To view the tables for this article, please download the pdf version.
Several biologic therapies have been FDA approved for the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis and other inflammatory diseases. These therapies currently belong to 1 of 2 categories: tumor necrosis factor (TNF) inhibitors, such as infliximab (Remicade), adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi) and certolizumab pegol (Cimzia) or the anti-interleukin (IL)-12/23 monoclonal antibody ustekinumab (Stelara). These therapies typically are effective and well-tolerated in the long-term, with the most common adverse effects being various types of infection, common or opportunistic.1
This 2-part review describes multiple, rare side effects with these biologic agents as documented in the literature. We have organized these adverse effects into 6 categories: inflammatory skin disease, atypical infectious events, blood disorders, connective tissue disease, neurologic events and cardiac/metabolic abnormalities (Table 1). The first 2 of these categories are presented in this article. Watch for Part 2 in the December issue.
Cutaneous Reactions And Inflammatory Skin Disease
Several different inflammatory skin diseases may be adverse events to biologic treatment. These events occur in patients whose underlying disease may involve the skin, joints/ligaments or gut (Table 2).
Cutaneous Drug Reactions
Hypersensitivity reactions have been reported for patients receiving TNF-alpha (TNF-α) inhibitors. One study of hypersensitivity reactions to TNF-α inhibitors found urticaria and angioedema in patients taking infliximab, etanercept and adalimumab.2 All patients receiving infliximab and some of the patients on etanercept had positive skin tests following intradermal injection with the respective drug. Infliximab is the most common cause of urticarial reactions in rheumatoid arthritis (RA) patients, with an estimated frequency of 4.2% of infusions.3,4 However, there have been individual cases of urticaria and/or angioedema in both RA and Crohn’s disease patients taking adalimumab and etanercept.5-7 Presentations included non-pitting edema of the extremities, periorbital swelling and facial erythema that cleared after the anti-TNF-α therapy was discontinued.
Sarcoidosis
Sarcoidosis is a granulomatous disease that may affect multiple organs, and for which TNF-α inhibitors are sometimes used as treatment.8 Rarely, however, certain individuals have developed sarcoidosis as an adverse event to anti-TNF-α therapy; this phenomenon has been documented in more than 30 case reports.9,10 These cases usually are associated with patients whose underlying disease is rheumatologic in nature, with sarcoidosis that affects multiple organs.
Specifically, sarcoidosis with uveitis as a complication to anti-TNF-α therapy has been documented in 6 cases.11 Sarcoid-like granulomatosis, most commonly with cutaneous and pulmonary manifestations, has been estimated to have an incidence of 0.04% of treated patients.12
Eczematous Reactions
An eczematous reaction to biologic therapy rarely occurs. Among prospective studies of patients with either Crohn’s disease or RA treated with TNF-α inhibitors, rates of reported eczematous reactions range from 4.4%-20.6%.13-15 However, another investigation found no statistically significant difference between the rate of eczema in rheumatoid patients receiving anti-TNF-α therapy and those who were not, suggesting this class of patients inherently may be at an elevated risk for this type of skin reaction, regardless of therapy. Eczematous reactions have not been reported to occur with TNF-α inhibitor therapy for dermatologic patients. In contrast, there has been a reported case of an eczematous drug eruption in a psoriasis patient following treatment with ustekinumab, the approved anti-IL-12/23 monoclonal antibody.16
Interface Dermatitis And Lichen Planus
Drug eruptions consistent with interface dermatitis have been recorded in patients receiving TNF-α inhibitors, but not anti-IL-12/23 antibodies. Specifically, cases of lichenoid dermatitis and erythema multiforme have been reported in RA and Crohn’s disease patients.17-19 There have also been 2 reported cases of interface dermatitis in psoriatic arthritis patients.20 Lichen planus specifically has been documented in several psoriasis patients between 2 and 16 months after beginning anti-TNF-α therapy.21,22 Clinical presentation includes typical highly pruritic lichen planus-like papules and plaques on the trunk and extremities, as well as lesions affecting the oral mucosa. Although the most frequently cited drugs to cause interface dermatitis are infliximab and etanercept, there has also been 1 reported case of lichen planus in a Crohn’s disease patient receiving certolizumab pegol.23
Neutrophilic Eccrine Hidradenitis
Neutrophilic eccrine hidradenitis and drug-induced Sweet’s syndrome have been reported in 2 cases as adverse reactions to TNF-α therapy, both of which involved adalimumab treatment.17,24 The patients’ underlying diagnoses were Crohn’s disease and refractory polychondritis. The latter responded to a switch to etanercept therapy. Lesions were reported as papules, nodules and pustules affecting all areas of the body, including mucosal surfaces.
Porokeratosis
There have been 3 documented cases of drug-induced porokeratosis in patients taking certolizumab pegol, adalimumab and etanercept.25-27 Lesions were reported as pruritic papules (in 1 case, over 100 total lesions) affecting the trunk and extremities, similar to disseminated superficial porokeratosis.
Eosinophilic Cellulitis
Eosinophilic cellulitis as an injection site reaction has been documented in 3 patients receiving etanercept, adalimumab or infliximab, all for the treatment of RA.28-30 These cases involved a pruritic dermatitis on the trunk with associated rigor, fatigue and malaise. Mild peripheral eosinophilia may be detected.
Alopecia Areata
Alopecia areata and alopecia universalis have been documented as adverse effects of both anti-TNF-α drugs and anti-IL-12/23 antibodies. The underlying diseases for patients receiving TNF-α inhibitors who experienced acute alopecia areata include psoriasis, psoriatic arthritis, RA, ankylosing spondylitis and Crohn’s disease.31-39
Interestingly, the TNF-α inhibitors have been suggested as treatment for alopecia areata, although 1 study demonstrated this approach as ineffective, and even noted an enrolled subject displaying worsening of alopecia while receiving etanercept.40 Finally, alopecia areata was documented as an adverse effect to the anti-IL-12/23 antibody ustekinumab in 2 patients being treated for psoriasis.41,42
Atypical Infectious Events
Table 3 lists the atypical infectious events related to biologics. Here, we will discuss each of these atypical infectious events in more detail.
Pustular Folliculitis And Staphylococcus
Aureus Infections
Pustular folliculitis with methicillin-sensitive Staphylococcus aureus infection has been observed in several patients treated with anti-TNF-α therapy for Crohn’s disease and RA.17,18 Other cases have also reported S aureus cutaneous abscesses associated with patients taking TNF-α inhibitors.43,44
The authors of this review have noted that numerous patients receiving both adalimumab and etanercept experienced folliculitis of the trunk and extremities that responds to short courses of oral antibiotics such as doxycycline. Clinical presentation may involve erythematous papules and nodules (some purulent) on the trunk and extremities.
