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Favalli E.G.,University of Milan | Pregnolato F.,Experimental Laboratory of Immunological and Rheumatologic Researches | Biggioggero M.,University of Milan | Meroni P.L.,University of Milan
Therapeutic Advances in Musculoskeletal Disease | Year: 2012

Objectives: All biologic agents approved for the treatment of rheumatoid arthritis (RA) have been tested versus methotrexate (MTX) for efficacy on damage progression in several randomized clinical trials (RCTs), but direct head-to-head comparisons have never been conducted. The purpose of this investigation is to analyse data coming from main RA RCTs and to perform an indirect comparison. Methods: A systematic review of literature from 1988 to 2011 was conducted. Only randomized, double-blind, controlled, comparative trials, with evaluation of radiographic progression were included. The radiographic score was standardized and mean difference in the percentage of the annual radiographic progression rate was used as the effect measure. Heterogeneity between studies was estimated by I2 test. For each trial, the effect was plotted according to its standard error in a funnel plot. Results: Of 44 potentially relevant trials, 12 RCTs were included in the study. In order to optimize RCTs comparison, studies were stratified in early and late RA group. Main population characteristics were similar in both early and late RA groups, whereas the standardized baseline radiographic score value significantly differs among trials in both early (range 2.7-21.9) and late (range 23.46-75) RA groups. The standardized annual estimated progression is similar across the late RA group. Strong evidence of heterogeneity (I2 = 97%, p = 0.00001) but no asymmetry of the funnel plot was observed in the early RA group. Total mean difference was -16.28 (95% confidence interval [CI] -24.42 to -8.14). For the late RA group a random model was used (I2 = 99%, p = 0.00001) and a total mean difference of -39.25 (95% CI -53.77 to -24.73) was found. Conclusions: All biologic agents provide a favourable effect on disease progression both in early and late RA. The significant heterogeneity among various RCTs did not allow an effective comparison of the performance of biologic agents in each study. © The Author(s), 2012. Source

Gerosa M.,University of Milan | Schioppo T.,University of Milan | Meroni P.L.,University of Milan | Meroni P.L.,Experimental Laboratory of Immunological and Rheumatologic Researches
Expert Opinion on Pharmacotherapy | Year: 2016

ABSTRACT: Introduction: Rheumatoid arthritis (RA) can spontaneously improve during pregnancy. However, a considerable proportion of patients can experience a flare and high disease activity has been associated with an increased risk of adverse pregnancy outcome. Thus, the treatment of RA in pregnant women should be selected taking into account both the potential harmful effects of the treatment and the risk associated with discontinuation. Areas covered: Recent publications regarding safety of the most important disease modifying anti-rheumatic drugs (DMARDs) during pregnancy has been reviewed. A systematic literature search of MEDLINE was conducted using pregnancy, teratogenicity, adverse effects, embryo/foetal-toxicity as key search terms for each DMARD. Expert opinion: A great body of evidence suggest that hydroxychloroquine, sulfasalazine, and non-fluorinated steroids can be continued throughout pregnancy, while methotrexate and leflunomide should be discontinued 3 months before pregnancy. Continuation of TNFi during the first part of pregnancy should be considered when benefits outweigh the potential risk of teratogenicity. Data regarding other biologics are scant and, at present, they should be stopped before pregnancy. © 2016 Informa UK Limited, trading as Taylor & Francis Group. Source

Favalli E.G.,Gaetano Pini Institute | Pregnolato F.,Experimental Laboratory of Immunological and Rheumatologic Researches | Biggioggero M.,Gaetano Pini Institute | Biggioggero M.,University of Milan | And 2 more authors.
Seminars in Arthritis and Rheumatism | Year: 2014

Objectives: To indirectly compare the 12-month effects of available biologic agents in slowing RA radiographic progression. Methods: A systematic review of literature of randomised, double-blind, controlled trials (RCTs) evaluating RA radiographic progression as end point was conducted using a PubMed searching of MEDLINE from January 1995 to May 2012. For each trial, the mean change from baseline of the standardised annual radiographic progression score (weighted for estimated annual progression rate) was estimated, and the effect size was calculated as the difference between biologic and non-biologic-treated groups. In order to optimise data homogeneity and improve RCTs comparison, a mixed-effect model was applied including previous responsiveness to methotrexate (MTX-experienced or MTX-naïve populations) and period of study enrolment as moderators. Results: The PubMed search resulted in 183 references, and 14 were eligible for the meta-analysis. The analysis of study distribution in forest plots showed a high correlation between the study period of enrolment and the impact of biological therapy in both MTX-naïve and MTX-experienced subgroups. In particular, effect size was the highest for older trials and progressively decreased in the most recent ones, suggesting a highest propensity to radiographic progression in populations enroled in older trials. Some statistically significant differences among RCTs were found in both subgroups but were significantly biased by the different propensity to radiographic progression due to period of enrolment. Conclusions: Our meta-analysis demonstrated that period of enrolment deeply influence study population propensity to radiographic progression in each trial. This finding does not allow the indirect comparison of various biologic agents, despite our mixed-model significantly reducing heterogeneity among RCTs. © 2014 Elsevier Inc. Source

