Both psoriasis and methotrexate are associated with an increased risk of nonmelanoma skin cancer. The effect of methotrexate on the development of nonmelanoma skin cancer in patients with psoriasis is currently unknown. To evaluate this relationship, a systematic review of the literature was conducted using databases including Ovid Medline (from 1946), Scopus (from 1970), and Embase (from 1974) through June 2019. Observational comparative and case-control studies comparing psoriasis patients treated with methotrexate to those not treated with methotrexate with data on the subsequent development of nonmelanoma skin cancer in both cohorts were included based on prespecified criteria. Two reviewers analyzed all studies for relevant data, which were analyzed using OpenMeta-Analyst statistical software. Quality was assessed with the Newcastle-Ottawa method. Nine cohort and case-control comparative studies of 1,486 screened abstracts met the inclusion criteria. Of 11,875 reported patients with psoriasis, 2,192 were taking methotrexate. A meta-analysis demonstrated an odds ratio of 2.8 (95% confidence interval = 1.47-5.39; p = 0.002) for nonmelanoma skin cancer development in patients with psoriasis taking methotrexate compared with those not taking methotrexate. Based on these findings, psoriasis patients treated with methotrexate are at a significantly increased (2.8 times higher) risk of developing nonmelanoma skin cancer. Risk counseling can improve healthcare outcomes in patients with psoriasis.
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: Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects the synovial fluid of joints, tendons, and some extra-articular sites. Biologic agents have been highly effective and are comparable in reducing RA symptoms, slowing disease progression, and improving physical function; however, concerns have been raised about the risks of several potential adverse effects. Thus, this study aimed to assess the safety of biological therapy in patients with rheumatoid arthritis in observational studies using administrative health databases. Methods: PubMed, Embase, Lilacs, Ovid, Scopus, and Web of Science were searched from inception to 21 October 2021. The analysis was divided into five groups: tumor necrosis factor inhibitors (TNFi) versus non-TNFi; TNFi versus csDMARDs; bDMARDs versus csDMARDs; abatacept versus bDMARDs; and TNFi versus Janus kinase inhibitors (JAKi). The adverse events were cancer, cardiovascular events, infection, herpes zoster, tuberculosis, and death. The methodological quality of the studies was assessed by the Newcastle-Ottawa Scale. A random-effects model estimated risk ratios with 95% confidence intervals. Results: Thirty-one studies were eligible for inclusion in the present systematic review, published from 2014 to 2021. A total of 1,039,398 RA patients were assessed. The 31 studies evaluated eleven different biological drugs. No significant differences were found regarding safety between TNFi versus non-TNFi (RR 1.08; 95% CI 0.92-1.28; p < 0.01; I2 = 93.0%), TNFi versus csDMARDs (RR 0.91; 95% CI 0.75-1.10; p < 0.01; I2 = 87.0%), bDMARDs versus csDMARDs (RR 0.99; 95% CI 0.82-1.20; p < 0.01; I2 = 93.0%), abatacept versus bDMARDs (RR 0.80; 95% CI 0.54-1.18; p < 0.01; I2 = 90.0%), and TNFi versus JAKi (RR 3.54; 95% CI 0.30-42.09; p = 0.01; I2 = 81.0%). In the subgroup analysis, among studies comparing abatacept to TNFi, a lower risk of cardiovascular events was associated with abatacept (RR 0.37; 95% CI 0.24-0.55). Conclusion: Our results do not suggest an increased risk of adverse events associated with biological therapy in treating RA patients, indicating a lower risk of cardiovascular events with abatacept than TNFi. However, these findings must be interpreted with caution given the limitations of this study and the low/very low certainty of the evidence. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?, identifier [CRD42020190838].
IMPORTANCE: Biologic therapies are widely prescribed immunomodulatory agents. There are concerns that compared with treatment with conventional systemic therapy, long-term biologic treatment for common immune-mediated inflammatory diseases, namely inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis, may be associated with increased risk of melanoma.
OBJECTIVE: To examine whether biologic treatment of IBD, RA, or psoriasis is associated with an increased risk of melanoma compared with conventional systemic therapy.
