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Thalidomide-induced granuloma annulare

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VOLUME 149 - No. 3 - JUNE 2014

OFFICIAL JOURNAL OF THE SOCIETÀ ITALIANA DI DERMATOLOGIA MEDICA,CHIRURGICA, ESTETICA E DELLE MALATTIE SESSUALMENTE TRASMESSE (SIDeMaST)

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Vol. 149 - No. 3 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 329

in the literature about the association between anti-tumor necrosis factor alpha (TNF-alpha) drugs and the occurrence of GA.12-17 The paradox of this last observation is that TNF inhibitors can be used for the treatment of refractory GA.18

Case report

A 75-year-old Caucasian male was admitted to our hospital because of the recent onset of erythematous ring-like firm papular lesions, mostly in annular configuration with clear centre and slightly elevated borders, localized on the dorsal aspect of both hands. The eruption occurred 15 days after the start of thalidomide therapy, at the start-ing dosage of 100 mg/day, then increased to 150 mg/day, for multiple myeloma. Dermatologic examination re-vealed asymptomatic multiple erythematous papules and annular plaques localized on lateral and dorsal aspect of both hands and fingers (Figure 1). No rash was present elsewhere. The mucous membranes, hair and nails were normal.

Laboratory examination of complete blood count, se-rum chemistries, liver and kidney function tests showed normal results, as well as rheumatoid factor, anti double-stranded DNA, antinuclear antibodies, CRP, pANCA and cANCA. The patient was otherwise healthy, no arthral-gias, or autoimmunity disorders were present. The past

1Unit of Dermatology M. Aresu Department of Medical Science

University of Cagliari, Cagliari, Italy2Unit of Dermatology, AOU Cagliari, Cagliari, Italy

3Unit of Internal Medicine, SS. Trinità Hospital ASL 8, Cagliari, Italy

G ITAL DERMATOL VENEREOL 2014;149:329-33

C. FERRELI 1, L ATZORI 1, F. MANUNZA 1, M. PAU 2, A. CADDORI 3

Thalidomide-induced granuloma annulare

Granuloma annulare (GA) is an acquired, usually self-lim-iting, asymptomatic granulomatous skin disease with well recognized clinical and histological features that occurs in children and adults generally before the age of 30. Five clinical types are described including the localized, gener-alized, subcutaneous, perforating, and patch forms. The possible role of immune dysregulation has been pointed out in the pathogenesis of GA, as it has been reported in as-sociation with several diseases and conditions like diabetes, thyroid diseases, malignancies, tuberculosis, human immu-nodeficiency, Epstein Barr and hepatitis C virus infection. Drug-induced GA is a rare presentation, that can appear similar or identical to idiopathic GA. We present a 75-year-old Caucasian man with a violaceous ring-like firm, papular eruption, localized on the dorsal aspect of both hands, with histological features of GA, which subsequently resolved with the discontinuation of thalidomide he had started 1 month earlier for the treatment of a multiple myeloma. The lesions appeared with renewed intensity after resuming a therapy cycle. Jones’s algorithm for the diagnosis of adverse drug reactions (ADR) showed a certain association, thus the final diagnosis of thalidomide-induced GA was made.

Key words: Granuloma annulare - Thalidomide - Drug-relat-Drug-relat-ed side effects and adverse reactions.

Drug induced GA is a rare entity, firstly described by Rothwell in 1980 induced by gold therapy.1

Since then, besides gold,2 it has been described in association with a number of medications, among them allopurinol,3-5 diclofenac,6 calcium channel blockers,7 antidepressants,8 anticonvulsants,9, 10 interferon.11 More recently, case reports came out

Corresponding author: C. Ferreli, M. Aresu Department of Medical Science, University of Cagliari, Via Ospedale 54, 09124 Cagliari, Italy. E-mail: ferreli@unica.it

Anno: 2014Mese: JuneVolume: 149No: 3Rivista: GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIACod Rivista: G ITAL DERMATOL VENEREOL

Lavoro: titolo breve: THALIDOMIDE INDUCED GRANULOMA ANNULAREprimo autore: FERRELIpagine: 329-33

FERRELI THALIDOMIDE INDUCED GRANULOMA ANNULARE

330 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA June 2014

Figure 4.—Palisading granulomas around degenerated collagen (H&E 40X).