Reactivation Of Viral Hepatitis
The reactivation of hepatitis B virus (HBV) is well documented in the context of anti-TNF-α therapy. Infliximab is the most often reported offending agent.45 Patients treated with TNF-α inhibitors for rheumatic diseases or psoriasis and who are considered asymptomatic HBV carriers are at increased risk of HBV reactivation.46-48 A retrospective study demonstrated that hepatitis B surface antigen (HBsAg)-positive carriers appear to have a higher risk of HBV reactivation than HBsAg-negative/anti-HBc-positive carriers (40% compared to 5%).49
Due to the increased risk of reactivation of HBV in patients receiving TNF-α inhibitor therapy, it is recommended that all patients be screened for HBsAg and anti-HB C prior to initiating treatment so that appropriate measures, such as beginning antiviral therapy, may be taken.50 Additionally, it is recommended that serum aminotransferase levels be monitored during therapy in patients with chronic hepatitis B to detect hepatotoxicity.
Along with HBV reactivation during TNF-α inhibitor therapy, there is at least 1 case documenting hepatitis B reactivation during therapy with ustekinumab.51 The patient was HBsAg-negative, anti-HBc-positive and anti-HBs-positive (17 mIU mL−1) before the initiation of treatment with ustekinumab. However, approximately 16 months later the patient’s HBV status was rechecked after exhibiting elevated alanine aminotransferase levels. HBsAg and hepatitis B envelope antigen were positively detected, with the HBV DNA load measured at 140,000 IUmL−1. While this conversion to positivity might not have been related to ustekinumab therapy, this case exemplifies the need for fastidious vigilance when treating all potential carriers of HBV.
Herpes Zoster
Prospective studies differ on whether there is a statistically significant increase in the risk of herpes zoster in patients receiving biologic therapy.52,53 Reported cases involve patients receiving either TNF-α inhibitors or ustekinumab for psoriasis, psoriatic arthritis or RA.54-56 The authors of this review have witnessed multiple cases of localized herpes zoster in patients newly started on TNF-α inhibitors.
Human Papilloma Virus And
Molluscum Contagiosum
Several case reports have documented an association between TNF-α inhibitors and the recurrence of human papilloma virus and/or molluscum contagiosum. The patients were being treated for psoriasis, psoriatic arthritis or Crohn’s disease when they developed typical lesions on the face, lower abdomen, genital and perianal areas.57-59 In at least 1 case, the lesion was consistent with penile intraepithelial neoplasia, a potential penile cancer precursor.60
Tinea Versicolor
There have been 2 reported cases of tinea versicolor in response to anti-TNF-α therapy. In at least 1 case, the patient, who was receiving etanercept for plaque psoriasis, developed tinea versicolor again on rechallenge.61,62
Conclusion
TNF inhibitors and ustekinumab overwhelmingly demonstrate a high benefit to risk ratio when used for the treatment of various diseases. However, the large number of treated patients worldwide has demonstrated rare instances of a variety of adverse effects. This review enumerates some adverse effects that are either inflammatory or infectious in nature. Of course, the ability to directly ascribe any rare adverse event to a given drug is tenuous. Regardless, in most instances, these events may be managed by either add-on care or switching to another therapy.
Importantly, some adverse events resolve with appropriate therapy and the same biologic may be continued. Clinicians should monitor for atypical reactions to biologic therapies and “alter course” accordingly.
Ms. Townsend is with The University of Connecticut Health Center in Farmington, CT.
Dr. Strober is with the department of dermatology at the University of Connecticut Health Center in Farmington, CT.
Disclosures: Dr. Strober is with the speakers bureau for AbbVie; consultant for AbbVie, Amgen, Celgene, Novartis, Merck, Lilly, Pfizer, Janssen and Maruho; investigator for AbbVie, Amgen, Novartis, Lilly and Janssen. Ms. Townsend has no conflicts of interest to report.
References
1. Rustin MH. Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data. Br J Dermatol. 2012;167(suppl 3):3-11.
2. Puxeddu I, Giori L, Rocchi V, et al. Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann Allergy Asthma Immunol. 2012;108(2):123-124.
3. Wasserman MJ, Weber DA, Guthrie JA, Bykerk VP, Lee P, Keystone EC. Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. J Rheumatol. 2004;31(10):1912-1917.
4. Lequerré T, Vittecoq O, Klemmer N, et al. Management of infusion reactions to infliximab in patients with rheumatoid arthritis or spondyloarthritis: experience from an immunotherapy unit of rheumatology. J Rheumatol. 2006;33(7):1307-1314.
5. Nikas SN, Voulgari PV, Drosos AA. Urticaria and angiedema-like skin reactions in a patient treated with adalimumab. Clin Rheumatol. 2007;26(5):787-788.
6. Adamiak T, Stephens M, Werlin SL. Angioedema occurring in pediatric patients with Crohn disease treated with adalimumab. J Pediatr Gastroenterol Nutr. 2010;51(2):223-225.
7. Sendur OF, Turan Y, Berkit IK, Tastaban E. Angio-oedema in a patient treated with etanercept for rheumatoid arthritis. Basic Clin Pharmacol Toxicol. 2009;104(6):488-490.
8. Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet. 2003;361(9363):1111-1118.
9. Cathcart S, Sami N, Elewski B. Sarcoidosis as an adverse effect of tumor necrosis factor inhibitors.
J Drugs Dermatol. 2012;11(5):609-612.
10. Lamrock E, Brown P. Development of cutaneous sarcoidosis during treatment with tumour necrosis alpha factor antagonists. Australas J Dermatol. 2012;53(4):e87-e90.
11. Fonollosa A, Artaraz J, Les I, et al. Sarcoid intermediate uveitis following etanercept treatment: a case report and review of the literature. Occul Immunol Inflamm. 2012;20(1):44-48.
12. 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.
13. Lee HH, Song IH, Friedrich M, et al. Cutaneous side-effects in patients with rheumatic diseases during application of tumour necrosis factor-alpha antagonists. Br J Dermatol. 2007;156(3):486-491.
14. Flendrie M, Vissers WH, Creemers MC, de Jong EM, van de Kerkhof PC, van Riel PL. Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2005;7(3):R666-R676.
15. Esmailzadeh A, Yousefi P, Farhi D, et al. Predictive factors of eczema-like eruptions among patients without cutaneous psoriasis receiving infliximab: a cohort study of 92 patients. Dermatology. 2009;219(3):263-267.
16. Pernet C, Guillot B, Bessis D. Eczematous drug eruption after ustekinumab treatment. Ach Dermatol. 2012;148(8):959-960.
17. Hawryluk EB, Linskey KR, Duncan LM, Nazarian RM. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists. J Cutan Pathol. 2012;39(5):481-492.
18. Laga AC, Vleugels RA, Qureshi AA, Velazquez EF. Hisopatholoical spectrum of psoriasiform skin reactions associated with tumor necrosis factor-α inhibitor therapy. A study of 16 biopsies. Am J Dermatopathol. 2010;32(6):58-73.
19. Vergara G, Silvestre JF, Betlloch I, Vela P, Albares MP, Pascual JC. Cutaneous drug eruption to infliximab: report of 4 cases with an interface dermatitis pattern. Arch Dermatol. 2002;138(9):1258-1259.
20. Garcovich S, Burlando M, Rongioletti F, Garcovich A, Parodi A, Amerio P. Cutaneous drug eruption with an interface dermatitis pattern due to anti-tumour necrosis factor-alpha agents: a relevant class-effect. Acta Derm Venereol. 2010; 90(3):311-312.
