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Therapy for severe necrotizing vasculitis with infliximab
Letters 321
J AM ACAD DERMATOL VOLUME 51, NUMBER 2
3. Obermoser G, Zelger B. ‘‘Multifocal’’ circumscribed palmar hypokeratosis: malformation or not? J Am Acad Dermatol 2003;49:1197-8.
doi:10.1016/j.jaad.2003.11.062
Therapy for severe necrotizing vasculitis with infliximab To the Editor: Vasculitis covers a broad heterogeneous group of different diseases characterized by inflammation and necrosis of blood vessels, caused by deposition of immune complexes in the vessel walls.1,2 Etiological factors include infections, drugs, and concomitant diseases such as inflammatory bowel diseases or malignant neoplasms.3,4 Here, we describe the case of a 62-year-old female patient with multiple leg ulcers (up to 12 3 4 cm in size) and livedo racemosa (Fig l). Repeated skin biopsy specimens of the ulcers showed leukocytoclastic vasculitis. Venous or arterial disorders for the ulcers could be excluded and no hint of hematological diseases or internal malignancy could be found. Serological tests for common viral or bacterial antibodies, including hepatitis A, B, and C showed negative results. Autoantibody screening, including anti-neutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, and cryoglobulins were negative and systemic manifestation of the vasculitis could be excluded. Treatment with glucocorticosteroids (60 mg/d, methylprednisolone) was ineffective.5 A trial with topical application of tacrolimus solution6 (Prograf, Fujisawa, Munich, Germany) and systemic treatment with immunoglobulins at a dose of 60 g/wk (Intraglobin F, Biotest, Frankfurt, Germany) administered intravenously for 5 weeks did not show any clinical efficacy.7 Because of further progression of the ulcers (Fig 2), we decided to use the anti-tumor necrosis factor alpha (TNF-a) monoclonal antibody infliximab (Remicade, Essex Pharma, Munich, Germany), which was given as two separate intravenous infusions at a dose of 2 mg/kg of body weight within a period of 4 weeks. Thereafter, the dose was increased to 4 mg/kg of body weight. After only 8 weeks, a significant reduction in ulcer size and increased formation of granulation tissue was observed. However, following the fourth application, the patient developed dyspnea and fever, and an oxacilline-resistant staphylococcal pneumonia was diagnosed and treated with high doses of antibiotics. After discontinuation of infliximab therapy, the ulcers again progressed in number and size. This exacerbation could be successfully treated with another two infusions of infliximab (Fig 3). Unfortunately,
Fig 1. Initial clinical appearance of vasculitic ulcers on the lower left leg.
Fig 2. Progress despite previous treatment with systemic glucocorticosteroids, topical application of tacrolimus solution, or intravenous administration of immunoglobulins.
Fig 3. Almost complete healing of the vasculitic ulcers following infliximab therapy (6 infusions of infliximab, week 24).
persistent colonization by oxacilline-resistant Staphylococcus aureus forced us to stop the TNF-a antibody treatment, once again leading to a severe relapse. Infliximab is a chimeric monoclonal antibody inhibiting TNF-a. As a result, the release of other cytokines, the expression of endothelial adhesion molecules, and the transendothelial migration of leukocytes are suppressed. Established indications for therapy with infliximab are inflammatory bowel diseases, rheumatoid arthritis, and, recently reported, the treatment of psoriasis and psoriatic arthritis.8-11
322 Letters
Based on the mechanisms of action of infliximab and the immunological features of vasculitis, we determined the therapeutic effectiveness of infliximab in the treatment of leukocytoclastic vasculitis. Beneficial effects could be observed shortly after the onset of treatment. The almost complete remission of vasculitis seen after 24 weeks is proposed to result from the immunosuppressive and anti-inflammatory potency of anti-TNF-a therapy. The use of immunomodulating agents such as infliximab is, however, not without risks, as indicated by the reported development of severe opportunistic infections,12 and as witnessed in our case. Our observations suggest that the inhibition of TNF-a with infliximab can be used to treat severe or recalcitrant cases of leukocytoclastic vasculitis, but confirm that severe side effects may occur. In addition, it has been observed that infliximab itself can induce autoimmune diseases such as vasculitis or lupus erythematosus.13 Renz Mang, MD Thomas Ruzicka, MD Helger Stege, MD Department of Dermatology Heinrich-Heine University Du¨sseldorf, Germany Correspondence to: Helger Stege, MD, Department of Dermatology, University of Duesseldorf, Moorenstrasse 5, 40225 Du¨sseldorf, Germany E-mail: [email protected] REFERENCES 1. Lotti T, Ghersetich I, Comacchi C, Jorizzo JL. Cutaneous smallvessel vasculitis. J Am Acad Dermatol 1998;39:667-87.
