Systemic autoimmune myopathies: a prospective phase 4 controlled trial of an inactivated virus vaccine against SARS-CoV-2.

OBJECTIVES: To evaluate immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in systemic autoimmune myopathies (SAMs) and the possible influence of baseline disease parameters, comorbidities and therapy on immune response. METHODS: This prospective controlled study included 53 patients with SAMs and 106 non-immunocompromised control group (CTRL). All participants received two doses of the Sinovac-CoronaVac vaccine (28-day interval). Immunogenicity was assessed by anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC), anti-S1/S2 IgG geometric mean titre (GMT), factor increase GMT (FI-GMT), neutralizing antibodies (NAb) positivity, and median neutralizing activity after each vaccine dose (D0 and D28) and six weeks after the second dose (D69). Participants with pre-vaccination positive IgG serology and/or NAb and those with RT-PCR confirmed COVID-19 during the protocol were excluded from immunogenicity analysis. RESULTS: Patients and CTRL had comparable sex (P>0.99) and age (P=0.90). Immunogenicity of 37 patients and 79 CTRL-naïve participants revealed at D69, a moderate but significantly lower SC (64.9% vs 91.1%, P<0.001), GMT [7.9 (95%CI 4.7-13.2) vs 24.7 (95%CI 30.0-30.5) UA/ml, P<0.001] and frequency of NAb (51.4% vs 77.2%, P<0.001) in SAMs compared with CTRL. Median neutralizing activity was comparable in both groups [57.2% (interquartile range (IQR) 43.4-83.4) vs 63.0% (IQR 40.3-80.7), P=0.808]. Immunosuppressives were less frequently used among NAb+ patients vs NAb- patients (73.7% vs 100%, P=0.046). Type of SAMs, disease status, other drugs or comorbidities did not influence immunogenicity. Vaccine-related adverse events were mild with similar frequencies in patients and CTRL (P>0.05). CONCLUSION: Sinovac-CoronaVac is safe and has a moderate short-term immunogenicity in SAMs, but reduced compared with CTRL. We further identified that immunosuppression is associated with diminished NAb positivity. TRIAL REGISTRATION: COVID-19 CoronaVac in Patients With Autoimmune Rheumatic Diseases and HIV/AIDS (CoronavRheum), http://clinicaltrials.gov/ct2/show/NCT04754698.

Hydroxychloroquine blood levels in stable lupus nephritis under low dose (2-3 mg/kg/day): 12-month prospective randomized controlled trial.

INTRODUCTION: The American Academy of Ophthalmology (2016-AAO) recommended hydroxychloroquine (HCQ) dose not to exceed 5 mg/kg/day (real body weight). Recently, it was reported that prescribed 2016-AAO dose provided adequate HCQ levels for most lupus nephritis (LN) patients, with low flare risk. However, the minimum HCQ dose required to keep adequate levels is unknown. OBJECTIVES: To evaluate if a further reduction in 2016-AAO dose (2-3 mg/kg/day) would sustain 12-month HCQ levels in LN patients with stable inactive disease. METHODS: Seventy-three stable LN patients under prescribed full HCQ 2016-AAO dose for ≥6 months and adequate baseline HCQ levels (≥613.5 ng/mL) were divided in two groups: reduced 2016-AAO dose (2-3 mg/kg/day), n = 32, and full 2016-AAO dose (5 mg/kg/day), n = 41. All patients were assessed at baseline, 3, 6, and 12 months. HCQ levels were measured by liquid chromatography-tandem mass spectrometry. Flare was defined as augment ≥ 3 in SLE Disease Activity Index-2000 and/or change in treatment. Rigorous clinical/laboratorial surveillance was performed. RESULTS: Prospective evaluation revealed for reduced 2016-AAO dose group a decrease of HCQ levels from baseline to 3 months (1,404.9 ± 492.0 vs. 731.6 ± 385.0 ng/mL, p < 0.01), and sustained levels at 6 months (p = 0.273) and 12 months (p = 0.091) compared to 3 months. For the full 2016-AAO dose group, a decrease occurred only from baseline to 12 months (1343.5 ± 521.5 vs. 991.6 ± 576.3 ng/mL, p < 0.001). Frequencies of patients with inadequate levels at 6 months was higher in reduced 2016-AAO group than full 2016-AAO dose (59% vs. 24%, p = 0.005), as well as at 12 months (66% vs. 32%, p = 0.002). Six-month and 12-month flare frequencies were comparable for both groups (p > 0.05). CONCLUSIONS: Prescribed HCQ low-dose regimen (2-3 mg/kg/day) does not sustain, for most patients, 6- and 12-month adequate HCQ levels. Full 2016-AAO dose maintained HCQ levels way above this limit. TRAIL REGISTRATION: ClinicalTrials.gov : NCT03122431, registered on April 20, 2017 Key Points • Reduced American Academy of Ophthalmology (2016-AAO) hydroxychloroquine (HCQ) dose (2-3 mg/kg/day, real body weight) is unable to sustain HCQ blood levels within the safe cut-off defined for flare risk. • Full 2016-AAO dose (5 mg/kg/day) maintains a safe pattern of HCQ levels up to 12 months.

