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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information

Objective

To analyze the incidence rate (IR) and risk factors of cutaneous adverse events (CAE) in patients with chronic inflammatory rheumatic diseases treated with tumor necrosis factor (TNF) antagonists.

Methods

We analyzed all patients from the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) registry treated with a TNF antagonist (infliximab, etanercept, or adalimumab). Data collected included age, sex, diagnosis and duration of rheumatic disease, type of TNF antagonist, and concomitant treatment. Type of CAE was classified as local or systemic cutaneous manifestation related to treatment administration (infusion reaction), infection, malignancy, or autoimmune skin disease. Time of onset of CAE and outcome were also recorded. The IRs of CAE per 1,000 patient-years of exposure with 95% confidence intervals (95% CIs) were estimated. Multivariable analysis was performed to identify potential risk factors for CAE.

Results

A total of 5,437 patients were included, representing 17,330 patient-years of exposure. A total of 920 CAE were reported; the IRs per 1,000 patient-years were 53 (95% CI 50–57) for CAE, 28 (95% CI 25–30) for infection, 15 (95% CI 13–17) for infusion reactions, 5 (95% CI 4–6) for autoimmune skin diseases, and 3 (95% CI 2–4) for skin malignancy. The mean time between starting TNF antagonist treatment and CAE was 1.78 years. In 32% of patients, CAE required TNF antagonist withdrawal. The main risk factors for CAE were female sex and treatment with infliximab, leflunomide, and glucocorticoids.

Conclusion

The IR of CAE in patients treated with TNF antagonists is significant and should be addressed carefully, and withdrawal of therapy is required in some cases.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information

Tumor necrosis factor (TNF) antagonists have demonstrated efficacy in randomized clinical trials in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis ([1-4]). However, some patients have to discontinue the medication due to adverse events. Most studies have shown an increased risk of serious infections compared with controls, with the risk varying according to the definition of serious infection ([5]). In addition, there is still controversy with respect to malignancies ([6]). Recently, reports of new onset of psoriasis ([7, 8]), alopecia areata ([9]), relapsing polychondritis ([10]), localized scleroderma ([11]), and vitiligo ([12]) have emphasized the importance of the skin as a possible target for adverse events associated with TNF antagonists. Nevertheless, much of this information comes from case series and case reports.

To help understand the association between TNF antagonists and cutaneous adverse events (CAE), our main objective was to estimate the frequency and risk factors of CAE in patients with chronic inflammatory rheumatic diseases treated with TNF antagonists, using data from the Spanish biologic registry BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología).

Box 1. Significance & Innovations

  • This study showed that cutaneous adverse events are frequently observed in patients receiving therapy with a biologic agent, suggesting the skin is a possible target for adverse events associated with tumor necrosis factor antagonists.
  • This study emphasized that, in addition to infections, a wide spectrum of cutaneous conditions may develop during therapy with a biologic agent.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information

BIOBADASER 2.0 is a national drug registry of patients with rheumatic diseases starting treatment with any biologic agent in 14 large Spanish public university hospitals (a list appears in Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22096/abstract). The registry was launched in February 2000. Patients entering the registry are followed prospectively and evaluated when an adverse event or change in therapy with a biologic agent (discontinuation or initiation) occurs. Data collected and monitored online include 1) clinical and epidemiologic data; 2) data on treatment, including dates and reason for discontinuation; and 3) data on adverse events, including date of occurrence. A full description of the registry has been published in detail elsewhere ([13]).

The protocol is available online (http://biobadaser.ser.es/biobadaser/eng/index.html). Procedures and materials comply with the principles of the Declaration of Helsinki recommendations and with Spanish regulations on data protection and research, and were approved by the Ethics Review Committee of the Hospital Ramon y Cajal (Madrid), acting as the reference committee.

In addition to continuous online monitoring, a random sample of 280 patients is selected and audited annually in situ at all centers. Further data validation includes direct consensual contact with patients or their families by project managers to confirm whether patients are alive or have been hospitalized for any reason in the preceding year.

