Efficacy and Safety of Biological Agents in Giant Cell Arteritis: An Updated Meta-Analysis.

We aimed to systematically review biological agents' efficacy and safety in patients with Takayasu arteritis (TAK). A systematic literature search of 7 electronic databases, including MEDLINE (via PubMed), EMBASE, Elsevier ScienceDirect, EBSCO, Springer Link, Web of Science, and Cochrane Library on the efficacy of biological agents on patients with TAK was conducted. Only studies published in English and with a sample size >5 patients with TAK were included. Two reviewers independently selected studies, extracted data and assessed its methodological quality. Random effects meta-analyses of various effect measures were performed. According to the title and abstract, 961 studies were identified and screened. Subsequently, 31 studies from 29 observational studies and 2 randomized-controlled trials (RCTs), which included a total of 517 patients with TAK that met the inclusion and exclusion criteria, were selected. Observational studies showed a high risk of bias. Pooled remission rates of biological agents were 66% (95% CI: 58%-73%; I2=59%), and the remission rates of anti-tumor necrosis factor (TNF) agents and tocilizumab (TCZ) were similar: 65% (95% CI: 56%-73%; I2=49%) and 70% (95% CI: 55%-86%; I2=69%), respectively. Pooled relapse rates were 23% (95% CI: 15%-31%; I2=66%). The relapse rate was 28% (95% CI: 16%-40%; I2=68%) for anti-TNF agents and 17% (95% CI: 7%-26%; I2=49%) for TCZ. The remission rate of TCZ was slightly higher (p>0.05), but the relapse rate was statistically significantly lower than that of anti-TNF agents (p=0.017). Furthermore, biological agents significantly decreased the doses of glucocorticoid (GC) and levels of acute phase inflammation markers (ESR, CRP) while the proportion of patients with new angiographic lesions or progression of previously noted lesions were 11% (95% CI: 4%-18%; I2=59%). RCTs with a small sample size showed abatacept was ineffective, and TCZ was underpowered to detect a difference in time to relapse compared to placebo. The most common adverse event of biological agents was infection (6%, 95%CI: 2%-10%). No deaths were reported. Although the beneficial effects of biological agents are encouraging in enhancing disease remission, reducing the levels of acute phase inflammation markers and decreasing the treatment doses of GC in patients with TAK, there is still a risk of relapse. More refined studies with larger cohorts are necessary before drawing a definitive opinion.

ObjectivesTo compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi.MethodsSWITCH-RA was...

Tumor necrosis factor (TNF) inhibitors are a mainstay in the treatment of rheumatoid arthritis (RA), as well as in the management of spondyloarthritis (SpA) and inflammatory bowel diseases (IBD). Unfortunately, a portion of patients taking these drugs require escalating doses within the approved label to achieve response, while others lose response altogether. This may be due to the development of antibodies against TNFi agents. Our objective was to examine the immunogenicity of TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) in RA, SpA, and IBD, and to examine the potential effect of anti-drug antibodies (ADABs) on the loss of clinical response through a systematic literature review and meta-analysis. We conducted a comprehensive literature search using three databases (PubMed, Web of Science, and the Cochrane library) to identify studies examining the immunogenicity of TNF inhibitors in autoimmune diseases between 1966 and 31 December 2013. Inclusion criteria required that studies be in English, be randomized controlled trials, observational studies, or case reports involving more than five patients, and that the patients be aged 18 years or older. Studies were excluded if they were strictly genetic with no clinical correlate, if the patients had concomitant cancer within 5 years of the study, or if the patients had a renal disease requiring dialysis. Double extraction was followed by a third extraction if needed. Consensus was reached by discussion when disagreements occurred. Random-effect models were generated for the meta-analysis of 68 studies to estimate the odds ratio (OR) of the ADAB effects on TNF inhibitor response. Regression analysis was used to compare among the drugs and diseases. A total of 68 studies (14,651 patients) matched the inclusion/exclusion criteria. Overall, the cumulative incidence of ADABs was 12.7 % [95 % confidence interval (CI) 9.5-16.7]. Of the patients using infliximab, 25.3 % (95 % CI 19.5-32.3) developed ADABs compared with 14.1 % (95 % CI 8.6-22.3) using adalimumab, 6.9 % (95 % CI 3.4-13.5) for certolizumab, 3.8 % (95 % CI 2.1-6.6) for golimumab, and 1.2 % (95 % CI 0.4-3.8) for etanercept. ADABs reduced the odds of clinical response by 67 % overall, although most of the data were derived from articles involving infliximab (nine) and adalimumab (eight). The summary effect for infliximab yielded an estimated OR (with ADABs vs. without) of 0.42 (95 % CI 0.30-0.58); the summary effect for adalimumab yielded an estimated OR (as above) of 0.13 (95 % CI 0.08-0.22); and the OR (as above) for golimumab was 0.42 (95 % CI 0.22-0.81). All figures were statistically significant. ADABS decreased response by 27 % in RA and 18 % in SpA, both of which were statistically significant. However, the effect of ADABS on response was not statistically significant for IBD when we only included the studies that reported the duration of exposure in the regression analysis. The use of concomitant immunosuppressives (methotrexate, 6-mercaptopurine, azathioprine, and others) reduced the odds of ADAB formation in all patients by 74 %. The OR for risk with immunosuppressives versus without was 0.26 (95 % CI 0.21-0.32). ADABs developed in 13 % of patients. All five TNF inhibitors were associated with ADABs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADABs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADAB formation.