DATA SOURCES: Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles published from January 1, 1995, to February 7, 2019, for eligible studies.
STUDY SELECTION: Randomized clinical trials, cohort studies, and nested case-control studies quantifying the risk of melanoma in biologic-treated patients with IBD, RA, and psoriasis compared with patients treated with conventional systemic therapy were included.
DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted key study characteristics and outcomes. Study-specific risk estimates were pooled, and random- and fixed-effects model meta-analyses were conducted. Heterogeneity was assessed using the I2 statistic. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines were followed.
MAIN OUTCOMES AND MEASURES: The pooled relative risk (pRR) of melanoma in biologic-treated patients with IBD, RA, and psoriasis compared with biologic-naive patients treated with conventional systemic therapy.
RESULTS: Seven cohort studies comprising 34 029 biologic-treated patients and 135 370 biologic-naive patients treated with conventional systemic therapy were eligible for inclusion. Biologic treatment was positively associated with melanoma in patients with IBD (pRR, 1.20; 95% CI, 0.60-2.40), RA (pRR, 1.20; 95% CI, 0.83-1.74), or psoriasis (hazard ratio, 1.57; 95% CI, 0.61-4.09) compared with those who received conventional systemic therapy, but the differences were not statistically significant. Adjustment for other risk factors was absent from most studies.
CONCLUSIONS AND RELEVANCE: The findings suggest that clinically important increases in melanoma risk in patients treated with biologic therapy for common inflammatory diseases cannot be ruled out based on current evidence. However, further studies with large patient numbers that adjust for key risk factors are needed to resolve the issue of long-term safety of biologic therapy.
La persistencia en el tratamiento es un marcador subrogante de éxito de tratamiento a largo plazo. Objetivo: Evaluar la persistencia de los agentes biológicos utilizados para el tratamiento de pacientes con artritis reumatoidea (AR) a un tiempo de 5 años y determinar las principales causas asociadas a persistencia o discontinuación. Material y métodos: Se realizó una revisión sistemática de la literatura (RSL), según las recomendaciones PRISMA, en las bases de datos Pubmed, Cochrane y Lilacs, y estudios presentados en los congresos ACR, EULAR, PANLAR (2018/2019) hasta Enero 2020. Dos revisoras independientes, evaluaron todas las publicaciones identificadas, por título y abstract y por full text, de acuerdo a la metodología PICO. Los criterios de elegibilidad fueron estudios de pacientes ≥ 18 años con diagnóstico de AR, en tratamiento con agentes biológicos, que midieran persistencia/discontinuación en un período de tiempo igual o superior a 5 años y que estuvieran en idioma inglés o español. En el caso de falta de acuerdo entre las dos revisoras, un tercer revisor fue consultado. La información extraída fue analizada mediante estadística descriptiva, se calculó el porcentaje promedio de persistencia de cada agente biológico a los 5 años. Resultados: Se seleccionaron 56 artículos luego de la remoción de los duplicados y de la exclusión por título/abstract, y por full text. De ellos 13, eran fase de extensión a largo plazo de estudios randomizados controlados, 15 cohortes retrospectivas, 18 cohortes prospectivas y 10 cohortes retro-prospectivas y correspondían a un total de 72177 (rango: 79-10396) pacientes con AR, con una edad media 53.8 años ± 12.1, 78.2% de sexo femenino y un tiempo promedio de evolución de la AR de 9.7 años ± 8.4. En 33.9% de los estudios, la terapia biológica estaba combinada con drogas modificadoras de la AR convencionales (DMARs-c), en 3.6% en monoterapia, 48.2% ambas modalidades y en 14.3% no informaba. Un estudio fue realizado en 1° línea (metotrexato näive), 29 estudios en 2° línea (respuesta inadecuada a MTX y/o DMARs-c), 5 en 3° línea (respuesta inadecuada a DMARs biológicas-b-), 12 en ≥2° línea terapéutica y en 9 no especificaban. En 30 estudios que evaluaron 2° línea terapéutica, la mayor persistencia correspondió a tocilizumab (TCZ) 66.41% (IC95% 57.8-79.94), abatacept (ABA) 57.91% (IC95% 50.96-64.87) y golimumab (GOL) 54.38% (IC95% 48.58-60.19). Y 10 estudios, en los cuales el DMAR-b había sido analizado en 3° línea terapéutica, las mayores tasas de retención correspondieron a rituximab (RTX) 61.19% (IC95% 57.53-66.22) y TCZ 61.1% (IC95% 58.81-63.32). Entre los estudios que evaluaron predictores, los más frecuentemente asociados a mayor sobrevida fueron: tratamiento combinado con DMAR-c, etanercept versus infliximab y adalimumab y 2° línea de tratamiento vs 3° o 4° línea y los asociados a menor sobrevida fueron: mayor uso de esteroides, mayor actividad basal de la enfermedad y sexo femenino. Conclusiones: En esta RSL, la persistencia de los DMAR-b a 5 años en pacientes con respuesta inadecuada a DMARs-c y DMARs-b fue numéricamente mayor para los agentes no TNFi. Y entre los TNFi, GOL presentó mayor retención en 2° línea terapéutica.