Cognitive dysfunction and serum levels of brain-derived neurotrophic factor (BDNF) in primary anti-phospholipid syndrome (PAPS).

OBJECTIVES: Cognitive dysfunction (CD) is a poorly understood non-stroke central neurological manifestation in anti-phospholipid syndrome (APS). Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in neural plasticity and could potentially be a biomarker of CD in primary APS (PAPS). The aim of the study is to assess CD in PAPS patients and to evaluate its association with clinical data, anti-phospholipid antibodies and serum BDNF levels. METHODS: This cross-sectional study compared 44 PAPS patients and 20 healthy controls matched for age, gender and education. PAPS patients and controls underwent a standardized cognitive examination. The demographic, clinical and laboratory characteristics of patients were recorded. Serum BDNF was measured by Enzyme Linked Immunosorbent. RESULTS: Fourteen (31.8%) of the 44 patients with PAPS had CD compared with only one (5%) healthy control (P =0.019). PAPS patients presented lower serum BDNF levels when compared with controls (P =0.007). Lower levels of BDNF were associated with CD in PAPS patients (P =0.032). In the univariate analysis, a positive association was found between CD and livedo reticularis, deep vein thrombosis, stroke, seizure, smoking as well as a negative association with Mini Mental State Examination and serum BDNF. According to multivariate analysis, the only independent predictor of CD in PAPS was stroke (OR 137.06; 95% CI: 4.73, 3974.32; P =0.004). CONCLUSIONS: CD is commonly reported in PAPS patients; however, its assessment lacks in standards and objective screening tests. The association between CD and low serum BDNF suggests that this neurotrophin can be a promising biomarker for PAPS cognitive impairment.

Anti-adalimumab antibodies kinetics: an early guide for juvenile idiopathic arthritis (JIA) switching.

OBJECTIVE: To assess the longitudinal production of anti-adalimumab antibody (AAA) and baseline risk factors for this antibody development in juvenile idiopathic arthritis (JIA) patients initiating adalimumab (ADA). METHOD: Thirty consecutive JIA patients under ADA therapy were prospectively followed. JIA clinical/laboratorial/treatment data and sera for ADA and AAA assays (ELISA and bridging ELISA) were obtained at baseline (BL), 2 months (2M), 3 months (3M), 6 months (6M), 12 months (12M), and 24 months (24M). Patients with therapy failure requiring ADA withdrawn had their sera evaluated at their last medical visit prior to biologic switch (blinded to ADA and AAA levels). RESULTS: AAA was absent at BL, first detected at 2M after ADA initiation in 2/30 (7%) patients with a significant increase at 3M (10/29 (34%), p = 0.013) and no major change in 6M (11/30 (37%)) and 12M (9/26 (35%)). Of note, at 3M, AAA levels correlated negatively with ADA levels (r = - 0.781, p = 0.0001). Analysis of BL predictors revealed a significantly higher risk of developing AAA in patients with female gender (OR 21; 95% CI 1.08-406.57; p = 0.044), ESR > 30 mm/1st hour (OR 5.44; 95% CI 1.04-28.53; p = 0.045), and leflunomide use (OR 9.33; 95% CI 1.51-57.66; p = 0.016). In contrast, concomitant use of methotrexate was protective for AAA appearance (OR 0.08; 95% CI 0.01-0.53; p = 0.009). After 12M of ADA, 60% of AAA-positive patients required drug switch for drug failure compared with 15% in AAA-negative group (p = 0.03). CONCLUSIONS: This study provides novel evidence of AAA production kinetics demonstrating a timely significant increase starting at 3M and stable throughout 24M. We also identified female gender, increased ESR, and leflunomide use as relevant risk factors for AAA production at BL, whereas methotrexate was protective. Early systematic monitoring of AAA at 3M may, therefore, guide drug switching in these patients.Key Points• Anti-adalimumab antibodies (AAA) production kinetics demonstrated a timely significant increase starting at 3M in juvenile idiopathic arthritis (JIA) patients under adalimumab therapy• Female gender, increased ESR, and leflunomide use were identified as relevant risk factors for AAA production in JIA, whereas methotrexate was protective.

Proposition of a novel animal model of systemic sclerosis induced by type V collagen in C57BL/6 mice that reproduces fibrosis, vasculopathy and autoimmunity.

