Granulomatous drug reactions from targeted therapeutics
Main Article Content
Abstract
Granulomatous drug reactions have been associated with many medications, including targeted therapeutics such as biologics and small molecule inhibitors. The four main clinicopathologic reaction patterns are drug-induced sarcoidosis-like reaction, reactive granulomatous dermatitis, granuloma annulare, and accelerated rheumatoid nodulosis. These reactions often develop months after exposure to the causative medication and clinically can mimic other granulomatous diseases or metastatic cancer, which may be differentiated with biopsy, tissue culture, and radiographic imaging. Granulomatous inflammation may be limited to the skin, where early recognition helps to facilitate diagnosis. Cutaneous manifestations vary by reaction pattern, ranging from erythema nodosum-like lesions to painful rheumatoid nodules to annular indurated plaques. Systemic granulomatous inflammation is typically only observed in sarcoidosis-like reaction or accelerated rheumatoid nodulosis and most often involves the lungs or lymph nodes. Targeted therapeutics implicated in granulomatous drug reactions are TNFα inhibitors, BRAF and MEK inhibitors, immune checkpoint inhibitors and, to a lesser extent, other cytokine modulators. TNFα inhibitors, in particular, are among the most common drugs in any class associated with the four primary granulomatous drug eruptions. We review the current literature on granulomatous reactions to these agents, including proposed mechanisms and the range of clinical manifestations. Management may include drug discontinuation, topical therapy, or systemic immunosuppression depending on the severity of the granulomatous drug reaction. In the setting of malignancy, granulomatous inflammation does not appear to be of prognostic value, although more studies are needed.
Article Details
How to Cite
DANDO, Emily E; ROSENBACH, Misha; ENGLISH III, Joseph C.
Granulomatous drug reactions from targeted therapeutics.
Medical Research Archives, [S.l.], v. 8, n. 6, june 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2138>. Date accessed: 24 apr. 2024.
doi: https://doi.org/10.18103/mra.v8i6.2138.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Rosenbach M, English JC. Reactive Granulomatous Dermatitis: A Review of Palisaded Neutrophilic and Granulomatous Dermatitis, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, and a Proposed Reclassification. Dermatol Clin. 2015;33(3):373-387.
3. Mater S, Lee JJ, Jedrych J, Rosenbach M, English JC. Topiramate-induced reactive granulomatous dermatitis. JAAD Case Rep. 2019;5(6):501-503.
4. Dai C, Shih S, Ansari A, Kwak Y, Sami N. Biologic Therapy in the Treatment of Cutaneous Sarcoidosis: A Literature Review. Am J Clin Dermatol. 2019;20(3):409-422.
5. Chen A, Truong AK, Worswick S. The role of biologics in the treatment of chronic granuloma annulare. Int J Dermatol. 2019;58(5):622-626.
6. Zeichner JA, Stern DW, Lebwohl M. Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol. 2006;54(3 Suppl 2):S120-121.
7. Suárez-Amor O, Pérez-Bustillo A, Ruiz-González I, Rodríguez-Prieto MA. Necrobiosis lipoidica therapy with biologicals: an ulcerated case responding to etanercept and a review of the literature. Dermatology. 2010;221(2):117-121.
8. Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J. Up regulation of the production of tumour necrosis factor alpha and interferon gamma by T cells in ankylosing spondylitis during treatment with etanercept. Ann Rheum Dis. 2003;62(6):561-564.
9. Crommelin H, Vorselaars A, van der Vis J, Deneer V, van Moorsel CHM. Pharmacogenetics of antitumor necrosis factor therapy in severe sarcoidosis. Curr Opin Pulm Med. 2020;26(3):267-276.
10. Wijnen PA, Cremers JP, Nelemans PJ, et al. Association of the TNF-α G-308A polymorphism with TNF-inhibitor response in sarcoidosis. Eur Respir J. 2014;43(6):1730-1739.
11. Chopra A, Nautiyal A, Kalkanis A, Judson MA. Drug-Induced Sarcoidosis-Like Reactions. Chest. 2018;154(3):664-677.
12. Cohen Aubart F, Lhote R, Amoura A, et al. Drug-induced sarcoidosis: an overview of the WHO pharmacovigilance database. J Intern Med. 2019.
13. Daïen CI, Monnier A, Claudepierre P, et al. Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases. Rheumatology (Oxford). 2009;48(8):883-886.
14. Cathcart S, Sami N, Elewski B. Sarcoidosis as an adverse effect of tumor necrosis factor inhibitors. J Drugs Dermatol. 2012;11(5):609-612.
