Rheumatology 2014;53:14651469 doi:10.1093/rheumatology/keu145 Advance Access publication 27 March 2014
RHEUMATOLOGY
Concise report
Abstract Objectives. The aim of this research was to describe the cases of TNF-a antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to investigate the association between exposure to TNF-a antagonists and occurrence of alopecia. Methods. All spontaneous reports of TNF-a antagonist-related alopecia recorded in the FPVD between January 2000 and April 2012 were colligated and described. We conducted disproportionality analyses (case/non-case method) to assess the link between the occurrence of alopecia and exposure to TNF-a antagonists. Cases were all reports of alopecia and non-cases were all other reports recorded during the study period. Exposure to TNF-a antagonists was sought in cases and in non-cases. Reporting odds ratios (RORs) were calculated to assess the association. Docetaxel was used as positive control and acetaminophen as negative control. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients. Results. Among 282 590 spontaneous reports of adverse drug reactions (ADRs) collated in the FPVD, 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) occurred during exposure to TNF-a antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Exposure to TNF-a antagonists was more frequent among alopecia reports than among other ADR reports for all TNF-a antagonists pooled (ROR 3.0, 95% CI 2.3, 4.0) as well as for each antagonist separately, with similar values. Sensitivity analyses yielded similar results. The RORs were 29.9 (95% CI 25.3, 35.5) with docetaxel and 0.3 (95% CI 0.2, 0.4) with acetaminophen. Conclusion. The present study confirms a strong link between TNF-a antagonist exposure (class effect) and the occurrence of alopecia. Key words: alopecia, TNF-a antagonist, infliximab, adalimumab, etanercept, adverse drug reaction, disproportionality analysis.
1
Regional Centre of Pharmacovigilance, Lille University Hospital, University of Lille 2, Lille, 3 Internal Medicine Department, Toulouse University Hospital, 4University of Toulouse, 5UMR INSERM-UPS 1027, Toulouse, 6Internal Medicine and Clinical Immunology Department, Lille University Hospital, 7Immunology Laboratory EA2686, Lille University Hospital, Lille, 8Rheumatology Department, Bethune Hospital, Bethune, 9Department of Pharmacy, Valenciennes Hospital, Valenciennes and 10Rheumatology Department, Nancy University Hospital, Nancy, France.
Introduction
2
Submitted 10 July 2013; revised version accepted 13 February 2014. Correspondence to: Johana Be´ne´, Centre Re´gional de PharmacoVigilance, Centre Hospitalier de Lille, 1 place de Verdun, 59045 Lille, France. E-mail: [email protected]
TNF-a antagonists have dramatically improved the management of some inflammatory and immune-mediated diseases, including RA, AS, chronic juvenile arthritis, Crohn’s disease, ulcerative rectocolitis and psoriasis [1]. Five TNF-a antagonists are currently marketed in France: three monoclonal antibodies (the chimeric antibody infliximab and the fully humanized antibodies adalimumab and golimumab), a soluble TNF-a receptor (etanercept) and an antibody Fab0 fragment (certolizumab pegol).
! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
CLINICAL SCIENCE
Johana Be´ne´1,2, Guillaume Moulis3,4,5, Marine Auffret1,2, Guillaume Lefevre6,7, Pascal Coquerelle8, Patrick Coupe9, Patrice Pe´re´10 and Sophie Gautier1,2
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
Alopecia induced by tumour necrosis factor-alpha antagonists: description of 52 cases and disproportionality analysis in a nationwide pharmacovigilance database
Johana Be´ne´ et al.
Materials and methods The French Pharmacovigilance Database The FPVD records all spontaneous reports of ADRs collected by the 31 French regional pharmacovigilance centres since 1985 [15, 16]. By law, every health care professional must report serious and/or unexpected ADRs to their regional pharmacovigilance centre. Serious ADRs are lethal, life threatening, lead to hospitalization (or prolongation of hospitalization), lead to persistent or significant disability or incapacity or are judged clinically relevant by the physician who reports the case. Unexpected ADRs are those not listed in the drug monograph. Every ADR report is analysed by a college of pharmacologists and physicians in the regional pharmacovigilance centre. Causality is assessed for every suspected drug according to the French imputability method [17]. ADRs are then registered in the FPVD. They are encoded according to Medical Dictionary for Regulatory Activities (MedDRA) classification.
interest is estimated by calculating the reporting odds ratio (ROR) and its 95% CI. The ROR is the odds of exposure to the drug among cases divided by the odds of exposure to the drug among non-cases. Drugs known to induce the ADR of interest can be used as positive controls to test the reliability of the method. Notably, the case/ non-case method reveals an association but does not quantify the risk of occurrence for a given patient exposed to the drug.
