Alejandro Souto

Lipid Profile Changes in Patients With Chronic Inflammatory Arthritis Treated With Biologic Agents and Tofacitinib in Randomized Clinical Trials: A Systematic Review and Meta-Analysis

To analyze lipid changes in patients with rheumatoid arthritis (RA) and patients with spondyloarthritis (SpA) treated with biologic agents or tofacitinib in randomized clinical trials (RCTs).

Risk of tuberculosis in patients with chronic immune-mediated inflammatory diseases treated with biologics and tofacitinib: a systematic review and meta-analysis of randomized controlled trials and long-term extension studies

OBJECTIVE The aim of this study was to assess the risk of active tuberculosis (TB) in patients with immune-mediated inflammatory diseases treated with biologics and tofacitinib in randomized controlled trials (RCTs) and long-term extension (LTE) studies. METHODS A systematic review of the English-language literature by was performed by searching the Medline, Embase, Cochrane and Web of Knowledge databases. The search strategy focused on synonyms of diseases, biologics and tofacitinib. Data from RCTs were combined to assess the rate of TB using a random effects model. The incidence rate (IR) of TB and its association with disease, location and treatment were assessed in LTE studies. RESULTS The search captured 11 130 articles and abstracts. One-hundred RCTs (75 000 patients) and 63 LTE studies (80 774.45 patient-years) met the inclusion criteria. There were 31 TB cases with TNF inhibitors, 1 with abatacept and none with rituximab, tocilizumab, ustekinumab or tofacitinib. The odds ratio for TNF inhibitors was 1.92 (95% CI 0.91, 4.03, P = 0.085). In LTE studies, the IR of TB was >40/100 000 with tofacitinib and all biologics except rituximab. IR was higher in RA patients with anti-TNF monoclonal antibodies [307.71 (95% CI 184.79, 454.93)] than in those with rituximab [20.0 (95% CI 0.10, 60)] and etanercept [67.58 (95% CI 12.1, 163.94)] or AS, PsA and psoriasis with etanercept [60.01 (95% CI 3.6, 184.79)]. The IR of TB was higher in high-background TB areas. CONCLUSION RCTs are not sensitive enough to assess the risk of reactivation of latent TB infection (LTBI). Disease, treatment and background TB rate are associated with different frequencies of active TB. The benefit/risk balance of preventing reactivation of LTBI in different backgrounds should be considered in clinical practice.

Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases

OBJECTIVES To assess the proportion of RA patients who discontinued biologics in world registries and health care databases and to identify causes and predictors of discontinuation. METHODS Medline, Embase, Cochrane Library and Web of Science electronic databases and ACR and EULAR meeting abstracts were used. The selection of studies from world registries and health care databases including RA patients treated with biologics was independently performed. Data extracted from articles and abstracts were combined using a random effects model. Meta-analyses of percentages and hazard ratios were used to assess discontinuation. RESULTS Ninety-eight studies with >200 000 patients from 11 242 articles and 119 abstracts met the inclusion criteria. Overall discontinuation rates of TNF inhibitors at 0.5, 1, 2, 3 and 4 years were 21, 27, 37, 44 and 52%, respectively. Discontinuation of etanercept was significantly lower at 3 and 4 years (35% and 41%, respectively) than infliximab and adalimumab (46% and 52%, respectively). Predictors of time to discontinuation were etanercept [hazard ratios (HRs) 0.58 and 0.77 versus infliximab and adalimumab, respectively), concomitant use of DMARDs (HR 0.77), disease duration (HR 1.01) and female sex (HR 1.18). Studies from registries conducted after 2005 and from countries with lower biologics access showed higher percentages of discontinuation. Relevant data on abatacept and tocilizumab were missing. CONCLUSION In RA, treatment with etanercept has a lower percentage of discontinuation than infliximab and adalimumab. Concomitant use of DMARDs, disease duration before treatment with a biologic and female sex predict time to discontinuation.

Predictors of response to TNF antagonists in patients with ankylosing spondylitis and psoriatic arthritis: systematic review and meta-analysis.

Objective To identify predictors of response to tumor necrosis factor (TNF) antagonists in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Methods Systematic review and meta-analysis of clinical trials and observational studies based on a systematic search. Meta-analyses of similar observations were performed using random effects computing summary OR. Heterogeneity was tested using I2, and risks of bias using funnel plots and the Egger test. Meta-regression was used to explore causes of heterogeneity. Results The electronic search captured 1340 references and 217 abstracts. 17 additional articles were identified after searching by hand. A total of 59 articles meet the purpose of the study and were reviewed. 37 articles (33 studies) included 6736 patients with AS and 23 articles (22 studies) included 4034 patients with PsA. 1 article included data on AS and PsA. Age (OR (95% CI) 0.91 (0.84 to 0.99), I2=84.1%), gender (1.57 (1.10 to 2.25), I2=0.0%), baseline BASDAI (1.31 (1.09 to 1.57), I2=0.0%), baseline BASFI (0.86 (0.79 to 0.93), I2=24.9%), baseline dichotomous C reactive protein (CRP) (2.14 (1.71 to 2.68), I2=22.3%) and human leucocyte antigen B27 (HLA-B27) (1.81 (1.35 to 2.42), I2=0.0%) predict BASDAI50 response in AS. No factor was identified as a source of heterogeneity. Only meta-analysis of baseline BASFI showed risk of publication bias (Egger test, p=0.004). Similar results were found for ASAS criteria response. No predictors of response were identified in PsA. Conclusions Young age, male sex, high baseline BASDAI, low baseline BASFI, high baseline CRP and HLA-B27 predict better response to TNF antagonists in AS but not in PsA.