21. Fernández-Torres R, Paradela S, Valbuena L, Fonseca E. Infliximab-induced lichen planopilaris. Ann Pharmacother. 2010;44(9):1501-1503.
22. Asarch A, Gottlieb AB, Lee J, et al. Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor alpha antagonists. J Am Acad Dermatol. 2009;61(1):104-111.
23. Mocciaro F, Orlando A, Renna S, Rizzuto MR, Cottone M. Oral lichen planus after certolizumab pegol treatment in a patient with Crohn’s disease. J Crohns Colitis. 2011;5(2):173-174.
24. Keidel S, McColl A, Edmonds S. Sweet’s syndrome after adalimumab therapy for refractory relapsing polychondritis. BMJ Case Rep. 2011. pii: bcr1020114935.
25. Brauer JA, Mandal R, Walters R, Solomon G, Kundu RV, Strober BE. Disseminated superficial porokeratosis. Dermatol Online J. 2010;16(11):20.
26. Guarneri C, Cannavò SP, Lentini M, Polimeni G. Adalimumab-induced disseminated superficial porokeratosis. Ann Pharmacother. 2011;45(2):280-281.
27. Stewart L, Howat A, Coulson I. Disseminated superficial porokeratosis secondary to immunosuppression induced by etanercept for extensive psoriasis. Arch Dermatol. 2010;146(10):1193-1194.
28. Boura P, Sarantopoulos A, Lefaki I, Skendros P, Papadopoulos P. Eosinophilic cellulitis (Wells’ syndrome) as a cutaneous reaction to the administration of adalimumab. Ann Rheum Dis. 2006;65(6):839-840.
29. Winfield H, Lain E, Horn T, Hoskyn J. Eosinophilic cellulitis-like reaction to subcutaneous etanercept injection. Arch Dermatol. 2006;142(2):218-220.
30. Tugnet N, Youssef A, Whallett AJ. Wells’ syndrome (eosinophilic cellulitis) secondary to infliximab. Rheumatology (Oxford). 2012;51(1):195-196.
31. Tosti A, Pazzaglia M, Starace M, Bellavista S, Vincenzi C, Tonelli G. Alopecia areata during treatment with biologic agents. Arch Dermatol. 2006;142(12):1653-1654.
32. Doyle LA, Sperling LC, Baksh S, et al. Psoriatic alopecia/alopecia areata-like reactions secondary to anti-tumor necrosis factor-α therapy: a novel cause of noncicatricial alopecia. Am J Dermatopathol. 2011;33(2):161-166.
33. Garcia Bartels N, Lee HH, Worm M, Burmester GR, Sterry W, Blume-Peytavi U. Development of alopecia areata universalis in a patient receiving adalimumab. Arch Dermatol. 2006;142(12):1654-1655.
34. 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:(8)1012.
35. Nakagomi D, Harada K, Yagasaki A, Kawamura T, Shibagaki N, Shimada S. Psoriasiform eruption associated with alopecia areata during infliximab therapy. Clin Exp Dermatol. 2009;34(8):923-924.
36. Pan Y, Rao NA Alopecia areata during etanercept therapy. Occul Immunol Inflamm. 2009;17(2):127-129.
37. Navarro R, Daudén E, Gallo E, Santiago Sánchez-Mateos D, García-Diez A. Alopecia areata during treatment of psoriasis with adalimumab and leflunomide: a case and review of the literature. Skin Pharmacol Physiol. 2012;25(2):107-110.
38. Pelivani N, Hassan AS, Braathen LR, Hunger RE, Yawalkar N. Alopecia areata universalis elicited during treatment with adalimumab. Dermatology. 2008;216(4):320-323.
39. Chaves Y, Duarte G, Ben-Said B, Tebib J, Berard F, Nicolas JF. Alopecia areata universalis during treatment of rheumatoid arthritis with anti-TNF-alpha antibody (adalimumab). Dermatology. 2008;217(4):380.
40. 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(6):1082-1084.
41. Verros C, Rallis E, Crowe M. Letter: Alopecia areata during ustekinumab administration: Co-existence or an adverse reaction? Dermatol Online J. 2012;18(7):14.
42. Słowi´nska M, Kardynal A, Warszawik O, Czuwara J, Rudnicka L. Alopecia areata developing parallel to improvement of psoriasis during ustekinumab therapy. J Dermatol Case Rep. 2010;4(1):15-17.
43. De Simone C, Murri R, Maiorino A, Venier A, Caldarola G. Management of recurrent cutaneous abscesses during therapy with infliximab. Clin Ther. 2011;33(12):1993-1996.
44. Kroesen S. Widmer AF, Tyndall A, Hasler P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford). 2003;42(5):617-621.
45. Calabrese LH, Zein NN, Vassilopolos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis. 2006;65(8):983-989.
46. Chung SJ, Kim JK, Park MC, Park YB, Lee SK. Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-alpha therapy. J Rheumatol. 2009;36(11):2416-2420.
47. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis. 2003;62(7):686-687.
48. Cho YT, Chen CH, Chiu HY, Tsai TF. Use of anti-tumor necrosis factor-α therapy in hepatitis B virus carriers with psoriasis or psoriatic arthritis: a case series in Taiwan. J Dermatol. 2012;39(3):269-273.
49. Perez-Alvarez R, Díaz-Lagares C, García-Hernández F, et al. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine (Baltimore). 2011;90(6):359-371.
50. Abramson A, Menter A, Perrillo R. Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: a review and recommendations for management. J Am Acad Dermatol. 2012;67(6):1349-1361.
51. Koskinas J, Tampaki M, Doumba PP, Rallis E. Hepatitis B virus reactivation during therapy with ustekinumab for psoriasis in a hepatitis B surface-antigen-negative anti-HBs-positive patient. Br J Dermatol. 2013;168(3):679-680.
52. Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009;301(7):737-744.
53. Winthrop KL, Baddley JW, Chen L, et al. Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster. JAMA. 2013;309(9):887-895.
54. Kinder A, Stephens S, Mortimer N, Sheldon P. Severe herpes zoster after infliximab infusion. Postgrad Med J. 2004;80(939):26.
55. Manzano V, Ruiz P, Torres M, Gomez F. Severe pneumonia by aciclovir-resistant varicella-zoster virus during etanercept therapy. Rheumatology (Oxford). 2010;49(9):1791-1793.
56. Failla V, Nikkels AF. Ustekinumab and herpes zoster. Dermatology. 2011;222(2):119-122.
57. Georgala S, Katoulis AC, Kanelleas A, Befon A, Georgala C. Letter: Human papilloma virus and molluscum contagiosum lesions related to infliximab therapy for psoriasis: a case series. Dermatol Online J. 2012;18(4):9.
58. Antoniou C, Kosmadaki MG, Stratigos AJ, Katsambas AD. Genital HPV lesions and molluscum contagiosum occurring in patients receiving anti-TNF-a therapy. Dermatology. 2008;216(4):364-365.
59. Somasekar A, Alcolado R. Genital condylomata in a patient receiving infliximab for Crohn’s disease. Postgrad Med J. 2004;80(944):358-359.