Objective To investigate the risk of squamous cell and basal cell skin cancer in patients with rheumatoid arthritis naive to biologic drugs, in patients starting tumour necrosis factor (TNF) inhibitor...

Rheumatoid arthritis (RA) and psoriasis have been linked with insulin resistance and diabetes mellitus (DM). Prior investigations suggest that systemic immunosuppressive drugs may improve insulin resistance and reduce the risk of DM. To compare the risk of newly recorded DM among participants diagnosed with RA or psoriasis based on use of a variety of disease-modifying antirheumatic drugs (DMARDs). A retrospective cohort study among 121,280 patients with a diagnosis of either RA or psoriasis on at least 2 visits. The analyses were conducted in the context of 2 large health insurance programs, 1 in Canada and 1 in the United States, using administrative data. The mean follow-up was 5.8 months and began with the first prescription for a DMARD after study eligibility was met. Drug regimens were categorized into 4 mutually exclusive groups: (1) tumor necrosis factor (TNF) inhibitors with or without other DMARDs; (2) methotrexate without TNF inhibitors or hydroxychloroquine; (3) hydroxychloroquine without TNF inhibitors or methotrexate; or (4) other nonbiologic DMARDs without TNF inhibitors, methotrexate, or hydroxychloroquine (reference exposure). Newly recorded DM as evidenced by a new diagnosis of DM with use of a DM-specific medication. The study cohort consisted of 13,905 participants with 22,493 treatment episodes starting 1 of the categories of DMARD regimens between January 1996 and June 2008. New diabetes cases and respective incidence rates per 1000 person-years were: other nonbiologic DMARDs (55 cases among 3993 treatment episodes; rate, 50.2; 95% confidence interval [CI], 47.3-53.2); TNF inhibitors (80 cases among 4623 treatment episodes; rate, 19.7; 95% CI, 19.1-20.3); methotrexate (82 cases among 8195 treatment episodes; rate, 23.8; 95% CI, 23.0-24.6); and hydroxychloroquine (50 cases among 5682 treatment episodes; rate, 22.2; 95% CI, 21.3-23.1). The multivariate adjusted hazard ratios for DM were 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, 0.77 (95% CI, 0.53-1.13) for methotrexate, and 0.54 (95% CI, 0.36-0.80) for hydroxychloroquine compared with other nonbiologic DMARDS. Among patients with RA or psoriasis, the adjusted risk of DM was lower for individuals starting a TNF inhibitor or hydroxychloroquine compared with initiation of other nonbiologic DMARDs.