Favalli E.G.,Gaetano Pini Institute | Pregnolato F.,Experimental Laboratory of Immunological and Rheumatologic Researches | Biggioggero M.,University of Milan | Becciolini A.,Gaetano Pini Institute | And 3 more authors.
Arthritis Care and Research | Year: 2016

Objective To evaluate the 12-year survival of the first tumor necrosis factor inhibitor (TNFi) treatment in a cohort of rheumatoid arthritis (RA) patients, comparing the between-groups discontinuation rates for infliximab, etanercept, and adalimumab. Methods RA patients treated with their first TNFi were investigated from a local registry. Before and after adjusting for propensity scores, overall and by individual TNFi 12-year drug retention was evaluated. Drug survival rates were calculated using the Kaplan-Meier method and compared by the Cox extended model. Subanalyses were performed according to concomitant methotrexate (MTX) and discontinuation reasons. Results Of 583 patients, 222 were treated with infliximab, 179 with etanercept, and 182 with adalimumab; 33.7% and 26% discontinued the first TNFi because of inefficacy or adverse events, respectively. The overall 12-year drug survival rate for the unmatched population was 23.4%. In the propensity score-adjusted population, the hazard ratio (HR) for treatment discontinuation was significantly greater for adalimumab and infliximab versus etanercept (HR 2.89 [95% confidence interval (95% CI) 2.2-3.78] and HR 2.56 [95% CI 1.92-3.4], respectively), and no difference was found between and for adalimumab versus infliximab (HR 1.16 [95% CI 0.91-1.47]). The incidence of withdrawal due to secondary inefficacy was stable from 3 to 12 years for etanercept, but progressively increased for the monoclonal antibodies. Concomitant MTX significantly increased the survival of both adalimumab and etanercept (HR 1.48 [95% CI 1.18-1.86]). Conclusion The overall 12-year drug survival rate was 23.4%, being significantly higher for etanercept than adalimumab and infliximab. Etanercept discontinuations for inefficacy did not increase from 3 to 12 years. Concomitant MTX increased adalimumab and etanercept drug survival. © 2016, American College of Rheumatology. Source

Brembilla N.C.,University of Geneva | Montanari E.,University of Geneva | Truchetet M.-E.,University of Geneva | Raschi E.,Experimental Laboratory of Immunological and Rheumatologic Researches | And 3 more authors.
Arthritis Research and Therapy | Year: 2013

Introduction: T helper (Th)-17 cells are increased in systemic sclerosis (SSc). We therefore assessed whether Th17 cells could modulate the inflammatory and fibrotic responses in dermal fibroblasts from healthy donors (HD) and SSc individuals.Methods: Fibroblasts were obtained from 14 SSc and 8 HD skin biopsies. Th17 clones were generated from healthy peripheral blood upon enrichment of CC chemokine receptor (CCR)-4/CCR6/CD161 expressing cells. Their cytokine production was assessed by flow cytometry and multiplex beads immunoassay. Fibroblast production of monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8, matrix metalloproteinase (MMP)-1, tissue inhibitor of metalloproteinase (TIMP)-1, MMP-2 and type-I collagen was quantified by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), and changes in their transcription levels assessed by real-time PCR. Intracellular signals were dissected by western blot and the use of pharmacological inhibitors. IL-17A, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) blocking reagents were used to assess the specificity of the observed effects.Results: IL-17A increased MCP-1, IL-8 and MMP-1 production in a dose-dependent manner while having no effect on type I collagen in HD and SSc fibroblasts both at protein and mRNA levels. Nuclear factor-kappa B (NF-κB) and p38 were preferentially involved in the induction of MCP-1 and IL-8, while MMP-1 was most dependent on c-Jun N-terminal kinase (JNK). Supernatants of activated Th17 clones largely enhanced MCP-1, IL-8 and MMP-1 while strongly inhibiting collagen production. Of note, the production of MCP-1 and IL-8 was higher, while collagen inhibition was lower in SSc compared to HD fibroblasts. The Th17 clone supernatant effects were mostly dependent on additive/synergistic activities between IL-17A, TNF and in part IFN-γ. Importantly, the inhibition of type I collagen production induced by the Th17 clone supernatants was completely abrogated by blockade of IL-17A, TNF and IFN-γ mostly in SSc fibroblasts, revealing an intrinsic resistance to inhibitory signals in SSc.Conclusions: Our findings demonstrate that in vitro Th17 cells elicit pro-inflammatory responses while restraining collagen production. Thus, the increased Th17 cell number observed in SSc may impact on the inflammatory component of the disease simultaneously potentially providing a protective role against fibrosis. © 2013 Brembilla et al.; licensee BioMed Central Ltd. Source

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