60. Kreuter A, Meyer MF, Wieland U. Occurrence of penile intraepithelial neoplasia following adalimumab treatment for psoriatic arthritis. Arch Dermatol. 2011;147(8):1001-1002.
61. Levy MS, Polsky D, Davidson A, Strober BE. Tinea versicolor associated with etanercept therapy. J Am Acad Dermatol. 2008;58(5 suppl 1):S99-S100.
62. Hannuksela, M. Cutaneous rash from the use of medicine for rheumatoid arthritis. Duodecim. 2006;122(1):105, 111.
To view the tables for this article, please download the pdf version.
Several biologic therapies have been FDA approved for the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis and other inflammatory diseases. These therapies currently belong to 1 of 2 categories: tumor necrosis factor (TNF) inhibitors, such as infliximab (Remicade), adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi) and certolizumab pegol (Cimzia) or the anti-interleukin (IL)-12/23 monoclonal antibody ustekinumab (Stelara). These therapies typically are effective and well-tolerated in the long-term, with the most common adverse effects being various types of infection, common or opportunistic.1
This 2-part review describes multiple, rare side effects with these biologic agents as documented in the literature. We have organized these adverse effects into 6 categories: inflammatory skin disease, atypical infectious events, blood disorders, connective tissue disease, neurologic events and cardiac/metabolic abnormalities (Table 1). The first 2 of these categories are presented in this article. Watch for Part 2 in the December issue.
Cutaneous Reactions And Inflammatory Skin Disease
Several different inflammatory skin diseases may be adverse events to biologic treatment. These events occur in patients whose underlying disease may involve the skin, joints/ligaments or gut (Table 2).
Cutaneous Drug Reactions
Hypersensitivity reactions have been reported for patients receiving TNF-alpha (TNF-α) inhibitors. One study of hypersensitivity reactions to TNF-α inhibitors found urticaria and angioedema in patients taking infliximab, etanercept and adalimumab.2 All patients receiving infliximab and some of the patients on etanercept had positive skin tests following intradermal injection with the respective drug. Infliximab is the most common cause of urticarial reactions in rheumatoid arthritis (RA) patients, with an estimated frequency of 4.2% of infusions.3,4 However, there have been individual cases of urticaria and/or angioedema in both RA and Crohn’s disease patients taking adalimumab and etanercept.5-7 Presentations included non-pitting edema of the extremities, periorbital swelling and facial erythema that cleared after the anti-TNF-α therapy was discontinued.
Sarcoidosis
Sarcoidosis is a granulomatous disease that may affect multiple organs, and for which TNF-α inhibitors are sometimes used as treatment.8 Rarely, however, certain individuals have developed sarcoidosis as an adverse event to anti-TNF-α therapy; this phenomenon has been documented in more than 30 case reports.9,10 These cases usually are associated with patients whose underlying disease is rheumatologic in nature, with sarcoidosis that affects multiple organs.
Specifically, sarcoidosis with uveitis as a complication to anti-TNF-α therapy has been documented in 6 cases.11 Sarcoid-like granulomatosis, most commonly with cutaneous and pulmonary manifestations, has been estimated to have an incidence of 0.04% of treated patients.12
Eczematous Reactions
An eczematous reaction to biologic therapy rarely occurs. Among prospective studies of patients with either Crohn’s disease or RA treated with TNF-α inhibitors, rates of reported eczematous reactions range from 4.4%-20.6%.13-15 However, another investigation found no statistically significant difference between the rate of eczema in rheumatoid patients receiving anti-TNF-α therapy and those who were not, suggesting this class of patients inherently may be at an elevated risk for this type of skin reaction, regardless of therapy. Eczematous reactions have not been reported to occur with TNF-α inhibitor therapy for dermatologic patients. In contrast, there has been a reported case of an eczematous drug eruption in a psoriasis patient following treatment with ustekinumab, the approved anti-IL-12/23 monoclonal antibody.16
Interface Dermatitis And Lichen Planus
Drug eruptions consistent with interface dermatitis have been recorded in patients receiving TNF-α inhibitors, but not anti-IL-12/23 antibodies. Specifically, cases of lichenoid dermatitis and erythema multiforme have been reported in RA and Crohn’s disease patients.17-19 There have also been 2 reported cases of interface dermatitis in psoriatic arthritis patients.20 Lichen planus specifically has been documented in several psoriasis patients between 2 and 16 months after beginning anti-TNF-α therapy.21,22 Clinical presentation includes typical highly pruritic lichen planus-like papules and plaques on the trunk and extremities, as well as lesions affecting the oral mucosa. Although the most frequently cited drugs to cause interface dermatitis are infliximab and etanercept, there has also been 1 reported case of lichen planus in a Crohn’s disease patient receiving certolizumab pegol.23
Neutrophilic Eccrine Hidradenitis
Neutrophilic eccrine hidradenitis and drug-induced Sweet’s syndrome have been reported in 2 cases as adverse reactions to TNF-α therapy, both of which involved adalimumab treatment.17,24 The patients’ underlying diagnoses were Crohn’s disease and refractory polychondritis. The latter responded to a switch to etanercept therapy. Lesions were reported as papules, nodules and pustules affecting all areas of the body, including mucosal surfaces.
Porokeratosis
There have been 3 documented cases of drug-induced porokeratosis in patients taking certolizumab pegol, adalimumab and etanercept.25-27 Lesions were reported as pruritic papules (in 1 case, over 100 total lesions) affecting the trunk and extremities, similar to disseminated superficial porokeratosis.
Eosinophilic Cellulitis
Eosinophilic cellulitis as an injection site reaction has been documented in 3 patients receiving etanercept, adalimumab or infliximab, all for the treatment of RA.28-30 These cases involved a pruritic dermatitis on the trunk with associated rigor, fatigue and malaise. Mild peripheral eosinophilia may be detected.
Alopecia Areata
Alopecia areata and alopecia universalis have been documented as adverse effects of both anti-TNF-α drugs and anti-IL-12/23 antibodies. The underlying diseases for patients receiving TNF-α inhibitors who experienced acute alopecia areata include psoriasis, psoriatic arthritis, RA, ankylosing spondylitis and Crohn’s disease.31-39
Interestingly, the TNF-α inhibitors have been suggested as treatment for alopecia areata, although 1 study demonstrated this approach as ineffective, and even noted an enrolled subject displaying worsening of alopecia while receiving etanercept.40 Finally, alopecia areata was documented as an adverse effect to the anti-IL-12/23 antibody ustekinumab in 2 patients being treated for psoriasis.41,42
Atypical Infectious Events
Table 3 lists the atypical infectious events related to biologics. Here, we will discuss each of these atypical infectious events in more detail.
Pustular Folliculitis And Staphylococcus
Aureus Infections
Pustular folliculitis with methicillin-sensitive Staphylococcus aureus infection has been observed in several patients treated with anti-TNF-α therapy for Crohn’s disease and RA.17,18 Other cases have also reported S aureus cutaneous abscesses associated with patients taking TNF-α inhibitors.43,44
The authors of this review have noted that numerous patients receiving both adalimumab and etanercept experienced folliculitis of the trunk and extremities that responds to short courses of oral antibiotics such as doxycycline. Clinical presentation may involve erythematous papules and nodules (some purulent) on the trunk and extremities.
