Tapering/Discontinuing Biologics

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Hi friends, on these days I’m in Brazil visiting my colleagues of this beautiful country. One of the principal purposes of this trip is to discuss with them the important issue of tapering (or discontinuing) biologics in rheumatic conditions, once the patient has achieved a good clinical status (remission or low disease activity). There is a lot of evidence, but unfortunately, many studies have been conducted in patients (that in our clinical setting) they shouldn’t be candidates to receive biologics. Nonetheless, after an extensive review, I could achieve some conclusions that I intend to share with you once my visit has ended. Then, it will be great getting your feedback. Now as a starter, I attach the outline of my presentation. Cheers…

Clazakizumab for Adults with Active PsA

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The Rheumatologist

Although the pathogenesis of psoriatic arthritis (PsA) is not fully understood, the pleiotropic inflammatory cytokine interleukin-6 (IL-6), which has a known role in synovitis, local and systemic inflammation, and the promotion of bone resorption in rheumatoid arthritis (RA), may play a role. Serum levels of IL-6 are increased in patients with psoriasis, and the up-regulation of proinflammatory cytokines, including IL-6, in PsA synovial tissue has been reported. In patients with PsA, IL-6 levels correlate with the number of affected joints, elevation of the erythrocyte sedimentation rate, and C-reactive protein (CRP) level. Additionally, a few case reports of successful use of anti–IL-6 receptor biologic therapy to treat PsA exist, although results have been conflicting. Taken together, these findings make IL-6 a potential therapeutic target in PsA.

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The Evolving Biosimilar Landscape: Approval of the First Etanercept Biosimilar in Europe

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An Interview With Emilio Martín-Mola

Received: 17.03.16 Accepted: 19.07.16
Citation: EMJ. 2016;1[3]:76-84.

Abstract

On January 14th 2016, SB4 (Benepali®) received marketing authorisation application approval from the European Commission (EC). It is the first biosimilar to etanercept available in Europe as well as the first subcutaneous anti-tumour necrosis factor biosimilar. Benepali® was approved for the treatment of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic spondyloarthritis), and plaque psoriasis.

SB4 adds to the available biologic armamentarium of biosimilars in rheumatology, which also includes two infliximab biosimilars; one under the brand names Remsima® and Inflectra®, and the other under the brand name Flixabi®. Unlike infliximab biosimilar, which is a chimeric monoclonal antibody, SB4 is a fusion protein.

We aimed to review the current European Medicines Agency (EMA) requirements for the approval of biosimilars and how these products can integrate into daily clinical practice in rheumatology.

To that effect, we recently discussed with Dr Emilio Martín-Mola about the European framework for approval of biosimilars and the controversies that may surround this new category of medicinal products. We discussed how the advent of biosimilars in rheumatology has the potential to truly be a game-changer for both physicians and patients

Infliximab Biosimilar Cross Reacts to Infliximab Antibodies

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The Rheumatologist

August 11, 2016 • By

Cross Reactions

A recent study published online in March in the Annals of the Rheumatic Diseases investigated if the infliximab biosimilar (CT-P13, infliximab-dyyb), which is marketed in Europe as Inflectra and Remsima, can be safely and effectively substituted for infliximab (Remicade).1 Infliximab and its biosimilar are manufactured via the same process. Researchers set out to determine whether those patients with antibodies to infliximab would mount a similar response to the infliximab biosimilar (CT-P13). Two-hundred and fifty patients with rheumatoid arthritis (RA) andspondyloarthritis undergoing infliximab treatment who had never been exposed to CT-P13 were evaluated.

All patients treated with infliximab who had antibodies to infliximab cross reacted with CT-P13, either Inflectra or Remsima. The authors note that the epitopes raising the immune response to infliximab demonstrate the same degree of reactivity to the infliximab biosimilar. However, due to different glycosylation patterns or impurities, CT-P13 may possess its own unique epitopes.

