Efficacy of Monotherapy with Biologics and JAK Inhibitors for the Treatment of Rheumatoid Arthritis: A Systematic Review.

Despite recommendations suggesting that biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) should be used in combination with methotrexate in the treatment of rheumatoid arthritis (RA), up to one-third of patients with RA are treated with monotherapy. The objective of the systematic literature review reported here was to evaluate the clinical evidence regarding the efficacy of b/tsDMARDs as monotherapy in the treatment of RA. MEDLINE®, Embase®, and the Cochrane Central Trials Register (to April 11, 2017) and the American College of Rheumatology and European League Against Rheumatism conference proceedings (2010-2016) were searched for randomized controlled trials evaluating the efficacy of b/tsDMARDs as monotherapy for RA in adults. Forty-four monotherapy studies of abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, sarilumab, sirukumab, tocilizumab, and tofacitinib reported in 71 publications were identified. Tocilizumab had the most studies (14), followed by etanercept (10) and adalimumab (9). These b/tsDMARDs were consistently shown to be efficacious treatments, regardless of whether patients were intolerant of or had never used conventional synthetic (cs) DMARDs. However, better treatment outcomes were usually achieved with combination therapy, and this was observed for all b/tsDMARDs assessed by this review. Only a few studies provided a head-to-head comparison between b/tsDMARD treatments or between b/tsDMARD monotherapy and combination therapy, and as many were initial RA treatments they were not generalizable to usual care. In conclusion, evidence from randomized trials suggests that the b/tsDMARDs studied are effective as monotherapy. In general, some patient responses seem better with combination therapy and the durability of monotherapy is less than combination therapy. There is, however, a need for longer-term head-to-head trials to establish positioning of these interventions in the treatment algorithm for RA. FUNDING: Pfizer.Plain Language Summary: Plain language summary available on the journal website.

The comparative immunogenicity of biologic therapy and its clinical relevance in psoriatic arthritis: a systematic review of the literature.

INTRODUCTION: Biologic agents have demonstrated efficacy in treating patients with psoriatic arthritis (PsA). Biologic agents also have an intrinsic capacity to induce an immune response in patients that could result in unwanted adverse events and/or treatment failure. AREAS COVERED: In this systematic literature review, the authors document the incidence of immune responses, primarily anti-drug antibodies (ADA), to the biologic therapeutic agents currently in clinical practice for the treatment of PsA. The authors discuss the importance of these responses with respect to clinical practice. EXPERT OPINION: Our evaluation of the published literature shows that the immune responses to the various biologic therapeutic agents currently being used to treat PsA are similar to those observed for these agents in other rheumatic diseases. Moreover, similar to observations in other rheumatic diseases, the incidence of ADA formation to biologic agents in patients with PsA is often decreased when patients are given concomitant treatment with disease-modifying anti-rheumatic drugs. These data strongly suggest that the immune response is a characteristic of the biologic agent. Using therapeutic drug monitoring may be an approach to assess the immune response to the agent and to mitigate the potential impact on efficacy and safety, and consequently optimize treatment.

Effects of biologic disease-modifying anti-rheumatic drugs on the radiographic progression of rheumatoid arthritis: a systematic literature review.

OBJECTIVES: To evaluate the effect of biologic disease-modifying anti-rheumatic drugs (bDMARDs) on radiographic progression in patients with rheumatoid arthritis (RA). METHODS: A systematic review of electronic databases and conference proceedings was conducted through January 2015, to identify randomised controlled trials (RCTs) and observational studies that assessed the impact of bDMARDs [± conventional synthetic DMARDs (csDMARDs), mainly methotrexate (MTX)], versus csDMARDs alone, on radiographic progression in patients with RA. RESULTS: Following screening of >5000 records, 104 publications covering 63 studies were included. Of 34 RCTs in patients with early, active (n=13) or established RA (n=21) [abatacept (1, 2); adalimumab (4, 2); certolizumab pegol (1, 4); etanercept (3, 3); golimumab (1, 4); infliximab (1, 1); rituximab (1, 1); tocilizumab (1, 5)], combination therapy with a bDMARD and MTX had a significantly greater effect than placebo or MTX alone, in inhibiting radiographic progression. This included patients previously unresponsive, or who responded incompletely, to MTX treatment alone, and was supported by data from observational studies. Findings from a smaller subset of these and other RCTs supported superiority of combination therapy over bDMARD monotherapy, and bDMARD monotherapy over MTX, in slowing radiographic progression. CONCLUSIONS: There is evidence from RCTs with a range of bDMARDs that improvement in radiographic outcomes for patients with early or established RA, when used in combination with MTX and to a lesser extent as monotherapy, are significantly greater than MTX alone. There was no evidence of a difference between bDMARDs on inhibition of radiographic progression.