Data collection We included all cases of alopecia recorded in the FPVD from 1 January 2000 to 30 April 2012. The cases were selected using the MedDRA high-level term alopecia. All cases of TNF-a antagonist-related alopecia were reviewed by pharmacologists (J.B., M.A. and S.G.) and an internist (G.M.).
Statistical analysis We applied the case/non-case method to estimate the association between alopecia and TNF-a antagonists in the FPVD by calculating RORs for TNF-a antagonist exposure. Woolf’s method was used to calculate the 95% CI. The null hypothesis was that there was no association between exposure to TNF-a antagonists and alopecia occurrence. If the 95% CI did not contain the value 1, the null hypothesis was rejected. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients (potential confounding factor). We used docetaxel (known to induce alopecia) as positive control and acetaminophen as negative control. The French Association of Regional Pharmacovigilance Centres, representing the French Pharmacovigilance Centres (which complements the FPVD), approved this study and use of the database.
Results During the study period, 282 590 spontaneous reports of ADRs were collated in the FPVD, among which 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) involved TNF-a antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Review of the cases did not detect misclassification.
The case/non-case method The case/non-case method measures the disproportionality between the combination of a given drug (here, a TNF-a antagonist) and a particular ADR (here, alopecia) in a pharmacovigilance database. It is a validated method of safety signal detection [1820]. In practice, cases are defined as all reports corresponding to the ADR of interest (here, alopecia) and non-cases are all reports of ADRs other than the ADR of interest during the same study period. Exposure is defined as exposure to the drug of interest (here, TNF-a antagonists) at the time of the ADR occurrence, whether it is suspected of causing the ADR or not. The strength of the association between exposure to a given drug and occurrence of the ADR of
1466
Characteristics of the cases The male:female sex ratio was 0.18 and the mean age was 39 years (see supplementary Tables S1S4, available at Rheumatology Online). Seventeen patients were treated for RA, 13 for AS, 12 for Crohn’s disease and 7 for psoriasis. The mean time from TNF-a antagonist introduction to alopecia onset was 11.3 months (range 4 days8 years). The TNF-a antagonist was withdrawn in 24 cases. Improvement was observed in 12 and worsening in 2, while in the remaining 10 cases the course was not described. TNF-a antagonists were maintained in 20 cases. In seven patients alopecia improved despite continued exposure to the drug, while only two of
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
The most common adverse drug reactions (ADRs) to these agents are acute infusion reactions, infections and gastrointestinal symptoms. Alopecia in patients exposed to these drugs was described in clinical trials before marketing. As a result, this ADR is mentioned in the French and international product monographs. Nevertheless, only a few case reports and small case series of TNF-a antagonist-related alopecia have been described in the literature [214]. All types of alopecia have been described, such as androgenic alopecia, alopecia areata and patchy alopecia. In most cases, because of exposure to other drugs known to induce alopecia (such as MTX) and active underlying disease such as psoriasis, it was thought that this association could be fortuitous. No comparative study assessing the link between exposure to TNF-a antagonist and alopecia had previously been conducted. The present study aimed to describe the cases of TNF-a antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to assess the putative association between exposure to TNF-a antagonists and occurrence of alopecia.