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Patients’ and rheumatologists’ preferences for the attributes of biological agents used in the treatment of rheumatic diseases in spain

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Joan M Nolla Manuel Rodríguez Emilio Martin-Mola Enrique Raya Isabel Ibero Gonzalo Nocea Belén Aragon Luis LIzán Miriam Prades

Patient Preference and Adherence 2016:10 1101–1113

Purpose: To de ne importance values assigned to attributes of biological agents (BAs) by Spanish patients with rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and rheumatologists. Patients and methods: This was an observational, cross-sectional design based upon a rank- based full-pro le conjoint analysis. A literature review and four focus groups were undertaken to identify attributes and levels. An orthogonal matrix, combining the selected levels of attri- butes, was used to de ne scenarios. Participants ranked eight scenarios from 1 (most preferred) to 8 (least preferred). The relative importance (RI) of attributes was calculated. Multivariate regression analysis was performed to identify the characteristics that in uenced the values of RI. A total of 488 patients (male 50.9%, mean age 50.6 [standard deviation {SD} 12.06] years, rheumatoid arthritis 33.8%, ankylosing spondylitis 32.4%, psoriatic arthritis 33.8%; mean time since diagnosis 12.6 [SD 8.2] years) and 136 rheumatologists (male 50.4%, mean age 46.4 [SD 9.1] years, mean time of practice 16.7 [SD 8.8] years) participated. Results: The ideal BAs for patients and physicians, respectively, should allow pain relief and improvement of functional capacity (RI 39% and 44.7%), with low risk of adverse events (RI 24.9% and 30.5%), a long time prior to perceiving the need for a new dose (RI 16.4% and 12.4%), and self-administration at home (RI 19.7% and 12.5%), as identi ed through their preferences. Conclusion: Although ef cacy and safety are paramount for patients and rheumatologists to make a choice regarding BAs, the need for a low frequency of administration and the administration method also play a role as preference attributes for BAs. Keywords: preferences, conjoint analysis, attributes, biological agents, rheumatic diseases

Anti‑citrullinated peptide antibodies and their value for predicting responses to biologic agents: a review

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Rheumatol Int DOI 10.1007/s00296-016-3506-3

Emilio Martin‑Mola1,7 · Alejandro Balsa1 · Rosario García‑Vicuna2 · Juan Gómez‑Reino3 · Miguel Angel González‑Gay4 · Raimon Sanmartí5 · Estíbaliz Loza

Abstract Anti-citrullinated peptide antibodies (ACPAs) play an important pathogenic role both at the onset and during the disease course. These antibodies precede the clinical appearance of rheumatoid arthritis (RA) and are associated with a less favorable prognosis, both clinically and radiologically. The objective of this work was to conduct a comprehensive review of studies published through September 2015 of ACPAs’ role as a predictor of the therapeutic response to the biological agents in RA patients. The review also includes summary of the biology and detection of ACPAs as well as ACPAs in relation to joint disease and CV disease and the possible role of seroconversion. The reviews of studies examining TNF inhibitors and tocilizumab yielded negative results. In the case of rituximab, the data indicated a greater probability of clinical benefit in ACPA+ patients versus ACPA− patients, as has been previously described for rheumatoid factor. Nonetheless, the effect is discreet and heterogeneous. Another drug that may have greater effectiveness in ACPA+ patients is abatacept. Some studies have suggested that the drug is more efficient in ACPA+ patients and that those patients show greater drug retention. In a subanalysis of the AMPLE trial, patients with very high ACPA titers who were treated with abatacept had a statistically significant response compared to patients with lower titers. In summary, the available studies suggest that the presence of or high titers of ACPA may predict a better response to rituximab and/or abatacept. Evidence regarding TNFi and tocilizumab is lacking. However, there is a lack of studies with appropriate designs to demonstrate that some drugs are superior to others for ACPA+ patients.

Baricitinib in Patients with Refractory Rheumatoid Arthritis

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Just published in the N Engl J Med Baricitinib a new jak inhibitor improved outcomes in RA patients who failed to biologics

Genovese M es al. N Engl J Med 2016;374:1243-1252

BACKGROUND

In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs).
Full Text of Background…
METHODS
In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire–Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose

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