Immunogenicity of biologics in inflammatory bowel disease.

Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10-14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required.

The Impact of Biologics and Tofacitinib on Cardiovascular Risk Factors and Outcomes in Patients with Rheumatic Disease: A Systematic Literature Review.

INTRODUCTION: Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients. METHODS: A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events. RESULTS: Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated. CONCLUSIONS: Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients.

Down-titration of biologics for the treatment of rheumatoid arthritis: a systematic literature review.

Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice.

Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review.

OBJECTIVES: A systematic review was conducted to explore the immunogenicity of biologic agents across inflammatory diseases and its potential impact on efficacy/safety. METHODS: Literature searches were conducted through November 2016 to identify controlled and observational studies of biologics/biosimilars administered for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), psoriasis (Ps), Crohn's disease, and ulcerative colitis. RESULTS: Of >21,000 screened publications, 443 were included. Anti-drug antibody (ADAb) rates varied widely among biologics across diseases (and are not directly comparable because of immunoassay heterogeneity); the highest overall rates were reported with infliximab (0-83%), adalimumab (0-54%), and infliximab biosimilar CT-P13 (21-52%), and the lowest with secukinumab (0-1%), ustekinumab (1-11%), etanercept (0-13%), and golimumab (0-19%). Most ADAbs were neutralizing, except those to abatacept and etanercept. ADAb+ versus ADAb- patients had lower rates of clinical response to adalimumab (RA, PsA, JIA, AS, Ps), golimumab (RA), infliximab (RA, PsA, AS, Ps), rituximab (RA), ustekinumab (Ps), and CT-P13 (RA, AS). Higher rates of infusion-related reactions were reported in infliximab- and CT-P13-treated ADAb+ patients. Background immunosuppressives/anti-proliferatives reduced biologic immunogenicity across diseases. CONCLUSIONS: Based on reviewed reports, biologic/biosimilar immunogenicity differs among agents, with the highest rates observed with infliximab and adalimumab. As ADAb formation in biologic-/biosimilar-treated patients may increase the risk of lost response, the immunogenicity of these agents is an important (albeit not the only) consideration in the treatment decision-making process.

Biosimilars for the Treatment of Cancer: A Systematic Review of Published Evidence.

BACKGROUND: Biologic treatments for cancer continue to place a significant economic burden on healthcare stakeholders. Biosimilar therapies may help reduce this burden through cost savings, thereby increasing patient access. OBJECTIVES: The purpose of this study was to collate all published data to assess the weight of available evidence (quantity and quality) for proposed monoclonal antibody biosimilars and intended copies, for the treatment of cancer. METHODS: MEDLINE®, Embase®, and ISI Web of Science® databases were searched to September 2015. Conference proceedings (17) were searched (2012 to July 2015). Searches of the United States National Library of Medicine ClinicalTrials.gov registry were also conducted. Risk of bias assessments were undertaken to assess data strength and validity. RESULTS: Proposed biosimilars were identified in 23 studies (36 publications) in oncology and ten studies in 14 publications in oncology and chronic inflammatory diseases for bevacizumab, rituximab, and trastuzumab originators. Based on our review of the included published studies, and as inferred from the conclusions of study authors, the identified proposed biosimilars exhibit close similarity to their originators. Published data were also retrieved on intended copies of rituximab. It remains unclear what role these agents may have, as publications on rigorous clinical studies are lacking for these molecules. CONCLUSION: While biosimilar products have the potential to improve patient access to important biologic therapies, robust evidence of outcomes for monoclonal antibody biosimilars in treating cancer patients, including data from comparative efficacy and safety trials, is not yet available in the published literature. Significant data gaps exist, particularly for intended copies, which reinforces the need to maintain a clear differentiation between these molecules and true biosimilars. As more biosimilars become available for use, it will be important for stakeholders to understand fully the robustness of overall evidence used to demonstrate biosimilarity and gain regulatory approval.