Figure 3.—Palisading infiltrate of histiocytes surrounding areas of collagen degeneration with a dense perivascular lymphocytic infiltrate (H&E 10X).

Figure 2.—Resolution of the rash after drug withdrawal.Figure 1.—Papular eruption on the dorsal aspect of both hands and fingers.

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Vol. 149 - No. 3 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 331

association (certain), and the diagnosis of drug-induced GA was made.

Discussion

GA is a relatively common idiopathic disorder occurring in all races and ages more frequently af-fecting women under 30 years of age. Five clini-cal variants are described, localized, generalized, subcutaneous, perforating, and patch forms, with often overlapping clinical features. The proposed pathogenetic mechanisms are many: they range from IFN-gamma producing lymphocytes in the setting of a Th1 inflammatory reaction,20 to type IV delayed hypersensitivity,21 lymphocytes mediated monocytes’ activation 22 and elastic fibers degen-eration.23 Several etiologic factors have been sug-gested, such as viral infections (HSV, EBV, HBV, HCV and HIV), insect bites and trauma,24 TB test-ing and sunlight 25 and neoplastic disorders,26 al-though they are still unproven.27 Drug induced GA has been described after exposure to a number of drugs and, more recently, anti TNF-alpha drugs have been added to the list.12-17

TNF-alpha is a cytokine that plays an important role in the normal host defence 28 but, when over-produced, it is implicated in the pathogenesis of several inflammatory conditions and autoimmune disorders by inducing and maintaining inflam-mation through lymphocytes’ activation and cy-tokine production.29 Thalidomide has re-emerged as a novel antineoplastic agent with antiangiogenic activities and it has been shown to down regulate the production of TNF-alpha, both in vivo and in vitro, suggesting its immunomodulatory role.30 In our patient thalidomide was administered for the treatment of multiple myeloma and the temporal relationship among the development of the der-matosis, its resolution upon drug discontinuation and its recurrence upon rechallenge of this drug, confirmed the iatrogenic nature of the rash. The chance that idiopathic GA had occurred in associa-tion with multiple myeloma is unlikely as our pa-tient did not have clinical evidence of GA prior to thalidomide treatment. Moreover, to the best of our knowledge, GA has never been reported in patients affected with multiple myeloma. Besides, there are several potentially drug induced entities that clini-cally resemble GA that should be regarded in the

medical history was remarkable for multiple myeloma re-lated pathological fractures on D12, L2-L5 and duodenal bulb disease. Histopathological examination of a biopsy taken from the dorsum of the hand showed a palisading infiltrate of histiocytes, surrounding areas of necrobiotic collagen fibres and a dense perivascular lymphocytic in-filtrate with few eosinophils, without vasculitis (Figures 3, 4). There was also a prominent interstitial histiocytic infiltrate and mucin deposition (Figure 5), with no evi-dence of interface dermatitis. Neither lymphoid atypia nor giant histiocytes were observed.

Thalidomide administration was suspected to have in-duced the lesions as its discontinuation produced a dra-matic improvement within one month (Figure 2). A re-challenge with thalidomide 100 mg/day associated with prednisone 25 mg/bid three months later resulted in the recurrence of lesions within two weeks. Thalidomide was definitely stopped with complete and persistent resolu-tion of the rash. Jones’s algorithm for the diagnosis of adverse drug reactions 19 confirmed the highly probable

Figure 5.—Mucin deposition in areas of interstitial histiocytic in-filtrate (Alcian blue 40X).

FERRELI THALIDOMIDE INDUCED GRANULOMA ANNULARE

332 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA June 2014

3. Singh SK, Manchanda K, Bhayana AA, Verma A. Allopurinol in-duced granuloma annulare in a patient of lepromatous leprosy. J Pharmacol Pharmacother 2013;4:152-4.

4. Becker D, Enk A, Bräuninger W, Knop J. Granuloma anu-lare disseminatum as a rare side effect of allopurinol. Hautarzt 1995;46:343-5.