Study groups and definitions

All BIOBADASER patients who had ever received a TNF antagonist with any of the following diagnoses were included: 1) RA; 2) AS; 3) PsA; 4) chronic arthritis, including undifferentiated spondyloarthritis, enteropathic arthritis, seronegative chronic polyarthritis, seronegative chronic oligoarthritis, Still's disease, juvenile undifferentiated spondyloarthritis, reactive arthritis, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), and juvenile AS; and 5) chronic immune-mediated diseases, including Behçet's disease, uveitis without rheumatic disease, vasculitis, systemic lupus erythematosus, polymyositis/dermatomyositis, sarcoidosis, relapsing polychondritis, Sjögren's syndrome, and systemic sclerosis.

We defined a CAE as any significant CAE that did not imply immediate danger to life but required an intervention to prevent a serious outcome. Additionally, all adverse events were filtered by the Medical Dictionary for Regulatory Activities system and organ classification and scanned manually. The diagnosis of the CAE was made and checked by a dermatologist (MA). When considered necessary, a skin biopsy was performed according to the judgment of the dermatologist. Prevalent skin conditions were also checked for and ruled out. Only de novo CAE occurring during TNF antagonist treatment were included. All diagnoses of skin lesions were reviewed by a dermatologist, who ruled out a flare of the underlying disease. All CAE were classified, with the help of a dermatologist, as 1) local or systemic cutaneous manifestation related to treatment administration (infusion reaction or injection site reactions), 2) infection, 3) malignancy, 4) autoimmune-related skin disease, or 5) other CAE. Serious CAE were defined as events that resulted in death or endangered life, required hospital admission, extended hospital stay, produced severe or persistent incapacity or congenital malformation, or were described as serious or fatal by the treating physician.

Exposure

Time of exposure was considered as the time from initiation of TNF antagonist therapy to the date of the last administration plus twice the TNF antagonist half-life (3 days for etanercept, 20 days for infliximab, and 14 days for adalimumab). Observation spanned from entry into the cohort (date of initiation of TNF antagonist) until the censor date (last visit in a patient lost to followup or treatment discontinuation date), death, or October 29, 2010, whichever occurred first. Only the first treatment was considered in the analysis. A lag window of 5 years was considered for cutaneous malignancies. Time to CAE occurrence and treatment discontinuation was also calculated. We only analyzed patients who had received infliximab, etanercept, or adalimumab, since the numbers for recently approved anti-TNF agents were too small for reliable conclusions.

Statistical analysis

We described the sociodemographic and clinical characteristics of the patients, including age, sex, diagnosis of rheumatic disease, and concomitant treatment by type of TNF antagonist. Continuous variables are expressed as means ± SDs and categorical variables are expressed as frequencies and percentages. Baseline characteristics by treatment group were compared using the chi-square test, analysis of variance, or the Kruskal-Wallis nonparametric test. The incidence rate (IR) of CAE was estimated per 1,000 patient-years of exposure with 95% confidence intervals (95% CIs), overall and by type of CAE.

Comparisons of the IR of CAE between TNF antagonists were investigated by generalized linear regression models, assuming a Poisson distribution of the data. Bivariable and multivariable analyses were performed. Multivariable models were created by backward stepwise selection of all variables with a value of P < 0.2 in the bivariable analysis. Sex, age, disease duration, diagnosis, baseline concomitant treatment, and comorbidity were included in the models. The results were expressed as the IR ratio (IRR) and 95% CI. All analyses were performed using Stata, version 11.2.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information

The analysis included 5,437 patients: 2,504 (46%) were treated with infliximab, 1,605 (30%) were treated with etanercept, and 1,328 (24%) were treated with adalimumab. Exposure was 17,330 patient-years for the 3 treatments combined: 8,790 patient-years for treatment with infliximab, 5,116 patient-years for treatment with etanercept, and 3,424 patient-years for treatment with adalimumab.

The baseline patient characteristics are shown in Table 1. Sex distribution, age at baseline, and disease duration differed between TNF antagonists. There were clear differences in the conditions treated with the TNF antagonists. RA was the condition most frequently treated with all 3 biologic agents, followed by AS for infliximab and PsA for etanercept and adalimumab. Infliximab was the leading TNF antagonist for off-label use in both chronic arthritis and chronic immune-mediated diseases. There were also differences between the TNF antagonists in methotrexate, leflunomide, and disease-modifying antirheumatic drug (DMARD) use, but not in comorbidity and concomitant glucocorticoid treatment.