Alopecia and TNF-alpha antagonists
TABLE 1 Association between TNF-a antagonists and alopecia measured with reporting odds ratio (ROR) Drug All TNF-a antagonists Infliximab Adalimumab Etanercept Certolizumab Acetaminophen (negative control) Docetaxel (positive control)
Cases (n = 1068) % (n) 4.9 1.7 1.6 1.4 0.2 2.1 16.2
(52) (18) (17) (15) (2) (22) (173)
Discussion We found a significant association between exposure to TNF-a antagonists and alopecia. Analysis of each TNF-a antagonist separately also showed a significant and stable association for infliximab, adalimumab and etanercept, suggesting a class effect independent of the TNF antagonist’s structure. The high ROR found with certolizumab deserves careful interpretation because of the small number of reports of alopecia with this drug, which was marketed in France at the end of 2010. Further studies may conclude whether there is a higher risk of alopecia with this drug. In our study, the alopecia induced by TNF-a antagonists appeared at various doses, but never during overdosage. In a few cases, another potential cause of alopecia was identified, i.e. concomitant use of immunosuppressant drugs (MTX, LEF, AZA or ciclosporin) [2123]. Nevertheless, some of these drugs have been successfully used for treating alopecia areata, underlining the complexity of the immune pathogenesis of this disease [24]. Sensitivity analyses confirmed the potential link
www.rheumatology.oxfordjournals.org
1.7 (4742) 0.9 (2517) 0.3 (960) 0.4 (1229) 0.01 (36) 7.0 (19,823) 0.6 (1817)
ROR (95% CI) 3.0 1.9 4.8 3.3 14.7 0.3 29.9
(2.3, 4.0) (1.2, 3.1) (2.9, 7.7) (2.0, 5.4) (3.5, 61.3) (0.2, 0.4) (25.3, 35.5)
between alopecia and TNF-a antagonists after exclusion of well-known causes of alopecia. Complete or partial remission in 12 patients after discontinuation of a TNF-a antagonist, as well as positive rechallenge in three cases, are additional arguments in favour of the causality. Use of the FPVD presents some advantages for such analyses. Unlike other national or international databases, notifications in the FPVD are reported by health care professionals and validated by a college of pharmacologists and clinicians before they are recorded. This ensures the reliability and quality of the reports. In our study, review of the 52 cases of alopecia occurring during exposure to TNF-a antagonists and recorded in the database did not reveal misclassification. Moreover, the method was validated by a positive control, docetaxel, an anti-mitotic chemotherapy medication well known to induce alopecia, and by a negative control, acetaminophen, which is not known to induce alopecia. However, working with a pharmacovigilance database carries a few limitations. The FPVD is composed of spontaneous reports of ADRs. In some reports, despite meticulous care in data recovery, missing data such as previous history of alopecia, concomitant treatments or other triggers of alopecia (iron or zinc deficiency) artificially decreased the causality assessment. In addition, ADRs are generally underreported (only 5% of ADRs are reported to the French regional pharmacovigilance centres) [25]. Nevertheless, bias in disproportionality measures only occurs when there is differential reporting between cases and non-cases exposed to the drug of interest. Alopecia induced by TNF-a antagonists is a rare and unrecognized ADR compared with the other ADRs induced by these drugs. As a result, we may hypothesize that TNFa antagonist-induced alopecia is underreported compared with other TNF-a antagonist-induced ADRs. Under this assumption, the RORs of this study may be underestimated. The mechanism by which TNF-a antagonists induce alopecia is not well understood. The immune system is very likely an integral part of normal hair growth and of the hair growth cycle since epidermal keratinocytes, including those of the hair follicle, synthesize numerous cytokines, including TNF-a. These cytokines have been particularly incriminated in alopecia areata. However,
1467
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
the seven received specific treatment for alopecia. In three cases a positive rechallenge was observed. Causality was rated as possible for 43 cases, probable for 4 cases, likely for 3 cases and unspecified for 2 cases. Another concomitant cause of alopecia was present in 17 cases. Two patients had a previous history of alopecia, one treated with adalimumab with a history of alopecia areata of the beard and scalp and one treated with etanercept. When the doses received were noted (n = 21), they were in accordance with the recommendations. Exposure to TNF-a antagonists was more frequent among alopecia reports than among other ADR reports. This disproportionality was observed for all pooled TNF-a antagonists (ROR 3.0, 95% CI 2.3, 4.0) and for each drug separately (Table 1). RORs were similar for monoclonal antibodies (infliximab and adalimumab) and soluble receptor (etanercept). In parallel, the ROR was 29.9 (95% CI 25.3, 35.5) for docetaxel and 0.3 (95% CI 0.2, 0.4) for acetaminophen. When performing sensitivity analysis with exclusion of androgenic alopecia, the ROR was 3.0 (95% CI 2.2, 3.9). The ROR was 2.6 (95% CI 1.9, 3.5) when excluding psoriatic patients.
Non-cases (n = 282 590) % (n)
Johana Be´ne´ et al.
in vitro, TNF-a, IL-1a and IL-1b significantly inhibit hair growth [26]. Consequently alopecia induced by TNF-a antagonists seems paradoxical. Nevertheless, these drugs are not effective for alopecia areata treatment [27]. A suggested explanation is that TNF-a is just one of numerous cytokines involved in the complex and poorly understood pathogenesis of the disease. Rheumatology key messages
Acknowledgements The authors wish to acknowledge the contribution of the French Association of Regional Pharmacovigilance Centres. Disclosure statement: The authors have declared no conflicts of interest.
Supplementary data Supplementary data are available at Rheumatology Online.
References 1 Wong M, Ziring D, Korin Y et al. TNFa blockade in human diseases: mechanisms and future directions. Clin Immunol 2008;126:12136. 2 Ettefagh L, Nedorost S, Mirmirani P. Alopecia areata in a patient using infliximab: new insights into the role of tumor necrosis factor on human hair follicles. Arch Dermatol 2004;140:1012. 3 Posten W, Swan J. Recurrence of alopecia areata in a patient receiving etanercept injections. Arch Dermatol 2005;141:75960. 4 Garcia Bartels N, Lee HH, Worm M et al. Development of alopecia areata universalis in a patient receiving adalimumab. Arch Dermatol 2006;142:16545.
