Epub 2020 Nov 29.

AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France; Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose, France; Sorbonne Université, UPMC Univ Paris 06, UMR 7211, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France; INSERM, UMR S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France. Electronic address:

Cryoglobulinemic vasculitis (CryoVas) is a small-to-medium vessel systemic vasculitis caused by the deposition of mixed cryoglobulins and immune complexes. Clinical spectrum of CryoVas ranges from mild symptoms to vasculitis involving multiple organs that may progress to more life-threatening ilness. Hepatitis C virus (HCV) chronic infection is the most frequent condition to be assessed in patients with CryoVas. The mortality rate among patients with HCV-associated CryoVas is 3× that of the general population, with a 63% 10-year survival rate. The recent advent of interferon-free direct-acting antivirals (DAAs), which have the potential to induce sustained virological response rates greater than 95%, has dramatically changed the management of chronic HCV infection and HCV-related CryoVas. B-cell depleting strategies, mainly with rituximab, are the main therapeutic option in severe and refractory cases of HCV-associated CryoVas. Despite the progress in the last years on the management of chronic HCV infection, there are still unmet needs regarding therapeutic management of severe and refractory HCV-associated CryoVas.
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http://dx.doi.org/10.1016/j.clinre.2020.11.005DOI Listing
November 2020

Rituximab plus belimumab in non-infectious refractory cryoglobulinemia vasculitis: A pilot study.

J Autoimmun 2021 Jan 25;116:102577. Epub 2020 Nov 25.

Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France; Centre national de références Maladies Autoimmunes et systémiques rares et Centre national de références Maladies Autoinflammatoires, UPMC Université Paris 6, INSERM, UMR S 959, Immunology-Immunopathology- Immunotherapy (I3), F-75005, Paris, France.

Objective: To report the efficacy of rituximab plus belimumab in patients with refractory cryoglobulinemia vasculitis (CV).

Methods: Belimumab was administered intravenously at a dose of 10 mg/kg on days 0, 14, 28 and then every month in association with rituximab in 4 patients with refractory CV. Demographic, clinical and laboratory characteristics, treatment modalities and outcomes were recorded.

Results: All patients had type II IgM Kappa cryoglobulinemia, which was associated with primary Sjögren syndrome (n = 1), hepatitis C virus infection (n = 1), and essential (n = 2). Main manifestations of CV included purpura (n = 4), arthralgia and peripheral neuropathy (n = 3), and glomerulonephritis and skin ulcers (n = 1). In all cases, CV was refractory and/or relapse following rituximab. Intravenous belimumab infusion along with rituximab resulted in rapid clinical response in the four patients. Osteitis and recurrent urinary tract infections occurred in two patients.

Conclusion: Belimumab along with rituximab showed promising results in refractory patients with CV.
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http://dx.doi.org/10.1016/j.jaut.2020.102577DOI Listing
January 2021

Performance of serum apolipoprotein-A1 as a sentinel of Covid-19.

PLoS One 2020 20;15(11):e0242306. Epub 2020 Nov 20.

Department of Internal Medicine and Clinical Immunology, Sorbonne Université, AP-HP Pitié-Salpêtrière, Paris, France.

Background: Since 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19.

Methods: We compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population.

Results: The mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2-95.1) and a specificity of 96.1% (95.7-96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957-0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02-31.0; P = 0.04).

Conclusion: Apolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242306PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679025PMC
December 2020

Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial.

Ann Rheum Dis 2020 Nov 18. Epub 2020 Nov 18.

Rheumatology, CHU Strasbourg, Centre National de Référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France

Objectives: No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren's syndrome-related systemic complications.

Methods: Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment.

Results: 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (Pr[Toc >Pla]=0.14).

Conclusion: Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo.

Trial Registration Number: NCT01782235.
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http://dx.doi.org/10.1136/annrheumdis-2020-218467DOI Listing
November 2020

Biotherapies in Uveitis.

J Clin Med 2020 Nov 8;9(11). Epub 2020 Nov 8.

Department of Internal Medicine and Clinical Immunology, AP-HP, Centre national de références Maladies Autoimmunes et systémiques rares et Maladies Autoinflammatoires rares, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France.

