Mast cells drive pathologic vascular lesions in Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TAK) is a large vessel vasculitis resulting in artery wall remodeling with segmental stenosis and/or aneurysm formation. Mast cells (MCs) are instrumental in bridging cell injury and inflammatory response. OBJECTIVES: This study sought to investigate the contribution of MCs on vessel permeability, angiogenesis, and fibrosis in patients with TAK. METHODS: MC activation and their tissue expression were assessed in sera and in aorta from patients with TAK and from healthy donors (HDs). In vivo permeability was assessed using a modified Miles assay. Subconfluent cultured human umbilic vein endothelial cells and fibroblasts were used in vitro to investigate the effects of MC mediators on angiogenesis and fibrogenesis. RESULTS: This study found increased levels of MC activation markers (histamine and indoleamine 2,3-dioxygenase) in sera of patients with TAK compared with in sera of HDs. Marked expression of MCs was shown in aortic lesions of patients with TAK compared with in those of noninflammatory aorta controls. Using Miles assay, this study showed that sera of patients with TAK significantly increased vascular permeability in vivo as compared with that of HDs. Vessel permeability was abrogated in MC-deficient mice. MCs stimulated by sera of patients with TAK supported neoangiogenesis (increased human umbilic vein endothelial cell proliferation and branches) and fibrosis by inducing increased production of fibronectin, type 1 collagen, and α-smooth muscle actin by fibroblasts as compared to MCs stimulated by sera of HD. CONCLUSIONS: MCs are a key regulator of vascular lesions in patients with TAK and may represent a new therapeutic target in large vessel vasculitis.

Anti-Tumor Necrosis Factor α versus Tocilizumab in the Treatment of Refractory Uveitic Macular Edema: A Multicenter Study from the French Uveitis Network.

PURPOSE: To analyze the factors associated with response (control of ocular inflammation and corticosteroid-sparing effect) to biologics (anti-tumor necrosis factor [TNF]-α agents and tocilizumab) in patients with refractory uveitic macular edema (ME). DESIGN: Multicenter, retrospective, observational study. PARTICIPANTS: Adult patients with uveitic ME refractory to systemic corticosteroids, disease-modifying antirheumatic drugs, or both. METHODS: Patients received anti-TNF-α agents (infliximab 5 mg/kg at week 0, 2, 6, and every 4-6 weeks [n = 69] and adalimumab 40 mg/2 weeks [n = 80]) and tocilizumab (8 mg/kg every 4 weeks intravenously [n = 39] and 162 mg/week subcutaneously [n = 16]). MAIN OUTCOME MEASURES: Analysis of complete and partial response rates, relapse rate, low vision (visual acuity in at least 1 eye of ≥ 1 logarithm of the minimum angle of resolution), corticosteroid-sparing effect, and adverse events at 6 months. RESULTS: Two hundred four patients (median age, 40 years [interquartile range, 28-58 years]; 42.2% men) were included. Main causes of uveitis included Behçet's disease (17.2%), birdshot chorioretinopathy (11.3%), and sarcoidosis (7.4%). The overall response rate at 6 months was 46.2% (21.8% of complete response) with anti-TNF-α agents and 58.5% (35.8% of complete response) with tocilizumab. In multivariate analysis, treatment with tocilizumab (odds ratio, 2.10; 95% confidence interval [CI], 1.06-4.06; P = 0.03) was associated independently with complete response of uveitic ME compared with anti-TNF-α agents. Anti-TNF-α agents and tocilizumab did not differ significantly in terms of relapse rate (hazard ratio, 1.00; 95% CI, 0.31-3.18; P = 0.99) or occurrence of low vision (odds ratio, 1.02; 95% CI, 0.51-2.07; P = 0.95) or corticosteroid-sparing effect (P = 0.29). Adverse events were reported in 20.6% of patients, including serious adverse events reported in 10.8% of patients. CONCLUSIONS: Tocilizumab seems to improve complete response of uveitic ME compared with anti-TNF-α agents.

Targeting JAK/STAT pathway in Takayasu's arteritis.