Table 1. Baseline characteristics of the patients by first treatment with a TNF antagonist*
 Etanercept (n = 1,605)Infliximab (n = 2,504)Adalimumab (n = 1,328)All 3 TNF antagonists (n = 5,437)Pa
  1. Values are the number (percentage) unless indicated otherwise. See the Methods for definitions of chronic arthritis and chronic immune-mediated diseases. TNF = tumor necrosis factor; DMARDs = disease-modifying antirheumatic drugs.

  2. a

    Comparisons are among the 3 TNF antagonists.

Women961 (60)1,502 (60)848 (64)3,311 (61)0.040
Age at baseline, mean ± SD years51 ± 1449 ± 1450 ± 1350 ± 14< 0.001
Disease duration at baseline, mean ± SD years10 ± 811 ± 810 ± 910 ± 80.032
Diagnosis    < 0.001
Rheumatoid arthritis890 (55)1,263 (50)804 (61)2,957 (54) 
Ankylosing spondylitis235 (15)546 (22)187 (14)968 (18) 
Psoriatic arthritis362 (23)320 (13)244 (18)926 (17) 
Chronic arthritis108 (7)276 (11)79 (6)463 (9) 
Chronic immune-mediated diseases10 (1)99 (4)14 (1)123 (2) 
Diabetes mellitus101 (6)138 (6)65 (5)304 (6)0.165
Hypercholesterolemia162 (10)284 (11)161 (12)607 (11)0.081
Hypertension298 (19)443 (18)230 (17)971 (18)0.644
Glucocorticoids634 (40)1,012 (40)560 (42)2,206 (41)0.169
Methotrexate673 (42)1,276 (51)643 (48)2,592 (48)< 0.001
Rheumatoid arthritis444 (66)740 (58)436 (68)1,620 (63) 
Ankylosing spondylitis38 (6)197 (15)42 (7)277 (11) 
Psoriatic arthritis148 (22)202 (16)132 (21)482 (19) 
Chronic arthritis41 (6)116 (9)30 (5)187 (7) 
Chronic immune-mediated diseases2 (0)21 (2)3 (0)26 (1) 
Leflunomide168 (10)264 (11)247 (19)679 (12)< 0.001
Rheumatoid arthritis127 (76)212 (80)193 (78)532 (78) 
Ankylosing spondylitis8 (5)11 (4)2 (1)21 (3) 
Psoriatic arthritis23 (14)28 (11)46 (19)97 (14) 
Chronic arthritis10 (6)12 (5)4 (2)26 (4) 
Chronic immune-mediated diseases0 (0)1 (0)2 (1)3 (0) 
Other DMARDs138 (9)290 (12)175 (13)603 (11)< 0.001
Rheumatoid arthritis64 (46)88 (30)94 (54)246 (41) 
Ankylosing spondylitis25 (18)88 (30)24 (14)137 (23) 
Psoriatic arthritis27 (20)32 (11)25 (14)84 (14) 
Chronic arthritis18 (13)59 (20)25 (14)102 (17) 
Chronic immune-mediated diseases4 (3)23 (8)7 (4)34 (6) 

A total of 920 CAE were reported, including 478 infections, 257 infusion reactions, 89 autoimmune-related diseases, 54 malignancies, and 42 other CAE, in an exposure of 17,330 patient-years. The IRs for all CAE and by type are shown in Table 2. Infections were the most frequent CAE (Table 2); among these, viral infections, especially herpesvirus infections, were more common (Table 3). CAE were more common in infliximab-treated patients than in etanercept-treated patients (IR 58, 95% CI 53–63 versus IR 45, 95% CI 39–51 per 1,000 patient-years; P = 0.004). No significant differences were observed when comparing etanercept versus adalimumab or infliximab versus adalimumab. The higher rate in infliximab compared with the other TNF antagonists was mainly due to cutaneous infections.