5. Goihman-Yahr M Disseminated granuloma annulare and intrana-sal calcitonin. Int J Dermatol 1993;32:150.

6. Le Corre Y, Léonard F, Fertin C, Kalis B. Granuloma-annulare type photosensitivity disorder caused by diclofenac. Ann Derma-tol Venereol 1992;119:932-3.

7. Lim AC, Hart K, Murrell D. A granuloma annulare-like erup-tion associated with the use of amlodipine. Australas J Dermatol 2002;43:24-7.

8. Álvarez-Pérez A, Gómez-Bernal S, Gutiérrez-González E, Ro-dríguez-Granados MT, Toribio J. Granuloma annulare photoin-duced by paroxetine. Photodermatol Photoimmunol Photomed 2012;28:47-9.

9. Lagier L, Dunoyer E, Estève E. Topiramate: a new inductor of granuloma annulare? 2011;138:141-3.

10. Cassone G, Tumiati B. Granuloma annulare as a possible new ad-verse effect of topiramate. Int J Dermatol 2014;53:259-61.

11. Kluger N, Moguelet P, Chaslin-Ferbus D, Khosrotherani K, Aract-Khosrotherani K, Aract-ingi S. Generalized Interstitial Granuloma Annulare Induced by Pegylated Interferon-Alpha. Dermatology 2006;213:248–249

12. Ratnarathorn M, Raychaudhuri S P, Naguwa S Disseminated granuloma annulare: a cutaneous adverse effect of anti-tnf agents Indian J Dermatol 2011;56:752-754.

13. Werchau S, Enk A, Hartmann M. Generalized interstitial granulo-ma annulare response to adalimumab. Int J Dermatol 2010;49:457-60

14. Voulgari PV, Markatseli TE, Exarchou SA, Zioga A, Drosos AA. Granuloma annulare induced by anti-tumour necrosis factor ther-apy. Ann Rheum Dis 2008;67:567-70.

15. Viguier M, Richette P, Bachelez H, Wendling D, Aubin F Para-doxical cutaneous manifestations during anti-TNF-alpha therapy. Ann Dermatol Venereol 2010;137:64-71.

16. Devos SA, van den Bossche N, De Vos M, Naeyaert JM. Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy. Dermatology 2003;206:388-90.

17. Lebas D, Staumont-Sallé D, Solau-Gervais E, Flipo RM, Delaporte E. Cutaneous manifestations during treatment with TNF-alpha blockers: 11 cases. Ann Dermatol Venereol 2007;134:337-42.

18. Kozic H, Webster GF. Treatment of widespread granuloma an-nulare with adalimumab: a case report. J Clin Aesthet Dermatol 2011;4:42-3.

19. Jones JK. Criteria for journal reports of suspected drug reactions. Clin Pharm 1982;1:554-5.

20. Fayyazi A,  Schweyer S,  Eichmeyer B,  Herms J,  Hemmerlein B,  Radzun HJ  et al. Expression of IFNgamma, coexpression of TNFalpha and matrix metalloproteinases and apoptosis of T lym-phocytes and macrophages in granuloma annulare. Arch Dermatol Res 2000;292:384-90.

21. Buechner SA, Winkelmann RK, Banks PM. Identification of T-cell subpopulations in granuloma annulare. Arch Derma-tol 1983;119:125-8.

22. Umbert P,  Winkelmann RK. Histologic, ultrastructural and histochemical studies of granuloma annulare. Arch Derma-tol 1977;113:1681-6.

23. Hanna WM,  Moreno-Merlo F,  Andrighetti L. Granuloma annu-lare: an elastic tissue disease? Case report and literature review. Ultrastruct Pathol 1999;23:33-8.