OBJECTIVE: Takayasu's arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK. METHODS: We analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK. RESULTS: Transcriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients. CONCLUSIONS: JAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.

Evolving spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors results from the WHO's pharmacovigilance database.

PURPOSE: Drug-induced uveitis is a rare but sight-threatening condition. We seek to determine the spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors (ICI). METHODS: Retrospective pharmacovigilance study based on adverse drug reactions reported within VigiBase, the WHO international pharmacovigilance database. We included deduplicated individual case safety reports (ICSRs) reported as 'uveitis' at Preferred Term level according to the Medical Dictionary for Drug Regulatory Activities between 1967 and 04/28/2019. We performed a case/non-case analysis to study if suspected drug-induced uveitis were differentially reported for each suspected treatment compared to the full database. We excluded drugs with potential indication bias. RESULTS: 1404 ICSRs corresponding to 37 drugs had a significant over-reporting signal with a median age of 57 [42-68] years and 45.7% of males. We identified five major groups of treatments: bisphosphonates (26.9%), non-antiviral anti-infectious drugs (25.4%), protein kinase inhibitors (15.5%), ICI (15.0%), and antiviral drugs (11.1%). Severe visual loss was reported in 12.1% of cases. ICI and protein kinase inhibitors were the most recently emerging signals. The time to onset between first infusion and uveitis was significantly different between groups ranging from 5 days [2-19] in the bisphosphonate group to 138.5 [47.25-263.75] in protein kinase inhibitors group (p < 0.0001). Anti-Programmed Cell death 1 represented more than 70% of ICI-induced uveitis. We identified Vogt-Koyanagi-Harada (VKH)-like syndrome as being associated with ICI use. CONCLUSIONS: The spectrum of drug-induced uveitis has changed with the evolution of pharmacopeia and the recent emergence of ICIs. VKH-like syndrome has been reported with ICI and protein kinase inhibitors therapy.

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinaemia vasculitis (CV). However, it remains unclear why only some individuals with HCV develop HCV-associated CV (HCV-CV). HCV-CV is characterized by the expansion of anergic CD19+CD27+CD21low/- atypical memory B cells (AtMs). Herein, we report the mechanisms by which AtMs participate in HCV-associated autoimmunity. METHODS: The phenotype and function of peripheral AtMs were studied by multicolour flow cytometry and co-culture assays with effector T cells and regulatory T cells in 20 patients with HCV-CV, 10 chronicallyHCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtMs stimulated or not by TLR9. Immunoglobulin gene repertoire and antibody reactivity profiles of AtM-expressing IgM antibodies were analysed following single B cell FACS sorting and expression-cloning of monoclonal antibodies. RESULTS: The Tbet+CD11c+CD27+CD21- AtM population is expanded in patients with HCV-CV compared to HCV controls without CV. TLR9 activation of AtMs induces a specific transcriptional signature centred on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in patients with HCV-CV. AtMs stimulated through TLR9 promote type 1 effector T cell activation and reduce the proliferation of CD4+CD25hiCD127-/lowFoxP3+ regulatory T cells. AtM expansions display intraclonal diversity with immunoglobulin features of antigen-driven maturation. AtM-derived IgM monoclonal antibodies do not react against ubiquitous autoantigens or HCV antigens including NS3 and E2 proteins. Rather, AtM-derived antibodies possess rheumatoid factor activity and target unique epitopes on the human IgG-Fc region. CONCLUSION: Our data strongly suggest a central role for TLR9 activation of AtMs in driving HCV-CV autoimmunity through rheumatoid factor production and type 1 T cell responses. LAY SUMMARY: B cells are best known for their capacity to produce antibodies, which often play a deleterious role in the development of autoimmune diseases. During chronic hepatitis C, self-reactive B cells proliferate and can be responsible for autoimmune symptoms (arthritis, purpura, neuropathy, renal disease) and/or lymphoma. Direct-acting antiviral therapy clears the hepatitis C virus and eliminates deleterious B cells.

Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis.

