Boxes indicate point estimates, with horizontal lines indicating 95% CIs. The size of the box is proportional to the weight of the study. Diamonds indicate pooled estimates with tips of the diamonds indicating 95% CIs. TNFI indicates tumor necrosis factor inhibitor.
Boxes indicate point estimates, with horizontal lines indicating 95% CIs. The size of the box is proportional to the weight of the study. Diamonds indicate pooled estimates with tips of the diamonds indicating 95% CIs.
eTable 1. Study Protocol
eTable 2. Search Strategy in Embase, MEDLINE, and Cochrane CENTRAL
eTable 3. MOOSE Checklist for Meta-analyses of Observational Studies
eTable 4. Newcastle-Ottawa Quality Assessment Scale for Cohort Studies Checklist
eTable 5. Newcastle-Ottawa Quality Assessment Scale for Cohort Studies Scores
eTable 6. Confounders Checklist
eFigure 1. Forest Plot of the Risk of Melanoma in Biologic-Treated IBD and RA Patients Compared With Patients Treated With Conventional Systemic Therapies Under a Fixed-Effects Model
eFigure 2. Funnel Plot for the Inspection of Publication Bias
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Esse S, Mason KJ, Green AC, Warren RB. Melanoma Risk in Patients Treated With Biologic Therapy for Common Inflammatory Diseases: A Systematic Review and Meta-analysis. JAMA Dermatol. 2020;156(7):787–794. doi:10.1001/jamadermatol.2020.1300
Are patients with inflammatory bowel disease, rheumatoid arthritis, and psoriasis who are treated with biologic therapies at a higher risk of melanoma compared with those treated with conventional systemic therapy?
In this systematic review and meta-analysis of 7 cohort studies comprising 34 029 biologic-treated and 135 370 biologic-naive, systemically treated patients, biologic-treated patients with inflammatory bowel disease, rheumatoid arthritis, and psoriasis had an increased risk of melanoma compared with those who received conventional systemic therapy, but the difference was not statistically significant.
The findings suggest that a clinically meaningful increase in melanoma risk cannot be ruled out; further studies adjusting for key risk factors are required.
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.
To examine whether biologic treatment of IBD, RA, or psoriasis is associated with an increased risk of melanoma compared with conventional systemic therapy.
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.
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.
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.
Crohn disease and ulcerative colitis, collectively known as inflammatory bowel disease (IBD); rheumatoid arthritis (RA); and psoriasis are immune-mediated inflammatory diseases with overlapping genetic susceptibility and several treatment modalities.1,2 The inflammatory cytokine tumor necrosis factor (TNF) α has proved to be critical in the immunopathogenesis of these diseases, and inhibition of this cytokine has revolutionized treatment outcomes.2,3 However, the standard paradigm of care for immune-mediated inflammatory diseases dictates that those requiring systemic therapy are initially treated with conventional systemic therapy, such as methotrexate. If such therapies are contraindicated or response is considered inadequate, treatment progresses to biologic therapy. Highly cost-effective biosimilar TNF inhibitors (TNFIs) are currently the first-line biologic for all 3 of these immune-mediated inflammatory diseases, although other biologic classes are also commonly used.4-7
Despite a large body of evidence establishing the short-term safety and efficacy of biologic therapy compared with conventional systemic therapy, there are concerns regarding the longer-term risk of cancer in patients treated with biologic therapy compared with conventional systemic therapy.8-11 Melanoma is a highly immunogenic skin cancer and therefore of concern to patients treated with TNFIs because melanoma risk increases with suppression of the immune system and TNF-α plays an important role in the immune surveillance of tumors.12,13
A number of studies14-19 in biologic-treated patients with IBD, RA, and psoriasis have reported an increased risk of melanoma, but these studies have typically used the general population as the comparator. To date, systematic reviews20,21 specifically examining the risk of melanoma in biologic-treated patients compared with biologic-naive patients treated with conventional systemic therapy have been limited to RA. A meta-analysis20 of studies of biologic-treated patients with RA found that treatment with TNFIs was not significantly associated with increased risk of melanoma compared with conventional systemic therapy (pooled relative risk [pRR], 1.4; 95% CI, 0.70-2.60), but the authors concluded that a clinically meaningful risk of melanoma could not be ruled out.