9 Herna´ndez MV, Nogue´s S, Ruiz-Esquide V et al. Development of alopecia areata after biological therapy with TNF-alpha blockers: description of a case and review of the literature. Clin Exp Rheumatol 2009;27: 8923. 10 Nakagomi D, Harada K, Yagasaki A et al. Psoriasiform eruption associated with alopecia areata during infliximab therapy. Clin Exp Dermatol 2009;34:9234. 11 Kirshen C, Kanigsberg N. Alopecia areata following adalimumab. J Cutan Med Surg 2009;13:4850. 12 Beccastrini E, Squatrito D, Emmi G, Fabbri P, Emmi L. Alopecia areata universalis during off-label treatment with Infliximab in a patient with Behc¸et disease. Dermatol Online J 2010;16:15. 13 Le Bidre E, Chaby G, Martin L et al. Alopecia areata during anti-TNF alpha therapy: nine cases. Ann Dermatol Venereol 2011;138:28593. 14 Ferran M, Calvet J, Almirall M, Pujol RM, Maymo´ J. Alopecia areata as another immune-mediated disease developed in patients treated with tumour necrosis factor-a blocker agents: report of five cases and review of the literature. J Eur Acad Dermatol Venereol 2011;25: 47984. 15 Moore N, Noblet C, Kreft-Jais C et al. French pharmacovigilance database system: examples of utilisation. Therapie 1995;50:55762. 16 Spreux A, Baldin B, Chichmanian RM. Pharmacovigilance in practice. Transfus Clin Biol 1999;6:2549. 17 Be´gaud B, Evreux JC, Jouglard J, Lagier G. [Imputation of the unexpected or toxic effects of drugs. Actualization of the method used in France]. Therapie 1985;40:1118. 18 Montastruc JL, Sommet A, Bagheri H et al. Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. Br J Clin Pharmacol 2011; 72:9058. 19 Moore N, Kreft-Jais C, Haramburu F et al. Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database. Br J Clin Pharmacol 1998;44:5138. 20 Egberts AC, Meyboom RH, van Puijenbroek EP. Use of measures of disproportionality in pharmacovigilance: three Dutch examples. Drug Saf 2002;25:4538. 21 Weinblatt ME. Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol Suppl 1985;12:359.
5 Tosti A, Pazzaglia M, Starace M et al. Alopecia areata during treatment with biologic agents. Arch Dermatol 2006;142:16534.
22 Gottenberg JE, Venancie PY, Mariette X. Alopecia areata in a patient with rheumatoid arthritis treated with leflunomide. J Rheumatol 2002;29:18067.
6 Chaves Y, Duarte G, Ben-Said B et al. Alopecia areata universalis during treatment of rheumatoid arthritis with anti-TNF-alpha antibody (adalimumab). Dermatology 2008;217:380.
23 Phillips MA, Graves JE, Nunley JR. Alopecia areata presenting in 2 kidney-pancreas transplant recipients taking cyclosporine. J Am Acad Dermatol 2005;53: S2525.
7 Pelivani N, Hassan AS, Braathen LR, Hunger RE, Yawalkar N. Alopecia areata universalis elicited during treatment with adalimumab. Dermatology 2008;216: 3203.
24 Joly P. The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis. J Am Acad Dermatol 2006; 55:6326.
1468
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
The suspected link between TNF-a antagonist exposure and the occurrence of alopecia is confirmed. . This concerns alopecia areata as reported in the literature but also other types of alopecia. . This adverse drug reaction appears to be a class effect. .
8 Fabre C, Dereure O. Worsening alopecia areata and de novo occurrence of multiple halo nevi in a patient receiving infliximab. Dermatology 2008;216:1856.
Alopecia and TNF-alpha antagonists
25 Be´gaud B, Martin K, Haramburu F, Moore N. Rates of spontaneous reporting of adverse drug reactions in France. JAMA 2002;288:1588. 26 Philpott MP, Sanders DA, Bowen J, Kealy T. Effects of interleukins, colony-stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible
role for interleukin-1 and tumour necrosis factor-alpha in alopecia areata. Br J Dermatol 1996;135:9428. 27 Strober BE, Siu K, Alexis AF et al. Etanercept does not effectively treat moderate to severe alopecia areata: an open-label study. J Am Acad Dermatol 2005;52: 10824.