BACKGROUND AND AIMS: Extrahepatic manifestations of HCV are responsible for morbidity and mortality in many chronically infected patients. New, interferon-free antiviral treatment regimens, which present the opportunity to treat all HCV-infected patients, call for a better understanding of the benefits of treating non-cirrhotic chronically infected individuals. METHODS: A systematic review was conducted. Identified studies from targeted database searches on Embase and Medline were screened. The methodological quality of the included publications was evaluated. Random-effect model meta-analyses were performed. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Data were extracted from a total of 48 identified studies. Achieving sustained virological response (SVR) was associated with reduced extrahepatic mortality (vs no SVR, OR 0.44 (95% CI 0.28 to 0.67)). SVR was associated with higher complete remissions in patients with cryoglobulinemia vasculitis (OR 20.76 (6.73 to 64.05)) and a higher objective response in those with malignant B-cell lymphoproliferative diseases (OR 6.49 (2.02 to 20.85)). Achieving SVR was also associated with reduced insulin resistance at follow-up (OR 0.42 (0.33 to 0.53)) and a significant protective effect on the incidence of diabetes (OR 0.34 (0.21 to 0.56)). Lack of randomised data comparing SVR versus non-SVR patients for the relevant extrahepatic indications attenuated these analyses. CONCLUSION: Antiviral therapy can reduce extrahepatic manifestations related to HCV when SVR is achieved. Higher quality data, and reporting over longer follow-up periods, will be required to thoroughly explore comprehensive HCV treatment strategies.

Direct-Acting Antiviral Therapy Restores Immune Tolerance to Patients With Hepatitis C Virus-Induced Cryoglobulinemia Vasculitis.

BACKGROUND & AIMS: Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity. METHODS: We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay. RESULTS: Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions of IgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P < .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P < .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P = .03), and positive correlations with numbers of Tfh cells (P = .03) and serum levels of cryoglobulin (P = .01). DAA therapy increased patients' numbers of T-regulatory cells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively). CONCLUSIONS: In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.

Prognostic value of viral eradication for major adverse cardiovascular events in hepatitis C cirrhotic patients.

BACKGROUND: The objective was to examine the role of a sustained virological response (SVR) on major adverse cardiovascular events (MACEs) in patients with compensated hepatitis C virus (HCV) cirrhosis. METHODS: Patients with the following criteria were enrolled in 35 French centers: (1) biopsy-proven HCV cirrhosis; (2) Child-Pugh A; (3) positive viremia; and (4) no prior liver complication, and then prospectively followed. All patients received HCV treatment after inclusion. MACEs included stroke, myocardial infarction, ischemic heart disease, heart failure, peripheral arterial disease, cardiac arrest, and cardiovascular death. SVR, defined as negative viremia 12 weeks posttreatment, was considered as a time-dependent covariate, and its effect on MACE occurrence was assessed. The median follow up was 57.5 months, ending in December 2015. RESULTS: Sixty-two of 878 (7.1%) patients presented a total of 79 MACEs. The main predictive baseline factors of MACEs were Asian ethnic origin, history of MACEs, arterial hypertension, diabetes mellitus, current smoking, low serum albumin level, high total bilirubin level, and low platelet count. In multivariate analysis, SVR was associated with a decreased risk of MACEs (hazard ratio=0.35, 95% CI 0.09-0.97, P=.044), whereas Asian ethnic origin, arterial hypertension, smoking, and low serum albumin level remained predictive of MACE occurrence. The 5-year survival rate was 60.1% versus 87.5% in patients who did versus those who did not present a MACE (P<.001). CONCLUSIONS: In patients with compensated HCV-related cirrhosis, Asian ethnic origin, arterial hypertension, smoking, and low serum albumin are independent predictive factors of cardiovascular events, whereas an SVR is associated with a decreased rate of cardiovascular events.

Effectiveness and cost of hepatitis C virus cryoglobulinaemia vasculitis treatment: From interferon-based to direct-acting antivirals era.