Biosimilars for the Treatment of Chronic Inflammatory Diseases: A Systematic Review of Published Evidence.

BACKGROUND: Clinicians are required to assimilate, critically evaluate, and extrapolate information to support appropriate use of biosimilars across indications. OBJECTIVES: The objective of this study was to systematically collate all published data in order to assess the weight (quantity and quality) of available evidence for each molecule and inform and support healthcare decision-making in chronic inflammatory diseases. METHODS: MEDLINE®, EMBASE®, and ISI Web of Science® were searched to September 2015. Selected conference proceedings were searched from 2012 to July 2015. Studies disclosing biosimilars with unique identifiers were categorized by originator, study type, and indication. Risk of bias assessments were performed. Intended copies were differentiated as commercially available agents without evidence of rigorous comparative biosimilarity evaluations. RESULTS: Proposed biosimilars for adalimumab, etanercept, infliximab, and rituximab are reported in the published literature. Across indications, approved biosimilars infliximab CT-P13, SB2, and etanercept SB4 have published studies involving the largest number of patients or healthy subjects (n = 1405, 743, and 734, respectively), mostly in rheumatoid arthritis. At data cut-off, only CT-P13 had published data in ankylosing spondylitis (n = 250; randomized control trial) and ulcerative colitis/Crohn's disease (n = 336; observational studies). Published data were not available for ongoing studies in psoriasis patients. Four intended copies were identified in published studies (total: n = 1430; n = 1372 in observational studies). Thematic analysis of non-empirical publications showed that indication extrapolation remains an issue, particularly for gastroenterologists. CONCLUSIONS: While most agents display a moderate to high degree of similarity to their originator in the published studies identified, large discrepancies persist in the overall amount and type of data available in the public domain. Significant gaps exist particularly for intended copies, reinforcing the need to maintain a clear differentiation between these molecules and true biosimilars.

Monoclonal Antibody and Fusion Protein Biosimilars Across Therapeutic Areas: A Systematic Review of Published Evidence.

BACKGROUND: Despite regulatory efforts to formalize guidance policies on biosimilars, there remains a need to educate healthcare stakeholders on the acknowledged definition of biosimilarity and the data that underpin it. OBJECTIVES: The objectives of the study were to systematically collate published data for monoclonal antibodies and fusion protein biosimilars indicated for cancer, chronic inflammatory diseases, and other indications, and to explore differences in the type and weight (quantity and quality) of available evidence. METHODS: MEDLINE, Embase, and ISI Web of Science were searched to September 2015. Conference proceedings (n = 17) were searched 2012 to July 2015. Included studies were categorized by originator, study type, and indication. To assess data strength and validity, risk of bias assessments were undertaken. RESULTS: Across therapeutic areas, 43 named (marketed or proposed) biosimilars were identified for adalimumab, abciximab, bevacizumab, etanercept, infliximab, omalizumab, ranibizumab, rituximab, and trastuzumab originators. Infliximab CT-P13, SB2, and etanercept SB4 biosimilars have the greatest amount of published evidence of similarity with their originators, based on results of clinical studies involving larger numbers of patients or healthy subjects (N = 1405, 743, and 734, respectively). Published data were also retrieved for marketed intended copies of etanercept and rituximab. CONCLUSIONS: This unbiased synthesis of the literature exposed significant differences in the extent of published evidence between molecules at preclinical, clinical, and post-marketing stages of development, providing clinicians and payers with a consolidated view of the available data and remaining gaps.