Granulomatous drug reactions from targeted therapeutics

Main Article Content

Emily E Dando, MD Misha Rosenbach, MD Joseph C English III, MD


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: <>. Date accessed: 15 july 2020. doi:
Review Articles


1. Dodiuk-Gad RP, Shear NH. Granulomatous Drug Eruptions. Dermatol Clin. 2015;33(3):525-539.
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.
38. Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225-1231.
39. Park JJ, Hawryluk EB, Tahan SR, Flaherty K, Kim CC. Cutaneous granulomatous eruption and successful response to potent topical steroids in patients undergoing targeted BRAF inhibitor treatment for metastatic melanoma. JAMA Dermatol. 2014;150(3):307-311.
40. Leal L, Agut-Busquet E, Romani J, et al. Cutaneous granulomatous panniculitis and sarcoidal granulomatous papular eruption in a patient with metastatic melanoma treated with a BRAF inhibitor. J Dermatol. 2016;43(6):715-716.
41. Jansen YJ, Janssens P, Hoorens A, et al. Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated with dabrafenib and trametinib. Melanoma Res. 2015;25(6):550-554.
42. Hui Ong EL, Sinha R, Jmor S, Fearfield L. BRAF Inhibitor-Associated Granulomatous Dermatitis: A Report of 3 Cases. Am J Dermatopathol. 2019;41(3):214-217.
43. Adam A, Thomas L, Bories N, et al. Sarcoidosis associated with vemurafenib. Br J Dermatol. 2013;169(1):206-208.
44. Lheure C, Kramkimel N, Franck N, et al. Sarcoidosis in Patients Treated with Vemurafenib for Metastatic Melanoma: A Paradoxical Autoimmune Activation. Dermatology. 2015;231(4):378-384.
45. Green JS, Norris DA, Wisell J. Novel cutaneous effects of combination chemotherapy with BRAF and MEK inhibitors: a report of two cases. Br J Dermatol. 2013;169(1):172-176.
46. Dimitriou F, Frauchiger AL, Urosevic-Maiwald M, et al. Sarcoid-like reactions in patients receiving modern melanoma treatment. Melanoma Res. 2018;28(3):230-236.
47. Winkler JK, Buder-Bakhaya K, Ellert E, et al. Acute heart failure as a result of granulomatous myocarditis: case report on a patient with metastatic melanoma treated with dabrafenib and trametinib. J Eur Acad Dermatol Venereol. 2018;32(1):e31-e32.
48. Giet G, Lebas E, Rorive A, Arrese JE, Nikkels AF. Granulomatous Reactions from Tattoos Following BRAF Inhibitor Therapy. Case Rep Dermatol. 2019;11(1):101-107.
49. Garrido MC, Gutierrez C, Riveiro-Falkenbach E, Ortiz P, Rodriguez-Peralto JL. BRAF Inhibitor-Induced Antitumoral Granulomatous Dermatitis Eruption in Advanced Melanoma. Am J Dermatopathol. 2015;37(10):795-798.
50. Iafolla MA, Ramsay J, Wismer J, McWhirter E. Cobimetinib- and vemurafenib-induced granulomatous dermatitis and erythema induratum: A case report. SAGE Open Med Case Rep. 2019;7:2050313X19847358.
51. Spengler EK, Kleiner DE, Fontana RJ. Vemurafenib-induced granulomatous hepatitis. Hepatology. 2017;65(2):745-748.
52. Eser Öztürk H, Süllü Y. Sarcoid-like Granulomatous Intraocular Inflammation Caused by Vemurafenib Treatment for Metastatic Melanoma. Turk J Ophthalmol. 2020;50(1):50-52.
53. Huynh S, Lheure C, Franck N, et al. Induced sarcoid-like reactions in patients with metastatic melanoma treated with dabrafenib and trametinib: a monocentric retrospective study. Melanoma Res. 2019.
54. Chen L, Hsi AC, Kothari A, Dehner LP, Hayashi RJ, Coughlin CC. Granulomatous dermatitis secondary to vemurafenib in a child with Langerhans cell histiocytosis. Pediatr Dermatol. 2018;35(6):e402-e403.
55. Korman AM, Nisar MS, Somach SC. Subclinical granulomas in benign skin lesions heralding the onset of. JAAD Case Rep. 2018;4(7):722-724.
56. Lee SB, Weide B, Ugurel S, Mössner R, Enk A, Hassel JC. Vemurafenib-induced granuloma annulare. J Dtsch Dermatol Ges. 2016;14(3):305-308.
57. Carlos G, Anforth R, Chou S, Fernandez-Peñas P. Dabrafenib-associated necrobiotic granulomatous reaction. Australas J Dermatol. 2014;55(4):306-308.
58. Zimmer L, Livingstone E, Hillen U, Dömkes S, Becker A, Schadendorf D. Panniculitis with arthralgia in patients with melanoma treated with selective BRAF inhibitors and its management. Arch Dermatol. 2012;148(3):357-361.
59. Ramani NS, Curry JL, Kapil J, et al. Panniculitis With Necrotizing Granulomata in a Patient on BRAF Inhibitor (Dabrafenib) Therapy for Metastatic Melanoma. Am J Dermatopathol. 2015;37(8):e96-99.
60. Martínez-Morán C, Nájera L, Ruiz-Casado AI, et al. Interstitial granulomatous drug reaction to sorafenib. Arch Dermatol. 2011;147(9):1118-1119.
61. Aria AB, Chen L, Huen AO. A case report of bosutinib-induced interstitial granulomatous drug reaction in a patient with chronic myelogenous leukemia: a case report. SAGE Open Med Case Rep. 2018;6:2050313X18795075.
62. Martín G, Cañueto J, Santos-Briz A, Alonso G, Unamuno PD, Cruz JJ. Interstitial granulomatous dermatitis with arthritis associated with trastuzumab. J Eur Acad Dermatol Venereol. 2010;24(4):493-494.