Non-infectious uveitis (NIU) represents one of the leading causes of blindness in developed countries. The therapeutic strategy aims to rapidly control intra-ocular inflammation, prevent irremediable ocular damage, allow corticosteroid sparing and save the vision, and has evolved over the last few years. Anterior NIU is mostly managed with topical treatment in adults. However, for intermediate, posterior and pan-uveitis, notably when both eyes are involved, systemic treatment is usually warranted. Biotherapies are recommended in case of inefficacy or non-tolerance of conventional immunosuppressive drugs in non-anterior NIU. Anti-tumor necrosis factor alpha (anti-TNF-α) agents are by far the most widely used, especially adalimumab (ADA) and infliximab (IFX). In case of sight-threatening uveitis in Behçet's disease or in case of risk of severe recurrences, respectively IFX and ADA may be recommended as first-line therapy. Many questions are left unanswered; how long to treat NIU, how to discontinue anti-TNF-α agents, what biologic to use in case of anti-TNF-α failure? The objective of this review is to present an updated overview of knowledge on the use of biological treatments in NIU.
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http://dx.doi.org/10.3390/jcm9113599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695328PMC
November 2020

Prognosis Factors and Outcomes of Neuro-ophthalmologic Sarcoidosis.

Ocul Immunol Inflamm 2020 Nov 9:1-8. Epub 2020 Nov 9.

Département de Médecine Interne et Immunologie Clinique, Sorbonne Université, Centre National De Référence Maladies Autoimmunes Systémiques Rares, Centre National De Référence Maladies Autoinflammatoires et Amylose Inflammatoire. INSERM UMRS 959, Immunologie-Immunopathologie-Immunotherapie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP , Paris, France.

: Neuro-ophthalmologic manifestations are uncommon in sarcoidosis. We aim to assess the prognostic factors and outcome of neuro-ophthalmic sarcoidosis. : We conducted a multicenter retrospective study on patients with neuro-ophthalmic sarcoidosis. Response to therapy was based on visual acuity, visual field, and orbital MRI exam. Factors associated with remission and relapse were analyzed. : Thirty-five patients [median (IQR) age of 37 years (26.5-53), 63% of women] were included. The diagnosis of sarcoidosis was concomitant of neuro-ophthalmologic symptoms in 63% of cases. Optic neuritis was the most common manifestation. All patients received corticosteroids and 34% had immunosuppressants. At 6 months, 61% improved, 30% were stable, and 9% worsened. Twenty percent of patients had severe visual deficiency at the end of follow-up. Nonresponders patients had significantly worse visual acuity at baseline ( = 0.01). Relapses were less frequent in patients with retro-bulbar optic neuropathy ( = 0.03). : Prognosis of neuro-ophthalmic sarcoidosis is poor.
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http://dx.doi.org/10.1080/09273948.2020.1834585DOI Listing
November 2020

[Better detect iron deficiency to treat it better, a realistic goal].

Ann Biol Clin (Paris) 2020 Dec;78(6):589-591

Inflammation-immunopathology-biotherapy department (DHU i2B), UMR 7211, UPMC Université Paris 6, Sorbonne-Université, Paris, France, Inserm, UMR_S 959, Paris, France, CNRS, FRE3632, Paris, France, Department of internal medicine and clinical immunology, AP-HP, Groupe hospitalier Pitié-Salpêtrière, Paris, France.

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http://dx.doi.org/10.1684/abc.2020.1605DOI Listing
December 2020

Temporal arteritis in IgG4 related disease.

Joint Bone Spine 2020 Oct 25;88(2):105087. Epub 2020 Oct 25.

Sorbonne Université, AP-HP, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology France, Centre national de référence maladies Autoimmunes Systémiques rares, Centre national de référence maladies Autoinflammatoires et Amylose, 75013 Paris, France; Inflammation-Immunopathology-Biotherapy Department (DMU i3), 75013 Paris, France; INSERM UMR S 959, 75013 Paris, France; CNRS, FRE3632, RHU iMAP, 75005 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2020.105087DOI Listing
October 2020

Delayed acute myocarditis and COVID-19-related multisystem inflammatory syndrome.

ESC Heart Fail 2020 Oct 26. Epub 2020 Oct 26.

Cardiology Department, APHP, Lariboisiere Hospital, Paris, France.