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.
BACKGROUND: Psoriatic arthritis (PsA) is a chronic and seronegative inflammatory arthritis occurring in patients with psoriasis. The current knowledge about the risk of malignancy associated with psoriatic arthritis (PsA) patients undergoing therapy is controversial. We focused on the relationship between malignancy and therapy and undertook a meta-analysis to address this issue.
METHODS: A systematic literature search of the PubMed, EMBASE, and Web of Science databases was performed to identify relevant studies and trials. Statistical analysis was conducted using STATA 11.2 software.
RESULTS: Nine cohort studies were included, corresponding to a total of 43,115 PsA patients undergoing therapy. A significant positive association between therapy and increased risk for overall malignancy was found relative to the general population as the reference group (pooled RR, 1.29; 95% CI: 1.04-1.60). High heterogeneity was found (I2 = 71.37%). Subgroup analysis reported that PsA patients treated with conventional synthetic disease modifying antirheumatic drugs (csDMARDs) presented increased cancer risk (pooled RR, 1.75; 95% CI: 1.40-2.18) but patients treated with biological disease modifying antirheumatic drugs (bDMARDs) did not (pooled RR, 0.957; 95% CI: 0.80-1.14). Compared to controls, patients with PsA undergoing treatment specifically are at increased risk for non-melanoma skin cancers (pooled RR, 2.46; 95% CI: 1.84-3.28).
CONCLUSIONS: This study allowed the estimation of cancer risk in PsA patients during therapy. Large-scale longitudinal studies will be essential to draw firm conclusions regarding PsA-associated risk for treatment-induced malignancy.
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.
Both psoriasis and methotrexate are associated with an increased risk of nonmelanoma skin cancer. The effect of methotrexate on the development of nonmelanoma skin cancer in patients with psoriasis is currently unknown. To evaluate this relationship, a systematic review of the literature was conducted using databases including Ovid Medline (from 1946), Scopus (from 1970), and Embase (from 1974) through June 2019. Observational comparative and case-control studies comparing psoriasis patients treated with methotrexate to those not treated with methotrexate with data on the subsequent development of nonmelanoma skin cancer in both cohorts were included based on prespecified criteria. Two reviewers analyzed all studies for relevant data, which were analyzed using OpenMeta-Analyst statistical software. Quality was assessed with the Newcastle-Ottawa method. Nine cohort and case-control comparative studies of 1,486 screened abstracts met the inclusion criteria. Of 11,875 reported patients with psoriasis, 2,192 were taking methotrexate. A meta-analysis demonstrated an odds ratio of 2.8 (95% confidence interval = 1.47-5.39; p = 0.002) for nonmelanoma skin cancer development in patients with psoriasis taking methotrexate compared with those not taking methotrexate. Based on these findings, psoriasis patients treated with methotrexate are at a significantly increased (2.8 times higher) risk of developing nonmelanoma skin cancer. Risk counseling can improve healthcare outcomes in patients with psoriasis.