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
www.rheumatology.oxfordjournals.org
1469
RHEUMATOLOGY
Concise report
Abstract Objectives. The aim of this research was to describe the cases of TNF-a antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to investigate the association between exposure to TNF-a antagonists and occurrence of alopecia. Methods. All spontaneous reports of TNF-a antagonist-related alopecia recorded in the FPVD between January 2000 and April 2012 were colligated and described. We conducted disproportionality analyses (case/non-case method) to assess the link between the occurrence of alopecia and exposure to TNF-a antagonists. Cases were all reports of alopecia and non-cases were all other reports recorded during the study period. Exposure to TNF-a antagonists was sought in cases and in non-cases. Reporting odds ratios (RORs) were calculated to assess the association. Docetaxel was used as positive control and acetaminophen as negative control. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients. Results. Among 282 590 spontaneous reports of adverse drug reactions (ADRs) collated in the FPVD, 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) occurred during exposure to TNF-a antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Exposure to TNF-a antagonists was more frequent among alopecia reports than among other ADR reports for all TNF-a antagonists pooled (ROR 3.0, 95% CI 2.3, 4.0) as well as for each antagonist separately, with similar values. Sensitivity analyses yielded similar results. The RORs were 29.9 (95% CI 25.3, 35.5) with docetaxel and 0.3 (95% CI 0.2, 0.4) with acetaminophen. Conclusion. The present study confirms a strong link between TNF-a antagonist exposure (class effect) and the occurrence of alopecia. Key words: alopecia, TNF-a antagonist, infliximab, adalimumab, etanercept, adverse drug reaction, disproportionality analysis.
1
Regional Centre of Pharmacovigilance, Lille University Hospital, University of Lille 2, Lille, 3 Internal Medicine Department, Toulouse University Hospital, 4University of Toulouse, 5UMR INSERM-UPS 1027, Toulouse, 6Internal Medicine and Clinical Immunology Department, Lille University Hospital, 7Immunology Laboratory EA2686, Lille University Hospital, Lille, 8Rheumatology Department, Bethune Hospital, Bethune, 9Department of Pharmacy, Valenciennes Hospital, Valenciennes and 10Rheumatology Department, Nancy University Hospital, Nancy, France.
Introduction
2
Submitted 10 July 2013; revised version accepted 13 February 2014. Correspondence to: Johana Be´ne´, Centre Re´gional de PharmacoVigilance, Centre Hospitalier de Lille, 1 place de Verdun, 59045 Lille, France. E-mail: [email protected]
TNF-a antagonists have dramatically improved the management of some inflammatory and immune-mediated diseases, including RA, AS, chronic juvenile arthritis, Crohn’s disease, ulcerative rectocolitis and psoriasis [1]. Five TNF-a antagonists are currently marketed in France: three monoclonal antibodies (the chimeric antibody infliximab and the fully humanized antibodies adalimumab and golimumab), a soluble TNF-a receptor (etanercept) and an antibody Fab0 fragment (certolizumab pegol).
! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
CLINICAL SCIENCE
Johana Be´ne´1,2, Guillaume Moulis3,4,5, Marine Auffret1,2, Guillaume Lefevre6,7, Pascal Coquerelle8, Patrick Coupe9, Patrice Pe´re´10 and Sophie Gautier1,2
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
Alopecia induced by tumour necrosis factor-alpha antagonists: description of 52 cases and disproportionality analysis in a nationwide pharmacovigilance database
Johana Be´ne´ et al.
Materials and methods The French Pharmacovigilance Database The FPVD records all spontaneous reports of ADRs collected by the 31 French regional pharmacovigilance centres since 1985 [15, 16]. By law, every health care professional must report serious and/or unexpected ADRs to their regional pharmacovigilance centre. Serious ADRs are lethal, life threatening, lead to hospitalization (or prolongation of hospitalization), lead to persistent or significant disability or incapacity or are judged clinically relevant by the physician who reports the case. Unexpected ADRs are those not listed in the drug monograph. Every ADR report is analysed by a college of pharmacologists and physicians in the regional pharmacovigilance centre. Causality is assessed for every suspected drug according to the French imputability method [17]. ADRs are then registered in the FPVD. They are encoded according to Medical Dictionary for Regulatory Activities (MedDRA) classification.
interest is estimated by calculating the reporting odds ratio (ROR) and its 95% CI. The ROR is the odds of exposure to the drug among cases divided by the odds of exposure to the drug among non-cases. Drugs known to induce the ADR of interest can be used as positive controls to test the reliability of the method. Notably, the case/ non-case method reveals an association but does not quantify the risk of occurrence for a given patient exposed to the drug.