15. van Ede A, den Broeder A, Wagenaar M, van Riel P, Creemers MC. Etanercept-related extensive pulmonary nodulosis in a patient with rheumatoid arthritis. J Rheumatol. 2007;34(7):1590-1592.
16. Toussirot E, Berthelot JM, Pertuiset E, et al. Pulmonary nodulosis and aseptic granulomatous lung disease occurring in patients with rheumatoid arthritis receiving tumor necrosis factor-alpha-blocking agent: a case series. J Rheumatol. 2009;36(11):2421-2427.
17. Cunnane G, Warnock M, Fye KH, Daikh DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum. 2002;47(4):445-449.
18. Hübscher O, Re R, Iotti R. Pulmonary rheumatoid nodules in an etanercept-treated patient. Arthritis Rheum. 2003;48(7):2077-2078.
19. Watson P, Simler N, Screaton N, Lillicrap M. Management of accelerated pulmonary nodulosis following etanercept therapy in a patient with rheumatoid arthritis. Rheumatology (Oxford). 2008;47(6):928-929.
20. Kekow J, Welte T, Kellner U, Pap T. Development of rheumatoid nodules during anti-tumor necrosis factor alpha therapy with etanercept. Arthritis Rheum. 2002;46(3):843-844.
21. Scrivo R, Spadaro A, Iagnocco A, Valesini G. Appearance of rheumatoid nodules following anti-tumor necrosis factor alpha treatment with adalimumab for rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(1):117.
22. Mackley CL, Ostrov BE, Ioffreda MD. Accelerated cutaneous nodulosis during infliximab therapy in a patient with rheumatoid arthritis. J Clin Rheumatol. 2004;10(6):336-338.
23. Kovács A, Baksay B, Cserenyecz A, Molnár K, Takács M, Szekanecz Z. Occurrence of pulmonary rheumatoid nodules following biological therapies. Clin Rheumatol. 2015;34(9):1639-1642.
24. Voulgari PV, Markatseli TE, Exarchou SA, Zioga A, Drosos AA. Granuloma annulare induced by anti-tumour necrosis factor therapy. Ann Rheum Dis. 2008;67(4):567-570.
25. Deng A, Harvey V, Sina B, et al. Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alpha inhibitors. Arch Dermatol. 2006;142(2):198-202.
26. Hu S, Cohen D, Murphy G, Mody E, Qureshi AA. Interstitial granulomatous dermatitis in a patient with rheumatoid arthritis on etanercept. Cutis. 2008;81(4):336-338.
27. Nguyen TA, Celano NJ, Matiz C. Palisaded Neutrophilic Granulomatous Dermatitis in a Child with Juvenile Idiopathic Arthritis on Etanercept. Pediatr Dermatol. 2016;33(2):e156-157.
28. Martorell-Calatayud A, Balmer N, Cardenas Cardona LF, Teague D. Interstitial granulomatous drug reaction to adalimumab. Am J Dermatopathol. 2010;32(4):408-409.
29. Stephenson SR, Campbell SM, Drew GS, Magro CM. Palisaded neutrophilic and granulomatous dermatitis presenting in a patient with rheumatoid arthritis on adalimumab. J Cutan Pathol. 2011;38(8):644-648.
30. Bremner R, Simpson E, White CR, Morrison L, Deodhar A. Palisaded neutrophilic and granulomatous dermatitis: an unusual cutaneous manifestation of immune-mediated disorders. Semin Arthritis Rheum. 2004;34(3):610-616.
31. Levine SD, Robinson M, Honda K, Nedorost S. Interstitial granulomatous dermatitis in a patient with rheumatoid arthritis on etanercept. Cutis. 2009;83(1):50.
32. Burns AM, Green PJ, Pasternak S. Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas resolving with adalimumab. J Cutan Pathol. 2012;39(2):289-293.
33. Jung JH, Kim JH, Song GG. Adalimumab-induced pulmonary sarcoidosis not progressing upon treatment with etanercept. Z Rheumatol. 2017;76(4):372-374.
34. Wallis RS, Ehlers S. Tumor necrosis factor and granuloma biology: explaining the differential infection risk of etanercept and infliximab. Semin Arthritis Rheum. 2005;34(5 Suppl1):34-38.
35. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2001;121(5):1088-1094.
36. Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest. 2003;124(1):177-185.
37. Wilmott JS, Haydu LE, Menzies AM, et al. Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment. J Immunol. 2014;192(5):2505-2513.
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