Table 2. Incidence rates of cutaneous adverse events by type*
 EtanerceptInfliximabAdalimumabAll 3 TNF antagonistsPa
  1. Values are the incidence rate per 1,000 patient-years (95% confidence interval). TNF = tumor necrosis factor.

  2. a

    Comparisons are among the 3 TNF antagonists.

Infusion or injection site reaction14 (12–18)13 (11–15)20 (16–26)15 (13–17)0.009
Autoimmune-related disease4 (2–6)5 (4–7)7 (5–10)5 (4–6)0.117
Infections22 (18–26)34 (30–38)20 (16–25)28 (25–30)< 0.001
Malignancies3 (2–5)4 (2–5)3 (1–5)3 (2–4)0.617
Other2 (1–4)3 (2–4)2 (1–5)2 (2–3)0.977
All cutaneous adverse events45 (39–51)58 (53–63)53 (45–61)53 (50–57)0.004
Table 3. Numbers and IRs of serious CAE by type*
 Serious CAE, no.Serious CAE, IR (95% CI)CAE, no.CAE, IR (95% CI)
  1. IR = incidence rate; CAE = cutaneous adverse events; 95% CI = 95% confidence interval.

  2. a

    Included all serious infections.

Infusion or injection site reaction    
Generalized rash20.12 (0.03–0.46)40.23 (0.09–0.61)
Skin ulcer20.12 (0.03–0.46)80.46 (0.23–0.92)
Infusion site reaction10.06 (0.01–0.41)160.92 (0.57–1.51)
Edema10.06 (0.01–0.41)10.06 (0.01–0.41)
Systemic inflammatory reaction syndrome10.06 (0.01–0.41)10.06 (0.01–0.41)
Autoimmune-related disease    
Psoriasis20.12 (0.03–0.46)402.31 (1.69–3.15)
Alopecia areata030.17 (0.06–0.54)
Relapsing polychondritis020.12 (0.03–0.46)
Localized scleroderma010.06 (0.01–0.41)
Vitiligo10.06 (0.01–0.41)10.06 (0.01–0.41)
Infections    
Bacterial infections352.02 (1.45–2.81)18110.44 (9.02–12.08)
Viral infections110.63 (0.35–1.15)21612.46 (10.90–14.24)
Herpes zoster60.35 (0.16–0.77)1257.21 (6.05–8.60)
Varicella30.17 (0.06–0.54)150.87 (0.52–1.44)
Tuberculosis infection20.12 (0.03–0.46)20.12 (0.03–0.46)
Fungal infections30.17 (0.06–0.54)744.27 (3.40–5.36)
Malignancies    
Nonmelanoma skin cancer191.10 (0.70–1.72)341.96 (1.40–2.74)
Malignant melanoma30.17 (0.06–0.54)30.17 (0.06–0.54)
Tongue neoplasm20.12 (0.03–0.46)20.12 (0.03–0.46)
Cutaneous T cell lymphoma10.06 (0.01–0.41)40.23 (0.09–0.61)
Fibroma10.06 (0.01–0.41)20.12 (0.03–0.46)
Other    
Drug hypersensitivity10.06 (0.01–0.41)20.12 (0.03–0.46)
Mouth cyst excision10.06 (0.01–0.41)10.06 (0.01–0.41)
Totala895.13 (4.17–6.32)59234.14 (31.50–37.01)

Cutaneous manifestations related to treatment administration were more common in adalimumab-treated patients than in infliximab-treated patients (IR 20, 95% CI 16–26 versus IR 13, 95% CI 11–15 per 1,000 patient-years; P = 0.009). There were no differences between the 3 TNF antagonists in the rate of autoimmune-related skin disease, malignancies, or other CAE.

The IR of serious CAE was 5.1 per 1,000 patient-years (95% CI 4.2–6.3) (Table 3). These included nonmelanoma and malignant melanoma skin malignancies and bacterial, viral, and other skin infections. Forty cases of psoriasis were reported: 16 in RA patients (0.54%), 13 in AS patients (1.34%), 6 in PsA patients (0.64%), 4 in chronic arthritis patients (0.86%), and 1 in chronic immune-mediated disease patients (0.81%). Nineteen cases of psoriasis were reported with infliximab, 11 with etanercept, and 10 with adalimumab, with IRs per 1,000 patient-years of 2.2 (95% CI 1.4–3.4), 2 (95% CI 1.1–3.6), and 3.2 (95% CI 1.8–5.8), respectively. Only 2 of the 40 reported cases of psoriasis were considered serious.