Data collection We included all cases of alopecia recorded in the FPVD from 1 January 2000 to 30 April 2012. The cases were selected using the MedDRA high-level term alopecia. All cases of TNF-a antagonist-related alopecia were reviewed by pharmacologists (J.B., M.A. and S.G.) and an internist (G.M.).
Statistical analysis We applied the case/non-case method to estimate the association between alopecia and TNF-a antagonists in the FPVD by calculating RORs for TNF-a antagonist exposure. Woolf’s method was used to calculate the 95% CI. The null hypothesis was that there was no association between exposure to TNF-a antagonists and alopecia occurrence. If the 95% CI did not contain the value 1, the null hypothesis was rejected. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients (potential confounding factor). We used docetaxel (known to induce alopecia) as positive control and acetaminophen as negative control. The French Association of Regional Pharmacovigilance Centres, representing the French Pharmacovigilance Centres (which complements the FPVD), approved this study and use of the database.
Results During the study period, 282 590 spontaneous reports of ADRs were collated in the FPVD, among which 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) involved TNF-a antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Review of the cases did not detect misclassification.
The case/non-case method The case/non-case method measures the disproportionality between the combination of a given drug (here, a TNF-a antagonist) and a particular ADR (here, alopecia) in a pharmacovigilance database. It is a validated method of safety signal detection [1820]. In practice, cases are defined as all reports corresponding to the ADR of interest (here, alopecia) and non-cases are all reports of ADRs other than the ADR of interest during the same study period. Exposure is defined as exposure to the drug of interest (here, TNF-a antagonists) at the time of the ADR occurrence, whether it is suspected of causing the ADR or not. The strength of the association between exposure to a given drug and occurrence of the ADR of
1466
Characteristics of the cases The male:female sex ratio was 0.18 and the mean age was 39 years (see supplementary Tables S1S4, available at Rheumatology Online). Seventeen patients were treated for RA, 13 for AS, 12 for Crohn’s disease and 7 for psoriasis. The mean time from TNF-a antagonist introduction to alopecia onset was 11.3 months (range 4 days8 years). The TNF-a antagonist was withdrawn in 24 cases. Improvement was observed in 12 and worsening in 2, while in the remaining 10 cases the course was not described. TNF-a antagonists were maintained in 20 cases. In seven patients alopecia improved despite continued exposure to the drug, while only two of
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
The most common adverse drug reactions (ADRs) to these agents are acute infusion reactions, infections and gastrointestinal symptoms. Alopecia in patients exposed to these drugs was described in clinical trials before marketing. As a result, this ADR is mentioned in the French and international product monographs. Nevertheless, only a few case reports and small case series of TNF-a antagonist-related alopecia have been described in the literature [214]. All types of alopecia have been described, such as androgenic alopecia, alopecia areata and patchy alopecia. In most cases, because of exposure to other drugs known to induce alopecia (such as MTX) and active underlying disease such as psoriasis, it was thought that this association could be fortuitous. No comparative study assessing the link between exposure to TNF-a antagonist and alopecia had previously been conducted. The present study aimed to describe the cases of TNF-a antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to assess the putative association between exposure to TNF-a antagonists and occurrence of alopecia.
Alopecia and TNF-alpha antagonists
TABLE 1 Association between TNF-a antagonists and alopecia measured with reporting odds ratio (ROR) Drug All TNF-a antagonists Infliximab Adalimumab Etanercept Certolizumab Acetaminophen (negative control) Docetaxel (positive control)
Cases (n = 1068) % (n) 4.9 1.7 1.6 1.4 0.2 2.1 16.2
(52) (18) (17) (15) (2) (22) (173)
Discussion We found a significant association between exposure to TNF-a antagonists and alopecia. Analysis of each TNF-a antagonist separately also showed a significant and stable association for infliximab, adalimumab and etanercept, suggesting a class effect independent of the TNF antagonist’s structure. The high ROR found with certolizumab deserves careful interpretation because of the small number of reports of alopecia with this drug, which was marketed in France at the end of 2010. Further studies may conclude whether there is a higher risk of alopecia with this drug. In our study, the alopecia induced by TNF-a antagonists appeared at various doses, but never during overdosage. In a few cases, another potential cause of alopecia was identified, i.e. concomitant use of immunosuppressant drugs (MTX, LEF, AZA or ciclosporin) [2123]. Nevertheless, some of these drugs have been successfully used for treating alopecia areata, underlining the complexity of the immune pathogenesis of this disease [24]. Sensitivity analyses confirmed the potential link