J AM ACAD DERMATOL AUGUST 2004
2. Csernok E, Gross WL. Primary vasculitides and vasculitis confined to skin: Clinical features and new pathogenic aspects. Arch Dermatol Res 2000;292:427-36. 3. Lotti TM, Comacchi C, Ghersetich I. Cutaneous necrotizing vasculitis. Relation to systemic disease. Adv Exp Med Biol 1999;455:115-25. 4. Kurzrock R, Cohen PR, Markowitz A. Clinical manifestations of vasculitis in patients with solid tumors. A case report and review of the literature. Arch Intern Med 1994;154:334-40. 5. Vena GA, Cassano N. Immunosuppressive therapy in cutaneous vasculitis. Clin Dermatol 1999;17:633-40. 6. Schuppe HC, Homey B, Assmann T, Martens R, Ruzicka T. Topical tacrolimus for pyoderma gangraenosum. Lancet 1998; 351:832. 7. Ong CS, Benson EM. Successful treatment of chronic leucocytoclastic vasculitis and persistent ulceration with intravenous immunoglobulin. Br J Dermatol 2000;143:447-9. 8. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 2000;343:1594-602. 9. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398405. 10. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infiiximab monotherapy for plaque-type psoriasis: A randomised trial. Lancet 2001;357: 1842-7. 11. Mang R, Stege H, Ruzicka T, Krutmann J. Response of severe psoriasis to infiiximab. Dermatology 2002;204:156-7. 12. Warris A, Bjomeklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med 2001; 344:1099-100. 13. Devos SA, Van Den Bossche N, De Vos M, Naeyaert JM. Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy. Dermatology 2003;206:388-90.
doi:10.1016/j.jaad.2004.01.003
J AM ACAD DERMATOL VOLUME 51, NUMBER 2
3. Obermoser G, Zelger B. ‘‘Multifocal’’ circumscribed palmar hypokeratosis: malformation or not? J Am Acad Dermatol 2003;49:1197-8.
doi:10.1016/j.jaad.2003.11.062
Therapy for severe necrotizing vasculitis with infliximab To the Editor: Vasculitis covers a broad heterogeneous group of different diseases characterized by inflammation and necrosis of blood vessels, caused by deposition of immune complexes in the vessel walls.1,2 Etiological factors include infections, drugs, and concomitant diseases such as inflammatory bowel diseases or malignant neoplasms.3,4 Here, we describe the case of a 62-year-old female patient with multiple leg ulcers (up to 12 3 4 cm in size) and livedo racemosa (Fig l). Repeated skin biopsy specimens of the ulcers showed leukocytoclastic vasculitis. Venous or arterial disorders for the ulcers could be excluded and no hint of hematological diseases or internal malignancy could be found. Serological tests for common viral or bacterial antibodies, including hepatitis A, B, and C showed negative results. Autoantibody screening, including anti-neutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, and cryoglobulins were negative and systemic manifestation of the vasculitis could be excluded. Treatment with glucocorticosteroids (60 mg/d, methylprednisolone) was ineffective.5 A trial with topical application of tacrolimus solution6 (Prograf, Fujisawa, Munich, Germany) and systemic treatment with immunoglobulins at a dose of 60 g/wk (Intraglobin F, Biotest, Frankfurt, Germany) administered intravenously for 5 weeks did not show any clinical efficacy.7 Because of further progression of the ulcers (Fig 2), we decided to use the anti-tumor necrosis factor alpha (TNF-a) monoclonal antibody infliximab (Remicade, Essex Pharma, Munich, Germany), which was given as two separate intravenous infusions at a dose of 2 mg/kg of body weight within a period of 4 weeks. Thereafter, the dose was increased to 4 mg/kg of body weight. After only 8 weeks, a significant reduction in ulcer size and increased formation of granulation tissue was observed. However, following the fourth application, the patient developed dyspnea and fever, and an oxacilline-resistant staphylococcal pneumonia was diagnosed and treated with high doses of antibiotics. After discontinuation of infliximab therapy, the ulcers again progressed in number and size. This exacerbation could be successfully treated with another two infusions of infliximab (Fig 3). Unfortunately,
Fig 1. Initial clinical appearance of vasculitic ulcers on the lower left leg.