The risk of melanoma in patients with IBD and psoriasis treated with biologic therapy compared with patients treated with conventional systemic therapy is even less clear.22,23 A meta-analysis24 examining risk of melanoma in patients with IBD did not include any study comparing biologic-treated patients with IBD with biologic-naive patients with IBD. To our knowledge, the only systematic review25 of any cancer in biologic-treated patients with psoriasis identified a single study examining the risk of melanoma compared with the general population.
Melanoma is a potentially aggressive cancer caused primarily by exposure to UV radiation (UVR) from natural (sunlight) or artificial (tanning bed) sources, with skin pigmentation being a key genetic risk factor.26,27 There has been a marked increase in the incidence of melanoma in recent decades in many countries, including the US, UK, Norway, and Sweden.28 Despite the implementation of skin cancer prevention programs, melanoma incidence rates are expected to continue increasing in these populations for the next few decades.28 Therefore, identifying whether patients with common immune-mediated inflammatory disorders who are increasingly prescribed immunomodulatory agents are at further increased risk of developing melanoma is important. We systematically reviewed all relevant published studies to date and conducted meta-analyses to estimate melanoma risk in patients with IBD, RA, and psoriasis treated with biologic therapy compared with those treated with only conventional systemic therapy.
The Embase, MEDLINE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for eligible studies published between January 1, 1995, and February 7, 2019 (eTable 1 in the Supplement). The details of the search strategy for Embase, MEDLINE, and CENTRAL are presented in eTable 2 in the Supplement. No geographic or language restrictions were imposed. The database search was supplemented with hand searching of the reference sections of retrieved articles. Randomized clinical trials, open-label extension trials, cohort studies, and nested case-control studies comparing the risk of melanoma in patients with IBD, RA, or psoriasis were identified. Studies in which patients were treated with biologic therapy for at least 12 months and were compared with biologic-naive patients with similar clinical and disease characteristics treated with conventional systemic therapy alone were eligible for inclusion. Study eligibility was independently assessed by 2 of us (S.E. and K.J.M.), who screened titles and abstracts of studies and then read the studies in full. Disagreements about eligibility were resolved by discussion with a third reviewer (R.B.W.). This systematic review and meta-analysis was conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines (eTable 3 in the Supplement).
The following items were extracted from included studies: lead author and year of publication, study design, source population and baseline demographics, type(s) of biologic therapy, comparator therapy, treatment duration, follow-up period, outcomes, and quantitative estimates with 95% CIs. Selection, matching, and outcome were assessed for included cohort studies using the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies29 (eTable 4 and eTable 5 in the Supplement). Studies were assessed for adjustment for the following risk factors: age, sex, UVR exposure, concomitant or previous exposure to conventional systemic therapy, exposure to phototherapy with psoralen–UV-A (PUVA), and skin color (eTable 6 in the Supplement).
The pRRs and 95% CIs were calculated for IBD and RA using the generic inverse variance approach. In studies providing multiple RR estimates, those adjusted for the greatest number of confounders were adopted. Statistical heterogeneity across the included studies was assessed using the Q statistic (χ2 test), with a 2-sided significance level of P < .05, and quantified by the I2 statistic. An I2 statistic of 50% or greater was considered to represent significant heterogeneity. The random-effects model was adopted in anticipation of clinical heterogeneity. Prespecified sensitivity analyses were performed by excluding point estimates from the meta-analysis to ensure that overall risk estimates were not markedly affected by individual studies. In response to the large number of TNFI-treated patients identified in our literature search, a post hoc secondary analysis of melanoma risk in TNFI-treated patients with IBD and RA under a fixed-effects model was performed. Factors considered for subgroup analyses were mechanism of biologic therapy, treatment duration, and adjustment for risk factors. Publication bias was evaluated through visual inspection of a funnel plot and using the Begg and Egger tests in which P ≤ .05 indicated significant publication bias. All analyses were conducted using Stata statistical software, version 14.1 (StataCorp).
