Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX). METHODS: This 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities. RESULTS: The proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms. CONCLUSIONS: Filgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab. TRIAL REGISTRATION NUMBER: NCT02889796.

Efficacy and safety of pateclizumab (anti-lymphotoxin-α) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study).

INTRODUCTION: Tumor necrosis factor (TNF) and, possibly, lymphotoxin alpha (LTα) signaling contribute to inflammation and rheumatoid arthritis (RA) pathogenesis. Pateclizumab (anti-lymphotoxin- alpha; MLTA3698A) is a humanized monoclonal antibody that blocks and depletes anti-LTα. This phase 2, randomized, head-to-head, active- and placebo-controlled trial examined the safety and efficacy of pateclizumab compared to adalimumab in RA patients with an inadequate response to disease-modifying antirheumatic drugs (DMARD-IR). METHODS: Patients (n = 214) with active RA (≥ 6 swollen and tender joints, C-reactive protein ≥ 10 mg/L) on oral DMARDs were randomized (2:2:1) to receive pateclizumab 360 mg, adalimumab 40 mg, or placebo subcutaneously every 2 weeks. The primary endpoint, 4-variable, 28-joint disease activity score erythrocyte sedimentation rate (DAS28(4)-ESR) response, was evaluated at 12 weeks using an analysis of covariance (ANCOVA) model with adjustments for concomitant DMARD use and geographic region. Secondary efficacy endpoints included American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses at Day 85. Pharmacokinetics, pharmacodynamics, and immunogenicity of pateclizumab were assessed. RESULTS: Pateclizumab reduced the DAS28(4)-ESR response (-1.89) at 12 weeks, however, this did not reach statistical significance compared to placebo (-1.54), while adalimumab (-2.52) differed significantly from both placebo and pateclizumab. Pateclizumab 12-week ACR20, ACR50 and ACR70 response rates (64%, 33%, and 14%) suggested clinical activity but were not statistically significant compared to placebo rates (46%, 24%, and 8%, respectively). CXCL13 serum levels decreased significantly following pateclizumab and adalimumab administration, demonstrating pharmacological target engagement by both drugs. Overall, adverse events (AEs) were comparable among all cohorts. Infections were the most common AE, occurring with comparable frequency in all groups. Serious AEs occurred in 0% of pateclizumab, 5.9% of adalimumab, and 2.3% of placebo patients, with serious infection in 2.3% of adalimumab patients and none in pateclizumab and placebo patients. CONCLUSIONS: Pateclizumab had a good safety profile in patients inadequately responsive to DMARDs, but no statistically significant improvement in RA signs and symptoms after 12 weeks of treatment. Adalimumab demonstrated efficacy and safety comparable to published results in this head-to-head comparison in DMARD-IR RA patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01225393, Registered 18 October 2010.

Open-label observation of addition of etanercept versus a conventional disease-modifying antirheumatic drug in subjects with active rheumatoid arthritis despite methotrexate therapy in the Latin American region.

BACKGROUND: Previous global studies examined etanercept (ETN) + methotrexate (MTX) for treatment of rheumatoid arthritis (RA), but included few subjects from Latin America. OBJECTIVE: The objective of this study was to compare the safety and efficacy of ETN + MTX versus a standard-of-care disease-modifying antirheumatic drug (DMARD) + MTX in Latin American subjects with moderate to severe active RA despite MTX therapy. METHODS: This open-label, active-comparator study (NCT00848354) randomized subjects 2:1 to ETN 50 mg/wk + MTX or investigator-selected DMARD (sulfasalazine or hydroxychloroquine) + MTX (ETN + MTX, n = 281; DMARD + MTX, n = 142). The primary end point was the proportion achieving American College of Rheumatology (ACR) 50 at week 24. Secondary end points included ACR20/70, disease activity score (DAS) 28 measures, and mean change in modified total Sharp score. Patient-reported outcomes were the Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment: RA (WPAI:RA), and Caregiver Burden and Resource Utilization. Statistical analyses were stratified by country; χ test and analysis of covariance were used. Adverse events were monitored. RESULTS: More subjects achieved ACR50 at week 24 with ETN + MTX versus DMARD + MTX (62% vs 23%, respectively), in addition to secondary end points (P < 0.0001 for all); mean change in modified total Sharp score was lower for the ETN + MTX group (0.4 vs 1.4, respectively; P = 0.0270). Improvements in patient-reported outcomes favored ETN + MTX for Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale for depression, WPAI:RA, and Caregiver Burden and Resource Utilization emergency department visits for RA (P < 0.01). Overall, adverse events were similar between the groups (69% vs 68%,); serious adverse events were also similar (4% vs 1%). The rate of overall infections was higher with ETN + MTX (38%) than DMARD + MTX (22%, P ≤ 0.001). CONCLUSIONS: Consistent with published global data among RA patients with inadequate response to MTX, adding ETN to MTX demonstrated better efficacy than adding one other conventional DMARD to MTX. No new safety issues were observed. ETN + MTX provided favorable benefit-risk profile among RA patients from LA region.