Precise descriptions of coronavirus disease 2019 (COVID-19)-related cardiac damage as well as underlying mechanisms are scarce. We describe clinical presentation and diagnostic workup of acute myocarditis in a patient who had developed COVID-19 syndrome 1 month earlier. A healthy 40-year-old man suffered from typical COVID-19 symptoms. Four weeks later, he was admitted because of fever and tonsillitis. Blood tests showed major inflammation. Thoracic computed tomography was normal, and RT-PCR for SARS-CoV-2 on nasopharyngeal swab was negative. Because of haemodynamic worsening with both an increase in cardiac troponin and B-type natriuretic peptide levels and normal electrocardiogram, acute myocarditis was suspected. Cardiac echographic examination showed left ventricular ejection fraction at 45%. Exhaustive diagnostic workup included RT-PCR and serologies for infectious agents and autoimmune blood tests as well as cardiac magnetic resonance imaging and endomyocardial biopsies. Cardiac magnetic resonance with T2 mapping sequences showed evidence of myocardial inflammation and focal lateral subepicardial late gadolinium enhancement. Pathological analysis exhibited interstitial oedema, small foci of necrosis, and infiltrates composed of plasmocytes, T-lymphocytes, and mainly CD163 macrophages. These findings led to the diagnosis of acute lympho-plasmo-histiocytic myocarditis. There was no evidence of viral RNA within myocardium. The only positive viral serology was for SARS-CoV-2. The patient and his cardiac function recovered in the next few days without use of anti-inflammatory or antiviral drugs. This case highlights that systemic inflammation associated with acute myocarditis can be delayed up to 1 month after initial SARS-CoV-2 infection and can be resolved spontaneously.
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http://dx.doi.org/10.1002/ehf2.13047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755006PMC
October 2020

Development of a multivariate prediction model of intensive care unit transfer or death: A French prospective cohort study of hospitalized COVID-19 patients.

PLoS One 2020 19;15(10):e0240711. Epub 2020 Oct 19.

Department of Internal Medicine and Clinical Immunology, Centre National de Références Maladies Autoimmunes et Systémiques Rares Maladies Autoinflammatoires Rares et des Myopathies Inflammatoires, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne University, Paris, France.

Prognostic factors of coronavirus disease 2019 (COVID-19) patients among European population are lacking. Our objective was to identify early prognostic factors upon admission to optimize the management of COVID-19 patients hospitalized in a medical ward. This French single-center prospective cohort study evaluated 152 patients with positive severe acute respiratory syndrome coronavirus 2 real-time reverse transcriptase-polymerase chain reaction assay, hospitalized in the Internal Medicine and Clinical Immunology Department, at Pitié-Salpêtrière's Hospital, in Paris, France, a tertiary care university hospital. Predictive factors of intensive care unit (ICU) transfer or death at day 14 (D14), of being discharge alive and severe status at D14 (remaining with ventilation, or death) were evaluated in multivariable logistic regression models; models' performances, including discrimination and calibration, were assessed (C-index, calibration curve, R2, Brier score). A validation was performed on an external sample of 132 patients hospitalized in a French hospital close to Paris, in Aulnay-sous-Bois, Île-de-France. The probability of ICU transfer or death was 32% (47/147) (95% CI 25-40). Older age (OR 2.61, 95% CI 0.96-7.10), poorer respiratory presentation (OR 4.04 per 1-point increment on World Health Organization (WHO) clinical scale, 95% CI 1.76-9.25), higher CRP-level (OR 1.63 per 100mg/L increment, 95% CI 0.98-2.71) and lower lymphocytes count (OR 0.36 per 1000/mm3 increment, 95% CI 0.13-0.99) were associated with an increased risk of ICU requirement or death. A 9-point ordinal scale scoring system defined low (score 0-2), moderate (score 3-5), and high (score 6-8) risk patients, with predicted respectively 2%, 25% and 81% risk of ICU transfer or death at D14. Therefore, in this prospective cohort study of laboratory-confirmed COVID-19 patients hospitalized in a medical ward in France, a simplified scoring system at admission predicted the outcome at D14.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240711PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571674PMC
November 2020

Reactive oxygen species and TNF-α: the interplay between obstructive sleep apnea and Behçet's disease.