63. von Euw E, Chodon T, Attar N, et al. CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. J Transl Med. 2009;7:35.
64. Cornejo CM, Haun P, English J, Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions. J Am Acad Dermatol. 2019;81(5):1165-1175.
65. Chorti E, Kanaki T, Zimmer L, et al. Drug-induced sarcoidosis-like reaction in adjuvant immunotherapy: Increased rate and mimicker of metastasis. Eur J Cancer. 2020;131:18-26.
66. Friedman BE, English JC. Drug-induced sarcoidosis in a patient treated with an interleukin-1 receptor antagonist for hidradenitis suppurativa. JAAD Case Rep. 2018;4(6):543-545.
67. Sacre K, Pasqualoni E, Descamps V, Choudat L, Debray MP, Papo T. Sarcoid-like granulomatosis in a patient treated by interleukin-1 receptor antagonist for TNF-receptor-associated periodic syndrome. Rheumatology (Oxford). 2013;52(7):1338-1340.
68. Regula CG, Hennessy J, Clarke LE, et al. Interstitial granulomatous drug reaction to anakinra. J Am Acad Dermatol. 2008;59(2 Suppl 1):S25-27.
69. Michailidou D, Voulgarelis M, Pikazis D. Exacerbation of interstitial granulomatous dermatitis with arthritis by anakinra in a patient with diffuse large B-cell lymphoma. Clin Exp Rheumatol. 2014;32(2):259-261.
70. Sharp M, Donnelly SC, Moller DR. Tocilizumab in sarcoidosis patients failing steroid sparing therapies and anti-TNF agents. Respir Med X. 2019;1.
71. Katsuda K, Arase N, Nakagawa Y, Tanemura A, Fujimoto M. Case of granuloma annulare after using tocilizumab. J Dermatol. 2020;47(4):e117-e119.
72. Nutz A, Pernet C, Combe B, Cohen JD. Sarcoidosis induced by tocilizumab: a paradoxical event? J Rheumatol. 2013;40(10):1773-1774.
73. Shono Y, Kamata M, Takeoka S, et al. Cutaneous sarcoidosis in a patient with rheumatoid arthritis receiving tocilizumab. J Dermatol. 2018;45(8):e217-e218.
74. Del Giorno R, Iodice A, Mangas C, Gabutti L. New-onset cutaneous sarcoidosis under tocilizumab treatment for giant cell arteritis: a quasi-paradoxical adverse drug reaction. Case report and literature review. Ther Adv Musculoskelet Dis. 2019;11:1759720X19841796.
75. Pelechas E, Papoudou-Bai A, Voulgari PV, Drosos AA. Granuloma annulare development in a patient with rheumatoid arthritis treated with tocilizumab: case-based review. Rheumatol Int. 2019;39(2):353-357.
76. Talotta R, Atzeni F, Batticciotto A, Ditto MC, Gerardi MC, Sarzi-Puttini P. Accelerated subcutaneous nodulosis in patients with rheumatoid arthritis treated with tocilizumab: a case series. J Med Case Rep. 2018;12(1):154.
77. Kobak S, Semiz H. Ustekinumab-induced sarcoidosis in a patient with psoriatic arthritis. Curr Drug Saf. 2020.
78. Powell JB, Matthews P, Rattehalli R, et al. Acute systemic sarcoidosis complicating ustekinumab therapy for chronic plaque psoriasis. Br J Dermatol. 2015;172(3):834-836.
79. Gad MM, Bazarbashi N, Kaur M, Gupta A. Sarcoid- like Phenomenon - ustekinumab induced granulomatous reaction mimicking diffuse metastatic disease: a case report and review of the literature. J Med Case Rep. 2019;13(1):257.
80. Judson MA, Baughman RP, Costabel U, et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J. 2014;44(5):1296-1307.
81. Bonomo L, Ghoneim S, Levitt J. A Case of Granuloma Annulare Associated with Secukinumab Use. Case Rep Dermatol Med. 2017;2017:5918708.
82. Clark ML, Tobin CA, Sutton A, Missall TA. Granuloma Annulare in the Setting of Secukinumab. Case Rep Dermatol Med. 2018;2018:5175319.
83. Hornick N, Wang A, Lim Y, et al. Development or worsening of sarcoidosis associated with IL-17 blockade for psoriasis. J Eur Acad Dermatol Venereol. 2020.
84. Wang A, Hornick N, Lim Y, et al. IL-17 blockade downregulates NOD2 in skin and may promote paradoxical sarcoidosis. J Eur Acad Dermatol Venereol. 2020.
85. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61(12):1693-1700.
86. Quaglino P, Marenco F, Osella-Abate S, et al. Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann Oncol. 2010;21(2):409-414.
87. Pan EY, Merl MY, Lin K. The impact of corticosteroid use during anti-PD1 treatment. J Oncol Pharm Pract. 2019:1078155219872786.
88. Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev. 1986;13(3):147-156.
89. Kurata A, Terado Y, Schulz A, Fujioka Y, Franke FE. Inflammatory cells in the formation of tumor-related sarcoid reactions. Hum Pathol. 2005;36(5):546-554.
90. Tsunoda K, Onodera H, Akasaka T. Case of malignant melanoma associated with a sarcoid reaction. J Dermatol. 2011;38(9):939-942.
91. Soukup T, Dosedel M, Nekvindova J, et al. The plausible association of MTHFR and ADORA2A polymorphisms with nodules in rheumatoid arthritis patients treated with methotrexate. Pharmacogenet Genomics. 2017;27(2):43-50.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.