Fig 2. Progress despite previous treatment with systemic glucocorticosteroids, topical application of tacrolimus solution, or intravenous administration of immunoglobulins.
Fig 3. Almost complete healing of the vasculitic ulcers following infliximab therapy (6 infusions of infliximab, week 24).
persistent colonization by oxacilline-resistant Staphylococcus aureus forced us to stop the TNF-a antibody treatment, once again leading to a severe relapse. Infliximab is a chimeric monoclonal antibody inhibiting TNF-a. As a result, the release of other cytokines, the expression of endothelial adhesion molecules, and the transendothelial migration of leukocytes are suppressed. Established indications for therapy with infliximab are inflammatory bowel diseases, rheumatoid arthritis, and, recently reported, the treatment of psoriasis and psoriatic arthritis.8-11
322 Letters
Based on the mechanisms of action of infliximab and the immunological features of vasculitis, we determined the therapeutic effectiveness of infliximab in the treatment of leukocytoclastic vasculitis. Beneficial effects could be observed shortly after the onset of treatment. The almost complete remission of vasculitis seen after 24 weeks is proposed to result from the immunosuppressive and anti-inflammatory potency of anti-TNF-a therapy. The use of immunomodulating agents such as infliximab is, however, not without risks, as indicated by the reported development of severe opportunistic infections,12 and as witnessed in our case. Our observations suggest that the inhibition of TNF-a with infliximab can be used to treat severe or recalcitrant cases of leukocytoclastic vasculitis, but confirm that severe side effects may occur. In addition, it has been observed that infliximab itself can induce autoimmune diseases such as vasculitis or lupus erythematosus.13 Renz Mang, MD Thomas Ruzicka, MD Helger Stege, MD Department of Dermatology Heinrich-Heine University Du¨sseldorf, Germany Correspondence to: Helger Stege, MD, Department of Dermatology, University of Duesseldorf, Moorenstrasse 5, 40225 Du¨sseldorf, Germany E-mail: [email protected] REFERENCES 1. Lotti T, Ghersetich I, Comacchi C, Jorizzo JL. Cutaneous smallvessel vasculitis. J Am Acad Dermatol 1998;39:667-87.
J AM ACAD DERMATOL AUGUST 2004
2. Csernok E, Gross WL. Primary vasculitides and vasculitis confined to skin: Clinical features and new pathogenic aspects. Arch Dermatol Res 2000;292:427-36. 3. Lotti TM, Comacchi C, Ghersetich I. Cutaneous necrotizing vasculitis. Relation to systemic disease. Adv Exp Med Biol 1999;455:115-25. 4. Kurzrock R, Cohen PR, Markowitz A. Clinical manifestations of vasculitis in patients with solid tumors. A case report and review of the literature. Arch Intern Med 1994;154:334-40. 5. Vena GA, Cassano N. Immunosuppressive therapy in cutaneous vasculitis. Clin Dermatol 1999;17:633-40. 6. Schuppe HC, Homey B, Assmann T, Martens R, Ruzicka T. Topical tacrolimus for pyoderma gangraenosum. Lancet 1998; 351:832. 7. Ong CS, Benson EM. Successful treatment of chronic leucocytoclastic vasculitis and persistent ulceration with intravenous immunoglobulin. Br J Dermatol 2000;143:447-9. 8. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 2000;343:1594-602. 9. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398405. 10. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infiiximab monotherapy for plaque-type psoriasis: A randomised trial. Lancet 2001;357: 1842-7. 11. Mang R, Stege H, Ruzicka T, Krutmann J. Response of severe psoriasis to infiiximab. Dermatology 2002;204:156-7. 12. Warris A, Bjomeklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med 2001; 344:1099-100. 13. Devos SA, Van Den Bossche N, De Vos M, Naeyaert JM. Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy. Dermatology 2003;206:388-90.
doi:10.1016/j.jaad.2004.01.003