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

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 I(2), 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), I(2)=84.1%), gender (1.57 (1.10 to 2.25), I(2)=0.0%), baseline BASDAI (1.31 (1.09 to 1.57), I(2)=0.0%), baseline BASFI (0.86 (0.79 to 0.93), I(2)=24.9%), baseline dichotomous C reactive protein (CRP) (2.14 (1.71 to 2.68), I(2)=22.3%) and human leucocyte antigen B27 (HLA-B27) (1.81 (1.35 to 2.42), I(2)=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

Effect of smoking on the efficacy of TNF inhibitors in the treatment of chronic inflammatory inmune-mediated diseases: systematic review and meta-analysis

Background: Chronic inflammatory immune-mediated diseases, as rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Ps), ankylosing spondylitis (AS), ulcerative colitis (UC) and Crohn’s disease (CD), have higher risks of morbidity and mortality and a great impact on quality of life of patients1. Drug inhibitors of tumor necrosis factor (TNF inhibitors) have demonstrated an adequate efficacy and security profile in these patients when classical treatments (as disease-modifying antirheumatic drugs) have been failed or patients were intolerant. TNF inhibitors are used to control inflammatory response and to improve quality of life, pain, functional capacity and progression of the disease2. Studies in RA show that smoking habit is related to more articular and extra-articular damage, worse prognosis, higher basal activity and higher risk of seropositive RA. It has been related also to greater number of different treatments and higher doses needed for patients by pharmacokinetic and pharmacodynamic processes. Data published until now suggest that smoking habit decreases efficacy of TNF inhibitors3. Objectives: To analyze the smoking habit influence on the efficacy of TNF inhibitors in patients diagnosed of chronic inflammatory immune-mediated diseases (RA, PsA, Ps, AS, UC, CD). Methods: It was made a systematic literature search using Cochrane Library, Medline, the Web of Science and Embase databases. Meta-analyses were performed using a random-effects model. Results: 37 of 3677 identified articles met the inclusion criteria. No documents with GOL were found. The analysis of all the diseases together gives a significant decrease on the response to TNF inhibitors in smoking patients [OR 0.812 (0.662-0.996), p=0.046]. This response also has a significant decrease in IBD maintained response in smoking patients [OR 0.467 (0.257-0.848), p=0.012]. A non-significant decrease in the treatment response of smoking patients with IBD clinical remission was found, in smoking patients versus ex-smoking and never smoking patients with IBD response, in ex-smoking patients versus never smoking patients with IBD partial response, in current and ex-smoking patients versus never smoking patients with IBD partial response, in current smoking patients versus ex-smoking patients with IBD partial response, in current smoking patients versus never and ex-smoking patients with IBD partial response, in current smoking patients versus never smoking patients with IBD partial response, in patients with AR EULAR and in patients with AR EULAR moderate response. Conclusion: Smoking habit is a poor prognosis factor in RA, AS, Ps, PsA, UC and CD. Its leaving will decrease cardiovascular risk, joint and bowel damage, will increase the efficacy of TNF inhibitors and will benefit the health of patients, not only in their particular disease, and it can be the first step on their treatment

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases

BACKGROUND: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs. METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs