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Vasculitis induced by infliximab
indian journal of rheumatology 10 (2015) 239–248
241
Vasculitis induced by infliximab Anti-tumor necrosis factor alpha (TNFa) therapy is widely used in the treatment of rheumatological and auto-immune diseases due to its proven efficacy in the treatment of these conditions.1 Anti-TNF agents had been reported to be safe, however, with the increasing use, rare adverse events like vasculitis are being recognized. We report the case of vasculitis developing in a patient with psoriasis and psoriatic arthritis treated with infliximab. A 29 year-old male patient with a history of psoriasis and psoriatic arthritis (PsA) was referred to our unit for persistently active PsA despite conventional treatment (salazopyrine and methotrexate). Infiximab was given at the dose of 5 mg/k/day for week 0, 2 and 6 weeks with prompt response. He received maintenance with 8 weekly infusion. Two weeks after the 6th infusion, the patient was admitted with abdominal pain, bleeding per rectum and skin lesions in the legs (Fig. 1). Physical examination revealed necrotic purpura in the lower legs, abdominal tenderness, however neurologic, pulmonary and cardiac examination were normal. Laboratory investigations revealed an erythrocyte sediment rate at 50 mm/1st hour; a normal hemoglobin, platelets and white cell count. There were no serological evidence of any auto anti-bodies including Antinuclear antibody (ANA), Antineutrophil cytoplasmic antibody (ANCA) or cryoglobulinemia. The infectious investigation was negative including serology for hepatitis B and C. The skin biopsy showed a leucocytoclastic vasculitis. The direct immunofluorescence study revealed the presence of vascular deposits of C3 (Fig. 2). The diagnosis of anti-TNFa associated vasculitis was considered and infliximab was withdrawn, and 120 mg of methylprednisolone was administrated, followed by prednisone 1 mg/kg/day. The vasculitis resolved at the cessation of the drug. Colonoscopy was not done as symptoms resolved with corticosteroids. The treatment was switched to Adalimumab. The vasculitis did not recur over a 12-month follow-up period.
TNFa is a cytokin involved in the pathogenesis of many chronic inflammatory diseases such as rhumatoïd arthritis, ulcerative colitis, Crohn's disease, psoriasis and PsA(2). TNFa blockers are an effective therapy to manage these conditions. Three anti-TNFa agents are available: infliximab which is an anti-TNFa monoclonal chimeric human murine antibody,1 adalimumab is a human anti-TNFa monoclonal antibody1 and etanercept is a fusion protein made up of the extracellular domain of the p75TNF receptor and the Fc region of a human IgG.1 With the increasing use of these agents, there are a growing number adverse event reports related to them: infections, increased risk of cancer or lymphoma, peripheral neuropathy, cardiovascular events, and occurrence of auto-immune disease.3–6 Several cases of vasculitis induced by TNFa antagonists were reported in the literature.2 Both, infliximab and etanercept were administrated in 47% cases while adalimumab in 6% cases.2 The mean duration of TNFa antagonist therapy at the vasculitis onset was 9.6 13.4 months).7 The vasculitis may involve skin, mainly cutaneous leucocytoclastic vasculitis,8–10 peripheral nervous system, kidneys, lungs, central nervous system, pleural and cardiac manifestations(2). Our patient had skin and gastrointestinal manifestation after infliximab infusion. The possibility that anti-TNFa agents may induce vasculitis is difficult to establish since they are used in diseases known to be potentially associated with vasculitis.2–7 The short interval between the treatment and the vasculitis onset, the resolution of the signs and symptoms at the withdrawal
[(Fig._2)TD$IG]
[(Fig._1)TD$IG]
Fig. 1 – Skin lesion.
Fig. 2 – Skin biopsy: polymorphic inflammatory granuloma with fibrinoid necrosis of the vascular wall and leucocytoclasy.
242
indian journal of rheumatology 10 (2015) 239–248
of the drug support the hypothesis of the drug induced vasculitis. Vasculitis may be caused due to: Immune complexes containing the drug and its target may deposit on vessel walls inducing activation of the complement system.7 Also a shift from T-helper 1 to T-helper 2 cytokins with anti-TNFa may promote antibody mediated immune response. Some studies suggest the individual genetic susceptibility in the occurrence of variable severe drug induced vasculitis.2 In most cases, discontinuation of the drug incriminated is sufficient for the resolution of the vasculitis. In some cases, corticosteroïds and even immunosuppressive agent may be needed.2–7 The advent of biologicals has greatly changed the management of auto-immune and rheumatological diseases. The widespread use of these drugs has led to recognition of rare adverse events like vasculitis.
Declaration of interest The authors report having no conflict of interest in relation to this article.
references
1. Valesini G, Iannuccelli C, Marocchi E, Pascoli L, Scalzi V, Di Franco M. Biological and clinical effects of anti-TNFa treatment. Autoimmun Rev. 2007;7:35–41. 2. Ramos-Casals M, Brito-Zerón P, Cuadrado MJ, Khamashta MA. Vasculitis induced by tumor necrosis factor–targeted therapies. Curr Rheumatol Rep. 2008;10:442–448. 3. Baronnet L, Barnetche T, Kahn V, Lacoin C, Richez C, Schaeverbeke T. Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review. Joint Bone Spine. 2011;78:279–284.
4. Marie I, Guglielmino E. Infections opportunistes non tuberculeuses au cours des traitements par les anti-TNFa. Rev Med Interne. 2010;5:353–360. 5. Lahita Robert Gbr, Vernace Melchiore Alh. Vasculitis, vitiligo, thyroiditis, and altered hormone levels after anti-tumor necrosis factor therapy. J Rheumatol. 2011;38:579–580. 6. Ramos-Casals M, Brito-Zero P, Soto MJ, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNFtargeted therapies. Best Pract Res Clin Rheumatol. 2008;22: 847–861. 7. Saint Marcoux B, De Bandt M. Vasculitides induced by TNFa antagonists: a study in 39 patients in France. Joint Bone Spine. 2006;73:710–713. 8. Srivastava MD, Alexandery F, Tuthillz RJ. Immunology of cutaneous vasculitis associated with both etanercept and infliximab. Scand J Immunol. 2005;61:329–336. 9. Fujikawa K, Kawakami A, Hayashi T, et al. Cutaneous vasculitis induced by TNF inhibitors: a report of three cases. Mod Rheumatol. 2010;20:86–89. 10. Livermore PA, Murray KJ. Anti-tumour necrosis factor therapy associated with cutaneous vasculitis. Rheumatology. 2002;41:1450–1452.
Najah Boussetta* Leila Metoui Imen Gharsallah Maroua Mrouki Salah Othmani Department of Internal Medicine of Tunis Military Hospital, Tunisia *Corresponding author E-mail address: [email protected] (N. Boussetta)
http://dx.doi.org/10.1016/j.injr.2015.05.005 0973-3698/ # 2015 Indian Rheumatology Association. Published by Elsevier B.V. All rights reserved.
Erythroderma: A unique presentation of acute lupus A 38-year-old lady with no known co morbidities presented with complaints of red scaly non itchy lesions over body of 16 days duration. Lesions started from face and increased rapidly to involve rest of the body over three days. There was associated history of photosensitivity, however there was no history of joint pains, oral ulcers, loss of hair, fever, dyspnea on exertion or chest pain. There was no history of similar lesions in past, preceding drug intake or history of atopy in self and family. General physical examination revealed pallor and pedal edema. Dermatological examination revealed generalised involvement of body with erythema and scaling, Nikolsky sign was negative and there was no oral, ocular or genital mucosal involvement (Fig. 1). Rest of the systemic examination was within normal limits. Investigations revealed Hemoglobin – 5.6 gm/dL, Total Leukocyte Count – 3800/ mm3, Platelet Count – 1.8 lakh/mm3, Blood Urea – 96 mg/dL, Serum Creatinine – 2.6 mg/dL, ANA – 27 IU/mL, Anti dsDNA – Positive. Anti Ro/La, liver function test including SGOT, SGPT
were within normal limits. Hepatitis B surface antigen, Antibodies to HCV and HIV were negative. Histopathological examination of skin biopsy revealed normal epidermis, degeneration of basal layer and interface dermatitis (Fig. 2). In view of erythroderma initially drug hypersensitivity and pemphigus foliaceus were considered, however in view of ANA and Anti dsDNA positivity, kidney involvement, anemia, thrombocytopenia and compatible histopathological features she was diagnosed as a case of acute lupus erythematosus. She was treated with Prednisolone 1 mg/kg apart from supportive therapy. Three days after admission she had severe metabolic acidosis and needed hemodialysis and mechanical ventilation. Her condition did not improve and she died on day 5 of admission. Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease of unknown etiology. Skin is one of the target organ which is involved in SLE and involvement of skin not only leads to morbidity in SLE but also helps in early
241
Vasculitis induced by infliximab Anti-tumor necrosis factor alpha (TNFa) therapy is widely used in the treatment of rheumatological and auto-immune diseases due to its proven efficacy in the treatment of these conditions.1 Anti-TNF agents had been reported to be safe, however, with the increasing use, rare adverse events like vasculitis are being recognized. We report the case of vasculitis developing in a patient with psoriasis and psoriatic arthritis treated with infliximab. A 29 year-old male patient with a history of psoriasis and psoriatic arthritis (PsA) was referred to our unit for persistently active PsA despite conventional treatment (salazopyrine and methotrexate). Infiximab was given at the dose of 5 mg/k/day for week 0, 2 and 6 weeks with prompt response. He received maintenance with 8 weekly infusion. Two weeks after the 6th infusion, the patient was admitted with abdominal pain, bleeding per rectum and skin lesions in the legs (Fig. 1). Physical examination revealed necrotic purpura in the lower legs, abdominal tenderness, however neurologic, pulmonary and cardiac examination were normal. Laboratory investigations revealed an erythrocyte sediment rate at 50 mm/1st hour; a normal hemoglobin, platelets and white cell count. There were no serological evidence of any auto anti-bodies including Antinuclear antibody (ANA), Antineutrophil cytoplasmic antibody (ANCA) or cryoglobulinemia. The infectious investigation was negative including serology for hepatitis B and C. The skin biopsy showed a leucocytoclastic vasculitis. The direct immunofluorescence study revealed the presence of vascular deposits of C3 (Fig. 2). The diagnosis of anti-TNFa associated vasculitis was considered and infliximab was withdrawn, and 120 mg of methylprednisolone was administrated, followed by prednisone 1 mg/kg/day. The vasculitis resolved at the cessation of the drug. Colonoscopy was not done as symptoms resolved with corticosteroids. The treatment was switched to Adalimumab. The vasculitis did not recur over a 12-month follow-up period.
TNFa is a cytokin involved in the pathogenesis of many chronic inflammatory diseases such as rhumatoïd arthritis, ulcerative colitis, Crohn's disease, psoriasis and PsA(2). TNFa blockers are an effective therapy to manage these conditions. Three anti-TNFa agents are available: infliximab which is an anti-TNFa monoclonal chimeric human murine antibody,1 adalimumab is a human anti-TNFa monoclonal antibody1 and etanercept is a fusion protein made up of the extracellular domain of the p75TNF receptor and the Fc region of a human IgG.1 With the increasing use of these agents, there are a growing number adverse event reports related to them: infections, increased risk of cancer or lymphoma, peripheral neuropathy, cardiovascular events, and occurrence of auto-immune disease.3–6 Several cases of vasculitis induced by TNFa antagonists were reported in the literature.2 Both, infliximab and etanercept were administrated in 47% cases while adalimumab in 6% cases.2 The mean duration of TNFa antagonist therapy at the vasculitis onset was 9.6 13.4 months).7 The vasculitis may involve skin, mainly cutaneous leucocytoclastic vasculitis,8–10 peripheral nervous system, kidneys, lungs, central nervous system, pleural and cardiac manifestations(2). Our patient had skin and gastrointestinal manifestation after infliximab infusion. The possibility that anti-TNFa agents may induce vasculitis is difficult to establish since they are used in diseases known to be potentially associated with vasculitis.2–7 The short interval between the treatment and the vasculitis onset, the resolution of the signs and symptoms at the withdrawal
[(Fig._2)TD$IG]
[(Fig._1)TD$IG]
Fig. 1 – Skin lesion.
Fig. 2 – Skin biopsy: polymorphic inflammatory granuloma with fibrinoid necrosis of the vascular wall and leucocytoclasy.
242
indian journal of rheumatology 10 (2015) 239–248
of the drug support the hypothesis of the drug induced vasculitis. Vasculitis may be caused due to: Immune complexes containing the drug and its target may deposit on vessel walls inducing activation of the complement system.7 Also a shift from T-helper 1 to T-helper 2 cytokins with anti-TNFa may promote antibody mediated immune response. Some studies suggest the individual genetic susceptibility in the occurrence of variable severe drug induced vasculitis.2 In most cases, discontinuation of the drug incriminated is sufficient for the resolution of the vasculitis. In some cases, corticosteroïds and even immunosuppressive agent may be needed.2–7 The advent of biologicals has greatly changed the management of auto-immune and rheumatological diseases. The widespread use of these drugs has led to recognition of rare adverse events like vasculitis.
Declaration of interest The authors report having no conflict of interest in relation to this article.
references
1. Valesini G, Iannuccelli C, Marocchi E, Pascoli L, Scalzi V, Di Franco M. Biological and clinical effects of anti-TNFa treatment. Autoimmun Rev. 2007;7:35–41. 2. Ramos-Casals M, Brito-Zerón P, Cuadrado MJ, Khamashta MA. Vasculitis induced by tumor necrosis factor–targeted therapies. Curr Rheumatol Rep. 2008;10:442–448. 3. Baronnet L, Barnetche T, Kahn V, Lacoin C, Richez C, Schaeverbeke T. Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review. Joint Bone Spine. 2011;78:279–284.
4. Marie I, Guglielmino E. Infections opportunistes non tuberculeuses au cours des traitements par les anti-TNFa. Rev Med Interne. 2010;5:353–360. 5. Lahita Robert Gbr, Vernace Melchiore Alh. Vasculitis, vitiligo, thyroiditis, and altered hormone levels after anti-tumor necrosis factor therapy. J Rheumatol. 2011;38:579–580. 6. Ramos-Casals M, Brito-Zero P, Soto MJ, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNFtargeted therapies. Best Pract Res Clin Rheumatol. 2008;22: 847–861. 7. Saint Marcoux B, De Bandt M. Vasculitides induced by TNFa antagonists: a study in 39 patients in France. Joint Bone Spine. 2006;73:710–713. 8. Srivastava MD, Alexandery F, Tuthillz RJ. Immunology of cutaneous vasculitis associated with both etanercept and infliximab. Scand J Immunol. 2005;61:329–336. 9. Fujikawa K, Kawakami A, Hayashi T, et al. Cutaneous vasculitis induced by TNF inhibitors: a report of three cases. Mod Rheumatol. 2010;20:86–89. 10. Livermore PA, Murray KJ. Anti-tumour necrosis factor therapy associated with cutaneous vasculitis. Rheumatology. 2002;41:1450–1452.
Najah Boussetta* Leila Metoui Imen Gharsallah Maroua Mrouki Salah Othmani Department of Internal Medicine of Tunis Military Hospital, Tunisia *Corresponding author E-mail address: [email protected] (N. Boussetta)
http://dx.doi.org/10.1016/j.injr.2015.05.005 0973-3698/ # 2015 Indian Rheumatology Association. Published by Elsevier B.V. All rights reserved.
Erythroderma: A unique presentation of acute lupus A 38-year-old lady with no known co morbidities presented with complaints of red scaly non itchy lesions over body of 16 days duration. Lesions started from face and increased rapidly to involve rest of the body over three days. There was associated history of photosensitivity, however there was no history of joint pains, oral ulcers, loss of hair, fever, dyspnea on exertion or chest pain. There was no history of similar lesions in past, preceding drug intake or history of atopy in self and family. General physical examination revealed pallor and pedal edema. Dermatological examination revealed generalised involvement of body with erythema and scaling, Nikolsky sign was negative and there was no oral, ocular or genital mucosal involvement (Fig. 1). Rest of the systemic examination was within normal limits. Investigations revealed Hemoglobin – 5.6 gm/dL, Total Leukocyte Count – 3800/ mm3, Platelet Count – 1.8 lakh/mm3, Blood Urea – 96 mg/dL, Serum Creatinine – 2.6 mg/dL, ANA – 27 IU/mL, Anti dsDNA – Positive. Anti Ro/La, liver function test including SGOT, SGPT
were within normal limits. Hepatitis B surface antigen, Antibodies to HCV and HIV were negative. Histopathological examination of skin biopsy revealed normal epidermis, degeneration of basal layer and interface dermatitis (Fig. 2). In view of erythroderma initially drug hypersensitivity and pemphigus foliaceus were considered, however in view of ANA and Anti dsDNA positivity, kidney involvement, anemia, thrombocytopenia and compatible histopathological features she was diagnosed as a case of acute lupus erythematosus. She was treated with Prednisolone 1 mg/kg apart from supportive therapy. Three days after admission she had severe metabolic acidosis and needed hemodialysis and mechanical ventilation. Her condition did not improve and she died on day 5 of admission. Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease of unknown etiology. Skin is one of the target organ which is involved in SLE and involvement of skin not only leads to morbidity in SLE but also helps in early