We identified 1532 records after removing duplicates (Figure 1). After title screening, we removed 1363 records, with an additional 107 records excluded by abstract screening. The remaining 62 articles along with 2 additional articles identified by hand-searching were read in full and screened for eligibility. After 57 articles were excluded for ineligibility, 7 studies remained for analysis.
The 7 included studies were published between 2007 and 2019, and all were cohort studies conducted in the US (n = 3), Denmark (n = 2), Sweden (n = 1), and Australia (n = 1). Most studies (n = 5) used population-based registries, with 2 studies performed using health insurance databases.30,31 Two studies were conducted with patients with IBD,30,32 4 with patients with RA,33-36 and 1 with patients with psoriasis.31 In total, 34 029 patients received biologic treatment and 135 370 biologic-naive patients received conventional systemic therapy. Mean patient follow-up duration ranged from 1.0 to 5.48 years, with study periods ranging from 1998 to 2015 (Table).
Most included studies (n = 6) consisted of patients treated with TNFIs.30,32-36 Five studies30,32-35 pooled all patients treated with TNFIs, and 1 study36 reported individual effect estimates for patients treated with the TNFIs adalimumab, etanercept, and infliximab. Asgari et al31 pooled all patients treated with biologic therapy (97% treated with TNFIs). In addition to TNFI-treated patients, patients treated with abatacept (CD-28 inhibitor) and rituximab (CD-20 inhibitor) were also included in the study by Wadström et al.35
Adjustment for age and sex was performed in all included studies. Adjustment for previous or concomitant exposures to immunosuppressive therapies was performed in 1 study,32 with adjustment for race/ethnicity (an indicator of skin color, a major risk factor for melanoma) performed in 1 study31 (eTable 6 in the Supplement). Exposure to UVR was not reported or adjusted for in any of the included studies.
Quiz Ref IDThe pRR estimates for patients treated with biologic therapy compared with conventional systemic therapy were 1.20 (95% CI, 0.60-2.40) for patients with IBD and 1.20 (95% CI, 0.83-1.74) for patients with RA (Figure 2 and eFigure 1 in the Supplement). Heterogeneity was not significant in the IBD (I2 = 0%) and RA (I2 = 34.9%) subgroups. There was no evidence of publication bias (Begg P = .87; Egger P = .16) (eFigure 2 in the Supplement).
Quiz Ref IDThe pRR estimate for patients with RA treated with only TNFI compared with those treated with conventional systemic therapy was 1.08 (95% CI, 0.81-1.43) (Figure 3). Compared with biologic-naive patients receiving conventional systemic therapy, the pRR of melanoma among the rituximab-treated patients with RA was 0.73 (95% CI, 0.38-1.39) and the pRR among the abatacept-treated patients with RA was 1.43 (95% CI, 0.66-3.09).35 Sensitivity analysis that involved the exclusion of individual RA studies produced pooled risk estimates ranging from 0.91 (95% CI, 0.69-1.18), with the exclusion of the study by Wolfe and Michaud,36 to 1.95 (95% CI, 1.16-3.30), with the exclusion of the study by Wadström et al.35
All included studies scored at least 7 of 9 and were deemed to be high quality; 5 of 7 studies scored 7 of 9, with the 2 remaining studies scoring 8 of 9 (eTable 5 in the Supplement). All these studies scored the maximum (4 of 4) for the selection domain and 2 of 3 for the outcome domain. The 2 highest-scoring studies scored the maximum of 2 of 2 for the matching domain because they adjusted for age, sex, and at least concomitant or previous exposure to immunosuppressive therapy or race/ethnicity.
