The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: A systematic review and meta-analysis of randomized controlled trials

doi:10.1016/j.jaad.2010.09.734

Journal of the American Academy of Dermatology

Volume 64, Issue 6, June 2011, Pages 1035-1050

Presented at the 70th Annual Meeting of the Society of Investigative Dermatology, May 5-8, 2010, in Atlanta, GA, and the abstract from this meeting was published (J Invest Dermatol 2010;130:S59).

https://doi.org/10.1016/j.jaad.2010.09.734 Get rights and content

Background

There is a need to better understand the safety of tumor necrosis factor (TNF) inhibitors in patients with psoriatic disease in whom TNF inhibitors are frequently used as monotherapy.

Objective

We sought to examine the risks of infection and malignancy with the use of TNF antagonists in adult patients with psoriatic disease.

Methods

We conducted a systematic search for trials of TNF antagonists for adults with plaque psoriasis and psoriatic arthritis. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, and certolizumab for the treatment of plaque psoriasis and psoriatic arthritis. Twenty of 820 identified studies with a total of 6810 patients were included. Results were calculated using fixed effects models and reported as pooled odds ratios.

Results

Odds ratios for overall infection and serious infection over a mean of 17.8 weeks were 1.18 (95% confidence interval [CI] 1.05-1.33) and 0.70 (95% CI 0.40-1.21), respectively. When adjusting for patient-years, the incidence rate ratio for overall infection was 1.01 (95% CI 0.92-1.11). The odds ratio for malignancy was 1.48 (95% CI 0.71-3.09) and 1.26 (95% CI 0.39-4.15) when nonmelanoma skin cancer was excluded.

Limitations

Short duration of follow-up and rarity of malignancies and serious infections are limitations.

Conclusions

There is a small increased risk of overall infection with the short-term use of TNF antagonists for psoriasis that may be attributable to differences in follow-up time between treatment and placebo groups. There was no evidence of an increased risk of serious infection and a statistically significant increased risk in cancer was not observed with short-term use of TNF inhibitors.

Section snippets

Methods

Based on the Cochrane Handbook for Systemic Reviews of Interventions guidelines,³⁰ we used a predefined, peer-reviewed protocol to perform the study selection, assessment of eligibility criteria, data extraction, and statistical analysis of RCTs of patients with PsO and PsA. This article was prepared in accordance with the PRISMA statement.³¹ This study was granted an institutional review board exemption by the University of Pennsylvania.

Search results and trial characteristics

Of 820 potentially relevant publications identified through database searching, 20 clinical trials including 6810 adult patients (5427 patients in PsO and 1383 patients in PsA studies) qualified for inclusion (Fig 1). Seven trials specifically included patients with active PsA unresponsive to disease-modifying antirheumatic drugs (DMARD), nonsteroidal anti-inflammatory drugs, or both, although 5 of these trials also required that patients have active psoriatic skin lesions, a documented history

Discussion

Our systematic review and meta-analysis combined data from 20 RCTs of adult patients with PsO and PsA treated with anti–TNF-alfa agents. To our knowledge, this is the largest review to date of RCTs examining the risk of infection and malignancy with the use of anti–TNF-alfa agents in patients with psoriatic disease.

Our study suggests that there may be a small increased risk of overall infection with the short-term use of TNF-alfa antagonists for psoriatic disease. However, 97.6% of reported