Apremilast for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the joints that occurs in patients with psoriasis. The spectrum of PsA includes arthritis, dactylitis, enthesitis, axial involvement, and skin lesions. Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and leflunomide, and biologic DMARDs such as tumor necrosis factor (TNF) antagonists and ustekinumab, have been used to treat PsA. Apremilast is a novel therapy that inhibits phosphodiesterase 4, increases intracellular cAMP levels, and modulates expression of inflammatory mediators in favor of anti-inflammatory activity. It decreases the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-23 and increases the anti-inflammatory cytokine IL-10 under certain conditions. One phase II and four phase III clinical trials as well as long-term extension studies showed significant and sustained clinical efficacy and an adequate safety profile for apremilast in patients with active psoriatic arthritis.

Artritis séptica por Sphingomonas paucimobilis en un paciente inmunocompetente

Septic arthritis is an inflammatory joint disease produced by invasion and multiplication of pathogenic microorganisms. Most cases of septic arthritis are caused by microorganisms of the genus Staphylococcus and Streptococcus. Non-fermenting Gramnegative bacilli (Pseudomonas, Stenotrophomonas, Acinetobacter, and Burkholderia) are a frequent causes of nosocomial infection associated with immunosuppression situations, and Sphingomonas paucimobilis (S. paucimobilis) (formerly Pseudomonas paucimobilis) is also a Gram-negative aerobic fermentor that now emerges as an opportunistic pathogen. We present a case of septic arthritis by S. paucimobilis in a 41year-old man with a history of frequent episodes of hyperuricemia and gout in his left knee. In the past year, he presented several episodes of acute monoarthritis treated with nonsteroidal antiinflammatory drugs, colchicine, and intraarticular infiltration of triamcinolone. The patient presented with symptoms of pain and swelling of left knee which had lasted for 3 months without fever. Physical examination showed: temperature 36.5 ◦C and left knee arthritis with preserved but painful active and passive mobility. Arthrocentesis was performed, resulting in inflammatory synovial fluid, without evidence microcrystals under the polarized light microscope. The fluid was sent to the microbiology department in a sterile syringe and blood culture bottles for aerobic and anaerobic culture. Gram stain showed abundant polymorphonuclear leukocytes and intracellular Gram-negative bacilli, and the culture-negative bacilli isolated were identified as S. paucimobilis by ID32GN Api (bioMerieux, Marcy L’etoile 3. France), sensitive to beta-lactams, aminoglycosides, quinolones, and cotrimoxazole. Laboratory analysis upon the patient’s admission showed 8070 leukocytes/L (70% neutrophils and 30% lymphocytes), erythrocyte sedimentation rate of 42 mm the first hour and CRP 8.04 mg/dl. CBC, coagulation, and biochemistry were normal. Echocardiogram was normal and Xrays showed a slight increase in soft tissue suprarrotulian density, indicative of effusion; the CT with intravenous contrast observed loosening of articular recesses, with slight enhancement of the synovium. Daily articular drainage was performed and the patient was treated with ceftazidime (6 g/24 h) plus gentamicin (240 mg/24 h),

Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis

OBJECTIVE To summarize and compare the risks of malignancies accompanying biologic DMARDs (b-DMARDs) and tofacitinib in rheumatoid arthritis (RA) in randomized clinical trials (RCTs) and long-term extension studies (LTEs). METHODS Articles in Medline, Embase, Cochrane Library, and the Web of Science dated from 2000 to February 2015. Selection criteria were as follows: (1) focus on RCTs or LTEs in RA; (2) treatment with b-DMARDs or tofacitinib; (3) data on malignancies; and (4) a minimum follow-up of 12 weeks. Data included publication details, study design, risk of bias, number and types of malignancies, and patient characteristics and treatments. DATA SYNTHESIS Of 113 articles and one updated report that were meta-analyzed, overall malignancies in RCTs showed odds ratio (95% confidence intervals) of 1.01 (0.72, 1.42) for all TNF antagonists, 1.12 (0.33, 3.81) for abatacept, 0.54 (0.20, 1.50) for rituximab, 0.70 (0.20, 2.41) for tocilizumab, and 2.39 (0.50, 11.5) for tofacitinib. Network meta-analysis of overall malignancies showed odds ratio (95% predictive intervals) of 1.68 (0.48-5.92) for infliximab, 0.79 (0.44-1.40) for etanercept, 0.93 (0.43-2.03) for adalimumab, 0.87 (0.28-2.75) for certolizumab, 0.87 (0.39-1.95) for golimumab, 1.04 (0.32-3.32) for abatacept, 0.58 (0.21-1.56) for rituximab, 0.60 (0.16-2.28) for tocilizumab, and 1.15 (0.24-5.47) for tofacitinib. Marginal numerical differences in the incidence rate of solid and hematological malignancies and non-melanoma skin cancers appeared in LTEs. CONCLUSIONS In RCTs, treatment of RA with b-DMARDs or tofacitinib does not increase the risk for malignancies. Generalizability of the differences in the rate of specific malignancies encountered in LTEs requires continuous pharmacovigilance of real-world patients.