G Model BONSOI-3952; No. of Pages 2
ARTICLE IN PRESS Joint Bone Spine xxx (2013) xxx–xxx
Available online at www.sciencedirect.com
Letter to the Editor Remission induced by infliximab in a childhood polyarteritis nodosa refractory to conventional immunosuppression and rituximab
a r t i c l e
i n f o
Keywords: Juvenile polyarteritis nodosa Juvenile cutaneous polyarteritis nodosa Remission Rituximab Infliximab
1. Introduction Cutaneous polyarteritis nodosa (PAN) is recognized as a separate entity and is characterized by skin involvement with no major organ affected [1]. Cutaneous PAN tends to remain localized to the skin, although some cases may evolve into full-blown PAN [2]. 2. Case report In 1998, a 3-year-old boy presented with a 1 month history of daily fever, ankles and knees arthritis and subcutaneous nodular, painful, purpuric lesions in his legs, arms and forearms. Investigations showed ESR 63 mm/h, CRP 7 mg/dL, normal kidney and liver function tests. Immunoglobulins and complement fractions were normal. Antinuclear antibodies, anti-neutrophil cytoplasm antibodies and rheumatoid factor were negative. Antistreptolysin O titers normal. Throat swab, blood and urine cultures were sterile. Serology for Epstein-Barr virus, cytomegalovirus, Hepatitis B virus, Parvovirus, Brucella mellitensis, Streptococcus pneumoniae and Borrelia burgdorferi were negative. Chest radiograph and echocardiogram were normal. Abdominal ultrasound showed mild splenomegaly. Skin biopsy showed a necrotizing nongranulomatous vasculitis typical of PAN. A diagnosis of cutaneous PAN was made. He was given 2 mg/kg/day of prednisolone (PDN) and after 24 h became asymptomatic. He remained asymptomatic for 10 years, without any therapy, but when he was 13 years old (2008) he had a relapse, with daily fever, arthritis, subcutaneous nodules, and raised inflammatory markers. He was started on 0.5 mg/kg/day (20 mg) of PDN and within 72 h became asymptomatic. Methotrexate (MTX) 15 mg/m2 (20 mg per week) was added, however he relapsed whenever PDN doses inferior to 20 mg/day (0.5 mg/kg/day) were used. A full reassessment was done, this time including also tuberculin skin test, electromyography and angio-CT, which were all normal. Skin biopsy was repeated showing again a necrotizing non-granulomatous vasculitis, with fibrin deposits and multiple neutrophils (Fig. 1).
Fig. 1. Nodule skin biopsy (histopathology) – necrotizing non-granulomatous vasculitis, with fibrin deposits and infiltrated by multiple neutrophils.
Six monthly pulses of 500 mg (370 mg/m2 ) intravenous cyclophosphamide (CYC) were given between 2009 and 2010, with no efficacy. In a subsequent attempt to wean corticosteroids, rituximab (RTX, 528 mg/weekly for 4 weeks-375 mg/m2 ) was administered in January 2011, again with symptoms relapsing whenever PDN was reduced. In September 2011, he was admitted with acute testicular vasculitis, which responded to 3 pulses of intravenously methylprednisolone (30 mg/kg/day, maximum 1 g/day). Infliximab (IFX) was started in October 2011, in a dose of 5 mg/kg at 0, 2 and 6 weeks and then every 8 weeks. Within one month, PDN dose was reduced from 40 mg to 30 mg with no disease flares. After 6 months on IFX, he was asymptomatic and on 10 mg of PDN. One year after starting IFX, the patient was in remission and off PDN. No side effects were observed.
3. Discussion This initially cutaneous PAN developed systemic symptoms, which were corticodependent, despite treatment with MTX and CYC. Recent reports suggest that patients refractory to conventional therapy might respond to TNF blockers or RTX [3–5]. We offered RTX treatment with no clinical benefit but the patient responded exceedingly well to IFX. This case highlights that cutaneous PAN can develop severe refractory systemic symptoms (in line with 5 previously reported cases) [6] and that IFX might be more effective than RTX for the treatment of refractory and corticosteroid dependent PAN.