In the bivariable analysis, risk factors for CAE (Table 4) were infliximab treatment, female sex, age, glucocorticoid use, hypertension, concomitant treatment with leflunomide, and concomitant treatment with other DMARDs. Analysis of age (stratified as 18–49 years, 50–65 years, and >65 years) showed a significant threshold in the age >65 years group (P = 0.016) that was not significant in the multivariable model (P = 0.245). Diagnoses of AS and PsA were associated with a lower risk of CAE compared with RA, which was used as the reference category in the analysis. In the final multivariable model, adjusted for all significant and clinically relevant variables, infliximab was associated with a higher risk of CAE, with an IRR of 1.24 (95% CI 1.03–1.49) compared with etanercept. A higher risk was found for women (IRR 1.49, 95% CI 1.25–1.78) and the use of glucocorticoids (IRR 1.36, 95% CI 1.15–1.61) and leflunomide (IRR 1.48, 95% CI 1.18–1.86).

Table 4. Risk factors for cutaneous adverse events*
 Bivariable, IRR (95% CI)Multivariable, IRR (95% CI)
  1. See the Methods for definitions of chronic arthritis and chronic immune-mediated diseases. IRR = incidence rate ratio; 95% CI = 95% confidence interval; TNF = tumor necrosis factor; DMARDs = disease-modifying antirheumatic drugs.

  2. a

    P < 0.01.

  3. b

    P < 0.05.

  4. c

    P < 0.001.

  5. d

    Other DMARDs included sulfasalazine, gold salts, azathioprine, antimalarials, mesalazine, cyclophosphamide, cyclosporine, and mycophenolate mofetil.

TNF antagonist  
EtanerceptReferenceReference
Infliximab1.3 (1.08–1.56)a1.24 (1.03–1.49)b
Adalimumab1.17 (0.93–1.49)1.06 (0.84–1.34)
Women1.59 (1.36–1.87)c1.49 (1.25–1.78)c
Age at baseline, years1.01 (1–1.02)c
Disease duration at baseline, years1 (0.99–1.01)
Diagnosis  
Rheumatoid arthritisReference
Ankylosing spondylitis0.72 (0.58–0.88)a1.03 (0.81–1.3)
Psoriasis arthritis0.7 (0.56–0.88)a0.91 (0.72–1.15)
Chronic arthritis0.89 (0.67–1.18)1.07 (0.8–1.43)
Chronic immune-mediated diseases1.43 (0.84–2.41)1.31 (0.78–2.21)
Diabetes mellitus1.24 (0.92–1.66)
Hypercholesterolemia1.12 (0.88–1.42)
Hypertension1.25 (1.03–1.51)b
Glucocorticoids1.57 (1.34–1.83)c1.36 (1.15–1.61)c
Methotrexate1.14 (0.98–1.34)
Leflunomide1.67 (1.34–2.09)c1.48 (1.18–1.86)c
Other DMARDsd1.35 (1.07–1.71)b1.29 (1.01–1.65)b
Start of treatment (period)  
2000–2003Reference
2004–20060.81 (0.68–0.96)b
2007–20100.89 (0.73–1.09)

The mean ± SD exposure time from treatment initiation to CAE onset was 1.78 ± 1.78 years, and was shorter in infusion or injection site reactions (1.23 ± 1.54 years) and longer in malignancies (2.87 ± 1.8 years) (Table 5). CAE occurred earlier with adalimumab and later with infliximab. Approximately one-third of patients discontinued treatment in relation to the development of a CAE (Table 5). The rate of discontinuation was 49% for infusion or injection site reactions, 62% for autoimmune diseases, 49% for infections, 65% for malignancies, and 52% for other reasons. The rate of discontinuation for all CAE was 53%.