Utility of stool sample-based tests for the diagnosis of Helicobacter pylori infection in children.

OBJECTIVE: Helicobacter pylori antigen or DNA in stool are meant to detect the bacteria; however, in children the colonization of the gastric mucosa by H pylori is usually weak and fecal excretion of antigen or DNA varies considerably, challenging the utility of these tests in this age group. The aim of the present study was to carry out a systematic review and meta-analysis to evaluate the performance of stool H pylori DNA and antigen tests for the diagnosis of infection in children. METHODS: We conducted a systematic review and meta-analysis to assess the accuracy of stool tests for diagnosis of H pylori infection in children. We searched PubMed, EMBASE, and LILACS databases. Selection criteria included participation of at least 30 children and the use of a criterion standard for H pylori diagnosis. In a comprehensive search, we identified 48 studies. RESULTS: Regarding antigen-detection tests, enzyme-linked immunosorbent assay (ELISA) monoclonal antibodies showed the best performance, with sensitivity and specificity of 97%, positive likelihood ratio (LR+) of 29.9, and negative likelihood ratio (LR-) of 0.03. ELISA polyclonal antibodies had sensitivity of 92%, specificity of 93%, LR+ of 16.2, LR- of 0.09, and high heterogeneity (P < 0.0001). One-step monoclonal antibody tests demonstrated sensitivity of 88%, specificity of 93%, LR+ of 10.6, and LR- of 0.11. For DNA detection, polymerase chain reaction-based test showed sensitivity of 80.8%, specificity of 98%, LR+ of 17.1, and LR- of 0.18. CONCLUSIONS: Detection of H pylori antigen in stools with ELISA monoclonal antibodies is a noninvasive efficient test for diagnosis of infection in children. One-step tests showed low accuracy and more studies are needed to obtain a useful office-based screening test. The available molecular tests are still unreliable.

Effect of the vehicle on the topical itraconazole efficacy for treating corneal ulcers caused by Aspergillus fumigatus.

BACKGROUND: The clinical behaviour of mycotic keratitis is aggressive, and the options for treating it are limited. This poses a need to explore new options for efficacious, low-cost treatment. Recent evidence suggests that topical itraconazole may be useful for treating this entity and that it may be possible to improve its efficacy using a suitable vehicle. METHODS: We included 12 New Zealand white (NZW) rabbits (24 eyes). The rabbits were infected with pathogenic strains of Aspergillus fumigatus and subsequently randomized to receive every 2 h for 5 weeks two different preparations of topical itraconazole 1%. In group 1 (12 eyes), ricinus oil and in group 2 (12 eyes), Systane were used as vehicle. Rabbits were evaluated every week by a masked ophthalmologist to determine the treatment response. RESULTS: The size of the ulcers was similar in the two groups at the baseline: group 1: 12.7 +/- 2.7 mm (median 12.8, range 9.8-15.5 mm); and group 2: 12.3 +/- 3.1 mm (median 12.1, range 9.8-20.8; P = 0.67). Although both groups responded well to the treatment, the response was better in the group 2, especially in weeks 2 and 3: week 1: 12.7 +/- 2.7 vs. 9.3 +/- 4.61 mm (P = 0.1); week 2: 9.4 +/- 3.4 vs. 4.1 +/- 2.9 mm (P = 0.004); week 3: 5.0 +/- 3.4 vs. 1.7 +/- 1.0 mm (P = 0.004); week 4: 1.9 +/- 1.9 vs. 1.0 +/- 1.2 mm (P = 0.1); and week 5: 0.68 +/- 1.2 vs. 0.0 +/- 0.0 mm (P = 0.3). CONCLUSION: Topical itraconazole may be useful for treating corneal ulcers caused by Aspergillus fumigatus, and its efficacy seems to be related with the vehicle solubility.