www.rheumatology.oxfordjournals.org
1.7 (4742) 0.9 (2517) 0.3 (960) 0.4 (1229) 0.01 (36) 7.0 (19,823) 0.6 (1817)
ROR (95% CI) 3.0 1.9 4.8 3.3 14.7 0.3 29.9
(2.3, 4.0) (1.2, 3.1) (2.9, 7.7) (2.0, 5.4) (3.5, 61.3) (0.2, 0.4) (25.3, 35.5)
between alopecia and TNF-a antagonists after exclusion of well-known causes of alopecia. Complete or partial remission in 12 patients after discontinuation of a TNF-a antagonist, as well as positive rechallenge in three cases, are additional arguments in favour of the causality. Use of the FPVD presents some advantages for such analyses. Unlike other national or international databases, notifications in the FPVD are reported by health care professionals and validated by a college of pharmacologists and clinicians before they are recorded. This ensures the reliability and quality of the reports. In our study, review of the 52 cases of alopecia occurring during exposure to TNF-a antagonists and recorded in the database did not reveal misclassification. Moreover, the method was validated by a positive control, docetaxel, an anti-mitotic chemotherapy medication well known to induce alopecia, and by a negative control, acetaminophen, which is not known to induce alopecia. However, working with a pharmacovigilance database carries a few limitations. The FPVD is composed of spontaneous reports of ADRs. In some reports, despite meticulous care in data recovery, missing data such as previous history of alopecia, concomitant treatments or other triggers of alopecia (iron or zinc deficiency) artificially decreased the causality assessment. In addition, ADRs are generally underreported (only 5% of ADRs are reported to the French regional pharmacovigilance centres) [25]. Nevertheless, bias in disproportionality measures only occurs when there is differential reporting between cases and non-cases exposed to the drug of interest. Alopecia induced by TNF-a antagonists is a rare and unrecognized ADR compared with the other ADRs induced by these drugs. As a result, we may hypothesize that TNFa antagonist-induced alopecia is underreported compared with other TNF-a antagonist-induced ADRs. Under this assumption, the RORs of this study may be underestimated. The mechanism by which TNF-a antagonists induce alopecia is not well understood. The immune system is very likely an integral part of normal hair growth and of the hair growth cycle since epidermal keratinocytes, including those of the hair follicle, synthesize numerous cytokines, including TNF-a. These cytokines have been particularly incriminated in alopecia areata. However,
1467
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
the seven received specific treatment for alopecia. In three cases a positive rechallenge was observed. Causality was rated as possible for 43 cases, probable for 4 cases, likely for 3 cases and unspecified for 2 cases. Another concomitant cause of alopecia was present in 17 cases. Two patients had a previous history of alopecia, one treated with adalimumab with a history of alopecia areata of the beard and scalp and one treated with etanercept. When the doses received were noted (n = 21), they were in accordance with the recommendations. Exposure to TNF-a antagonists was more frequent among alopecia reports than among other ADR reports. This disproportionality was observed for all pooled TNF-a antagonists (ROR 3.0, 95% CI 2.3, 4.0) and for each drug separately (Table 1). RORs were similar for monoclonal antibodies (infliximab and adalimumab) and soluble receptor (etanercept). In parallel, the ROR was 29.9 (95% CI 25.3, 35.5) for docetaxel and 0.3 (95% CI 0.2, 0.4) for acetaminophen. When performing sensitivity analysis with exclusion of androgenic alopecia, the ROR was 3.0 (95% CI 2.2, 3.9). The ROR was 2.6 (95% CI 1.9, 3.5) when excluding psoriatic patients.
Non-cases (n = 282 590) % (n)
Johana Be´ne´ et al.
in vitro, TNF-a, IL-1a and IL-1b significantly inhibit hair growth [26]. Consequently alopecia induced by TNF-a antagonists seems paradoxical. Nevertheless, these drugs are not effective for alopecia areata treatment [27]. A suggested explanation is that TNF-a is just one of numerous cytokines involved in the complex and poorly understood pathogenesis of the disease. Rheumatology key messages
Acknowledgements The authors wish to acknowledge the contribution of the French Association of Regional Pharmacovigilance Centres. Disclosure statement: The authors have declared no conflicts of interest.
Supplementary data Supplementary data are available at Rheumatology Online.
References 1 Wong M, Ziring D, Korin Y et al. TNFa blockade in human diseases: mechanisms and future directions. Clin Immunol 2008;126:12136. 2 Ettefagh L, Nedorost S, Mirmirani P. Alopecia areata in a patient using infliximab: new insights into the role of tumor necrosis factor on human hair follicles. Arch Dermatol 2004;140:1012. 3 Posten W, Swan J. Recurrence of alopecia areata in a patient receiving etanercept injections. Arch Dermatol 2005;141:75960. 4 Garcia Bartels N, Lee HH, Worm M et al. Development of alopecia areata universalis in a patient receiving adalimumab. Arch Dermatol 2006;142:16545.