Table 5. Time of onset of CAE and posterior outcome related to the TNF antagonist received*
 TNF antagonistsTotal
EtanerceptInfliximabAdalimumab
  1. Values are the mean ± SD time of therapy with a biologic agent until development of a cutaneous adverse event (years) unless indicated otherwise. CAE = cutaneous adverse events; TNF = tumor necrosis factor.

Infusion or injection site reaction0.78 ± 1.191.83 ± 1.820.75 ± 0.961.23 ± 1.54
Autoimmune diseases2.26 ± 1.952.02 ± 1.921.36 ± 1.261.91 ± 1.8
Infections1.83 ± 1.892.1 ± 1.831.59 ± 1.541.95 ± 1.81
Malignancies2.54 ± 1.813.11 ± 1.662.65 ± 2.362.87 ± 1.8
Other1.74 ± 1.861.91 ± 2.110.93 ± 0.711.67 ± 1.83
All CAE1.56 ± 1.772.08 ± 1.851.27 ± 1.411.78 ± 1.78
Discontinuation due to CAE, %37293632

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information

This study has described CAE in patients treated with TNF antagonists recorded in the BIOBADASER registry. There were overall IRs of 53 CAE per 1,000 patient-years and 5.13 serious CAE per 1,000 patient-years in patients with chronic inflammatory joint conditions receiving treatment with infliximab, etanercept, or adalimumab. Our results provide a comparative picture of the incidence and type of CAE in a large population of patients with rheumatic conditions treated with TNF antagonists.

In clinical trials, CAE related to infusion or subcutaneous administration, infections, and malignancies have been reported ([14-16]). In clinical practice, few descriptive reports have been published focused on CAE induced by TNF antagonists ([17-20]). The reported incidence of CAE varies from 12.7% ([18]) to 25% ([19]).

In our study, the most frequent CAE was infection, especially herpesvirus infections. This is in agreement with a previous study by our group ([21]) and with other reported studies ([22, 23]). Published rates of skin and soft tissue infections vary widely, from 12–18 per 1,000 patient-years in the British Society for Rheumatology Biologics Register ([23, 24]) to 37–76 per 1,000 patient-years in the RABBIT (Rheumatoid Arthritis–Observation of Biologic Therapy) German registry ([25]). In a large US multi-institutional collaboration study, the IR of herpes zoster in RA was 1.21 (95% CI 1.07–1.36) per 1,000 patient-years and was similar between TNF antagonists and non–biologic agent initiators ([26]). Infection was also the most frequent serious CAE in our study. These results are in agreement with published reports ([19, 24, 27]), highlighting the physiologic role of the skin as a defense against infections. TNF is synthesized in epidermal keratinocytes together with other cytokines ([28]) and plays an important role in the innate immunity against infections. Dermal dendritic cells are crucial for the detection and processing of allergens and host defense against bacteria by releasing cytokines such as TNF ([29]). Inhibition of TNF could potentially impair the protective role of the skin against infection.

One of the most surprising results in our study is the wide range of immune-mediated cutaneous diseases identified. Psoriasis, which was first reported as “psoriasis de novo,” was one of the first immune-mediated cutaneous diseases following therapy with TNF antagonists to be described ([7]). It was considered a “paradoxical response” linked mainly to the use of monoclonal antibodies ([8, 30]). Cases of worsening or relapse of psoriasis have also been described. Nevertheless, a systematic review recently reported more than 200 cases of psoriasis de novo ([31]). It has been suggested that this condition is associated with disruption of the cytokine milieu with unopposed interferon-α production by plasmacytoid dendritic cells in genetically predisposed individuals ([31]). Apart from psoriasis, other immune-mediated conditions recorded in our study included alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, vitiligo, localized morphea, and relapsing polychondritis confined to the skin. Some of these CAE, including alopecia areata ([17, 18, 20, 32, 33]), cutaneous lupus erythematosus ([17, 18, 34]), vitiligo ([12, 17, 18]), skin vasculitis ([18, 35]), lichenoid eruption ([18, 19, 35]), morphea ([36]), and granuloma annulare ([18, 37]), have been reported previously. These autoimmune CAE conditions may occur at any time during treatment with TNF antagonists, although they frequently occur within the first year. Withdrawal of therapy with a biologic agent was frequently followed by complete recovery ([9, 11]). Therefore, the prognosis and outcome of these events differ from non–drug-induced immune-mediated conditions. In cases of alopecia areata, inhibition of TNF could promote the dysregulation of interferon-α and activation of self-reactive T cells leading to skin lesions ([9, 11]). In morphea, it has been suggested that TNF antagonists may induce the profibrotic cytokine transforming growth factor β1, involved in skin thickening, although T cell activation has been reported as well ([9, 11]).

