Leukocytoclastic vasculitis drug reaction to certolizumab pegol Meghan Woody, MD, MPH, Donald Warren, MD, Laura Speck, MD, and Julie Jackson, MD
a
b
Tumor necrosis factor (TNF)-alpha antagonists are a common treatment modality for autoimmune disorders, but their use can be associated with many side effects, including various dermatologic conditions. Certolizumab pegol, a newer TNF antagonist that lacks the Fc portion of the IgG antibody, has recently been approved to treat psoriatic arthritis, rheumatoid arthritis, and Crohn’s disease. Though other TNF antagonists have been Figure. (a) Pruritic inflammatory macules and papules on the patient’s legs and feet. (b) Extensive small vesicles associated with leukocytoclastic vasculi- on the plantar surface of the patient’s feet. tis, this finding has not yet been reported with certolizumab pegol. We present a case report of leukocytoclastic legs and feet and extensive small vesicles were evident on the plantar surface of the patient’s feet (Figure). Several months after vasculitis caused by certolizumab pegol.
C
ertolizumab pegol (CZP) is a pegylated, humanized, tumor necrosis factor (TNF)-alpha inhibitor that differs from other TNF-alpha inhibitors by being solely composed of a Fab fragment and lacking the Fc portion of the IgG antibody (1, 2). By lacking the Fc portion, CZP cannot activate complement nor mediate antibody-dependent cell-mediated cytotoxicity; theoretically, this should reduce the potential for CZP to have Fc-mediated effects. While the other TNF-alpha antagonists have been cited to cause leukocytoclastic vasculitis (LCV), we believe this is the first report of CZP causing LCV. CASE PRESENTATION A 28-year-old woman with Crohn’s disease and ankylosing spondylitis presented for evaluation of a rash on her bilateral lower legs, feet, palms of hands, and plantar surface of her feet 6 months after beginning CZP. At age 26, she was diagnosed with severe ankylosing spondylitis; 6 months after diagnosis, she was placed on CZP as sole therapy. She received 400 mg of subcutaneous CZP every 4 weeks for approximately 1 year. She initially developed a rash after being on CZP for 6 months and remained on the CZP for an additional 6 months, due to the effective control of ankylosing spondylitis. Initially, many pruritic inflammatory macules and papules involved the patient’s Proc (Bayl Univ Med Cent) 2017;30(2):213–214
the initial presentation, the eruption extended to the patient’s trunk and scalp, with the scalp lesions appearing as sebopsoriasis. The eruption progressed to include a folliculitis-like rash on the patient’s thighs and arms. The patient additionally reported lower extremity edema with prolonged standing and lower leg muscle soreness. The patient had documented intolerance for TNF-alpha inhibitors previously. At the initial diagnosis of Crohn’s disease, she was treated with adalimumab but had intolerable side effects including alopecia, scalp psoriasis, severe hidradenitis of the groin and axillae, and vesicular eruption on her palms and soles. Adalimumab was thus discontinued and the patient subsequently underwent subtotal colectomy. The patient underwent a punch biopsy of her left foot and right leg. Microscopic evaluation of the left foot demonstrated an unremarkable epidermis overlying dermal infiltrates, composed mostly of neutrophils and scattered eosinophils. Chemotaxis of neutrophils leading to vessel wall injury, fibrin deposition, and erythrocyte extravasation along with fragmented neutrophils were also noted. Microscopic evaluation of the right leg From the University of Texas Dell Medical School, Austin, Texas (Woody); Baylor Scott & White, Marble Falls, Texas (Warren); and Westlake Dermatology, Austin, Texas (Speck, Jackson). Corresponding author: Meghan Woody, MD, MPH, University of Texas Dell Medical School, Austin, TX (e-mail: [email protected]). 213
showed superficial and deep perivascular and dermal infiltrates of neutrophils and eosinophils. Both biopsies were consistent with LCV with significant tissue eosinophilia. Against the patient’s rheumatologist’s recommendations, the patient stopped taking CZP and began a 3-week prednisone taper, which entailed taking 60 mg by mouth for week 1, 40 mg by mouth for week 2, and 20 mg by mouth for week 3. The patient additionally received 50 mg of dapsone once daily for 1 month. The rash cleared completely approximately 3 months after cessation of CZP.
infiltrate to a mononuclear-predominant infiltrate (7). Furthermore, drug-induced LCV is often characterized as having an eosinophilic-predominant infiltrate (8). CZP is approved for treatment of psoriatic arthritis in many countries, including the US (1). With the increasing use of CZP, physicians should be aware of this side effect and consider drug cessation if indicated.