1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.11.009
Please cite this article in press as: Campanilho-Marques R, et al. Remission induced by infliximab in a childhood polyarteritis nodosa refractory to conventional immunosuppression and rituximab. Joint Bone Spine (2013), doi:10.1016/j.jbspin.2013.11.009
G Model BONSOI-3952; No. of Pages 2
ARTICLE IN PRESS Letter to the Editor / Joint Bone Spine xxx (2013) xxx–xxx
2
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments The authors thank Prof. Soares de Almeida from the Dermatology Department and Dr Fátima Morais from the Radiology Department, both from Hospital de Santa Maria for the clinical discussion and for sharing the images. References [1] Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis 2010;69:798–806. [2] Dillon MJ, Eleftheriou D, Brogan PA. Medium-size-vessel vasculitis. Pediatr Nephrol 2010;25:1641–52. [3] Eleftheriou D, Melo M, Marks SD, et al. Biologic therapy in primary systemic vasculitis of the young. Rheumatology 2009;48:978–86. [4] de Kort S, van Rossum MAJ, Ten Cate R. Infliximab in a child with therapyresistant systemic vasculitis. Clin Rheumatol 2006;25:769–71. [5] Ribeiro E, Cressend T, Duffau P. Rituximab Efficacy during a Refractory Polyarteritis Nodosa Flare. Case Rep Med 2009;2009:738293.
[6] Bansal NK, Houghton KM. Cutaneous polyarteritis nodosa in childhood: a case report and review of the literature. Arthritis 2010, doi:10.1155/2010/687547.
Raquel Campanilho-Marques ∗ Filipa Ramos Rheumatology Department, Lisbon Academic Medical Centre, Portugal Helena Canhão João Eurico Fonseca Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal ∗ Corresponding author. Rheumatology Department, Hospital de Santa Maria, CHLN, Avenida Professor Egas Moniz, 1649-035 Lisbon, Portugal. Tel.: +35 121 780 5000. E-mail address: [email protected] (R. Campanilho-Marques)
Accepted 18 November 2013 Available online xxx
Please cite this article in press as: Campanilho-Marques R, et al. Remission induced by infliximab in a childhood polyarteritis nodosa refractory to conventional immunosuppression and rituximab. Joint Bone Spine (2013), doi:10.1016/j.jbspin.2013.11.009
ARTICLE IN PRESS Joint Bone Spine xxx (2013) xxx–xxx
Available online at www.sciencedirect.com
Letter to the Editor Remission induced by infliximab in a childhood polyarteritis nodosa refractory to conventional immunosuppression and rituximab
a r t i c l e
i n f o
Keywords: Juvenile polyarteritis nodosa Juvenile cutaneous polyarteritis nodosa Remission Rituximab Infliximab
1. Introduction Cutaneous polyarteritis nodosa (PAN) is recognized as a separate entity and is characterized by skin involvement with no major organ affected [1]. Cutaneous PAN tends to remain localized to the skin, although some cases may evolve into full-blown PAN [2]. 2. Case report In 1998, a 3-year-old boy presented with a 1 month history of daily fever, ankles and knees arthritis and subcutaneous nodular, painful, purpuric lesions in his legs, arms and forearms. Investigations showed ESR 63 mm/h, CRP 7 mg/dL, normal kidney and liver function tests. Immunoglobulins and complement fractions were normal. Antinuclear antibodies, anti-neutrophil cytoplasm antibodies and rheumatoid factor were negative. Antistreptolysin O titers normal. Throat swab, blood and urine cultures were sterile. Serology for Epstein-Barr virus, cytomegalovirus, Hepatitis B virus, Parvovirus, Brucella mellitensis, Streptococcus pneumoniae and Borrelia burgdorferi were negative. Chest radiograph and echocardiogram were normal. Abdominal ultrasound showed mild splenomegaly. Skin biopsy showed a necrotizing nongranulomatous vasculitis typical of PAN. A diagnosis of cutaneous PAN was made. He was given 2 mg/kg/day of prednisolone (PDN) and after 24 h became asymptomatic. He remained asymptomatic for 10 years, without any therapy, but when he was 13 years old (2008) he had a relapse, with daily fever, arthritis, subcutaneous nodules, and raised inflammatory markers. He was started on 0.5 mg/kg/day (20 mg) of PDN and within 72 h became asymptomatic. Methotrexate (MTX) 15 mg/m2 (20 mg per week) was added, however he relapsed whenever PDN doses inferior to 20 mg/day (0.5 mg/kg/day) were used. A full reassessment was done, this time including also tuberculin skin test, electromyography and angio-CT, which were all normal. Skin biopsy was repeated showing again a necrotizing non-granulomatous vasculitis, with fibrin deposits and multiple neutrophils (Fig. 1).
