Eva Salgado

Immunogenicity of Monoclonal Antibodies Against Tumor Necrosis Factor Used in Chronic Immune-Mediated Inflammatory Conditions: Systematic Review and Meta-analysis

IMPORTANCE Knowledge of the immunogenicity of biologic agents may be helpful for the development of strategies for treatment of chronic immune-mediated inflammatory diseases. OBJECTIVE To summarize the influence of antibodies against biologic agents (AABs [seropositivity]) on efficacy and safety in immune-mediated inflammatory diseases. DATA SOURCES MEDLINE, EMBASE, Cochrane Library, and the Web of Knowledge were searched for articles published in English, Spanish, French, Italian, or Portuguese between 2000 and March 2012. The search strategy focused on synonyms of diseases, immunogenicity, and biologic agents. Abstracts from 2001 to 2011 of the European League Against Rheumatism and American College of Rheumatology congresses were also included. STUDY SELECTION The selection criteria were (1) observational or interventional studies in rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis; (2) studies including patients who received biologic agents; and (3) studies collecting data on AABs. DATA EXTRACTION AND SYNTHESIS Data collected included publication details, study design, characteristics of patients and treatments, presence of antibodies, and definition of response. MAIN OUTCOMES AND MEASURES The primary end point was the association of AABs with response to treatment. Secondary end points were the association of AABs with safety, the association of AABs with concentration of the drug, and the influence of use of concomitant immunosuppressive therapy in the formation of AABs. RESULTS The search captured 10 728 articles and abstracts. By hand and reverse search, 31 articles were additionally included. After evaluation of the full reports, 60 references were selected. They included 59 studies of anti-tumor necrosis factor monoclonal antibodies: 1 with etanercept, 2 with rituximab, and 2 with abatacept. In rheumatoid arthritis but not in inflammatory bowel disease or spondyloarthritis, seropositive patients presented worse clinical response at 6 months or less (odds ratio [OR], 0.03; 95% CI, 0.01-0.21), and at 6 months or more (0.03; 0.00-0.30) by meta-analysis. In rheumatoid arthritis, discontinuation of the biologic agent for all reasons was more common in seropositive patients (OR, 3.53; 95% CI, 1.60-7.82). In all conditions, seropositive patients had a higher risk of hypersensitivity reactions (OR, 3.97; 95% CI, 2.36-6.67). Overall, concomitant treatment with disease-modifying antirheumatic drugs, including azathioprine, decreased the risk of seropositivity (OR, 0.32; 95% CI, 0.25-0.42). CONCLUSIONS AND RELEVANCE Presence of antibodies against anti-tumor necrosis factor monoclonal antibodies confers a risk of discontinuation of treatment in rheumatoid arthritis and a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases. The combined use of anti-tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks. Information on other biologic agents is fragmentary.

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.

Rheumatoid factor as predictor of response to abatacept, rituximab and tocilizumab in rheumatoid arthritis: Systematic review and meta-analysis☆

OBJECTIVE To identify if rheumatoid factor (RF) is predictor of response to rituximab (RTX), abatacept (ABT), and tocilizumab (TCZ) in rheumatoid arthritis (RA). METHODS Systematic review and meta-analysis of clinical trials and observational studies based on a sensitive search. Meta-regression was used to explore causes of heterogeneity. Unpublished data of clinical trials provided by the authors were also included. RESULTS The electronic search captured 3221 references and 422 meeting abstracts. By hand search, four additional articles were also identified. A total of 23 studies meet the purpose of the study and were included in the review. RF positivity at starting predicts better ACR20 [OR, 1.95 (1.24, 3.08)], ACR50 [OR, 5.38 (2.50, 11.60)] and EULAR response [OR, 3.52 (1.66, 7.45)] in 14 studies with RTX, and better ACR20 [OR, 1.51 (1.21, 1.90)] in 6 studies with TCZ. In 3 studies with ABT, no association was found between response and RF [OR 1.36 (0.97, 1.90)]. No asymmetries in the funnel plots or significant variables were found in the meta-regression. CONCLUSION In RA, RF positivity predicts better response to RTX and TCZ but not to ABT.

Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis

Objective To summarise the adverse events (AE) reported in patients with rheumatoid arthritis (RA) treated with protein kinase inhibitors (PKi), and identify family and molecule-related AEs. Methods Systematic review of the PKi used in clinical trials (CTs) in RA. Medline, Embase, Cochrane Library, Web of Knowledge, and international abstracts of congress were reviewed, (up to 31 October 2012). Search was limited to interventional studies of PKi used in CTs in RA, written in English, and reporting frequencies of AE. Diseases with similar comorbidity burden also were included. Frequency of AE, serious AE (SAE), death and discontinuation due to AEs (DCAE) were recorded. Risk of bias was assessed. Meta-analysis was carried using pooled relative risk (RR) with 95% CI as effect measure. Results The search produced 4410 hits. Forty-one articles reporting data on 21 PKi of the Janus kinase (JAK), SYK, p38 and cKit families were selected for detailed analysis. In patients treated with p38 inhibitors, RR for dizziness was 2.36 (1.20 to 4.63), and in patients treated with c-Kit inhibitors, RR for oedema was 3.43 (1.58 to 7.42). In patients treated with the JAK inhibitor tofacitinib, RR for hypercholesterolaemia was 1.70 (1.10 to 2.63) that was dose related. In patients treated with the Syk inhibitor fostamatinib, pooled RR for hypertransaminasaemia, hypertension, diarrhoea and neutropenia were 2.93 (1.02 to 8.43), 2.80 (1.58 to 5.99), 5.20 (3.19 to 8.49) and 9.24 (2.22 to 38.42), respectively. Serious infections and malignancies were not significantly more frequent in PKi-treated patients than in comparator groups. Conclusions Event rates of serious infections and malignancies with PKi are not different from biologics. In addition, PKi have a unique safety profile related to target and off-target inhibition of kinases, at times dose related.

