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Concept: Etanercept

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Anti-drug antibodies (ADAs) against biologic agents may be clinically significant and potentially alter a biologic drug’s treatment efficacy. This systematic review aims to 1) determine the prevalence of ADAs against infliximab, etanercept, adalimumab, and ustekinumab in psoriasis patients; 2) ascertain whether ADAs are associated with changes in drug efficacy; and 3) explore the use of concomitant methotrexate to prevent ADA formation. Through a systematic search using MEDLINE and EMBASE from January 29, 1950 to March 29, 2013, we identified 25 studies that met the inclusion criteria. Of 7,969 psoriasis patients, 950 patients tested positive for ADAs. Antibodies against infliximab, etanercept, adalimumab, and ustekinumab were reported in 5.4%-43.6%, 0.0%-18.3%, 6.6%-44.8%, and 3.8%-5.5% of patients, respectively. Anti-infliximab antibodies were associated with lower serum infliximab concentrations in three studies and decreased treatment response in five studies. ADAs against etanercept were non-neutralizing and not associated with any apparent effects on clinical response. Anti-adalimumab antibodies were associated with lower serum adalimumab concentrations in three of five studies and reduced clinical efficacy in four studies. Two of six studies reported that anti-ustekinumab antibodies were associated with lower PASI responses, and three ustekinumab studies noted that most of these antibodies were neutralizing. Although the use of concomitant methotrexate with biologic agents to prevent ADA formation in other immune-mediated diseases is promising, their use in psoriasis is sparse. ADA development remains a challenge with biologic therapies and therefore should be considered in psoriasis patients who experience diminished treatment response. This article is protected by copyright. All rights reserved.

Concepts: Monoclonal antibodies, Rheumatoid arthritis, Infliximab, Ankylosing spondylitis, Psoriatic arthritis, Psoriasis, Etanercept, Adalimumab

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In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR’s most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.

Concepts: Rheumatoid arthritis, Rheumatology, Infliximab, Psoriatic arthritis, Etanercept, Disease-modifying antirheumatic drug, Adalimumab, TNF inhibitor

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Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has shown superior efficacy to etanercept with similar safety in moderate to severe plaque psoriasis (FIXTURE study).

Concepts: Ultraviolet, Randomized controlled trial, Monoclonal antibodies, Infliximab, Psoriatic arthritis, Psoriasis, Etanercept, Adalimumab

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To assess the efficacy and safety of switching from the infliximab reference product (RP; Remicade) to its biosimilar CT-P13 (Remsima, Inflectra) or continuing CT-P13 in patients with rheumatoid arthritis (RA) for an additional six infusions.

Concepts: Rheumatoid arthritis, Rheumatology, Infliximab, Methotrexate, Ankylosing spondylitis, Psoriatic arthritis, Etanercept, Adalimumab

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Background Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. Methods We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. Results In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. Conclusions In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512 , NCT01597245 , and NCT01646177 , respectively.).

Concepts: Clinical trial, ClinicalTrials.gov, Infliximab, Inflammatory bowel disease, Placebo, Psoriasis, Etanercept, Adalimumab

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OBJECTIVE:: Colchicine is the mainstay treatment for Familial Mediterranean Fever (FMF). However 5% to 10% of the patients with FMF are unresponsive or intolerant to colchicine. Biologics are efficient in many rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, cryopyrin-associated periodic syndromes. We performed a systematic review to analyze patients with FMF, including juvenile patients who received treatment with biologics. METHODS:: A MEDLINE search, including articles published in English language between 1990 and May 2012, was performed. Patients who had MEFV variants but could not be classified as FMF according to Tel-Hashomer criteria were excluded. RESULTS:: There is no controlled trial on the efficacy and safety of biologics in FMF. Fifty-nine (32 female and 27 male) patients with FMF who had been treated with biologics (infliximab, etanercept, adalimumab, anakinra, and canakinumab) were reported in 24 single reports and 7 case series. There were 16 children and 43 adults (7- to 68-year olds). Five patients were reported to have colchicine intolerance or had adverse events related to colchicine use, and the rest 54 were unresponsive to colchicine treatment. CONCLUSIONS:: The current data are limited to case reports, and it is difficult to obtain a quantitative evaluation of response to biologic treatments. However, on the basis of reported cases, biologic agents seem to be an alternative treatment for patients with FMF who are unresponsive or intolerant to colchicine therapy and seem to be safe. Controlled studies are needed to better evaluate the safety and efficacy of biologics in the treatment of patients with FMF.