Quiz Ref IDIn this systematic review and meta-analysis, we did not find a statistically significant association between biologic exposure and development of melanoma in patients with IBD, RA, and psoriasis compared with patients receiving conventional systemic therapy. Our meta-analysis is the first, to our knowledge, to specifically examine the risk of melanoma in biologic-treated patients with IBD and psoriasis compared with their biologic-naive counterparts receiving conventional systemic therapy. To date, the only other systematic review and meta-analysis24 examining the risks of melanoma in IBD reported an increased risk of melanoma in patients with IBD independent of treatment with TNFIs. However, this finding was based on a subgroup analysis of 2 studies,37,38 neither of which compared TNFI-treated patients with biologic-naive patients with IBD. The absence of a biologic-naive comparator group with IBD consisting of patients treated with systemic therapy in both studies leaves unanswered the question of whether any observed effect is attributable to the primary disease, treatment with systemic therapy, or both. Our study represents a more robust and clinically relevant analysis of the risk of melanoma in biologic-treated patients with IBD than the previous meta-analysis24 because we restricted our inclusion criteria to studies that directly compared biologic-treated patients with IBD with biologic-naive patients with IBD.
The only published systematic review,25 to our knowledge, that examined the risk of cancer in biologic-treated patients with psoriasis did not identify any published study that compared the risk of melanoma with that of biologic-naive patients treated with conventional systemic therapy for inclusion. Although we were unable to perform a meta-analysis for this subgroup, we included the only published study,31 to our knowledge, comparing the risk of melanoma between biologic-treated patients and biologic-naive patients treated with conventional systemic therapy, suggesting no statistically significant increased risk of melanoma in biologic-treated patients.
Our study updates and extends another meta-analysis20 of melanoma risk in biologic-treated patients with RA by including more recent reports from the Swedish35 and Australian34 registries. We also expanded the previous analysis20 by including point estimates for rituximab and abatacept.35 The results of our study correspond with those of the previous analysis, suggesting that treatment with biologics is not significantly associated with an increased risk of melanoma in patients with RA compared with biologic-naive patients treated with conventional systemic therapy.
Future population-based studies will need to account for the rapidly changing landscape of biologic treatment in IBD, RA, and psoriasis. The introduction of biologic therapies that target interleukins 6, 23, and 17 has expanded the available treatment options for patients initiating biologic therapy. Future studies should consider the various biological mechanisms of these therapies, their potential role in the development of melanoma, and how exposure to multiple classes of biologic therapies might affect a patient’s risk of melanoma. To account for confounding by indication, studies should compare patients treated with TNFIs with patients treated with the newer biologics and those treated with more than 1 type of biologic.
Another development in the treatment of IBD, RA, and psoriasis is the introduction of TNFI biosimilars. Provision of biologic therapy varies globally, with health economic considerations often dictating access and uptake. Switching patients from reference TNFIs to biosimilars for cost-effectiveness has led to significant savings for health care practitioners in the UK, with similar savings projected for other European countries. This finding may lead to greater access for patients requiring these treatments, with possible earlier intervention in patients with IBD and psoriasis currently treated with only nonbiologic systemic therapy.39-42
The main strengths of our study included the use of a predefined protocol with strict inclusion and exclusion criteria. The systematic and comprehensive nature of our literature search of multiple databases, guided by our protocol, addressed a focused and clinically relevant research question with standardized data extraction and quality assessment to minimize errors.