Fig. 1. Nodule skin biopsy (histopathology) – necrotizing non-granulomatous vasculitis, with fibrin deposits and infiltrated by multiple neutrophils.
Six monthly pulses of 500 mg (370 mg/m2 ) intravenous cyclophosphamide (CYC) were given between 2009 and 2010, with no efficacy. In a subsequent attempt to wean corticosteroids, rituximab (RTX, 528 mg/weekly for 4 weeks-375 mg/m2 ) was administered in January 2011, again with symptoms relapsing whenever PDN was reduced. In September 2011, he was admitted with acute testicular vasculitis, which responded to 3 pulses of intravenously methylprednisolone (30 mg/kg/day, maximum 1 g/day). Infliximab (IFX) was started in October 2011, in a dose of 5 mg/kg at 0, 2 and 6 weeks and then every 8 weeks. Within one month, PDN dose was reduced from 40 mg to 30 mg with no disease flares. After 6 months on IFX, he was asymptomatic and on 10 mg of PDN. One year after starting IFX, the patient was in remission and off PDN. No side effects were observed.
3. Discussion This initially cutaneous PAN developed systemic symptoms, which were corticodependent, despite treatment with MTX and CYC. Recent reports suggest that patients refractory to conventional therapy might respond to TNF blockers or RTX [3–5]. We offered RTX treatment with no clinical benefit but the patient responded exceedingly well to IFX. This case highlights that cutaneous PAN can develop severe refractory systemic symptoms (in line with 5 previously reported cases) [6] and that IFX might be more effective than RTX for the treatment of refractory and corticosteroid dependent PAN.
1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.11.009
Please cite this article in press as: Campanilho-Marques R, et al. Remission induced by infliximab in a childhood polyarteritis nodosa refractory to conventional immunosuppression and rituximab. Joint Bone Spine (2013), doi:10.1016/j.jbspin.2013.11.009
G Model BONSOI-3952; No. of Pages 2
ARTICLE IN PRESS Letter to the Editor / Joint Bone Spine xxx (2013) xxx–xxx
2
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments The authors thank Prof. Soares de Almeida from the Dermatology Department and Dr Fátima Morais from the Radiology Department, both from Hospital de Santa Maria for the clinical discussion and for sharing the images. References [1] Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis 2010;69:798–806. [2] Dillon MJ, Eleftheriou D, Brogan PA. Medium-size-vessel vasculitis. Pediatr Nephrol 2010;25:1641–52. [3] Eleftheriou D, Melo M, Marks SD, et al. Biologic therapy in primary systemic vasculitis of the young. Rheumatology 2009;48:978–86. [4] de Kort S, van Rossum MAJ, Ten Cate R. Infliximab in a child with therapyresistant systemic vasculitis. Clin Rheumatol 2006;25:769–71. [5] Ribeiro E, Cressend T, Duffau P. Rituximab Efficacy during a Refractory Polyarteritis Nodosa Flare. Case Rep Med 2009;2009:738293.
[6] Bansal NK, Houghton KM. Cutaneous polyarteritis nodosa in childhood: a case report and review of the literature. Arthritis 2010, doi:10.1155/2010/687547.
Raquel Campanilho-Marques ∗ Filipa Ramos Rheumatology Department, Lisbon Academic Medical Centre, Portugal Helena Canhão João Eurico Fonseca Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal ∗ Corresponding author. Rheumatology Department, Hospital de Santa Maria, CHLN, Avenida Professor Egas Moniz, 1649-035 Lisbon, Portugal. Tel.: +35 121 780 5000. E-mail address: [email protected] (R. Campanilho-Marques)
Accepted 18 November 2013 Available online xxx
Please cite this article in press as: Campanilho-Marques R, et al. Remission induced by infliximab in a childhood polyarteritis nodosa refractory to conventional immunosuppression and rituximab. Joint Bone Spine (2013), doi:10.1016/j.jbspin.2013.11.009