The risk of tuberculosis in patients treated with TNF antagonists

Over the last 12 years, TNF antagonists have been successfully used for the treatment of numerous patients afflicted by chronic inflammatory disorders. However, data from clinical trials and registries have shown that patients treated with these biologics have an increased risk of reactivating latent TB. The fact that TNF plays a role in the immune cell response and, more specifically, in maintenance of granuloma integrity is the accepted grounds for reactivation of TB following inhibition of TNF. Appropriate screening of latent TB and proper management of cases substantially reduces the incidence of active TB. Nevertheless, debate still remains regarding the value of the tuberculin skin test and IFN-γ-release assays as diagnostic tools, and treatment across guidelines and recommendations. This largely reflects differences in background population.

Maintenance therapy of lupus nephritis with mycophenolate or azathioprine: systematic review and meta-analysis

OBJECTIVE The objective of this study was to summarize the comparative efficacy and safety of MMF and AZA as maintenance therapy for LN. METHODS Systematic review and meta-analysis of randomized clinical trials of MMF and AZA as maintenance therapy for LN were performed based on a sensitive search. Meta-regression was used to explore causes of heterogeneity. Safety was explored using crude and combined incidence rate ratios (IRRs) of the more frequent adverse events (AEs). RESULTS The search produced 7341 hits. Four randomized clinical trials and one long-term study were selected for detailed analysis. No significant differences between MMF and AZA were found in sustained remission, relapse, renal failure, creatinine increase or death. However, there was high heterogeneity in the design of studies, drug doses and treatment in the previous induction phase. Significant lower rates of discontinuation due to AEs occurred in the MMF group, with a relative risk (RR) of 0.60 (95% CI 0.41, 0.88) but significant risk of publication bias (Egger test, P = 0.012). Gastrointestinal manifestations were more common [combined IRR 1.68 (95% CI 1.06, 2.68)] and leucopoenia less frequent in the MMF group [combined IRR 0.14 (95% CI 0.05, 0.42)]. CONCLUSION The available data does not support the superiority of MMF or AZA as maintenance therapy for LN. Nevertheless, the high heterogeneity of studies included in the analysis makes this contention questionable.

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.

High Sodium Intake Is Associated With Self-Reported Rheumatoid Arthritis: A Cross Sectional and Case Control Analysis Within the SUN Cohort.

Abstract Sodium intake is a potential environmental factor for immune-mediated inflammatory diseases. The aim of this study is to investigate the association of sodium intake with rheumatoid arthritis. We performed a cross-sectional study nested in a highly educated cohort investigating dietary habits as determinants of disease. Daily sodium intake in grams per day was estimated from a validated food frequency questionnaire. We identified prevalent self-reported cases of rheumatoid arthritis. Logistic regression models were used to estimate the odds ratio for rheumatoid arthritis by sodium intake adjusting for confounders. Linear trend tests and interactions between variables were explored. Sensitivity analyses included age- and sex-matched case–control study, logistic multivariate model adjusted by residuals, and analysis excluding individuals with prevalent diabetes or cardiovascular disease. The effective sample size was 18,555 individuals (mean age 38-years old, 60% women) including 392 self-reported rheumatoid arthritis. Median daily sodium intake (estimated from foods plus added salt) was 3.47 (P25–75: 2.63–4.55) grams. Total sodium intake in the fourth quartile showed a significant association with rheumatoid arthritis (fully adjusted odds ratio 1.5; 95% CI 1.1–2.1, P for trend = 0.02). Never smokers with high sodium intake had higher association than ever smokers with high sodium intake (P for interaction = 0.007). Dose-dependent association was replicated in the case–control study. High sodium intake may be associated with a diagnosis of rheumatoid arthritis. This confirms previous clinical and experimental research.

Rheumatoid factor and response to TNF antagonists in rheumatoid arthritis: Systematic review and meta-analysis of observational studies

OBJECTIVE To systematically analyze literature with the aim of examining whether rheumatoid factor (RF) is a predictor of response to tumor necrosis factor (TNF) antagonists in rheumatoid arthritis (RA). METHODS A systematic review and meta-analysis of observational studies were conducted. All studies on the association of baseline RF (titer and/or status) and response to any TNF antagonists, or with enough information to estimate this association were included. Qualitative analysis and meta-analysis using random-effects approach by type of outcome response and RF test was performed. Risk of publication bias was also evaluated. RESULTS The systematic review included 18 studies of 4163 identified articles, involving 5703 patients with homogeneous baseline characteristics. The most common outcome to assess response was European League Against Rheumatism (EULAR) response criteria, normally merging good and moderate categories as response. The weighted mean difference (WMD) of baseline IgM RF titer in meta-analysis was higher in the non-responders group [-101.58 (95% CI -156.58,-46.59) I2=0.0]. Combined odds ratios (ORs) of positive IgM RF, positive IgA RF, and positive IgG RF to achieve good/moderate response were 1.08 (0.80, 1.47), I2=40.9%; 0.83 (0.39, 1.73), I2=39.8%, and 1.30 (0.48, 3.51), I2=62.9%, respectively. We did not find an association between a positive IgM RF and EULAR good response or remission. CONCLUSIONS This meta-analysis does not support baseline IgM RF titer as a predictor of response to TNF antagonists in RA. However, this conclusion is hampered by high heterogeneity in the studies included in this meta-analysis.