24. Smith MD, Downie JB, DiCostanzo D. Granuloma annulare. Int J Dermatol 1997;36:326-33.

25. Stewart LR, George S Hamacher K L, Hsu S. Granuloma annulare of the palms. Dermatol Online J 2011;17:5.

26. Hawryluk EB, Izikson L. English JC 3rd. Non-infectious granulo-

differential diagnosis, such as interstitial granulo-matous dermatitis (IGD),31 palisaded neutrophilic and granulomatous dermatitis (PNGD),32 intersti-tial granulomatous drug reaction (IGDR),33 and a GA in the setting of systemic disease.34 In the case reported herein histologic features supporting the diagnosis of GA included collagen necrobiosis, in-terstitial histiocytosis and abundant mucin deposi-tion, in the absence of interface dermatitis and lym-phoid atypia, features generally found in IGDR. The occurrence of drug induced GA following anti-TNF-alpha treatment has been primarily de-scribed in patients with collagen vascular diseases, mainly rheumatoid arthritis, after administration of new “biologic” anti-TNF-alpha agents,35 but it has not yet been described in association with tha-lidomide therapy. Conversely, thalidomide, an old anti-TNF-alpha inhibitor, and its derivative lenal-idomide, have been reported to induce IGDR 29, 36 suggesting that there is a spectrum of drug induced granulomatous reactions with often subtle clini-cal findings and variable histopathologic pictures. The pathogenesis of the granulomatous reaction developing in the course of TNF-alpha inhibitors could be related to some specific hystiocyte and/or lymphocyte activity regulated by this cytokine and the immunologic burden in genetically predisposed individuals. Further reports might unravel the ques-tion and convey new insights on this unusual cuta-neous adverse drug reaction.

Conclusions

The occurrence of GA during the administration of TNF-alpha inhibitors has been described mainly in patient affected by rheumatoid arthritis, and has encouraged the hypothesis that this drugs can pro-mote a disease specific reaction. Our case occurred in absence of rheumatoid arthritis, therefore sug-gesting that the drug is primarily responsible for the cutaneous reaction due to a kind of immunologic suppression induced by this class of drugs.

References

1. Rothwell R. S, Schloss E H. Granuloma Annulare and Gold Ther-apy Arch Dermatol 1980;116:863

2. Martin N, Belinchón I, Fuente C, Vélez A, Sánchez-Yus E. Granu-Granu-loma annulare and gold therapy. Arch Dermatol 1990;126:1370-1.

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33. Hernández N, Peñate Y, Borrego L. Generalized erythematous-violaceous plaques in a patient with a history of dyslipidemia. Interstitial granulomatous drug reaction (IGDR). Int J Dermatol 2013;52:393-4.

34. Thornsberry LA, English JC 3rd. Etiology, diagnosis, and thera-peutic management of granuloma annulare: an update. Am J Clin Dermatol 2013;14:279-90.

35. Wendling D, Prati C. Paradoxical effects of anti-TNF-α agents in inflammatory diseases. Expert Rev Clin Immunol  2014;10:159-69.

36. Yazganoğlu KD, Tambay E, Mete O, Ozkaya E. Interstitial granu-lomatous drug reaction due to thalidomide. J Eur Acad Dermatol Venereol 2009;23:490-3.

Presented at the 88th SIDeMaST National Congress.Conflicts of interest.—The authors certify that there is no conflict

of interest with any financial organization regarding the material dis-the material dis-cussed in the manuscript.

matous diseases of the skin and their associated systemic diseases: an evidence-based update to important clinical questions. Am J Clin Dermatol 2010;11:171-81.

27. Dahl MV Granuloma annulare: long-term follow-up. Arch Derma-tol 2007;143:946-7.

28. Saripalli YV, Gaspari AA. Focus on: biologics that affect thera-peutic agents in dermatology. J Drugs Dermatol 2005;4:233-45.

29. Deng A, Harvey V, Sina B, Strobel D, Badros A, Junkins-Hopkins JM et al. Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alpha inhibitors. Arch Dermatol 2006;142:198-202.

30. Klausner JD, Freedman VH, Kaplan G. Thalidomide as an Anti-TNF-a Inhibitor: Implications for Clinical Use Clin Immunol and Immunopathol 1996;81:219-23.

31. Tomasini C, Pippione M. Interstitial granulomatous dermatitis with plaques. J Am Acad Dermatol 2002;46:892-9.

32. Gordon K, Miteva M, Torchia D, Romanelli P. Allopurinol-in-duced palisaded neutrophilic and granulomatous dermatitis. Cutan Ocul Toxicol 2012;31:338-40.

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