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Objective: Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions., Methods: Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed., Results: 2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time., Conclusion: The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To assess long-term efficacy, safety and tolerability of secukinumab up to 104 weeks in patients with active PsA., Methods: Patients with PsA (n = 397) were randomized to s.c. secukinumab 300, 150 or 75 mg or placebo at baseline, weeks 1, 2, 3 and 4 and every 4 weeks thereafter. Placebo-treated patients were re-randomized to receive secukinumab 300 or 150 mg s.c. from week 16 (placebo non-responders) or week 24 (placebo responders). Exploratory endpoints at week 104 included 20, 50 and 70% improvement in ACR criteria (ACR20, 50, 70); 75 and 90% improvement in the Psoriasis Area Severity Index, 28-joint DAS with CRP, presence of dactylitis and enthesitis and other patient-reported outcomes. For binary variables, missing values were imputed; continuous variables were analysed by a mixed-effects model for repeated measures., Results: A total of 86/100 (86%), 76/100 (76%) and 65/99 (66%) patients in the secukinumab 300, 150 and 75 mg groups, respectively, completed 104 weeks. At week 104, ACR20 response rates after multiple imputation in the 300, 150 and 75 mg groups were 69.4, 64.4 and 50.3%, respectively. Sustained clinical improvements were observed through week 104 with secukinumab across other clinically important domains of PsA. Responses were sustained through week 104 regardless of prior anti-TNF-α use. Over the entire treatment period the incidence, type and severity of adverse events were consistent with those reported previously., Conclusion: Secukinumab provided sustained improvements in signs and symptoms and multiple clinical domains in patients of active PsA through 2 years of therapy. Secukinumab was well tolerated, with a safety profile consistent with that reported previously., Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT01752634., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody and IL-6 receptor antagonist, currently approved for the treatment of systemic juvenile idiopathic arthritis (sJIA) and polyarticular juvenile idiopathic arthritis (pJIA) in children aged 2 years or older refractory to conventional treatment. The most common adverse events in patients treated with TCZ were infections, especially in the respiratory tract. The most frequent laboratory abnormalities were altered liver function, neutropenia and elevated cholesterol levels. Areas covered: The safety of TCZ in the treatment of children with JIA was determined based on a review of published clinical trials, including two multicenter studies of patients with sJIA and pJIA (the TENDER and CHERISH trials, respectively). The frequency of adverse events (AEs), serious adverse events (SAEs) and deaths reported in these studies was analyzed and discussed. Expert opinion: TCZ was effective and well tolerated in the treatment of severe forms of sJIA and pJIA, and can be considered a treatment of choice for these conditions. The risk of infections and laboratory abnormalities, such as neutropenia, should be constantly monitored. There is still a need for comparative studies of the risks and benefits of biological agents in patients with refractory JIA.

Objective: The main aim of this study was to examine the differences between triple therapy (T: SSZ and HCQ added to MTX) and etanercept (E) added to MTX with regard to the infectious and gastrointestinal (GI) adverse events (AEs) reported in The Rheumatoid Arthritis Comparison of Active Therapies Trial., Methods: The patients were 353 RA MTX incomplete responders who were randomized to T (n = 178) or E (n = 175). Of these, 88 patients were switched to the alternative treatment from the initial treatment (E or T) at 24 weeks per protocol. Infectious and GI serious AEs (SAEs) and non-serious AEs (NAEs) were reported during 48 and 4 weeks after the intervention period. Generalized linear models were used to estimate the incidence rate ratios (IRRs) of AEs between the two therapies., Results: Patients on E therapy were more likely to have infectious NAEs (IRR = 1.56, 95% CI: 1.11, 2.19). There was a greater number of infectious SAEs that occurred when patients received E than T therapy [12 E (6.9%) vs 4 T (2.2%), P = 0.19]. Pneumonia was the most common infectious SAE for both treatments [6 E (3.4%) and 2 T (1.1%)]. Conversely, patients who were on E were less likely to have GI NAEs than those on T therapy (IRR = 0.62, 95% CI: 0.40, 0.94). The most common GI SAE reported was GI haemorrhage, which occurred among three patients on E (1.7%)., Conclusion: This study provides evidence of different likelihoods of infectious and GI AEs associated with two common, equally effective treatments for RA patients who have had incomplete responses to MTX., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT00405275., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: To compare the efficacy and safety of ABT-494, a novel selective JAK-1 inhibitor, with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti-tumor necrosis factor (anti-TNF) agent., Methods: In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti-TNF agent were randomized equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12., Results: At week 12, significantly more patients receiving ABT-494 (53-71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose-response relationship among all ABT-494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT-494 (36-42% and 22-26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) were significantly greater for all doses of ABT-494 than for placebo (P ≤ 0.01). Onset of action of ABT-494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28-CRP (P < 0.001 for 6-18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT-494, but no infections were serious. No deaths were reported among those receiving ABT-494., Conclusion: In patients with an inadequate response or intolerance to anti-TNF agents, ABT-494 added to MTX showed rapid, dose-dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified., (© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objective: Interleukin-20 (IL-20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109-0012, a selective anti-IL-20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy., Methods: Sixty-seven patients with RA were enrolled and randomized (2:1) to receive NNC0109-0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double-blind, 12-week trial with a 13-week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C-reactive protein level (DAS28-CRP) from baseline to week 12., Results: In patients treated with NNC0109-0012, the primary end point, improvement in the DAS28-CRP at week 12, was achieved (estimated difference -0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference -1.66; P < 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109-0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index (P = 0.047). The most frequent adverse events reported with NNC0109-0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109-0012 were observed., Conclusion: In this phase IIa trial, treatment with NNC0109-0012 (anti-IL-20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109-0012 administration., (© 2015, American College of Rheumatology.)

