Recientemente la Dra. Chamaida Plasencia y yo, hemos tenido la oprtunidad de estudiar este importante aspecto relacionado con la seguridad de los biológicos. Tras revisar extensamente la literatura hemos llegado a las siguientes conclusiones
• En primer lugar, es muy complicado establecer una relación entre una enfermedad tan frecuente como el cáncer y el tratamiento con biológicos. Los motivos son diversos, pero entre ellos hay que destacar los distintos factores exógenos y genéticos que están relacionados con el origen de la enfermedad tumoral y la dificultad que existe para deslindar éstos del efecto causal de un determinado medicamento, como en este caso serían los biológicos. Si a esto le sumamos, que cualquier factor externo causal de un tumor, puede desarrollar la enfermedad muchos años después de haber sido eliminado (el mejor ejemplo es el tabaco, ya que se estima que desde su suspensión y aunque la probabilidad de desarrollar un cáncer va disminuyendo de forma paulatina, el riesgo de padecer un cáncer, probablemente, siempre será algo superior que el de la población que no fue fumadora), las conclusiones se complican aún más.
• Con respecto a las enfermedades autoinmunes y cáncer, hoy parece establecido, que algunas de ellas ya tienen per se mayor probabilidad de desarrollar un tumor, al margen de la terapia. El ejemplo más representativo es el linfoma no Hodgkin y la artritis reumatoide. Hoy está aceptado que esta enfermedad cuando no se controla adecuadamente, tiene un riesgo superior a desarrollar este linfoma que la población general. Sin embargo, y aunque existen estudios contradictorios, la inmensa mayoría de los metaanálisis y estudios de registros, no han podido demostrar que la terapia biológica aumente ese riesgo. Si el etanercept, el único anti-TNF que no es un anticuerpo monoclonal, tiene menos riesgo para desarrollar linfoma que los anticuerpos monoclonales, sigue siendo tema de debate, aunque los estudios de autores franceses y británicos apuntarían en esa dirección.
Kevin D. Deane, MD, PhD
Stopping Tumor Necrosis Factor Inhibitor Therapy in Patients With Established Rheumatoid Arthritis in Remission or With Stable Low Disease Activity: A Pragmatic Multicenter, Open-Label Randomized Controlled Trial
Ghiti Moghadam M, Vonkeman HE, Ten Klooster PM, et al; Dutch National POET Collaboration
Arthritis Rheumatol. 2016;68:1810-1817
In this study, Ghiti Moghadam and colleagues from The Netherlands used a pragmatic trial design to investigate rates of rheumatoid arthritis (RA) flare after cessation of anti-tumor necrosis factor (anti-TNF) therapy. They analyzed 817 patients, all of whom had a Disease Activity Score in 28 joints (DAS28) < 3.2 for 6 months before inclusion.
Individuals with RA were randomized in a 2:1 ratio to stop or continue anti-TNF therapy (531 and 286 patients, respectively). The primary outcome was flare of disease, as determined by a DAS28 ≥ 3.2 over 12 months of follow-up or an increase in score ≥ 0.6.
At 12 months, the anti-TNF discontinuation group had more flares (approximately 51% vs 18%; P < .001) and a higher mean DAS28 (P < .001). Of the 195 patients who restarted anti-TNF therapy, around 85% regained a DAS28 < 3.2 after 6 months. Besides stopping anti-TNF therapy, predictors of time to a flare were a higher baseline DAS28 and disease duration > 10 years at the time of study entry. In terms of safety, there was one death due to an infection in the continuation group, and 34 hospitalizations in the discontinuation group compared with seven in the continuation group (P = .012)
Increasing numbers of studies have been investigating the possibility that individuals with RA can decrease therapy and yet continue to have excellent disease control. These studies were reviewed in an outstanding article by Schett and colleagues that was published in the May 2016 edition of the Annals of Rheumatic Diseases. Results have been variable, although there has been substantial heterogeneity across the studies.
Introduction: Since the introduction of anti-TNF therapy in inflammatory diseases, paradoxical reactions are increasingly reported. One of these paradoxical reactions is the development of sarcoidosis-like lesions. This presentation is paradoxical since anti-TNF therapy can also be therapeutic in refractory cases of sarcoidosis.
Methods: We report two cases of sarcoidosis-like lesions under anti-TNF therapy. Both were patients with inflammatory bowel disease (IBD), treated successfully with adalimumab. Next, we reviewed the literature for similar cases. Medical subject heading (MeSH) terms “adalimumab”, “infliximab”, “etanercept”, “golimumab” or “certolizumab”, and “sarcoidosis” were used to perform key word searches of the PubMed database.