Vitiligo improvement in a patient with ankylosing spondylitis treated with infliximab.

Ankylosing spondylitis (AS) is a disabling disease affecting the enthesis and joints of the spine and peripheral sites. Tumour necrosis factor alpha (TNF-alpha) is a proinflammatory mediator which plays a significant role in the pathogenesis of AS. Infliximab (a chimeric monoclonal antibody which blocks the activity of TNF-alpha) is one of the most effective therapies of AS thus far. Vitiligo is a depigmenting disorder of the skin of unknown aetiology affecting 0.5-1% of the population. Here we describe the effect of infliximab on vitiligo in a patient with AS.

Weekly dose of leflunomide for the treatment of refractory rheumatoid arthritis: an open pilot comparative study.

AIMS: To assess the therapeutic effect of leflunomide in weekly dose of 100 mg in patients with refractory rheumatoid arthritis. MATERIAL AND METHODS: Sixteen patients were included (18-72 years, disease duration 2-32 years). Eight patients received a weekly dose of 100 mg of leflunomide and 8 the conventional dose. Current treatment was not modified. All patients underwent a monthly evaluation for one year, applying the 1995 ACR preliminary definition of improvement in rheumatoid arthritis. RESULTS: After 2 months, the group treated with the conventional leflunomide dose evidenced a remarkable improvement (7/8 patients achieving ACR 20), while the group receiving the weekly dose, the improvement was not as clearly evident (3/8 patients achieving ACR 20). By the fourth to sixth month, the response was comparable on both groups (6/6 and 6/8 patients achieving ACR 50 in the daily and weekly dose, respectively) and prevailed through the end of the study. There were no statistical differences between groups at any evaluation. Side effects made itself clear in 6 patients in the daily leflunomide group, and 2 patients withdrawn leflunomide because severe gastrointestinal symptoms and hepatotoxicity, respectively. In the group of weekly leflunomide 2 patients presented side effects which disappeared spontaneously. CONCLUSION: The use of leflunomide in a weekly dose of 100 mg proved to have similar therapeutic benefit as that of the conventional scheme and might represent a new option for the treatment of refractory rheumatoid arthritis patients.

Serum hyperviscosity syndrome responding to therapeutic plasmapheresis in a patient with primary Sjögren's syndrome.

Hyperviscosity syndrome is a disorder first described in patients with Waldenström's macroglobulinemia and is not commonly seen in rheumatic diseases. Its association with Sjögren's syndrome is very rare and it has been reported in very few patients. We report the case of a patient with primary Sjögren's syndrome presenting as hyperviscosity syndrome who was successfully treated with therapeutic plasma exchange.

Terapia biológica en artritis reumatoide / Biologic theraphy in rheumatoid arthritis

La artritis reumatoide es una enfermedad autoinmune de causa desconocida que afecta aproximadamente al 2 por ciento de la población económicamente activa, por lo cual representa un problema de salud pública. El tratamiento con drogas citotóxicas ha permitido mejorar la calidad de vida de estos pacientes; sin embargo todavía existe un número importante que no responde o que tiene poca tolerancia a esta modalidad de tratamiento. El avance de la biotecnología ha permitido el surgimiento de una nueva modalidad de tratamiento conocida como terapia biológica; la cual ha creado expectativas interesantes sobre su efecto en pacientes con artritis reumatoide. El objetivo de esta publicación, es revisar las diferentes modalidades de esta terapia y los resultados iniciales en pacientes con artritis reumatoide.

¿Cuál es la definición de Rhupus? / What is the Rhupus definition?

En los últimos 30 años se han descrito cuando menos 50 casos de coexistencia de artritis reumatoide y lupus eritematoso generalizado (Rhupus), pero hasta la fecha no se han establecido parámetros claros para definir esta entidad. Esto ha llevado a confusiones y a cuestionar sí realmente existe el Rhupus. El objetivo de esta revisión es establecer las bases de la definición del Rhupus.