Reactivation Of Viral Hepatitis
The reactivation of hepatitis B virus (HBV) is well documented in the context of anti-TNF-α therapy. Infliximab is the most often reported offending agent.45 Patients treated with TNF-α inhibitors for rheumatic diseases or psoriasis and who are considered asymptomatic HBV carriers are at increased risk of HBV reactivation.46-48 A retrospective study demonstrated that hepatitis B surface antigen (HBsAg)-positive carriers appear to have a higher risk of HBV reactivation than HBsAg-negative/anti-HBc-positive carriers (40% compared to 5%).49
Due to the increased risk of reactivation of HBV in patients receiving TNF-α inhibitor therapy, it is recommended that all patients be screened for HBsAg and anti-HB C prior to initiating treatment so that appropriate measures, such as beginning antiviral therapy, may be taken.50 Additionally, it is recommended that serum aminotransferase levels be monitored during therapy in patients with chronic hepatitis B to detect hepatotoxicity.
Along with HBV reactivation during TNF-α inhibitor therapy, there is at least 1 case documenting hepatitis B reactivation during therapy with ustekinumab.51 The patient was HBsAg-negative, anti-HBc-positive and anti-HBs-positive (17 mIU mL−1) before the initiation of treatment with ustekinumab. However, approximately 16 months later the patient’s HBV status was rechecked after exhibiting elevated alanine aminotransferase levels. HBsAg and hepatitis B envelope antigen were positively detected, with the HBV DNA load measured at 140,000 IUmL−1. While this conversion to positivity might not have been related to ustekinumab therapy, this case exemplifies the need for fastidious vigilance when treating all potential carriers of HBV.
Herpes Zoster
Prospective studies differ on whether there is a statistically significant increase in the risk of herpes zoster in patients receiving biologic therapy.52,53 Reported cases involve patients receiving either TNF-α inhibitors or ustekinumab for psoriasis, psoriatic arthritis or RA.54-56 The authors of this review have witnessed multiple cases of localized herpes zoster in patients newly started on TNF-α inhibitors.
Human Papilloma Virus And
Molluscum Contagiosum
Several case reports have documented an association between TNF-α inhibitors and the recurrence of human papilloma virus and/or molluscum contagiosum. The patients were being treated for psoriasis, psoriatic arthritis or Crohn’s disease when they developed typical lesions on the face, lower abdomen, genital and perianal areas.57-59 In at least 1 case, the lesion was consistent with penile intraepithelial neoplasia, a potential penile cancer precursor.60
Tinea Versicolor
There have been 2 reported cases of tinea versicolor in response to anti-TNF-α therapy. In at least 1 case, the patient, who was receiving etanercept for plaque psoriasis, developed tinea versicolor again on rechallenge.61,62
Conclusion
TNF inhibitors and ustekinumab overwhelmingly demonstrate a high benefit to risk ratio when used for the treatment of various diseases. However, the large number of treated patients worldwide has demonstrated rare instances of a variety of adverse effects. This review enumerates some adverse effects that are either inflammatory or infectious in nature. Of course, the ability to directly ascribe any rare adverse event to a given drug is tenuous. Regardless, in most instances, these events may be managed by either add-on care or switching to another therapy.
Importantly, some adverse events resolve with appropriate therapy and the same biologic may be continued. Clinicians should monitor for atypical reactions to biologic therapies and “alter course” accordingly.
Ms. Townsend is with The University of Connecticut Health Center in Farmington, CT.
Dr. Strober is with the department of dermatology at the University of Connecticut Health Center in Farmington, CT.
Disclosures: Dr. Strober is with the speakers bureau for AbbVie; consultant for AbbVie, Amgen, Celgene, Novartis, Merck, Lilly, Pfizer, Janssen and Maruho; investigator for AbbVie, Amgen, Novartis, Lilly and Janssen. Ms. Townsend has no conflicts of interest to report.
References
1. Rustin MH. Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data. Br J Dermatol. 2012;167(suppl 3):3-11.
2. Puxeddu I, Giori L, Rocchi V, et al. Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann Allergy Asthma Immunol. 2012;108(2):123-124.
3. Wasserman MJ, Weber DA, Guthrie JA, Bykerk VP, Lee P, Keystone EC. Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. J Rheumatol. 2004;31(10):1912-1917.
4. Lequerré T, Vittecoq O, Klemmer N, et al. Management of infusion reactions to infliximab in patients with rheumatoid arthritis or spondyloarthritis: experience from an immunotherapy unit of rheumatology. J Rheumatol. 2006;33(7):1307-1314.
5. Nikas SN, Voulgari PV, Drosos AA. Urticaria and angiedema-like skin reactions in a patient treated with adalimumab. Clin Rheumatol. 2007;26(5):787-788.
6. Adamiak T, Stephens M, Werlin SL. Angioedema occurring in pediatric patients with Crohn disease treated with adalimumab. J Pediatr Gastroenterol Nutr. 2010;51(2):223-225.
7. Sendur OF, Turan Y, Berkit IK, Tastaban E. Angio-oedema in a patient treated with etanercept for rheumatoid arthritis. Basic Clin Pharmacol Toxicol. 2009;104(6):488-490.
8. Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet. 2003;361(9363):1111-1118.
9. Cathcart S, Sami N, Elewski B. Sarcoidosis as an adverse effect of tumor necrosis factor inhibitors.
J Drugs Dermatol. 2012;11(5):609-612.
10. Lamrock E, Brown P. Development of cutaneous sarcoidosis during treatment with tumour necrosis alpha factor antagonists. Australas J Dermatol. 2012;53(4):e87-e90.
11. Fonollosa A, Artaraz J, Les I, et al. Sarcoid intermediate uveitis following etanercept treatment: a case report and review of the literature. Occul Immunol Inflamm. 2012;20(1):44-48.
12. 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.
13. Lee HH, Song IH, Friedrich M, et al. Cutaneous side-effects in patients with rheumatic diseases during application of tumour necrosis factor-alpha antagonists. Br J Dermatol. 2007;156(3):486-491.
14. Flendrie M, Vissers WH, Creemers MC, de Jong EM, van de Kerkhof PC, van Riel PL. Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2005;7(3):R666-R676.
15. Esmailzadeh A, Yousefi P, Farhi D, et al. Predictive factors of eczema-like eruptions among patients without cutaneous psoriasis receiving infliximab: a cohort study of 92 patients. Dermatology. 2009;219(3):263-267.
16. Pernet C, Guillot B, Bessis D. Eczematous drug eruption after ustekinumab treatment. Ach Dermatol. 2012;148(8):959-960.
17. Hawryluk EB, Linskey KR, Duncan LM, Nazarian RM. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists. J Cutan Pathol. 2012;39(5):481-492.
18. Laga AC, Vleugels RA, Qureshi AA, Velazquez EF. Hisopatholoical spectrum of psoriasiform skin reactions associated with tumor necrosis factor-α inhibitor therapy. A study of 16 biopsies. Am J Dermatopathol. 2010;32(6):58-73.