Infliximab, an anti-TNF-alpha agent, is highly effective against rheumatoid arthritis and Crohn's disease. However, respiratory infection can occur as a complication. We report two cases complicated by respiratory infection following administration of infliximab. The first case, a 67-year-old woman with rheumatoid arthritis, developed pneumocystis pneumonia after three courses of infliximab therapy. The second case, a 31-year-old man with Crohn's disease, developed pulmonary tuberculosis after four courses of infliximab therapy. Respiratory complications associated with anti-TNF therapy include infectious diseases such as pneumocystis pneumonia, tuberculosis, and bacterial pneumonia. They often lead a fulminant course, and early diagnosis is essential. The final report of a survey of the initial 5000 cases with rheumatoid arthritis treated with infliximab in Japan was released in April 2006; pulmonary infectious complications included 22 cases of pneumocystis pneumonia, 14 cases of tuberculosis, and 108 cases of bacterial pneumonia. The growing use of anti-TNF therapy might lead to increasing pulmonary complications. Accumulation of similar cases is expected to elucidate the mechanism of the complications and methods for effective prophylaxis.

Objective: To evaluate the rate of infections in rheumatic patients treated with tumour necrosis factor (TNF)-alpha blockers in daily practice and to determine potential risk factors of infections., Methods: Systematic retrospective study was conducted in a tertiary-referral centre of all patients receiving at least one TNF-alpha blocker, between 1997 and December 2004. Serious infections were defined as life-threatening, requiring hospitalization or sequelae. The incidence of infections during the first TNF-alpha blocker course was compared with the incidence during the period just before such therapy, in the same patients and a number needed to harm was calculated. Univariate and multivariate analysis between patients who suffered from at least one infection during treatment or not, was conducted in order to determine potential associated risk factors., Results: Among the 709 patients treated with at least one TNF-alpha blocker, 57.7% had rheumatoid arthritis; a total of 275 infectious events in 245 patients (34.5%) were reported during all treatment courses. Among these infections, 47 infections in 44 patients (6.2%) fulfilled the definition of serious infections. The incidence rate of serious infections was 3.4 +/- 38.7 per 100 patient-yrs before TNF-alpha blocker therapy vs 10.5 +/- 86.9 during the first TNF-alpha blocker course (P = 0.03, number needed to harm = 14). The single risk factor picked up by multivariate analysis to explain infections was previous joint surgery [odds ratio (OR) = 2.07, 95% confidence interval (CI) = (1.43-2.98), P < 0.0001] and, if surgery was taken out of the model, the cumulative dose of steroids [OR = 1.28 (1.04-1.59), P = 0.02]., Conclusion: The rate of serious infections during TNF-alpha blocker treatment observed in daily practice conditions was much higher than in phase III trials evaluating TNF-alpha blockers. Serious infections are frequent in daily practice and close monitoring is required.

Objective: To evaluate the long-term safety and efficacy of etanercept in patients with rheumatoid arthritis., Methods: 549 patients entered this 5-year, open-label extension study and received etanercept 25 mg twice weekly. All patients showed inadequate responses to disease-modifying antirheumatic drugs before entry into the double-blind studies. Safety assessments were carried out at regular intervals. Primary efficacy end points were the numbers of painful and swollen joints; secondary variables included American College of Rheumatology (ACR) response rate, Disease Activity Score and acute-phase reactants. Efficacy was analysed using the last-observation-carried-forward approach., Results: Of the 549 patients enrolled in the open-label trial, 467 (85%), 414 (75%) and 371 (68%) completed 1, 2 and 3 years, respectively; 363 (66%) remained in the study at the time of this analysis. A total exposure of 1498 patient-years, including the double-blind study, was accrued. In the open-label trial, withdrawals for efficacy-related and safety-related reasons were 11% and 13%, respectively. Frequent adverse events included upper respiratory infections, flu syndrome, rash and injection-site reactions. Rates of serious infections and malignancies remained unchanged over the course of the study; there were no reports of patients with central demyelinating disease or serious blood dyscrasias. After 3 years, ACR20, ACR50 and ACR70 response rates were 78%, 51% and 27%, respectively. The Disease Activity Score score was reduced to 3.0 at 3 months and 2.6 at 3 years from 5.1. A sustained improvement was found in Health Assessment Questionnaire scores throughout the 3-year time period., Conclusion: After 3 years of treatment, etanercept showed sustained efficacy and a favourable safety profile.

