OBJECTIVES: To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).
METHODS: SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.
RESULTS: Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.
CONCLUSION: The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.
Background: Adalimumab, golimumab, infliximab, certolizumab, and etanercept are five anti-tumor necrosis factor (anti-TNF) medicines that have been approved for use in rheumatology. Apart from their well-established therapeutic usefulness, -it is unclear to what extent -they are linked to an increased risk of various side effects. The present meta-analysis was carried out to assess the risk of infection and other side effects after anti-TNF- α for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Methods: We searched PubMed, Cinahl (via Ebsco), Scopus, and Web of Sciences databases for trials comparing anti-TNF medications to placebo or no therapy in adult patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis from August 2006 to August 2020. A total of 23 articles were used for meta-analysis. The Cochrane Collaboration’s risk of bias tool was used to assess the methodological quality of the included studies. In addition, a random-effects model was used to calculate the pooled odds ratio, and Forest plots were constructed to determine the risk of infections and cancer following the use of anti-TNF treatment. Results: Treatment with anti-TNFα agents resulted in an increase in the risk of serious infections (OR: 1.72, 95% CI: 1.56–1.90, p < 0.00001) and an increase in cancer risk (OR: 1.36, 95% CI: 1.20–1.53, p < 0.00001) whereas the risk of developing tuberculosis was not significantly different with anti-TNFα agents versus those without treatment with anti-TNFα agents (OR: 2.55, 95% CI: 0.40–16.23, p = 0.32) although the number of studies is limited to make a definitive conclusion. The risk of bias of the included studies was unclear to high across most domains, and there was evidence of publication bias for most outcomes. Conclusion: The present meta-analysis suggests an increased risk of infectious adverse events, including overall adverse events and cancer following anti-TNFα treatment, whereas the risk of tuberculosis was not significantly different. Although anti-TNF agents have shown promise to treat inflammatory conditions, their use should be balanced by the risk-benefit ratio as suggested by the meta-analysis.
OBJECTIVE: To assess the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and the risk of cardiovascular events in patients with systemic inflammatory conditions.
METHODS: Eligible cohort studies or randomized controlled trials (RCTs) from inception to January 2021 were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for cardiovascular outcomes were calculated in the fixed- and random-effects model accordingly. Associated factors with risks of cardiovascular events were also studied in sensitivity analyses and metaregression analyses.
RESULTS: Compared with non-bDMARD users, the risks of myocardial infarction (MI) (OR = 0.74, 95% CI, 0.63 to 0.87), heart failure (OR = 0.84, 95% CI, 0.74 to 0.95), cardiovascular (CV) death (OR = 0.62, 95% CI, 0.40 to 0.95), all-cause mortality (OR = 0.64, 95% CI, 0.58 to 0.70), and 3P-MACE (composite endpoint of MI, stroke, and CV death) (OR = 0.69, 95% CI, 0.53 to 0.89) were significantly reduced in bDMARD users, which were mainly driven by the risk reduction in patients with rheumatoid arthritis (RA). TNF-α inhibitors exhibited consistent benefits in reducing the risks of MI, heart failure, CV death, all-cause mortality, and 3P-MACE. Moreover, the risks of heart failure, CV death, all-cause mortality, and 3P-MACE were significantly reduced in bDMARD users with follow-up over one year.
CONCLUSIONS: The use of bDMARDs might be associated with the reduced risks of CV events, especially in patients with RA. The CV events might be less frequent in bDMARD users with TNF-α inhibitors or follow-up over one year. More investigations are needed to validate conclusions.
OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the comparative effects of tumor necrosis factor-α inhibitors (TNFi), non-TNFi biologic and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on cardiovascular risk in rheumatoid arthritis (RA).
METHODS: Through a systematic search through May 8, 2018, we included 14 observational studies in adults with RA treated with TNFi, non-TNFi biologics, tofacitinib or csDMARDs, reporting the risk of major adverse cardiovascular events (MACE) or stroke. Only studies reporting active comparators were included. We performed random effects meta-analysis and estimated odds ratios (OR) and 95% confidence interval (CI).