SAT0114 Biological Agents DID not Increase the Risk of Nontuberculous Mycobacterium Infection in Rheumatoid Arthritis Patients: A Retrospective Single Center Study

Rheumatology meeting: Efficacy, safety of biologics central focus

To assess the safety of rituximab in combination with a tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) in patients with rheumatoid arthritis (RA). Adult patients with active RA (≥ 5 swollen and ≥ 5 tender joints) receiving a stable dose of MTX (10-25 mg/week) and stable dose of TNF inhibitor (etanercept or adalimumab) for ≥ 12 weeks were randomized 2:1 to receive one course of rituximab or placebo, given intravenously at a dose of 2 × 500 mg. The primary end point was the proportion of patients developing ≥ 1 serious infection through week 24. Fifty-one patients were treated with either rituximab or placebo in combination with background MTX and a TNF inhibitor. Baseline characteristics were generally balanced between groups, except for corticosteroid usage (36% in the rituximab arm versus 17% in the placebo arm). A serious infection (pneumonia) was observed in 1 patient (3%) in the rituximab group after 14.4 patient-years of exposure (6.95 events per 100 patient-years, 95% confidence interval 0.98-49.35), compared with none in the placebo group at week 24. Infections were reported in 18 patients (55%) and 11 patients (61%) in the rituximab and placebo groups, respectively. Grade 3 infections were reported in 3 patients (9%) receiving rituximab and in none of the patients receiving placebo. No grade 4 infections were observed, nor were there any opportunistic, fungal, or tuberculosis infections. Serious adverse events (SAEs) were reported in 2 rituximab-treated patients (pneumonia and coronary artery occlusion), whereas there were no SAEs reported in placebo-treated patients. At week 24, the percentage of patients achieving an American College of Rheumatology 20% (ACR20) improvement response was 30% in the rituximab group compared with 17% in the placebo group, and ACR50 responses were achieved by 12% and 6% of patients, respectively. The preliminary safety profile of rituximab in combination with a TNF inhibitor and MTX was consistent with the safety profile of rituximab in combination with MTX in other RA trials without a TNF inhibitor, with no new safety signals observed. SAEs were numerically more frequent in the rituximab group, and there was no clear evidence of an efficacy advantage in patients receiving rituximab in combination with a TNF inhibitor and MTX.

A 61-year-old man presented to the emergency department with acute anterior ST-segment myocardial infarction. A 12-lead ECG showed normofrequent sinus rhythm, a right bundle-branch block, significant ST-segment elevations in precordial leads V1 through V4 (Figure 1), and increased troponin I of 5.219 μg/L (normal range, 0–0.045 μg/L). Typical angina pectoris worsened during exercise to Canadian Cardiovascular Society grade II to III for almost 3 days and finally sustained at rest for the last 2 hours (Canadian Cardiovascular Society grade IV). Physical activity was markedly limited over the past weeks to New York Heart Association grade III. The patient´s cardiovascular risk profile consisted of active smoking status and arterial hypertension, whereas comorbidity was characterized by chronic obstructive pulmonary disease, and seropositive rheumatoid arthritis, as well (Figure 2). Daily medication consisted of methotrexate 15 mg (1 time/wk), folic acid (1 time/wk), torsemide (5 mg/d), and tiotropiumbromid and formoterol aerosol sprays. Figure 1. Initial 12-lead ECG demonstrated normofrequent sinus rhythm, a right bundle-branch block, and significant ST-segment elevations in precordial leads V1 through V4. Figure 2. Patient´s hands are affected by rheumatoid arthritis, as indicated by swollen joints, rheumatoid nodules, and palmar erythema. Primary coronary angiography revealed 3-vessel coronary artery disease with concomitant severe ectatic malformation of coronary vessels. The culprit lesion was a subtotal stenosis of the proximal left anterior descending artery with reduced thrombolysis in myocardial infarction flow (Figure 3A). The proximal part of the circumflex artery had a 90% stenosis, and the proximal left obtuse marginal artery did as well (Figure 3A). In addition, a chronic total occlusion (CTO) was verified at the proximal right coronary artery (RCA; thrombolysis in myocardial infarction flow 0; Movie I in the online-only Data Supplement) with retrograde filling from the left posterolateral artery through epimyocardial collaterals to the right posterior interventricular artery (Figure 3B and 3C; Movie …

TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex

Despite similar clinical effectiveness of tumor necrosis factor (TNF) inhibitors in the treatment of inflammatory joint diseases, they differ in effectiveness in other diseases and the exact mechanisms of their actions remain unclear. The aim of this study was to determine whether TNF inhibitors - etanercept and monoclonal antibodies affect intracellular cytokine production by T cell subsets. Anti-TNF-naive patients with inflammatory arthritis (rheumatoid arthritis or spondyloarthritis), characterized by high disease activity, were treated with TNF inhibitor - etanercept (14 patients) or monoclonal antibody (16 patients) for 12 weeks, while 11 patients received placebo. At baseline, 4, and 12 weeks after introducing anti-TNF treatment, intracellular production of TNF, interferon gamma (IFNγ), interleukin 17A (IL-17A), and IL-4 by T cell subsets was assessed using flow cytometry and analyzed by repeated measures two-way ANOVA. There were no differences in TNF, IFNγ, or IL-4-positive CD4, CD8, and CD3+CD4-CD8- (double negative, DN) cells between groups, neither while comparing effects of all TNF inhibitors jointly to placebo nor while analyzing effects in etanercept, monoclonal antibodies or placebo receiving groups. Similarly, there was no difference in IL-17A+CD4+ cells; however, a decrease in the percentage of IL-17A-positive DN T cells was observed in the etanercept-treated group (mean±SEM: 0.82±0.55, 0.41±0.16, 0.13±0.07) in comparison to placebo (0.23±0.10, 0.32±0.12, 0.49±0.15), (p=0.014), and an opposite; however, insignificant trend was observed in the monoclonal antibody-receiving group (0.41±0.13, 0.53±0.17, 0.82±0.3), (p=0.056 vs. etanercept). In summary, we ascertain that treatment with TNF inhibitors does not affect Th1, Th2, or Th17 responses. Etanercept and monoclonal antibodies differ in their effect on IL-17A+DN T cells.

ABSTRACTIntroduction: Despite the therapeutic effectiveness of biologics targeting immune cells or cytokines in patients with inflammatory arthritis, which reflects their pathogenic roles, an increased infection risk is observed in those undergoing biological treatment. However, there are limited data regarding the comparison of infection risks in inflammatory arthritis patients treated with non-biologics (csDMARDs), biologics (bDMARDs), including tumor necrosis factor (TNF) inhibitors and non-TNF inhibitors, or targeted synthetic (ts)DMARDs.Areas covered: Through a review of English-language literature as of 30 June 2019, we focus on the existing evidence on the risk of infections caused by bacteria, Mycobacterium tuberculosis, and hepatitis virus in inflammatory arthritis patients undergoing treatment with csDMARDs, bDMARDs, or tsDMARDs.Expert opinion: While the risks of bacterial and mycobacterial infection are increased in arthritis patients treated with csDMARDs, the risks are further higher in those receiving bDMARDs therapy, particularly TNF inhibitors. Regarding HBV infection, antiviral therapy may effectively prevent HBV reactivation in patients receiving bDMARDs, especially rituximab. However, more data are needed to establish effective preventive strategies for HBsAg-negative/HBcAb-positive patients. It seems safe to use cyclosporine and TNF inhibitors in patients with HCV infection, while those undergoing rituximab therapies should be frequently monitored for HCV activity.Abbreviations: ABT: abatacept; ADA: adalimumab; AS: ankylosing spondylitis; bDMARDs: biologic disease-modifying anti-rheumatic drugs; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CS: corticosteroids; CsA: cyclosporine A; csDMARDs: conventional synthetic disease-modifying anti-rheumatic drugs; CZP: certolizumab; DAAs: direct-acting antiviral agents; DM: diabetes mellitus; DOT: directly observed therapy; EIN: Emerging Infections Network; ETN: etanercept; GOL: golimumab; GPRD: General Practice Research Database; HBV: hepatitis B virus; HBVr: HBV reactivation; HBsAg+: HBsAg-positive; HBsAg-/anti-HBc+: HBsAg-negative anti-HBc antibodies-positive; HCV: hepatitis C virus; HCQ: hydroxychloroquine: IFX: infliximab; IL-6: interleukin-6; JAK: Janus kinase; LEF: leflunomide; LTBI: latent tuberculosis infection; mAb: monoclonal antibody; MTX: methotrexate; OR: odds ratio; PsA: psoriatic arthritis; PMS: post-marketing surveillance; RA: rheumatoid arthritis; TNF: tumor necrosis factor; TNFi: tumor necrosis factor inhibitor; SCK: secukinumab; SSZ: sulfasalazine; TOZ: tocilizumab; RCT: randomized controlled trial; RR: relative risk; RTX: rituximab; 3HP: 3-month once-weekly isoniazid plus rifapentine; TB: tuberculosis; tsDMARDs: targeted synthetic disease-modifying anti-rheumatic drugs; UTK: ustekinumab; WHO: World Health Organization