BACKGROUND: Type V collagen (Col V) has the potential to become an autoantigen and has been associated with the pathogenesis of systemic sclerosis (SSc). We characterized serological, functional, and histopathological features of the skin and lung in a novel SSc murine model induced by Col V immunization. METHODS: Female C57BL/6 mice (n = 19, IMU-COLV) were subcutaneously immunized with two doses of Col V (125 µg) emulsified in complete Freund adjuvant, followed by two intramuscular boosters. The control group (n = 19) did not receive Col V. After 120 days, we examined the respiratory mechanics, serum autoantibodies, and vascular manifestations of the mice. The skin and lung inflammatory processes and the collagen gene/protein expressions were analyzed. RESULTS: Vascular manifestations were characterized by endothelial cell activity and apoptosis, as shown by the increased expression of VEGF, endothelin-1, and caspase-3 in endothelial cells. The IMU-COLV mice presented with increased tissue elastance and a nonspecific interstitial pneumonia (NSIP) histologic pattern in the lung, combined with the thickening of the small and medium intrapulmonary arteries, increased Col V fibers, and increased COL1A1, COL1A2, COL3A1, COL5A1, and COL5A2 gene expression. The skin of the IMU-COLV mice showed thickness, epidermal rectification, decreased papillary dermis, atrophied appendages, and increased collagen, COL5A1, and COL5A2 gene expression. Anti-collagen III and IV and ANA antibodies were detected in the sera of the IMU-COLV mice. CONCLUSION: We demonstrated that cutaneous, vascular, and pulmonary remodeling are mimicked in the Col V-induced SSc mouse model, which thus represents a suitable preclinical model to study the mechanisms and therapeutic approaches for SSc.

Autoantibody profile in the experimental model of scleroderma induced by type V human collagen.

UNLABELLED: The aim of this study is to evaluate the humoral autoimmune response in the experimental model of systemic sclerosis (SSc) induced by human type V collagen (huCol V). New Zealand rabbits were immunized with huCol V in Freund's complete adjuvant (FCA) and boosted twice with 15 days intervals with huCol V in Freund's incomplete adjuvant. Control groups included animals injected only with FCA or bovine serum albumin. Bleeding was done at days 0, 30, 75 and 120. Tissue specimens were obtained for histopathological investigation. Serological analysis included detection of antibodies against huCol V and anti-topoisomerase I (Anti-Scl70) by enzyme-linked immunosorbent assay, antinuclear antibodies (ANA) by indirect immunofluorescence, and rheumatoid factor (RF) by a latex agglutination test. Target antigens were characterized by immunoblot. Histological analysis revealed extracellular matrix remodeling with fibrosis and vasculitis. Anti-Scl70 and ANA were detected as early as 30 days in all huCol V animals. The universal ANA staining pattern was Golgi-like. This serum reactivity was not abolished by previous absorption with huCol V. Characterization of the target antigen by immunoblot revealed two major protein fractions of 175,000 and 220,000 MW. Similarly to ANA, there was a gradual increase of reactivity throughout the immunization and also it was not abolished by preincubation of serum samples with huCol V. RF testing was negative in hyperimmune sera. CONCLUSION: The production of autoantibodies, including anti-Scl70, a serological marker for SSc associated with histopathological alterations, validates huCol V induced-experimental model and brings out its potential for understanding the pathophysiology of SSc.

Perfil demográfico, clínico e laboratorial de 100 pacientes com lúpus eritematoso sistêmico no Estado da Bahia / Demographic, clinical, and laboratory profile of 100 patients with systemic lupus erythematosus in the State of Bahia

Objetivos: Descrever as características demográficas, clínicas e laboratoriais de pacientes com LES em acompanhamento em serviço de referência no Estado da Bahia. Desenho do estudo: Descritivo, tipo corte transversal. Análise dos dados: Foram utilizados os testes do qui-quadrado e t de student para testar diferenças entre variáveis categóricas e contínuas, respectivamente. A comparação entre mais de duas médias foi feita através do teste F (ANOVA). Resultados: Cem pacientes, sendo 97 por cento mulheres, participaram do estudo. Entre esses, 62 eram mulatos, 22 brancos e 16 negros. A média de idade de ínicio da doença foi de 28,1 anos (7-55 anos). Comprometimentos das articulações e da pele foram as manifestações clínicas mais frequentes (97 e 87 por cento, respectivamente), seguidas pelas alterações hematológicas (57 por cento), renais (39 por cento), de serosas (27 por cento) e neurológicas (26 por cento). Houve maior frequência de nefropatia na raça branca. O FAN foi positivo em 100 por cento dos pacientes, anti-RNP em 34 por cento, anti-SSA em 20 por cento, anti-dsDNA em 17 pr cento, anti-Sm em 13 por cento e anti-SSB em 2 por cento. Anti-RNP foi mais frequente na raça negra. O anti-dsDNA apresentou associação com nefropatia, vasculites e eritema malar: e o anti RNP, associação com úlcera de mucosas e o anti-SSA com comprometimento mucocutâneo. Conclusão: O LES foi três vezes mais frequente entre as mulheres que na maioria dos relatos de literatura; as frequências dos comprometimentos clínicos foram semelhantes às das encontradas por outros autores; não houve predomínio da doença na raça negra; houve maior prevalência de nefropatia entre os pacientes brancos; o anti-RNP foi mais frequente entre os doentes negros e mulatos