RESULTS: As compared to TNFi, tocilizumab was associated with a decreased risk of MACE (OR, 0.59 [0.34-1.00]), whereas csDMARDs were associated with increased risk of MACE (csDMARDs, including methotrexate: OR, 1.45 [1.09-1.93]; without methotrexate: OR, 2.57 [1.32-5.00]), without heterogeneity (I2 =0%); there was no difference in risk of MACE between abatacept and TNFi (OR, 0.89 [0.71-1.11]), or between tocilizumab and abatacept (OR, 0.81 [0.57-1.16]). Based on 11 cohorts (n=135,053 patients), as compared to TNFi, csDMARDs were associated with increased risk of stroke (OR, 1.17 [1.01-1.36]); there was no difference in risk of stroke between different biologics (tocilizumab vs. TNFi: OR, 0.98 [0.59-1.61]; abatacept vs. TNFi: OR, 1.08 [0.86-1.34]; tocilizumab vs. abatacept: OR, 0.73 [0.39-1.38]), without heterogeneity (I2 =0%). No comparative studies on cardiovascular risk with tofacitinib were identified.
CONCLUSION: Based on meta-analysis, as compared to TNFi, tocilizumab may be associated with reduced risk of MACE, whereas csDMARDs may be associated with increased risk of MACE and stroke.
BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis.
METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990 through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events.
RESULTS: We identified 973 studies; of these 82 were included in the final analysis, comprising 66159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of and serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared to patients given placebo or active comparator (relative risk 0.72; 95% CI, 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% CI, 1.04-2.37).
CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.
OBJECTIVES: To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).
METHODS: An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures.
RESULTS: Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1-3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6-4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors.
CONCLUSION: Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.
OBJECTIVE: To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes.
DESIGN: Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data.
DATA SOURCES: Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks.
RESULTS: 45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included.
CONCLUSIONS: For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.
Antecedentes: Los pacientes con trastornos mediados por el sistema inmune tales como la espondilitis anquilosante, la enfermedad inflamatoria intestinal, la psoriasis y la artritis reumatoide se tratan cada vez más con inhibidores del factor de necrosis tumoral (TNF). La seguridad de la terapia anti-TNF en pacientes con antecedentes de cáncer requiere una evaluación adicional. Realizamos una revisión sistemática y un metanálisis de estudios observacionales incluyendo pacientes con antecedentes de cáncer expuestos a terapia anti-TNF evaluando el riesgo de nuevo cáncer o recurrencia de cáncer. MATERIALES Y MÉTODOS: Se realizó una búsqueda informatizada de la literatura de MEDLINE, Google scholar y Cochrane Database of Systematic Reviews hasta el 1 de septiembre de 2015. Se evaluaron las características del estudio, la calidad y el riesgo de sesgo. Se utilizaron metanálisis de modelos de efectos aleatorios para estimar el riesgo de nuevo desarrollo de cáncer o recurrencia de cáncer. RESULTADOS: Se identificaron nueve estudios observacionales en inglés que incluyeron pacientes con antecedentes de cáncer y expuestos a terapia anti-TNF. La relación de tasa de incidencia agrupada de cáncer nuevo o recurrente entre individuos con antecedentes de cáncer expuestos al tratamiento anti-TNF no fue significativamente diferente en comparación con las terapias de control (tasa de incidencia, 0,90; intervalo de confianza del 95%: 0,59-1,37). Los análisis de subgrupos se realizaron según el tipo de enfermedad, el diagnóstico subyacente del cáncer, el tiempo hasta el inicio del tratamiento anti-TNF y la calidad del estudio. La heterogeneidad de las poblaciones de estudio, la heterogeneidad de los subtipos de cáncer incluidos y la utilización de estudios observacionales limita la calidad del estudio. El riesgo de nuevo cáncer o recurrencia de cáncer entre los pacientes con antecedentes de cáncer y el uso de terapia anti-TNF es similar al riesgo con terapias no biológicas modificadoras de la enfermedad. Estos resultados apoyan el uso de medicamentos anti-TNF en poblaciones seleccionadas a pesar del diagnóstico previo de cáncer.