DISCUSSION LCV may have a multitude of presentations, making it difficult to diagnose. While the initial presentation is often cutaneous, LCV may cause a variety of other problems including myopathy, gastrointestinal bleeding, and renal insufficiency (3, 4). It can also result in permanent scarring (5). Common presentations of LCV include palpable purpura, urticaria, ulcers, or nodules (3, 6). These lesions may be exquisitely painful or pruritic, and lower leg edema and myalgias are frequently present (3). Histopathologically, LCV is described as fibrinoid necrosis of dermal small vessels, hemorrhage, thrombosis, and perivascular polymorphonuclear leukocytes (3, 6). However, the histologic variability of LCV has been reported to morph over the course of 24 to 48 hours from a neutrophilic-predominant
3.
214
1. 2.
4.
5.
6.
7.
8.
Hansen RB, Kavanaugh A. Certolizumab pegol for the treatment of psoriatic arthritis. Expert Rev Clin Immunol 2015;11(3):307–318. Jinesh S. Pharmaceutical aspects of anti-inflammatory TNF-blocking drugs. Inflammopharmacology 2015;23(2–3):71–77. Sams WM Jr, Thorne EG, Small P, Mass MF, McIntosh RM, Stanford RE. Leukocytoclastic vasculitis. Arch Dermatol 1976;112(2):219–226. Tsai MH, Yang JH, Kung SL, Hsiao YP. Levamisole-induced myopathy and leukocytoclastic vasculitis: a case report and literature review. Dermatol Ther (Heidelb) 2013;26(6):476–480. Butts GT, Bishop PR, Wyatt JP, Nowicki MJ. Leukocytoclastic vasculitis in an adolescent with ulcerative colitis: report of a case and review of the literature. Sage Open Med Case Rep 2014;2:2050313X14547609. Ekenstam EAF, Callen JP. Cutaneous leukocytoclastic vasculitis: clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol 1984;120(4):484–489. Zax RH, Hodge SJ, Callen JP. Cutaneous leukocytoclastic vasculitis: serial histopathologic evaluation demonstrates the dynamic nature of the infiltrate. Arch Dermatol 1990;126(1):69–72. Bahrami S, Malone JC, Webb KG, Callen JP. Tissue eosinophilia as an indicator of drug-induced cutaneous small-vessel vasculitis. Arch Dermatol 2006;142(2):155–161.
Baylor University Medical Center Proceedings
Volume 30, Number 2
a
b
Tumor necrosis factor (TNF)-alpha antagonists are a common treatment modality for autoimmune disorders, but their use can be associated with many side effects, including various dermatologic conditions. Certolizumab pegol, a newer TNF antagonist that lacks the Fc portion of the IgG antibody, has recently been approved to treat psoriatic arthritis, rheumatoid arthritis, and Crohn’s disease. Though other TNF antagonists have been Figure. (a) Pruritic inflammatory macules and papules on the patient’s legs and feet. (b) Extensive small vesicles associated with leukocytoclastic vasculi- on the plantar surface of the patient’s feet. tis, this finding has not yet been reported with certolizumab pegol. We present a case report of leukocytoclastic legs and feet and extensive small vesicles were evident on the plantar surface of the patient’s feet (Figure). Several months after vasculitis caused by certolizumab pegol.