Sleep Breath 2020 Oct 12. Epub 2020 Oct 12.

INSERM, UMR S 959, Immunology-Immunopathology - Immunotherapy (I3), Sorbonne Universités, F-75005, Paris, France.

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http://dx.doi.org/10.1007/s11325-020-02220-zDOI Listing
October 2020

Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence.

Arthritis Res Ther 2020 09 25;22(1):223. Epub 2020 Sep 25.

AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.

Background: Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients.

Methods: HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL.

Results: The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76-0.94) and specificity of 0.89 (95% CI 0.72-0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL).

Conclusions: These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.
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http://dx.doi.org/10.1186/s13075-020-02291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517694PMC
September 2020

Cytokine profile as a prognostic tool in coronavirus disease 2019. Comment on "Urgent avenues in the treatment of COVID-19: Targeting downstream inflammation to prevent catastrophic syndrome" by Quartuccio et al. Joint Bone Spine. 2020;87:191-93.

Joint Bone Spine 2021 01 17;88(1):105074. Epub 2020 Sep 17.

Centre National de Références Maladies Autoimmunes et systémiques rares Maladies Autoinflammatoires Rares et des Myopathies Inflammatoires, Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, 75013 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497797PMC
January 2021

Cardiac sarcoidosis: A long term follow up study.

PLoS One 2020 18;15(9):e0238391. Epub 2020 Sep 18.

Department of Biostatistics and Medical Information, AP-HP Hôpital Saint Louis, Paris, France.

Background: Prognostic factors are lacking in cardiac sarcoidosis (CS), and the effects of immunosuppressive treatments are unclear.

Objectives: To identify prognostic factors and to assess the effects of immunosuppressive drugs on relapse risk in patients presenting with CS.

Methods: From a cohort of 157 patients with CS with a median follow-up of 7 years, we analysed all cardiac and extra-cardiac data and treatments, and assessed relapse-free and overall survival.

Results: The 10-year survival rate was 90% (95% CI, 84-96). Baseline factors associated with mortality were the presence of high degree atrioventricular block (HR, 5.56, 95% CI 1.7-18.2, p = 0.005), left ventricular ejection fraction below 40% (HR, 4.88, 95% CI 1.26-18.9, p = 0.022), hypertension (HR, 4.79, 95% CI 1.06-21.7, p = 0.042), abnormal pulmonary function test (HR, 3.27, 95% CI 1.07-10.0, p = 0.038), areas of late gadolinium enhancement on cardiac magnetic resonance (HR, 2.26, 95% CI 0.25-20.4, p = 0.003), and older age (HR per 10 years 1.69, 95% CI 1.13-2.52, p = 0.01). The 10-year relapse-free survival rate for cardiac relapses was 53% (95% CI, 44-63). Baseline factors that were independently associated with cardiac relapse were kidney involvement (HR, 3.35, 95% CI 1.39-8.07, p = 0.007), wall motion abnormalities (HR, 2.30, 95% CI 1.22-4.32, p = 0.010), and left heart failure (HR 2.23, 95% CI 1.12-4.45, p = 0.023). After adjustment for cardiac involvement severity, treatment with intravenous cyclophosphamide was associated with a lower risk of cardiac relapse (HR 0.16, 95% CI 0.033-0.78, p = 0.024).

Conclusions: Our study identifies putative factors affecting morbidity and mortality in cardiac sarcoidosis patients. Intravenous cyclophosphamide is associated with lower relapse rates.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238391PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500618PMC
October 2020

Tocilizumab in treatment-naïve patients with Takayasu arteritis: TOCITAKA French prospective multicenter open-labeled trial.

Arthritis Res Ther 2020 09 17;22(1):218. Epub 2020 Sep 17.

Sorbonne Universités AP-HP, Hôpital Saint Antoine, service de médecine interne et Inflammation-Immunopathology-Biotherapy Department (DMU 3iD), Faculté de Médecine Sorbonne Université, F-75012, Paris, France.

Objectives: To assess long-term efficacy of tocilizumab in treatment-naive patients with Takayasu arteritis (TAK).

Methods: Prospective open-labeled trial in naïve patients with TAK who received steroids at the dose of 0.7 mg/kg/day and 7 infusions of 8 mg/kg/month of tocilizumab. The primary endpoint was the number of patients who discontinued steroids after 7 infusions of tocilizumab. Secondary endpoints included disease activity and the number of relapses during 18-month follow-up.