BACKGROUND: The net benefits of new hepatitis C virus (HCV) direct-acting antiviral drugs (DAA) in patients with cryoglobulinaemia vasculitis (CryoVas) are unknown. OBJECTIVE: To analyse the effectiveness and cost of all treatments used for HCV-CryoVas in the DAA vs pre-DAA era. METHODS: A chart review of all HCV-CryoVas patients who received antivirals from 1993 to 2016 in a tertiary centre was performed. Treatment effectiveness was analysed for clinical, immunological and virological responses. Cost analyses included anti-HCV treatments, non-antiviral drugs, plasmapheresis, dialysis and hospitalizations. We compared main data in the pre-DAA vs DAA period. RESULTS: About 201 HCV-CryoVas patients were included (women, 53.2%; mean age, 59.2 years; Metavir score F3-F4, 36.7%; genotype 1, 64.2%). Patients in the DAA era (n=27) compared to those in the pre-DAA era (n=174) showed higher rates of clinical (96.3% vs. 78.6%), immunological (89.5% vs. 77.1%), and sustained virological response (75.0% vs. 42.8%). Death rate was 14.8% vs. 24.4% respectively. In the DAA compared to pre-DAA era, mean cost of anti-HCV drugs increased from 11 855 to 57 632 € while mean CryoVas-related cost decreased for both hospitalizations (from 33 510 to 21 347€) and non-antiviral treatments (from 17 347 to 11 397€). CONCLUSION: Improved antiviral efficacy of HCV drugs in the DAA era led to increased clinical and immunological efficacy and a lower death rate. Use of DAAs was associated to higher costs for HCV drugs while costs related to both hospitalizations and non-antiviral treatments decreased.

Hepatitis C virus infection and chronic kidney disease: Time for reappraisal.

Hepatitis C virus (HCV) infection is associated with tremendous morbidity and mortality due to liver complications. HCV infection is also associated with many extrahepatic manifestations including cardiovascular diseases, glucose metabolism impairment, cryoglobulinemia vasculitis, B cell non-Hodgkin lymphoma and chronic kidney disease (CKD). Many studies have shown a strong association between HCV and CKD, by reporting (i) an increased prevalence of HCV infection in patients on haemodialysis, (ii) an increased incidence of CKD and proteinuria in HCV-infected patients, and (iii) the development of membranoproliferative glomerulonephritis secondary to HCV-induced cryoglobulinemia vasculitis. HCV seropositivity is found to be associated with an increased relative risk for all-cause and cardiovascular mortality in the dialysis population. HCV seropositivity is linked to lower patient and graft survival after kidney transplantation. Such poor HCV-associated prognosis should have encouraged clinicians to treat HCV in CKD patients. However, due to frequent side effects and the poor efficacy of interferon-based treatments, very few HCV dialysis patients have received HCV medications until now. The emergence of new direct acting, interferon-free antiviral treatment, leading to HCV cure in most cases with a satisfactory safety profile, will shortly modify the management of HCV infection in CKD patients. In patients with a glomerular filtration rate (GFR) >30ml/min, the choice of DAA is not restricted. In those with a GFR <30 and >15ml/min, only paritaprevir/ritonavir/ombitasvir/dasabuvir or a grazoprevir plus elbasvir regimen are approved. In patients with end stage renal disease (GFR <15ml/min or dialysis), current data only allows for the use of a grazoprevir plus elbasvir combination. No doubt these data will be modified in the future with the advent of new studies including larger cohorts of HCV patients with renal impairment.

Methotrexate versus conventional disease-modifying antirheumatic drugs in the treatment of non-anterior sarcoidosis-associated uveitis.