9 Herna´ndez MV, Nogue´s S, Ruiz-Esquide V et al. Development of alopecia areata after biological therapy with TNF-alpha blockers: description of a case and review of the literature. Clin Exp Rheumatol 2009;27: 8923. 10 Nakagomi D, Harada K, Yagasaki A et al. Psoriasiform eruption associated with alopecia areata during infliximab therapy. Clin Exp Dermatol 2009;34:9234. 11 Kirshen C, Kanigsberg N. Alopecia areata following adalimumab. J Cutan Med Surg 2009;13:4850. 12 Beccastrini E, Squatrito D, Emmi G, Fabbri P, Emmi L. Alopecia areata universalis during off-label treatment with Infliximab in a patient with Behc¸et disease. Dermatol Online J 2010;16:15. 13 Le Bidre E, Chaby G, Martin L et al. Alopecia areata during anti-TNF alpha therapy: nine cases. Ann Dermatol Venereol 2011;138:28593. 14 Ferran M, Calvet J, Almirall M, Pujol RM, Maymo´ J. Alopecia areata as another immune-mediated disease developed in patients treated with tumour necrosis factor-a blocker agents: report of five cases and review of the literature. J Eur Acad Dermatol Venereol 2011;25: 47984. 15 Moore N, Noblet C, Kreft-Jais C et al. French pharmacovigilance database system: examples of utilisation. Therapie 1995;50:55762. 16 Spreux A, Baldin B, Chichmanian RM. Pharmacovigilance in practice. Transfus Clin Biol 1999;6:2549. 17 Be´gaud B, Evreux JC, Jouglard J, Lagier G. [Imputation of the unexpected or toxic effects of drugs. Actualization of the method used in France]. Therapie 1985;40:1118. 18 Montastruc JL, Sommet A, Bagheri H et al. Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. Br J Clin Pharmacol 2011; 72:9058. 19 Moore N, Kreft-Jais C, Haramburu F et al. Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database. Br J Clin Pharmacol 1998;44:5138. 20 Egberts AC, Meyboom RH, van Puijenbroek EP. Use of measures of disproportionality in pharmacovigilance: three Dutch examples. Drug Saf 2002;25:4538. 21 Weinblatt ME. Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol Suppl 1985;12:359.
5 Tosti A, Pazzaglia M, Starace M et al. Alopecia areata during treatment with biologic agents. Arch Dermatol 2006;142:16534.
22 Gottenberg JE, Venancie PY, Mariette X. Alopecia areata in a patient with rheumatoid arthritis treated with leflunomide. J Rheumatol 2002;29:18067.
6 Chaves Y, Duarte G, Ben-Said B et al. Alopecia areata universalis during treatment of rheumatoid arthritis with anti-TNF-alpha antibody (adalimumab). Dermatology 2008;217:380.
23 Phillips MA, Graves JE, Nunley JR. Alopecia areata presenting in 2 kidney-pancreas transplant recipients taking cyclosporine. J Am Acad Dermatol 2005;53: S2525.
7 Pelivani N, Hassan AS, Braathen LR, Hunger RE, Yawalkar N. Alopecia areata universalis elicited during treatment with adalimumab. Dermatology 2008;216: 3203.
24 Joly P. The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis. J Am Acad Dermatol 2006; 55:6326.
1468
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
The suspected link between TNF-a antagonist exposure and the occurrence of alopecia is confirmed. . This concerns alopecia areata as reported in the literature but also other types of alopecia. . This adverse drug reaction appears to be a class effect. .
8 Fabre C, Dereure O. Worsening alopecia areata and de novo occurrence of multiple halo nevi in a patient receiving infliximab. Dermatology 2008;216:1856.
Alopecia and TNF-alpha antagonists
25 Be´gaud B, Martin K, Haramburu F, Moore N. Rates of spontaneous reporting of adverse drug reactions in France. JAMA 2002;288:1588. 26 Philpott MP, Sanders DA, Bowen J, Kealy T. Effects of interleukins, colony-stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible
role for interleukin-1 and tumour necrosis factor-alpha in alopecia areata. Br J Dermatol 1996;135:9428. 27 Strober BE, Siu K, Alexis AF et al. Etanercept does not effectively treat moderate to severe alopecia areata: an open-label study. J Am Acad Dermatol 2005;52: 10824.
Downloaded from http://rheumatology.oxfordjournals.org/ at University Library, University of Illinois at Chicago on October 23, 2014
www.rheumatology.oxfordjournals.org
1469