19. Vergara G, Silvestre JF, Betlloch I, Vela P, Albares MP, Pascual JC. Cutaneous drug eruption to infliximab: report of 4 cases with an interface dermatitis pattern. Arch Dermatol. 2002;138(9):1258-1259.
20. Garcovich S, Burlando M, Rongioletti F, Garcovich A, Parodi A, Amerio P. Cutaneous drug eruption with an interface dermatitis pattern due to anti-tumour necrosis factor-alpha agents: a relevant class-effect. Acta Derm Venereol. 2010; 90(3):311-312.
21. Fernández-Torres R, Paradela S, Valbuena L, Fonseca E. Infliximab-induced lichen planopilaris. Ann Pharmacother. 2010;44(9):1501-1503.
22. Asarch A, Gottlieb AB, Lee J, et al. Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor alpha antagonists. J Am Acad Dermatol. 2009;61(1):104-111.
23. Mocciaro F, Orlando A, Renna S, Rizzuto MR, Cottone M. Oral lichen planus after certolizumab pegol treatment in a patient with Crohn’s disease. J Crohns Colitis. 2011;5(2):173-174.
24. Keidel S, McColl A, Edmonds S. Sweet’s syndrome after adalimumab therapy for refractory relapsing polychondritis. BMJ Case Rep. 2011. pii: bcr1020114935.
25. Brauer JA, Mandal R, Walters R, Solomon G, Kundu RV, Strober BE. Disseminated superficial porokeratosis. Dermatol Online J. 2010;16(11):20.
26. Guarneri C, Cannavò SP, Lentini M, Polimeni G. Adalimumab-induced disseminated superficial porokeratosis. Ann Pharmacother. 2011;45(2):280-281.
27. Stewart L, Howat A, Coulson I. Disseminated superficial porokeratosis secondary to immunosuppression induced by etanercept for extensive psoriasis. Arch Dermatol. 2010;146(10):1193-1194.
28. Boura P, Sarantopoulos A, Lefaki I, Skendros P, Papadopoulos P. Eosinophilic cellulitis (Wells’ syndrome) as a cutaneous reaction to the administration of adalimumab. Ann Rheum Dis. 2006;65(6):839-840.
29. Winfield H, Lain E, Horn T, Hoskyn J. Eosinophilic cellulitis-like reaction to subcutaneous etanercept injection. Arch Dermatol. 2006;142(2):218-220.
30. Tugnet N, Youssef A, Whallett AJ. Wells’ syndrome (eosinophilic cellulitis) secondary to infliximab. Rheumatology (Oxford). 2012;51(1):195-196.
31. Tosti A, Pazzaglia M, Starace M, Bellavista S, Vincenzi C, Tonelli G. Alopecia areata during treatment with biologic agents. Arch Dermatol. 2006;142(12):1653-1654.
32. Doyle LA, Sperling LC, Baksh S, et al. Psoriatic alopecia/alopecia areata-like reactions secondary to anti-tumor necrosis factor-α therapy: a novel cause of noncicatricial alopecia. Am J Dermatopathol. 2011;33(2):161-166.
33. Garcia Bartels N, Lee HH, Worm M, Burmester GR, Sterry W, Blume-Peytavi U. Development of alopecia areata universalis in a patient receiving adalimumab. Arch Dermatol. 2006;142(12):1654-1655.
34. 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:(8)1012.
35. Nakagomi D, Harada K, Yagasaki A, Kawamura T, Shibagaki N, Shimada S. Psoriasiform eruption associated with alopecia areata during infliximab therapy. Clin Exp Dermatol. 2009;34(8):923-924.
36. Pan Y, Rao NA Alopecia areata during etanercept therapy. Occul Immunol Inflamm. 2009;17(2):127-129.
37. Navarro R, Daudén E, Gallo E, Santiago Sánchez-Mateos D, García-Diez A. Alopecia areata during treatment of psoriasis with adalimumab and leflunomide: a case and review of the literature. Skin Pharmacol Physiol. 2012;25(2):107-110.
38. Pelivani N, Hassan AS, Braathen LR, Hunger RE, Yawalkar N. Alopecia areata universalis elicited during treatment with adalimumab. Dermatology. 2008;216(4):320-323.
39. Chaves Y, Duarte G, Ben-Said B, Tebib J, Berard F, Nicolas JF. Alopecia areata universalis during treatment of rheumatoid arthritis with anti-TNF-alpha antibody (adalimumab). Dermatology. 2008;217(4):380.
40. 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(6):1082-1084.
41. Verros C, Rallis E, Crowe M. Letter: Alopecia areata during ustekinumab administration: Co-existence or an adverse reaction? Dermatol Online J. 2012;18(7):14.
42. Słowi´nska M, Kardynal A, Warszawik O, Czuwara J, Rudnicka L. Alopecia areata developing parallel to improvement of psoriasis during ustekinumab therapy. J Dermatol Case Rep. 2010;4(1):15-17.
43. De Simone C, Murri R, Maiorino A, Venier A, Caldarola G. Management of recurrent cutaneous abscesses during therapy with infliximab. Clin Ther. 2011;33(12):1993-1996.
44. Kroesen S. Widmer AF, Tyndall A, Hasler P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford). 2003;42(5):617-621.
45. Calabrese LH, Zein NN, Vassilopolos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis. 2006;65(8):983-989.
46. Chung SJ, Kim JK, Park MC, Park YB, Lee SK. Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-alpha therapy. J Rheumatol. 2009;36(11):2416-2420.
47. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis. 2003;62(7):686-687.
48. Cho YT, Chen CH, Chiu HY, Tsai TF. Use of anti-tumor necrosis factor-α therapy in hepatitis B virus carriers with psoriasis or psoriatic arthritis: a case series in Taiwan. J Dermatol. 2012;39(3):269-273.
49. Perez-Alvarez R, Díaz-Lagares C, García-Hernández F, et al. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine (Baltimore). 2011;90(6):359-371.
50. Abramson A, Menter A, Perrillo R. Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: a review and recommendations for management. J Am Acad Dermatol. 2012;67(6):1349-1361.
51. Koskinas J, Tampaki M, Doumba PP, Rallis E. Hepatitis B virus reactivation during therapy with ustekinumab for psoriasis in a hepatitis B surface-antigen-negative anti-HBs-positive patient. Br J Dermatol. 2013;168(3):679-680.
52. Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009;301(7):737-744.
53. Winthrop KL, Baddley JW, Chen L, et al. Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster. JAMA. 2013;309(9):887-895.
54. Kinder A, Stephens S, Mortimer N, Sheldon P. Severe herpes zoster after infliximab infusion. Postgrad Med J. 2004;80(939):26.
55. Manzano V, Ruiz P, Torres M, Gomez F. Severe pneumonia by aciclovir-resistant varicella-zoster virus during etanercept therapy. Rheumatology (Oxford). 2010;49(9):1791-1793.
56. Failla V, Nikkels AF. Ustekinumab and herpes zoster. Dermatology. 2011;222(2):119-122.
57. Georgala S, Katoulis AC, Kanelleas A, Befon A, Georgala C. Letter: Human papilloma virus and molluscum contagiosum lesions related to infliximab therapy for psoriasis: a case series. Dermatol Online J. 2012;18(4):9.