The incidence of malignancy, especially melanoma, was low in our study, with an IR of 3 per 1,000 patient-years. A 5-year lag window has been proposed to account for all slowly developing malignancies, based on our previous work ([38]). A shorter lag window is not recommended, with an “ever exposed” analysis being proposed ([39]). It is disputed whether the risk of nonmelanoma skin cancer is increased in patients treated with TNF antagonists ([38, 40, 41]). A recent meta-analysis ([42]) shows that patients treated with TNF antagonists have a significantly increased risk of nonmelanoma skin cancer (1.45, 95% CI 1.15–1.76). A revised analysis by the same authors ([43]) is consistent with the original conclusion, although the lower 95% CI limit is only just above 1.0. Our results did not show an increased rate of nonmelanoma skin cancer. Several risk factors increase the chance of developing skin cancer, including ethnic background and solar damage to the skin, among others ([44]). The difference in the rate of skin cancer in different populations may explain this lack of agreement.

We also found a lower incidence of CAE in AS and PsA patients compared with RA patients (Table 4). Reports describe an increase in cutaneous lesions ([45]) and skin malignancies in RA patients ([46]) and an increase in the rate of infections, including cutaneous infections ([47]) and viral infections, especially herpesvirus ([22, 26]). The reason for this is not clear. However, RA patients are exposed to glucocorticoids more often than AS and PsA patients, and glucocorticoids are associated with cutaneous lesions ([48]). Various studies have reported an association between the use of leflunomide and skin lesions ([49]), especially in patients who received leflunomide in combination with TNF antagonists ([50]).

A major limitation of information from databases is a lack of consistency. In the BIOBADASER 2.0, with long-term followup representative of clinical practice in Spain, data quality is assured by a clear definition of its aim, an optimized number of variables, and an easy method of data collection that allows for consistency checks. BIOBADASER 2.0 data were validated by calling and checking with patients. The data were found to be accurate, and all inconsistencies were corrected. This consistency, valuable for data interpretation, strengthens the relevance of the present study. Other strengths are the continuous online monitoring and the yearly in situ audit of a random sample of 280 patients at all centers. Patient records are used as source documents, and audits include medication use and dates of use. However, due to the characteristics of the registry, which has no control group, we cannot be sure whether the incidence of some CAE is higher than in patients not treated with TNF antagonists. Another limitation is that, for most diagnoses, numbers are not large enough to provide meaningful estimators and precise CIs, and adjustments for confounding would be close to impossible.

Another possible limitation of our study is that patients with CAE did not undergo skin biopsy and histopathologic examination to confirm the diagnosis. Nevertheless, the diagnosis was always confirmed by a dermatologist, and a skin biopsy was performed in selected cases to clarify or confirm the diagnosis.

In conclusion, in patients treated with TNF antagonists, CAE include not only infections and malignancies, but also localized cutaneous autoimmune diseases. Discontinuation of therapy with a biologic agent commonly leads to resolution of the event.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Hernández had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Hernández, Sanmartí, Carmona, Gomez-Reino.

Acquisition of data. Hernández, Sanmartí, Cañete, Alsina.

Analysis and interpretation of data. Hernández, Sanmartí, Cañete, Descalzo, Alsina, Gomez-Reino.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information

Roche, Abbott, BMS, MSD, and Pfizer had no role in the study design, data collection, data analysis, or writing of the manuscript, as well as approval of the content of the submitted manuscript. Publication of this article was not contingent on the approval of Roche, Abbott, BMS, MSD, and Pfizer.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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ACR_22096_sm_SupplAppA.doc24KSupplementary Data

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