C
ertolizumab pegol (CZP) is a pegylated, humanized, tumor necrosis factor (TNF)-alpha inhibitor that differs from other TNF-alpha inhibitors by being solely composed of a Fab fragment and lacking the Fc portion of the IgG antibody (1, 2). By lacking the Fc portion, CZP cannot activate complement nor mediate antibody-dependent cell-mediated cytotoxicity; theoretically, this should reduce the potential for CZP to have Fc-mediated effects. While the other TNF-alpha antagonists have been cited to cause leukocytoclastic vasculitis (LCV), we believe this is the first report of CZP causing LCV. CASE PRESENTATION A 28-year-old woman with Crohn’s disease and ankylosing spondylitis presented for evaluation of a rash on her bilateral lower legs, feet, palms of hands, and plantar surface of her feet 6 months after beginning CZP. At age 26, she was diagnosed with severe ankylosing spondylitis; 6 months after diagnosis, she was placed on CZP as sole therapy. She received 400 mg of subcutaneous CZP every 4 weeks for approximately 1 year. She initially developed a rash after being on CZP for 6 months and remained on the CZP for an additional 6 months, due to the effective control of ankylosing spondylitis. Initially, many pruritic inflammatory macules and papules involved the patient’s Proc (Bayl Univ Med Cent) 2017;30(2):213–214
the initial presentation, the eruption extended to the patient’s trunk and scalp, with the scalp lesions appearing as sebopsoriasis. The eruption progressed to include a folliculitis-like rash on the patient’s thighs and arms. The patient additionally reported lower extremity edema with prolonged standing and lower leg muscle soreness. The patient had documented intolerance for TNF-alpha inhibitors previously. At the initial diagnosis of Crohn’s disease, she was treated with adalimumab but had intolerable side effects including alopecia, scalp psoriasis, severe hidradenitis of the groin and axillae, and vesicular eruption on her palms and soles. Adalimumab was thus discontinued and the patient subsequently underwent subtotal colectomy. The patient underwent a punch biopsy of her left foot and right leg. Microscopic evaluation of the left foot demonstrated an unremarkable epidermis overlying dermal infiltrates, composed mostly of neutrophils and scattered eosinophils. Chemotaxis of neutrophils leading to vessel wall injury, fibrin deposition, and erythrocyte extravasation along with fragmented neutrophils were also noted. Microscopic evaluation of the right leg From the University of Texas Dell Medical School, Austin, Texas (Woody); Baylor Scott & White, Marble Falls, Texas (Warren); and Westlake Dermatology, Austin, Texas (Speck, Jackson). Corresponding author: Meghan Woody, MD, MPH, University of Texas Dell Medical School, Austin, TX (e-mail: [email protected]). 213
showed superficial and deep perivascular and dermal infiltrates of neutrophils and eosinophils. Both biopsies were consistent with LCV with significant tissue eosinophilia. Against the patient’s rheumatologist’s recommendations, the patient stopped taking CZP and began a 3-week prednisone taper, which entailed taking 60 mg by mouth for week 1, 40 mg by mouth for week 2, and 20 mg by mouth for week 3. The patient additionally received 50 mg of dapsone once daily for 1 month. The rash cleared completely approximately 3 months after cessation of CZP.
infiltrate to a mononuclear-predominant infiltrate (7). Furthermore, drug-induced LCV is often characterized as having an eosinophilic-predominant infiltrate (8). CZP is approved for treatment of psoriatic arthritis in many countries, including the US (1). With the increasing use of CZP, physicians should be aware of this side effect and consider drug cessation if indicated.
DISCUSSION LCV may have a multitude of presentations, making it difficult to diagnose. While the initial presentation is often cutaneous, LCV may cause a variety of other problems including myopathy, gastrointestinal bleeding, and renal insufficiency (3, 4). It can also result in permanent scarring (5). Common presentations of LCV include palpable purpura, urticaria, ulcers, or nodules (3, 6). These lesions may be exquisitely painful or pruritic, and lower leg edema and myalgias are frequently present (3). Histopathologically, LCV is described as fibrinoid necrosis of dermal small vessels, hemorrhage, thrombosis, and perivascular polymorphonuclear leukocytes (3, 6). However, the histologic variability of LCV has been reported to morph over the course of 24 to 48 hours from a neutrophilic-predominant
3.
214
1. 2.
4.
5.
6.
7.
8.
Hansen RB, Kavanaugh A. Certolizumab pegol for the treatment of psoriatic arthritis. Expert Rev Clin Immunol 2015;11(3):307–318. Jinesh S. Pharmaceutical aspects of anti-inflammatory TNF-blocking drugs. Inflammopharmacology 2015;23(2–3):71–77. Sams WM Jr, Thorne EG, Small P, Mass MF, McIntosh RM, Stanford RE. Leukocytoclastic vasculitis. Arch Dermatol 1976;112(2):219–226. Tsai MH, Yang JH, Kung SL, Hsiao YP. Levamisole-induced myopathy and leukocytoclastic vasculitis: a case report and literature review. Dermatol Ther (Heidelb) 2013;26(6):476–480. Butts GT, Bishop PR, Wyatt JP, Nowicki MJ. Leukocytoclastic vasculitis in an adolescent with ulcerative colitis: report of a case and review of the literature. Sage Open Med Case Rep 2014;2:2050313X14547609. Ekenstam EAF, Callen JP. Cutaneous leukocytoclastic vasculitis: clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol 1984;120(4):484–489. Zax RH, Hodge SJ, Callen JP. Cutaneous leukocytoclastic vasculitis: serial histopathologic evaluation demonstrates the dynamic nature of the infiltrate. Arch Dermatol 1990;126(1):69–72. Bahrami S, Malone JC, Webb KG, Callen JP. Tissue eosinophilia as an indicator of drug-induced cutaneous small-vessel vasculitis. Arch Dermatol 2006;142(2):155–161.
Baylor University Medical Center Proceedings
Volume 30, Number 2