Results: We identified 90 reported cases of sarcoidosis-like lesions, which developed during anti-TNF therapy. In most cases, the culprit anti-TNF drug was etanercept. The median age was 43 years and there was a predominance of female patients. The underlying disease was rheumatoid arthritis in most cases, followed by ankylosing spondylitis and psoriasiform arthritis. In six cases, the underlying disease was IBD. In 71 cases there was at least a partial resolution by discontinuation of the anti-TNF treatment, initiation of steroids or both. Re-initiation of anti-TNF therapy gave relapse in 7 out of 20 cases.
Conclusion: Sarcoidosis-like lesions are increasingly reported during anti-TNF treatment. Vigilance is appropriate when patients present with symptoms compatible with sarcoidosis.
- ‘tumor necrosis factor antagonists and inhibitors’
- ‘inflammatory bowel disease’
- Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: firstname.lastname@example.org
July 15, 2016 • By
During the July meeting of the U.S. Food and Drug Administration’s Arthritis Advisory Committee in Silver Spring, Md., the FDA voted to approve two new biosimilars for use by rheumatologists
GP2015, a proposed biosimilar of etanercept(Enbrel), was evaluated at the FDA‘s Arthritis Advisory Committee meeting.1 The panel voted unanimously to recommend approval of GP2015.
The treatment’s proposed indications were:
- Reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in patients with moderate to severe active rheumatoid arthritis (RA) in combination with methotrexate (MTX) or as monotherapy;
- Reducing signs and symptoms of moderate to severe active polyarticular juvenile idiopathic arthritis in patients aged two years and older;
- Reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis in combination with MTX in patients who do not respond adequately to MTX alone;
- Reducing signs and symptoms in patients with active ankylosing spondylitis; and
- Treating patients 18 years of age or older with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
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.
Biologics: Targets and Therapy (Open access)
Simon Francis Thomsen1,2 Freja Lærke Sand1,2 1Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark; 2Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
Dear editor We read with interest the recent paper by Cooke et al about the use of biologic agents for intractable urticaria.1 Particularly, the authors reckon that the evidence supporting the use of anti-TNFs is limited by the small numbers of patients in non-controlled studies, often with urticarial disorders not typical of chronic urticaria such as vasculitis and delayed pressure urticaria. However, we want to draw the authors’ and readers’ attention to our report from 2013 about the use of adalimumab and etanercept in 20 patients with chronic urticaria with or without angioedema2 (updated in 2015 with an additional five patients).3 This report is to date the largest series of patients published and adds substantially to the small body of evidence supporting the use of anti-TNFs in subgroups of patients with chronic urticaria unresponsive to conventional therapy or omalizumab. Notably, 60% of our patients obtained complete or almost complete resolution of urticaria and angioedema after onset of therapy with either adalimumab or etanercept, whereas another 15% of our patients experienced partial response to therapy. Some of our patients were previously unresponsive to or experienced side effects from omalizumab. Duration of treatment ranged between 2 and 39 months. We observed side effects in 30% of our patients, particularly mild recurrent upper respiratory infections, whereas one patient experienced severe central nervous system toxicity. We propose that adalimumab and etanercept may be effective in some patients with chronic urticaria who do not respond sufficiently to high-dose antihistamines or in whom other immunosuppressive drugs or omalizumab are ineffective or associated with unacceptable side effects. However, patients should be monitored closely due to the possibility of severe side effects of anti-TNF treatment. We agree that larger randomized controlled trials are needed before a definite recommendation can be made in regards to the use of anti-TNFs for chronic urticaria. Disclosure The authors report no conflict of interest in this communication
Levels of certain microRNAs were associated with response to treatment with an anti–tumor necrosis factor–alpha agent and conventional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis, according to a study conducted by Dr. Carmen Castro-Villegas and her associates.
In patients who responded to the combination therapy, 91% had overexpressed miRNA, while 9% had downregulated miRNA. Of the 10 miRNA selected for analysis, 6 had been significantly upregulated by the therapy (miR-16-5p, miR-23-3p, miR125b-5p, miR-126-3p, miR-146a-5p, miR-223-3p), and only patients who responded to the therapy showed an increase in these miRNA. The miRNA increase also paralleled a reduction in TNF-alpha, interleukins, rheumatoid factor, and C-reactive protein.
Further analyses showed that miR-23-3p and miR-223-3p can act to predict patients who would not benefit from combination therapy with anti-TNF-alpha agents and conventional disease-modifying antirheumatic drugs or indicate treatment efficacy or the degree of response, the investigators said.
Find the full study in Arthritis Research & Therapy (doi:10.1186/s13075-015-0555-z).