A case of fatal pulmonary Mycobacterium abscessus infection in a 56-year-old man is reported. The patient had a longstanding history of seropositive, nodular rheumatoid arthritis with severe joint manifestations that had been treated with a regimen of prednisone, leflunomide, and etanercept. He presented to our facility with complaint of productive cough, persistent fevers, pleuritic chest discomfort, and dyspnea at rest. The patient was admitted to hospital, placed in isolation, a left-sided chest tube was inserted (left pneumothorax identified), and sputum acid-fast bacteria stains and cultures were obtained. Fluorochrome stains demonstrated numerous acid-fast bacteria, and M. abscessus was recovered from the culture media. He was treated with a regimen of amikacin, cefoxitin, and clarithromycin. He initially responded well, and was discharged home with this regimen. He remained afebrile with decreased cough and sputum production until 15 days after discharge when he was again admitted to hospital, with acute onset dyspnea and right-sided chest discomfort (right pneumothorax identified). He ultimately expired, due to overwhelming pulmonary infection, 20 days after readmission to hospital. Autopsy revealed acid fast bacilli in the setting of numerous, bilateral, necrotic, granulomatous, cavitary pulmonary lesions. Based on its mechanism of action, we propose an association between the use of etanercept, a tumor necrosis factor alpha (TNF-alpha) inhibitor, and this case of fatal pulmonary mycobacterial infection. We recommend that physicians exercise cautious clinical judgment when initiating etanercept therapy in persons with underlying lung disease, especially in communities in which mycobacterial organisms are highly prevalent. We also advise physicians to maintain a high level of vigilance for late onset granulomatous infection in persons using etanercept.

Introduction: Treatment of rheumatoid arthritis (RA) has changed with the release of more efficient disease-modifying anti-inflammatory drugs (DMARDs) and biologicals, such as methotrexate, leflunomide and TNF blockers, respectively. However they are prone to trigger potential pulmonary side effects. STATE OF KNOWLEDGES: Diffuse interstitial pneumonitis with alveolar lymphocytosis are induced by methotrexate. This drug increases also the risk of opportunistic infections (Pneumocyctis carinii) and of delayed lymphomas. Many intracellular bacterial infections, about 80 cases of diffuse pneumonitis, and rare vasculitis are attributable to leflunomide., Perspectives: The TNF blocking agents (infliximab, etanercept and adalimumab) trigger immunization and consequently, rare type I and III hypersensitivity pneumonitis, serological lupus-like reactions usually without any clinical manifestations. Indeed the risk of infection with intracellular agents remains the first concern. Several hundreds of cases of pulmonary and non pulmonary tuberculosis (TB) have been described. They present as disseminated forms, with pulmonary manifestations present in half cases; of note, other sites are atypical, namely meningitis, lymph node, and digestive involvement. Pathological diagnosis can be difficult since granulomas are sparse or absent. Therefore TB can be lethal because of delayed diagnosis and treatment., Conclusion: To prevent this major risk when using TNF blockers, the French agency AFFSAPS recommends to screen and treat susceptible patients such as latent tuberculosis. Specifically, antituberculous drugs have to be started three weeks before anti-TNF agents. During biological therapy, physicians must regularly look for usual and unusual symptoms of TB. When TB is diagnosed, anti -TNF agents have to be discontinued, probably definitively, and appropriate antituberculosis treatment started in order to achieve an uneventful course.

Etanercept (Enbrel, Immunex Corporation, Seattle, Washington, USA) is a new biological disease-modifying antirheumatic drug (DMARD) for the treatment of active rheumatoid arthritis (RA). It is one of two TNF-alpha blockers to be licensed for the treatment of active RA and is classified as a recombinant human soluble TNF receptor. The drug competitively inhibits the binding of TNF to cell surface receptors and thus renders TNF biologically inactive. In doing so, etanercept inhibits the pro-inflammatory effects of TNF and results in a reduction of joint inflammation in patients with RA. Etanercept has shown a statistically significant reduction in swollen and inflamed joint counts, biochemical markers such as erythrocyte sedimentation rate and C-reactive protein and shown significant improvements in quality of life measures (HAQ and global assessment scores) in all studies. In early disease, etanercept has shown a reduction in joint space narrowing equal to methotrexate (MTX) and a reduction in the appearance of new erosions significantly better than MTX after 1 year of treatment. Etanercept has a rapid onset of action which is significantly faster than standard DMARDs. Etanercept was well-tolerated in clinical trials. The commonest side effects were injection site reactions and upper respiratory tract infections. Etanercept therapy has resulted in serious infections in some patients and should be used with caution in any patient with a history of recurring infections or with disease states that may predispose to infections. In summary, etanercept is an effective and well-tolerated agent that is a significant breakthrough in the treatment of this disabling condition.