Quiz Ref IDThe main limitation of our systematic review and meta-analysis was the small number of disease-specific studies that examined the risk of melanoma between biologic-treated patients and patients treated with conventional systemic therapy. Despite our extensive literature search, we identified only 2 studies on IBD and 1 study on psoriasis that were eligible for inclusion. The small number of studies eligible for inclusion meant that the pooled risk estimates were likely to be disproportionately affected by single studies. In our sensitivity analysis that accounted for the effects of singular studies, we found that the pooled risk estimate in the RA group increased from 1.20 (95% CI, 0.83-1.74) to 1.95 (95% CI, 1.16-3.30), suggesting a near 2-fold statistically significant increased risk of melanoma with the exclusion of the study by Wadström et al.35 Any future update of our study through the inclusion of newly published studies may produce significantly different pooled risk estimates than those reported in our meta-analysis.
Another potential limitation of our study was the inclusion of studies performed using health insurance databases.30,31 Unlike pharmacovigilance registries, health care insurance databases are primarily designed to collect health data for financial reimbursement and not to answer research questions related to treatment safety and effectiveness.43 These studies had a greater risk of selection bias because patients were derived from databases that do not include uninsured patients or those with other health insurance policies. Health insurance database studies can also be prone to misclassifications of exposure because of treatment status being identified through prescriptions and the healthy user or adherer effect, in which patients who comply with treatment for a prolonged time are more likely to be healthy.44
Quiz Ref IDA major weakness of the studies included in our analysis was the absence of adjustment for established risk factors for melanoma, such as UVR exposure and race/ethnicity. Significant differences in the cumulative exposure to UVR in the form of holiday sun exposure and prevalent tanning bed use or the number of patients from nonwhite racial/ethnic groups between the biologic-treated patients and biologic-naive patients treated with conventional systemic therapy could have led to an underestimation or overestimation of melanoma risk. Phototherapy with PUVA, formerly a common treatment for patients with psoriasis, is associated with an increased risk of melanoma.45,46 Although the study by Asgari et al31 reportedly adjusted for previous phototherapy, it was not clear whether treatment with PUVA was included.
Treatment duration for conventional systemic therapy was poorly reported in the included studies (Table). Adjustment for differences in concomitant and historical treatment with conventional systemic therapy was absent from most of the included studies. Significant differences in duration (and therefore cumulative amount) of these immunosuppressive treatments between the biologic-treated patients and the patients treated with conventional systemic therapy could have biased our results. Moreover, given the generally long latency period between causal exposure and the development of melanoma, follow-up periods for biologic-treated patients in the included studies may not have been long enough and could have resulted in an underestimation of risk.
This study did not find a significant association between biologic exposure and development of melanoma compared with conventional systemic treatment. We advocate for more large, well-designed studies of this issue to be performed to help improve certainty. Prospective cohort studies using an active-comparator, new-user study design providing detailed information on treatment history, concomitant treatments, biologic and conventional systemic treatment duration, recreational and treatment-related UV exposure, skin color, and date of melanoma diagnosis are required to help improve certainty. These studies would also need to account for key risk factors and the latency period of melanoma.
Accepted for Publication: March 21, 2020.
Corresponding Author: Shamarke Esse, MRes, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Oxford Road, Room 1.725, Stopford Building, Manchester M13 9PT, United Kingdom (firstname.lastname@example.org).
Published Online: May 20, 2020. doi:10.1001/jamadermatol.2020.1300
Author Contributions: Mr Esse had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Esse, Green.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Esse.
Obtained funding: Mason, Green, Warren.
Administrative, technical, or material support: Mason.
Supervision: Mason, Green, Warren.
Conflict of Interest Disclosures: Dr Mason reported receiving personal fees from Janssen, LEO Pharma, Lilly, and Novartis outside the submitted work. Dr Warren reported receiving grants from AbbVie, Almirall, Amgen, Celgene, Janssen, Lilly, LEO Pharma, Novartis, and Pfizer during the conduct of the study and receiving personal fees from AbbVie, Almirall, Amgen, Arena, Avillion, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi, and UCB outside the submitted work. No other disclosures were reported.
Funding/Support: Mr Esse is funded by a Psoriasis Association PhD studentship (reference ST3/17).
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Psoriasis Association.
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