Results: Thirteen patients with TAK were included, with a median age of 32 years [19-45] and 12 (92%) females. Six (54%) patients met the primary end-point. A significant decrease of disease activity was observed after 6 months of tocilizumab therapy: decrease of median NIH scale (3 [3, 4] at baseline, versus 1 [0-2] after 6 months; p < 0.001), ITAS-2010 score (5 [2-7] versus 3 [0-8]; p = 0.002), and ITAS-A score (7 [4-10] versus 4 [1-15]; p = 0.0001)]. During the 12-month follow-up after tocilizumab discontinuation, a relapse occurred among 5 patients (45%) out of 11 in which achieved remission after 6 months of tocilizumab.

Conclusion: Tocilizumab seems an effective steroid sparing therapy in TAK, but maintenance therapy is necessary.

Trial Registration: ClinicalTrials.gov NCT02101333 . Registered on 02 April 2014.
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http://dx.doi.org/10.1186/s13075-020-02311-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500024PMC
September 2020

Iron deficiency markers in patients undergoing iron replacement therapy: a 9-year retrospective real-world evidence study using healthcare databases.

Sci Rep 2020 09 11;10(1):14983. Epub 2020 Sep 11.

Université de Paris, UFR de Médecine Xavier Bichat, Centre de Recherche Sur L'Inflammation (CRI), INSERM UMRs 1149, 75018, Paris, France.

The diagnosis and treatment of iron deficiency is a primary public health goal. This study aimed to make an inventory of the use of biomarkers to assess the iron supply in patients given iron replacement therapy. A retrospective longitudinal real-world study of a cohort of patients receiving iron replacement therapy was conducted using data from healthcare coverage databases between January 2006 and December 2015 in France. The frequency of oral or intravenous iron treatment episodes preceded and/or followed by a biological assessment of iron deficiency was described. We then differentiate patients with or without chronic inflammatory diseases, which could impact the prescription. The evolution between 2006 and 2015 was also studied. The 96,724 patients received an average of 4.9 administrations of iron per patient, corresponding to 1.7 treatment episodes. In one-third of treatment episodes (34.6%), patients had a pre-treatment biological assessment, 15.5% a post-treatment assessment, and 7.3% both. The post-treatment measure of iron supply markers (i.e., Ferritin and transferrin saturation) was more frequent in patients suffering from chronic inflammatory diseases than in those without underlying chronic condition (22.6% to 41.0% vs. 3.1%; p < 0.0001). Serum ferritin was measured 30 times more than transferrin saturation measurements. The use of both tests increased steadily during the study period, although remaining low. Despite the recommendations, biological assessments of iron status are seldom prescribed and/or performed in the context of a pre- or post-treatment assessment, although more frequently realized in patients with chronic inflammatory diseases.
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http://dx.doi.org/10.1038/s41598-020-72057-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486365PMC
September 2020

Pregnancy issues in Takayasu arteritis.

Semin Arthritis Rheum 2020 10 9;50(5):911-914. Epub 2020 Aug 9.

Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires, F-75013, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France; INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière. Electronic address:

Takayasu arteritis (TAK) is a chronic inflammatory vasculitis of unknown origin affecting large vessels, predominantly the aorta and its main branches. TAK usually affects young women and the management of pregnancy during this vasculitis may be a challenging situation. After a review of the literature, we analysed the data of 505 pregnancies in 373 TAK patients. We discuss main results to clarify if the pregnancy outcome is affected by TAK, especially during disease clinical onset or disease activity. We also discuss the potential impact of pregnancy on TAK prognosis. Disease activity of TAK appears independently associated with a poor pregnancy outcome. More than 5% of pregnant women with TAK develop a life-threatening maternal cardiovascular complication. A good control of TAK disease activity and arterial hypertension before conception and during pregnancy is critical to improve both maternal and foetal outcomes. Pregnancies in the setting of TAK should be considered high-risk, requiring a close collaboration between specialists involved in the care of TAK and obstetricians.
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http://dx.doi.org/10.1016/j.semarthrit.2020.08.001DOI Listing
October 2020