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Medline and Cochrane databases were systematically searched up to March 2021 for randomized controlled trials (RCTs) performed in patients with PsA or axial spondyloarthritis treated with biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). Global infections (any infections reported, including bacterial, viral and fungal infections, except serious infections) were the primary outcome. Secondary outcomes included serious infections defined as life-threatening infections or any infection requiring intravenous antibiotics or hospitalization. The relative risk of infections was determined by meta-analysis of RCTs.
A total of 60 RCTs were included (20,418 patients), encompassing 17 b/tsDMARDs, compared with placebo, conventional synthetic drugs (csDMARDs) or non-steroidal anti-inflammatory drugs (NSAIDs). An increased risk of any infection for patients exposed to these drugs was found (RR 1.15, 95% CI [1.06–1.25]), mainly with high doses and longer duration of treatment. Most infections were respiratory tract or ear, nose, and throat (ENT) infections. Subgroup analyses showed a statistically significant increased risk of infections for axial spondyloarthritis patients (RR 1.32, 95% CI [1.14–1.52]), but not for PsA patients (RR 1.05, 95% CI [0.97–1.14]). Infection risk was highest with TNF inhibitors (RR 1.23, 95% CI [1.11–1.37]) and IL-17 inhibitors (RR 1.30, 95% CI [1.07–1.59]). No increased risk of serious infections was shown.
In contrast to serious infections, the risk of global infections is moderately increased with b/tsDMARDs in spondyloarthritis, and is associated in particular with use of TNF and IL-17 inhibitors.
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Autoinflammatory disorders and autoimmune diseases result from abnormal deviations of innate and adaptive immunity that heterogeneously affect organs and clinical phenotypes. Despite having etiologic and phenotypic differences, these two conditions share the onset of an aberrant inflammatory process. Targeting the main drivers controlling inflammation is useful to treat both autoimmune and autoinflammatory syndromes. TNF-α is a major player in the inflammatory immune response, and anti-TNF-α antibodies have been a revolutionary treatment in many autoimmune disorders. However, production difficulties and high development costs hinder their implementation, and accessibility to their use is still limited. Innovative strategies aimed at overcoming the limitations associated with anti-TNF-α antibodies are being explored, including RNA-based therapies.
Here we summarize the central role of TNF-α in immune disorders and how anti-TNF-based immunotherapies changed the therapeutic landscape, albeit with important limitations related to side effects, tolerance, and resistance to therapies. We then outline how nanotechnology has provided the final momentum for the use of nucleic acids in the treatment of autoimmune and autoinflammatory diseases, with a focus on inflammatory bowel diseases (IBDs). The example of IBDs allows the evaluation and discussion of the nucleic acids-based treatments that have been developed, to identify the role that innovative approaches possess in view of the treatment of autoinflammatory disorders and autoimmune diseases.
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El desarrollo del actual arsenal terapéutico fundamentado en las terapias biológicas, la experiencia acumulada en ensayos clínicos y en práctica clínica real y los nuevos conocimientos sobre la patogénesis en psoriasis permiten posibilidades de individualización y hace adecuada una actualización de las recomendaciones en cuanto a la gestión del riesgo en pacientes tratados con estos fármacos.
El Grupo de Psoriasis de la Academia Española de Dermatología y Venereología (GPS) trabaja desde su creación en la actualización continua de las recomendaciones para el tratamiento de la psoriasis, basándose en la mejor evidencia disponible e incorporando propuestas orientadas desde y para la práctica clínica.
Para la elaboración del consenso se siguió la metodología de grupos nominales, con ayuda de una scoping review. Tras designar a un coordinador, se seleccionó un grupo de trabajo constituido por integrantes del GPS con base en su experiencia y conocimiento en psoriasis. El coordinador definió los objetivos y puntos clave del documento y con ayuda de un documentalista se realizó una scoping review incluyendo datos de Medline, Embase y Cochrane Library (hasta enero del 2021). Se seleccionaron revisiones sistemáticas, metaanálisis y ensayos clínicos no incluidos en las mismas, guías de práctica clínica y documentos de consenso nacionales e internacionales, así como estudios de calidad en vida real. El coordinador generó las recomendaciones preliminares que fueron evaluadas y modificadas en una reunión de grupo nominal. Tras varios procesos de revisión, que incluyeron la revisión externa por parte de los miembros del GPS, se redactó el documento definitivo.
Se presentan en este documento recomendaciones prácticas y actualizadas relativas a la toma de decisiones terapéuticas con el uso de las terapias biológicas en pacientes que pertenecen a poblaciones especiales (ancianos, edad pediátrica, mujeres embarazadas o con deseo gestacional) o que presentan comorbilidades (obesidad, artritis psoriásica, enfermedad inflamatoria intestinal, depresión, cáncer, síndrome metabólico, diabetes, hígado graso no alcohólico, enfermedad cardiovascular, insuficiencia cardiaca y enfermedad renal o neurológica). Se aborda también la gestión del riesgo con el uso de terapias biológicas, analizando los riesgos potenciales previos al tratamiento y durante el mismo, así como los acontecimientos adversos más frecuentes, todo ello desde una orientación práctica y adaptada a la práctica clínica habitual.
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Citation Excerpt :
However, at the time the study was conducted, the number of patients who were taking biologics was small. Overall, during the last few years the majority of studies did not support an elevated risk of malignancy (apart of NMSCs) with either biologics or csDMARDs [19–21,31–35]. Medications were not found to be predictors of malignancy in the present study.
To estimate the prevalence and incidence of malignancy and its types in psoriatic arthritis (PsA) and psoriasis without arthritis (PsC) patients, in comparison to the general population, and to identify the predictive factors for developing cancer in psoriatic disease (PsD).
PsA patients followed prospectively since 1978 and PsC patients followed since 2006 at 6-to-12 month intervals according to a standard protocol were included. Malignancies were recorded prospectively and linkages with Cancer Care Ontario and the Death Registry were carried out to confirm the presence and type of malignancy up to December 2016. Standardized incidence ratios (SIR) were calculated for overall cancers and by age and sex. Cox regression analysis was conducted to identify risk factors associated with the development of malignancy after the diagnosis of PsD.
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In this long-term prospective follow-up of patients with PsA and PsC the overall malignancy risk was not found to be higher than the general population, while skin cancer increased.