Inhibition of tumor necrosis factor (TNF) activity has profoundly changed the management of several immune-mediated inflammatory diseases with great benefit for patients. The application of TNF inhibitors (TNFi), however, also brings a new concern, malignancy. We performed a systemic review to collect the studies reporting cancer incidences and risks in TNFi users regardless of indications. TNFi were most frequently used in treating patients with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). In RA patients without prior cancer history, the incidences of malignancies ranged from the lowest rate 0 per 1000 person-years in etanercept users regarding lymphoma to the highest rate 35.62 per 1000 person-years in adalimumab users on non-melanoma skin cancer (NMSC), while in those patients with prior cancer history, the recurrent incidences of malignancies ranged from the lowest rate 5.05 per 1000 person-years regarding melanoma to the highest rate 63.20 per 1000 person-years on basal cell carcinoma (BCC) in TNFi users. In IBD patients, incidences ranged from 0 per 1000 person-years in TNFi users on lymphoma to 34.0 per 1000 person-years in infliximab users on overall cancer. However, these incidence rates of overall cancer, lymphoma and melanoma were not higher in comparison with those patients who were not treated with TNFi. Compared to general population, incidences of lymphoma were elevated in RA patients and rates of NMSC were higher in patients with psoriasis, RA and IBD. In conclusion, cancer incidences vary across different studies, indications, cancer types and studies with different individual TNFi. Treatment with TNFi is not associated with increased malignant risks of overall cancer, lymphoma or melanoma. Results of NMSC risk were inconsistent among studies. A latest prospective registry study demonstrated a small increased risk of squamous cell cancer in RA patients treated with TNFi (one additional case for every 1600years of treatment experience). Further prospective studies are needed to verify whether TNFi users have higher NMSC risk than non-TNFi users.
OBJETIVOS: Evaluar la seguridad de los fármacos antirreumáticos modificadores de la enfermedad (DMARD) sintéticos y biológicos para el tratamiento de la artritis reumatoide (RA) para informar a la Liga Europea contra el Reumatismo de las recomendaciones para el tratamiento de la AR. MÉTODOS: Revisión sistemática de la literatura (SLR) de estudios observacionales comparando cualquier DMARD con otra intervención para el manejo de pacientes con AR. Se incluyeron todos los resultados de seguridad. Se requirió un grupo de comparación para incluir el estudio. El riesgo de sesgo se evaluó con la herramienta de Hayden. RESULTADOS: Veintiséis estudios observacionales que abordaron diversos resultados de seguridad del tratamiento con bDMARDs cumplieron con los criterios de elegibilidad (15 en infecciones graves, 4 en neoplasias malignas). La heterogeneidad sustancial impidió el metanálisis. Junto con la evidencia de la SLR 2013, basada en 15 estudios, 7 con bajo riesgo de sesgo, los pacientes en bDMARDs en comparación con los pacientes en sDMARDs convencionales tuvieron un mayor riesgo de infecciones graves (HR ajustada 1,1 a 1,8) A través de bDMARDs-un mayor riesgo de tuberculosis (aHR 2,7 a 12,5), pero no hay mayor riesgo de infección por herpes zoster. Los pacientes con bDMARDs no tuvieron un mayor riesgo de neoplasias malignas en general, linfoma o cáncer de piel no melanoma, pero el riesgo de melanoma puede estar ligeramente aumentado (aHR 1,5). CONCLUSIONES: Estos hallazgos confirman el patrón de seguridad conocido de los bDMARDs, incluyendo el inhibidor del factor de necrosis tumoral (TNFi) y no TNFi, para el tratamiento de la AR.
To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).
METHODS:
SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.
RESULTS:
Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.
CONCLUSION:
The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.