Concepts: Familial Mediterranean fever, Rheumatoid arthritis, Rheumatology, Infliximab, Arthritis, Ankylosing spondylitis, Etanercept, Adalimumab

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Palmoplantar pustulosis is characterized by sterile pustules with hyperkeratosis, erythema, scaling, and fissuring on the palms and soles.(1) It has been reported to be more frequent in middle-aged women, smokers, and diabetic patients(2) , and it is increasingly reported as a paradoxical reaction to antitumor necrosis factor alpha (anti-TNF) biological agents.(3, 4.) It can present itself alone (PPP), or in association with psoriasis vulgaris (palmoplantar pustular psoriasis, PPPP).

Concepts: Ultraviolet, Tumor necrosis factor-alpha, Psoriatic arthritis, Psoriasis, Etanercept, Pustulosis palmaris et plantaris, Ustekinumab, Adalimumab

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The time necessary for a treatment to become effective is crucial for patients and physicians but has been largely neglected in the reporting and comparison of clinical trials in dermatology. The aim of this systematic review is to determine the time until the onset of action of systemic agents approved for moderate-to-severe psoriasis. Primary outcome is the time until onset of action (TOA) defined as the weighted mean time until 25% of the patients achieved a PASI 75 response. Among the biologics, infliximab has the shortest TOA (3.5 weeks) followed by ustekinumab (high dose 4.6/low dose 5.1 weeks/not weight adapted), adalimumab (4.6 weeks), etanercept (high dose 6.6/low dose 9.5 weeks) and alefacept (high dose 15.4 weeks/ low dose: no data). Among the conventional treatments, good data is available for CsA (TOA: 6.0 weeks), limited data was found for MTX (TOA: high dose 3.2/low dose 9.9 weeks). No data are available for fumaric acid esters and retinoids. This systematic review provides clinically relevant information on the onset of action of antipsoriatic agents although the data currently available allows only a limited assessment. Psoriasis trials should consider including the time until the onset of action as an additional outcome measure.Journal of Investigative Dermatology accepted article preview online, 20 February 2013; doi:10.1038/jid.2013.78.

Concepts: Rheumatoid arthritis, Infliximab, Psoriatic arthritis, Psoriasis, Etanercept, Immunosuppressants, Adalimumab, Fumaric acid

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To investigate the relationship between antidrug antibodies (ADA), adalimumab concentrations and clinical response in patients with psoriatic arthritis (PsA) during 52 weeks of follow-up.

Concepts: Rheumatoid arthritis, Infliximab, Arthritis, Psoriatic arthritis, Psoriasis, Etanercept, Adalimumab

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Abstract Objective Evaluate efficacy of infliximab with response-driven dosing in patients with active RA. Research design and methods: Patients (n=203) with active RA despite methotrexate+etanercept/adalimumab, participated in this active-infliximab-switch study. Infliximab 3mg/kg was infused at Weeks0, 2, 6, 14 and 22 with escalation to 5 or 7mg/kg depending on EULAR response at Week14 and 22. The primary endpoint was EULAR response at Week10. Safety was assessed through Week30. Infliximab levels and antibodies to infliximab (ATI) were measured at Weeks 0, 6, 14 and 26. Clinical trial registration: NCT 00714493, EudraCT 2007-003288-36 Results: Of 197 evaluable patients, 120/77 previously received etanercept/adalimumab. Baseline mean(SD) swollen and tender joint counts: 17.3(10.54) and 30.2(16.89), respectively; mean DAS28-ESR: 6.19(0.981). At Week10, 98 (49.7%; 95% CI: 42.6%, 56.9%) patients achieved EULAR response, with a significantly improved DAS28-ESR (mean[SD] change -1.1[1.15]; p<0.001). EULAR response was achieved by 41.7/62.3% of patients previously receiving etanercept/adalimumab (p=0.006). At Week26, 51.8% (95%CI: 44.6%, 58.9%) of patients achieved or maintained EULAR response. Infliximab dose was escalated in 100 patients, 52% achieved EULAR response at Week26. Median serum concentration levels at Week26 showed that dose escalation helped EULAR non-responders achieve levels similar to or higher than the levels seen in responders. ATI were associated with lower serum concentrations of infliximab, consistent with lower efficacy rates among ATI-positive patients. Conclusion: Infliximab, in treat-to-target settings with individual dose escalation, demonstrated significant efficacy at Weeks10 and 26 in patients switched to infliximab after inadequate response to etanercept/adalimumab. The observed efficacy indicated that the switch to infliximab and ability to increase dose in a targeted fashion were beneficial.

Concepts: Rheumatoid arthritis, Rheumatology, Infliximab, Ankylosing spondylitis, Psoriatic arthritis, Etanercept, Adalimumab, Escalation