AIMS: To compare the safety and efficacy of methotrexate (MTX), mycophenolate mofetil (MMF) and azathioprine (AZA) in non-anterior sarcoidosis-associated uveitis. METHODS: Retrospective study including non-anterior sarcoidosis-associated uveitis according to the revised International Workshop on Ocular Sarcoidosis criteria. The primary outcome was defined as the median time to relapse or occurrence of serious adverse events leading to treatment discontinuation. RESULTS: 58 patients with non-anterior sarcoidosis-associated uveitis (MTX (n=33), MMF (n=16) and AZA (n=9)) were included. The time to treatment failure (ie, primary outcome) after adjustment for corticosteroids dose and the presence of vasculitis was significantly higher with MTX (median time of 34.5 months with MTX (IQR: 11.8 -not reached) vs 8.4 months (3.1-22.9) with MMF and 16.8 months (8.0-90.1) with AZA (p=0.020)). The risk of relapse at 12 months was more than twice lower in MTX as compared with MMF (p=0.046). Low visual acuity at the last visit was significantly lower with MTX (4% vs 9% in MMF vs 57% in AZA group (p=0.008)). Regarding all 75 lines of treatment (MTX (n=39), MMF (n=24) and AZA (n=12)), MTX was more effective than MMF and AZA to obtain treatment response at 3 months (OR 10.85; 95% CI 1.13 to 104.6; p=0.039). Significant corticosteroid-sparing effect at 12 months (p=0.035) was only observed under MTX. Serious adverse events were observed in 6/39 (15%), 5/24 (21%) and 2/12 (17%) with MTX, MMF and AZA, respectively. CONCLUSION: In non-anterior sarcoidosis-associated uveitis, MTX seems to be more efficient compared with AZA and MMF and with an acceptable safety profile.

Cannabis-associated arterial disease.

BACKGROUND: The aim of this study was to describe the different arterial complications reported in cannabis smokers. METHODS: This study was a literature review. RESULTS: Cannabis use was found to be associated with stroke, myocardial infarction, and lower limb arteritis. Arterial disease involved especially young men. There was a very strong temporal link between arterial complications and cannabis use for stroke and myocardial infarction episodes. Patient outcome was closely correlated with cannabis withdrawal and relapses associated with cannabis rechallenge. Cannabis use was associated with particular characteristics of arterial disease. The increased risk of myocardial infarction onset occurred within 1 hour of smoking marijuana compared with periods of non-use. Strokes occurred mainly in the posterior cerebral circulation. Compared with cohorts of thromboangiitis obliterans patients, those with cannabis-associated limb arteritis were younger, more often male, and had more frequent unilateral involvement of the lower limbs at clinical presentation. CONCLUSION: Cannabis use is associated with arterial disease such as stroke, myocardial infarction, and limbs arteritis. It appears essential to investigate cannabis use in young patients presenting with such arterial manifestations, as outcome is closely correlated with cannabis withdrawal.

Behçet's Disease Uveitis.

Uveitis in Behçet's disease (BD) is frequent (40% of cases) and is a major cause of morbidity. The age of onset of uveitis is between 20 and 30 years. Ocular involvement includes anterior, posterior, or panuveitis. Uveitis may be the first sign of the disease in 20% of cases or it may appear 2 or 3 years after the first symptoms. Panuveitis is the most common presentation and is more commonly found in men. Bilateralization usually occurs on average 2 years after the first symptoms. The estimated risk of blindness at 5 years is 10-15%. BD uveitis has several ophthalmological features that distinguish it from other uveitis. The main goals in the management of patients are the rapid resolution of intraocular inflammation, the prevention of recurrent attacks, the achievement of complete remission, and the preservation of vision. Biologic therapies have changed the management of intraocular inflammation. The aim of this review is to provide an update to a previous article by our team on pathogenesis, diagnostic approaches, and the therapeutic strategy of BD uveitis.

Prognosis Factors and Outcomes of Neuro-ophthalmologic Sarcoidosis.

BACKGROUND: Neuro-ophthalmologic manifestations are uncommon in sarcoidosis. We aim to assess the prognostic factors and outcome of neuro-ophthalmic sarcoidosis. METHODS: 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. RESULTS: 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 (p = 0.01). Relapses were less frequent in patients with retro-bulbar optic neuropathy (p = 0.03). CONCLUSION: Prognosis of neuro-ophthalmic sarcoidosis is poor.

Lower Relapses Rate With Infliximab Versus Adalimumab in Sight-Threatening Uveitis: A Multicenter Study of 330 Patients.