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: Supported in part by grants K23AR051125 and RC1 ARO58204 from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (Dr Gelfand), and a National Research Service Award from the National Institute of Health (Dr Dommasch).

: Disclosure: Dr Gelfand receives grant support and is an investigator for Amgen, Abbott, Novartis, and Pfizer. He is a consultant for Pfizer, Genentech, Celgene, Amgen, Centocor, Novartis, and Abbott. Dr Dommasch, Dr Abuabara, Mr Shin, Dr Nguyen, and Dr Troxel have no conflicts of interest to declare.

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Original articleThe risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: A systematic review and meta-analysis of randomized controlled trials

Background

Objective

Methods

Results

Limitations

Conclusions

Section snippets

Methods

Search results and trial characteristics

Discussion

Determinants of quality of life in patients with psoriasis: a study from the US population

J Am Acad Dermatol

The risk of lymphoma in patients with psoriasis

J Invest Dermatol

Risk of myocardial infarction in patients with psoriasis

JAMA

The risk of mortality in patients with psoriasis: results from a population-based study

Arch Dermatol

The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004

J Am Acad Dermatol

Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the general practice research database

Eur Heart J

Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the United Kingdom

Br J Dermatol

Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials

JAMA

The safety of anti-tumor necrosis factor treatments in rheumatoid arthritis: meta and exposure adjusted pooled analyses of serious adverse events

Ann Rheum Dis

Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis

Ann Rheum Dis

The impact of treatment with tumor necrosis factor-alpha; antagonists on the course of chronic viral infections: a review of the literature

Br J Dermatol

The risk of infections with biologic therapies for rheumatoid arthritis

Semin Arthritis Rheum

Infections in patients with rheumatoid arthritis treated with biologic agents

Arthritis Rheum

Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-{alpha} therapy

Rheumatology

Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-{alpha} agents

JAMA

Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients

Autoimmun Rev

Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report

Arthritis Rheum

Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomized controlled trials

Ann Rheum Dis

Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials

Clin Gastroenterol Hepatol

Hematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumor necrosis factor antagonists

Ann Rheum Dis

Anti-TNF therapy in RA and risk of malignant lymphomas: relative risks and time-trends in the Swedish biologics register

Ann Rheum Dis

Tumor necrosis factor blockers do not increase overall tumor risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas

Ann Rheum Dis

A review of malignancies observed during efalizumab (Raptiva®) clinical trials for plaque psoriasis

Dermatology

Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients

Arthritis Rheuma

Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study

Arthritis Rheuma

The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation

Arthritis Rheum

Is there truly a risk of lymphoma from biologic therapies?

Dermatol Ther

Combination immunosuppressive therapies: the promise and the peril

Arch Dermatol

Pharmacovigilance: verifying that drugs remain safe

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Ann Intern Med

Assessing the quality of reports of randomized clinical trials: is blinding necessary?

Control Clin Trials

Measuring inconsistency in meta-analyses

BMJ

Statistical aspects of the analysis of data from retrospective studies of disease

J Natl Cancer Inst

Meta-analytic methods for pooling rates when follow-up duration varies: a case study

BMC Med Res Methodol

What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data

Stat Med

Original article
The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: A systematic review and meta-analysis of randomized controlled trials