Objectives: Tumor necrosis factor (TNF) inhibitors have made great progress in the management of axial spondyloarthritis (axSpA).An increase in malignancies associated with TNF inhibitors has always raised suspicions but is unproven.The aim of this study is to investigate whether there is an increase in the frequency of thyroid nodules in axSpA patients treated with TNF inhibitors and to determine the predictive factors. Methods:In this retrospective case-control study, axSpA patients who received and did not receive TNF inhibitor treatment were divided into two groups.Patients were enrolled by age, gender, symptom duration, duration of anti-TNF therapy, human leukocyte antigen B27 (HLA-B27) status, smoking history (current smokers), and family history of thyroid malignancy.Thyroid ultrasound was performed in all patients, and thyroid nodule positivity, number, and nodule characteristics were recorded.Results: A total of 75 patients with axSpA (37 patients were in the TNF inhibitor group and 38 patients were in the control group) were included in the study.Nodule positivity was similar in both groups (p=0.571), and no malignancy was detected in patients with thyroid nodules.No difference was found between nodule positivity and gender, HLA B27, smoking, or family history (p=0.10,p=0.10, p=0.726, and p=0.843, respectively).Age was the only predictor for thyroid nodule positivity in all axSpA patients (p:0.009,95% of CI: 0.004-0.02). Conclusion:TNF inhibitors do not increase thyroid nodules or malignancies in axSpA patients.

Tumor necrosis factor (TNF) inhibitors have been established as therapeutic agents for treating refractory systemic rheumatic diseases including rheumatoid arthritis and ankylosing spondylitis. While TNF inhibitors can effectively decrease the inflammation, they also decrease resistance to infection and affect immune surveillance mechanisms. Clinicians are sometimes faced with special situations such as chronic hepatitis B infection, pregnancy, complicated medical problems and older populations when prescribing TNF inhibitors. These conditions are affected by TNF inhibitors, which may induce poor clinical outcomes as well as side effects. To date, there are limited clinical data and recommendation guidelines on patients receiving TNF inhibitors in these special situations. We reviewed the effect of TNF inhibitors on each condition with review of the literatures concerning the clinical trials of TNF inhibitors in various rheumatic conditions. TNF inhibitors should be introduced carefully in special situations affecting the outcome of underlying illness, depending on the risk/benefit profiles in each case.

Purpose: Tumor necrosis factor (TNF) inhibitors are useful in the treatment of immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). These agents are also used to treat psoriasis, yet recent evidence suggests that TNF inhibitors induce psoriasiform lesions in IBD and RA patients that often require discontinuation of effective therapy. Whether this paradoxical relationship may be a class versus individual drug effect is unknown. Methods: Data from the FDA Adverse Event Reporting System (AERS) were analyzed for the period 2004 through September, 2011 (>13 million reports). Adverse event reports for infliximab, adalimumab, certolizumab, and etanercept were reviewed, along with the pre-selected “control” drugs propranolol, lithium (due to suspected relationship with psoriasis) and mesalamine. Proportional reporting ratios (PRRs) for psoriasis adverse events were calculated for TNF inhibitors versus control drugs (null value=1.0), including trends over time (years 2004-2011). Results: On an annual basis and compared to the control drugs, PRRs were significantly higher for all TNF inhibitors: infliximab (3.45 to 15.24); adalimumab (2:12 to 16.04); certolizumab (3.57 to 7.17); etanercept (7.84 to 45.42). However, the proportion of all adverse reports listed as psoriasis remained relatively constant for infliximab over the 8-year period (0.91% to 1.91%), yet steadily increased for adalimumab (0.29% to 4.32%), and certolizumab (years 2009-2011: 0.67% to 1.93%). From 2006 to 2011, the proportion of psoriasis adverse reports for etanercept was relatively constant (5.70% to 6.73%), yet substantially elevated compared to infliximab. Conclusion: Data from the FDA AERS suggest that TNF inhibitors exert a significant class effect on the risk of psoriasiform lesions, and that the various TNF inhibitors may differ in risk potential; however, the reason for the observed differences in absolute risk is not clear and cannot be extrapolated from the FDA AERS. Future studies should aim to determine whether there is a true mechanistic difference among the TNF inhibitors in inducing psoriasiform lesions.Table: Proportional reporting ratios (PRRs)