PURPOSE: To compare the relapse rate of sight-threatening noninfectious uveitis (NIU) in patients treated with infliximab (IFX) or adalimumab (ADA). DESIGN: Observational retrospective multicenter study. METHODS: A total of 330 patients (median age, 36 years; interquartile range, 27-54), 45.2% men) with sight-threatening NIU (ie, retinal vasculitis and/or macular edema) treated with anti-tumor necrosis factor [TNF]-α agents (IFX intravenously at 5 mg/kg at weeks 0, 2, 6, and every 4 to 6 weeks or ADA subcutaneously at 80 mg, then 40 mg every 2 weeks). Data were obtained retrospectively from patients' medical records. Main outcome measures were relapse rate, complete response of NIU, corticosteroid sparing effect, and safety. RESULTS: Main etiologies of uveitis included Behçet disease (27%), idiopathic juvenile arthritis (5.8%), and sarcoidosis (5.5%). The estimated relapse rate at 6 months after introduction of biological agents was 13% (95% CI = 0.009-0.16). IFX was associated with less relapse risk than ADA (hazard ratio [HR] = 0.52, 95% CI = 0.36- 0.77, P = .001). ADA and IFX were comparable in terms of complete response rate of NIU as well as corticosteroid-sparing effect. Behçet disease was associated with higher odds of complete response (HR = 2.04, 95% CI = 1.16 -3.60, P = .01] and lower relapse rate (HR = 0.53, 95% CI = 0.33-0.85, P = .009) than other causes of NIU with anti-TNF-α agents. CONCLUSIONS: In sight-threatening NIU, IFX seems to be associated with a lower relapse rate than ADA.

Prognostic Factors and Treatment Efficacy in Spinal Cord Sarcoidosis: An Observational Cohort With Long-term Follow-up.

BACKGROUND AND OBJECTIVES: Spinal cord sarcoidosis is a rare manifestation of sarcoidosis with a consequent risk of neurologic sequelae for the patient. We investigated prognostic factors and efficacy of immunosuppressive treatments in a longitudinal cohort. METHODS: We retrospectively studied patients with spinal cord sarcoidosis followed between 1995 and 2021 in 7 centers in France. Patients with definite, probable, or possible spinal cord sarcoidosis according to the Neurosarcoidosis Consortium Consensus Group criteria and with spinal cord involvement confirmed by MRI were included. We analyzed relapse or progression rate with a Poisson model, initial Rankin score with a linear model, and change in the Rankin score during follow-up with a logistic model. RESULTS: A total of 97 patients were followed for a median of 7.8 years. Overall mean relapse or progression rate was 0.17 per person-year and decreased over time. At last visit, 46 (47.4%) patients had a loss of autonomy (Rankin score ≥2). The main prognostic factors significantly associated with relapse or progression rate were gadolinium enhancement (relative rate [95% CI] 0.61 [0.4, 0.95]) or meningeal involvement (relative rate [95% CI] 2.05 [1.31, 3.19]) on spinal cord MRI and cell count (relative rate [95% CI] per 1 log increase 1.16 [1.01, 1.33]) on CSF analysis. Relapse or progression rate was not significantly associated with initial Rankin score or Expanded Disability Status Scale. Tumor necrosis factor-α (TNF-α) antagonists significantly decreased relapse or progression rate compared with corticosteroids alone (relative rate [95% CI] 0.33 [0.11, 0.98]). Azathioprine was significantly less effective than methotrexate on relapse or progression rate (relative rate [95% CI] 2.83 [1.04, 7.75]) and change in Rankin score (mean difference [95% CI] 0.65 [0.23, 1.08]). DISCUSSION: Regarding the relapse or progression rate, meningeal localization of sarcoidosis was associated with a worse prognosis, TNF-α antagonists resulted in a significant decrease compared to corticosteroids alone, and methotrexate was more effective than azathioprine. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with spinal cord neurosarcoidosis, TNF-α antagonists were associated with decreased relapse or progression rate compared to corticosteroids alone, but other therapies showed no significant benefit.