58. Antoniou C, Kosmadaki MG, Stratigos AJ, Katsambas AD. Genital HPV lesions and molluscum contagiosum occurring in patients receiving anti-TNF-a therapy. Dermatology. 2008;216(4):364-365.
59. Somasekar A, Alcolado R. Genital condylomata in a patient receiving infliximab for Crohn’s disease. Postgrad Med J. 2004;80(944):358-359.
60. Kreuter A, Meyer MF, Wieland U. Occurrence of penile intraepithelial neoplasia following adalimumab treatment for psoriatic arthritis. Arch Dermatol. 2011;147(8):1001-1002.
61. Levy MS, Polsky D, Davidson A, Strober BE. Tinea versicolor associated with etanercept therapy. J Am Acad Dermatol. 2008;58(5 suppl 1):S99-S100.
62. Hannuksela, M. Cutaneous rash from the use of medicine for rheumatoid arthritis. Duodecim. 2006;122(1):105, 111.
To view the tables for this article, please download the pdf version.
Several biologic therapies have been FDA approved for the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis and other inflammatory diseases. These therapies currently belong to 1 of 2 categories: tumor necrosis factor (TNF) inhibitors, such as infliximab (Remicade), adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi) and certolizumab pegol (Cimzia) or the anti-interleukin (IL)-12/23 monoclonal antibody ustekinumab (Stelara). These therapies typically are effective and well-tolerated in the long-term, with the most common adverse effects being various types of infection, common or opportunistic.1
This 2-part review describes multiple, rare side effects with these biologic agents as documented in the literature. We have organized these adverse effects into 6 categories: inflammatory skin disease, atypical infectious events, blood disorders, connective tissue disease, neurologic events and cardiac/metabolic abnormalities (Table 1). The first 2 of these categories are presented in this article. Watch for Part 2 in the December issue.
Cutaneous Reactions And Inflammatory Skin Disease
Several different inflammatory skin diseases may be adverse events to biologic treatment. These events occur in patients whose underlying disease may involve the skin, joints/ligaments or gut (Table 2).
Cutaneous Drug Reactions
Hypersensitivity reactions have been reported for patients receiving TNF-alpha (TNF-α) inhibitors. One study of hypersensitivity reactions to TNF-α inhibitors found urticaria and angioedema in patients taking infliximab, etanercept and adalimumab.2 All patients receiving infliximab and some of the patients on etanercept had positive skin tests following intradermal injection with the respective drug. Infliximab is the most common cause of urticarial reactions in rheumatoid arthritis (RA) patients, with an estimated frequency of 4.2% of infusions.3,4 However, there have been individual cases of urticaria and/or angioedema in both RA and Crohn’s disease patients taking adalimumab and etanercept.5-7 Presentations included non-pitting edema of the extremities, periorbital swelling and facial erythema that cleared after the anti-TNF-α therapy was discontinued.
Sarcoidosis
Sarcoidosis is a granulomatous disease that may affect multiple organs, and for which TNF-α inhibitors are sometimes used as treatment.8 Rarely, however, certain individuals have developed sarcoidosis as an adverse event to anti-TNF-α therapy; this phenomenon has been documented in more than 30 case reports.9,10 These cases usually are associated with patients whose underlying disease is rheumatologic in nature, with sarcoidosis that affects multiple organs.
Specifically, sarcoidosis with uveitis as a complication to anti-TNF-α therapy has been documented in 6 cases.11 Sarcoid-like granulomatosis, most commonly with cutaneous and pulmonary manifestations, has been estimated to have an incidence of 0.04% of treated patients.12
Eczematous Reactions
An eczematous reaction to biologic therapy rarely occurs. Among prospective studies of patients with either Crohn’s disease or RA treated with TNF-α inhibitors, rates of reported eczematous reactions range from 4.4%-20.6%.13-15 However, another investigation found no statistically significant difference between the rate of eczema in rheumatoid patients receiving anti-TNF-α therapy and those who were not, suggesting this class of patients inherently may be at an elevated risk for this type of skin reaction, regardless of therapy. Eczematous reactions have not been reported to occur with TNF-α inhibitor therapy for dermatologic patients. In contrast, there has been a reported case of an eczematous drug eruption in a psoriasis patient following treatment with ustekinumab, the approved anti-IL-12/23 monoclonal antibody.16
Interface Dermatitis And Lichen Planus
Drug eruptions consistent with interface dermatitis have been recorded in patients receiving TNF-α inhibitors, but not anti-IL-12/23 antibodies. Specifically, cases of lichenoid dermatitis and erythema multiforme have been reported in RA and Crohn’s disease patients.17-19 There have also been 2 reported cases of interface dermatitis in psoriatic arthritis patients.20 Lichen planus specifically has been documented in several psoriasis patients between 2 and 16 months after beginning anti-TNF-α therapy.21,22 Clinical presentation includes typical highly pruritic lichen planus-like papules and plaques on the trunk and extremities, as well as lesions affecting the oral mucosa. Although the most frequently cited drugs to cause interface dermatitis are infliximab and etanercept, there has also been 1 reported case of lichen planus in a Crohn’s disease patient receiving certolizumab pegol.23
Neutrophilic Eccrine Hidradenitis
Neutrophilic eccrine hidradenitis and drug-induced Sweet’s syndrome have been reported in 2 cases as adverse reactions to TNF-α therapy, both of which involved adalimumab treatment.17,24 The patients’ underlying diagnoses were Crohn’s disease and refractory polychondritis. The latter responded to a switch to etanercept therapy. Lesions were reported as papules, nodules and pustules affecting all areas of the body, including mucosal surfaces.
Porokeratosis
There have been 3 documented cases of drug-induced porokeratosis in patients taking certolizumab pegol, adalimumab and etanercept.25-27 Lesions were reported as pruritic papules (in 1 case, over 100 total lesions) affecting the trunk and extremities, similar to disseminated superficial porokeratosis.
Eosinophilic Cellulitis
Eosinophilic cellulitis as an injection site reaction has been documented in 3 patients receiving etanercept, adalimumab or infliximab, all for the treatment of RA.28-30 These cases involved a pruritic dermatitis on the trunk with associated rigor, fatigue and malaise. Mild peripheral eosinophilia may be detected.
Alopecia Areata
Alopecia areata and alopecia universalis have been documented as adverse effects of both anti-TNF-α drugs and anti-IL-12/23 antibodies. The underlying diseases for patients receiving TNF-α inhibitors who experienced acute alopecia areata include psoriasis, psoriatic arthritis, RA, ankylosing spondylitis and Crohn’s disease.31-39
Interestingly, the TNF-α inhibitors have been suggested as treatment for alopecia areata, although 1 study demonstrated this approach as ineffective, and even noted an enrolled subject displaying worsening of alopecia while receiving etanercept.40 Finally, alopecia areata was documented as an adverse effect to the anti-IL-12/23 antibody ustekinumab in 2 patients being treated for psoriasis.41,42
Atypical Infectious Events
Table 3 lists the atypical infectious events related to biologics. Here, we will discuss each of these atypical infectious events in more detail.
Pustular Folliculitis And Staphylococcus
Aureus Infections
Pustular folliculitis with methicillin-sensitive Staphylococcus aureus infection has been observed in several patients treated with anti-TNF-α therapy for Crohn’s disease and RA.17,18 Other cases have also reported S aureus cutaneous abscesses associated with patients taking TNF-α inhibitors.43,44
The authors of this review have noted that numerous patients receiving both adalimumab and etanercept experienced folliculitis of the trunk and extremities that responds to short courses of oral antibiotics such as doxycycline. Clinical presentation may involve erythematous papules and nodules (some purulent) on the trunk and extremities.
Reactivation Of Viral Hepatitis
The reactivation of hepatitis B virus (HBV) is well documented in the context of anti-TNF-α therapy. Infliximab is the most often reported offending agent.45 Patients treated with TNF-α inhibitors for rheumatic diseases or psoriasis and who are considered asymptomatic HBV carriers are at increased risk of HBV reactivation.46-48 A retrospective study demonstrated that hepatitis B surface antigen (HBsAg)-positive carriers appear to have a higher risk of HBV reactivation than HBsAg-negative/anti-HBc-positive carriers (40% compared to 5%).49
Due to the increased risk of reactivation of HBV in patients receiving TNF-α inhibitor therapy, it is recommended that all patients be screened for HBsAg and anti-HB C prior to initiating treatment so that appropriate measures, such as beginning antiviral therapy, may be taken.50 Additionally, it is recommended that serum aminotransferase levels be monitored during therapy in patients with chronic hepatitis B to detect hepatotoxicity.
Along with HBV reactivation during TNF-α inhibitor therapy, there is at least 1 case documenting hepatitis B reactivation during therapy with ustekinumab.51 The patient was HBsAg-negative, anti-HBc-positive and anti-HBs-positive (17 mIU mL−1) before the initiation of treatment with ustekinumab. However, approximately 16 months later the patient’s HBV status was rechecked after exhibiting elevated alanine aminotransferase levels. HBsAg and hepatitis B envelope antigen were positively detected, with the HBV DNA load measured at 140,000 IUmL−1. While this conversion to positivity might not have been related to ustekinumab therapy, this case exemplifies the need for fastidious vigilance when treating all potential carriers of HBV.
Herpes Zoster
Prospective studies differ on whether there is a statistically significant increase in the risk of herpes zoster in patients receiving biologic therapy.52,53 Reported cases involve patients receiving either TNF-α inhibitors or ustekinumab for psoriasis, psoriatic arthritis or RA.54-56 The authors of this review have witnessed multiple cases of localized herpes zoster in patients newly started on TNF-α inhibitors.
Human Papilloma Virus And
Molluscum Contagiosum
Several case reports have documented an association between TNF-α inhibitors and the recurrence of human papilloma virus and/or molluscum contagiosum. The patients were being treated for psoriasis, psoriatic arthritis or Crohn’s disease when they developed typical lesions on the face, lower abdomen, genital and perianal areas.57-59 In at least 1 case, the lesion was consistent with penile intraepithelial neoplasia, a potential penile cancer precursor.60
Tinea Versicolor
There have been 2 reported cases of tinea versicolor in response to anti-TNF-α therapy. In at least 1 case, the patient, who was receiving etanercept for plaque psoriasis, developed tinea versicolor again on rechallenge.61,62
Conclusion
TNF inhibitors and ustekinumab overwhelmingly demonstrate a high benefit to risk ratio when used for the treatment of various diseases. However, the large number of treated patients worldwide has demonstrated rare instances of a variety of adverse effects. This review enumerates some adverse effects that are either inflammatory or infectious in nature. Of course, the ability to directly ascribe any rare adverse event to a given drug is tenuous. Regardless, in most instances, these events may be managed by either add-on care or switching to another therapy.
Importantly, some adverse events resolve with appropriate therapy and the same biologic may be continued. Clinicians should monitor for atypical reactions to biologic therapies and “alter course” accordingly.
Ms. Townsend is with The University of Connecticut Health Center in Farmington, CT.
Dr. Strober is with the department of dermatology at the University of Connecticut Health Center in Farmington, CT.
Disclosures: Dr. Strober is with the speakers bureau for AbbVie; consultant for AbbVie, Amgen, Celgene, Novartis, Merck, Lilly, Pfizer, Janssen and Maruho; investigator for AbbVie, Amgen, Novartis, Lilly and Janssen. Ms. Townsend has no conflicts of interest to report.
References
1. Rustin MH. Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data. Br J Dermatol. 2012;167(suppl 3):3-11.
2. Puxeddu I, Giori L, Rocchi V, et al. Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann Allergy Asthma Immunol. 2012;108(2):123-124.
3. Wasserman MJ, Weber DA, Guthrie JA, Bykerk VP, Lee P, Keystone EC. Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. J Rheumatol. 2004;31(10):1912-1917.
4. Lequerré T, Vittecoq O, Klemmer N, et al. Management of infusion reactions to infliximab in patients with rheumatoid arthritis or spondyloarthritis: experience from an immunotherapy unit of rheumatology. J Rheumatol. 2006;33(7):1307-1314.
5. Nikas SN, Voulgari PV, Drosos AA. Urticaria and angiedema-like skin reactions in a patient treated with adalimumab. Clin Rheumatol. 2007;26(5):787-788.
6. Adamiak T, Stephens M, Werlin SL. Angioedema occurring in pediatric patients with Crohn disease treated with adalimumab. J Pediatr Gastroenterol Nutr. 2010;51(2):223-225.
7. Sendur OF, Turan Y, Berkit IK, Tastaban E. Angio-oedema in a patient treated with etanercept for rheumatoid arthritis. Basic Clin Pharmacol Toxicol. 2009;104(6):488-490.
8. Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet. 2003;361(9363):1111-1118.
9. Cathcart S, Sami N, Elewski B. Sarcoidosis as an adverse effect of tumor necrosis factor inhibitors.
J Drugs Dermatol. 2012;11(5):609-612.
10. Lamrock E, Brown P. Development of cutaneous sarcoidosis during treatment with tumour necrosis alpha factor antagonists. Australas J Dermatol. 2012;53(4):e87-e90.
11. Fonollosa A, Artaraz J, Les I, et al. Sarcoid intermediate uveitis following etanercept treatment: a case report and review of the literature. Occul Immunol Inflamm. 2012;20(1):44-48.
12. 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.
13. Lee HH, Song IH, Friedrich M, et al. Cutaneous side-effects in patients with rheumatic diseases during application of tumour necrosis factor-alpha antagonists. Br J Dermatol. 2007;156(3):486-491.
14. Flendrie M, Vissers WH, Creemers MC, de Jong EM, van de Kerkhof PC, van Riel PL. Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2005;7(3):R666-R676.
15. Esmailzadeh A, Yousefi P, Farhi D, et al. Predictive factors of eczema-like eruptions among patients without cutaneous psoriasis receiving infliximab: a cohort study of 92 patients. Dermatology. 2009;219(3):263-267.
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