http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(4): 688–689 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.874737
Young male patient diagnosed with cutaneous polyarteritis nodosa successfully treated with etanercept Lara Valor, Indalecio Monteagudo, Inmaculada de la Torre, Carlos González Fernández, María Montoro, Javier López Longo, and Luis Carreño Rheumatology Department, Gregorio Marañón University, General Hospital, Madrid, Spain Abstract
Cutaneous polyarteritis nodosa (CPAN) is a form of necrotizing vasculitis of small and mediumsized arteries. It is limited to the skin and has a recurrent and chronic course, possibly associated with fever, arthralgia, myalgia and neuropathy, but without visceral involvement. We report the clinical case of a 7-year-old male patient with CPAN refractory to treatment with high doses of corticoids and cyclophosphamide, who was successfully treated with the TNF-α (tumor necrosis factor-alpha) inhibitor, etanercept, in monotherapy.
Polyarteritis nodosa, Cutaneous polyarteritis nodosa (CPAN), Etanercept, TNF-α, Anti-TNF-α
Introduction Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis aﬀecting small and medium-sized muscular arteries, resulting in secondary tissue ischemia involving the kidneys, skin, joints, muscle, peripheral nerves and GI tract. The typical manifestations include systemic symptoms (fever, fatigue, malaise), and biopsy and/or arteriography are usually required for a deﬁnitive diagnosis [1, 2]. Cutaneous polyarteritis nodosa (CPAN) diﬀers from the systemic form of PAN in that it is limited to the skin and there is a lack of visceral involvement. Treatment with corticosteroids alone or in combination with cyclophosphamide, methotrexate or azathioprine, depending on disease severity, has been shown to be eﬀective [3, 4] and a risk of progression to systemic disease has been reported . TNF-α is a cytokine mainly produced by monocytes, macrophages and T-cells. It mediates inﬂammatory response and has immunoregulatory activity, aﬀecting lymphocyte activation and ﬁbroblast proliferation, regulating other cytokines, chemokines, prostaglandins, metalloproteinases, and aﬀecting blood vessels by promoting de novo angiogenesis, up-regulation of adhesion molecules and transendothelial leucocyte migration . Etanercept is a fully humanized, soluble TNF-α receptor that prevents soluble TNF-α from binding to its speciﬁc cell membrane receptor, leading to inhibition of the resulting inﬂammatory events . Paradoxically, anti-TNF-α therapy may also be associated with the induction of skin reactions, such as erythema nodosum and cutaneous vasculitis .
Case report A 7-year-old male patient with no history of allergies, previous infections requiring antibiotics or trauma, presented with L. Valor and I. Monteagudo contributed equally to this work. Correspondence to: L. Valor, Rheumatology Department, Gregorio Marañón University, General Hospital, Dr. Esquerdo 46, 28007 Madrid, Spain. Tel: ⫹ 34-91-5869211. Fax: ⫹ 34-91-5869210. E-mail: lvalor. [email protected]
History Received 26 June 2012 Accepted 28 December 2012 Published online 30 January 2013
multiple tender erythematous subcutaneous nodules, induration and ulcers in the lumbosacral region, right upper arm and lower limbs (including the heel of the right foot). The patient could not stand or walk. Pedal pulses were strong and symmetric. There were no clinical signs of peripheral neurologic involvement, and abdominal ultrasound examination and chest X-rays showed no systemic disease involvement. Laboratory ﬁndings were non-speciﬁc. Perinuclear antineutrophil cytoplasmic antibody (p-ANCA), anti-nuclear autoantibody (ANA), and parvovirus and cytomegalovirus (CMV) antibody testing were negative. Hepatitis B and C virus serology was also negative. Echocardiography and liver and renal function tests were normal. C-reactive protein (CRP) as an inﬂammation marker and other determinations, such as rheumatoid factor (RF), complement components (C3 and C4), cryoglobulin and immunoglobulin (IgA, IgM and IgG) levels, were consistently within normal limits. Antistreptolysin O (ASLO) titers were found to be positive in two sequential determinations with no clinical or microbiological correlation. Punch biopsy samples that included epidermis, superﬁcial dermis, deeper dermis and subcutaneous fat revealed dilated dermal vessels surrounded by a mixed inﬂammatory inﬁltrate, with clear predominance of neutrophils. The inﬂammatory lymphocyte inﬁltration, vessel occlusion and partially re-canalized thrombotic vessels were compatible with cutaneous vasculitis. CPAN was diagnosed and treatment with oral glucocorticoids was initiated (1 mg/kg/day), producing a partial response. Two weeks later, due to the persistence of lesions in the lower limbs and signiﬁcant functional limitations, the treatment strategy was switched to methylprednisolone (750 mg i.v. twice a week) and cyclophosphamide (2 mg/kg/day). This combination was discontinued after 3 months due to lack of eﬃcacy. Because it can be administered subcutaneously at low doses (25 mg/week), treatment with etanercept on a compassionate use basis was then suggested. Procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 1983. Written
Case report 689
monoclonal anti-TNF antibodies, the small amount of data available on biologic therapy in children with vasculitis, such as the retrospective study by Eleftheriou and colleagues , does seem to warrant the need for further investigation, including controlled studies, to establish the eﬀectiveness of therapeutic alternatives for this disease.
Acknowledgments We would like to thank the patient and his family for kindly granting permission to publish the pictures that illustrate this case report. The authors have no funding to declare.
Conﬂict of interests None. Figure 1. Appearance of the lesions on both feet, with indurated, erythematous nodules.
informed consent was obtained from the patient prior to publication of this case report and any accompanying images. Etanercept monotherapy administered subcutaneously 25 mg once a week led to a marked improvement of the patient’s lesions within 1 month. After the fourth injection, most of the subcutaneous nodules and skin ulcers had disappeared. Three months later, the patient presented complete clinical remission of his CPAN. To date, 7 years after diagnosis, there has been no recurrence with this treatment plan and the patient continues to receive etanercept at a dose of 25 mg/2 weeks. The patient currently remains in absolute clinical remission and any attempt to further reduce etanercept dosing or any lengthening of the intervals between doses have resulted in prompt appearance of painful nodular skin lesions (Fig. 1).
Discussion In spite of the fact that the underlying cause of pathogenic CPAN is still unknown, deregulated immune mechanisms appear to be involved. No predisposing antigen has been identiﬁed to date, although some evidence indicates that immune complexes (IgM) caused by infectious agents could precipitate complement activation. Patients with certain lymphomas, leukemias, rheumatoid arthritis or Sjögren’s syndrome may develop systemic or cutaneous PAN, and infectious diseases, such as streptococcal infection, have also been associated with onset of the disease [9, 10]. Anti-TNF-α drugs, monoclonal antibodies (adalimumab and inﬂiximab) and the soluble TNF-α-receptor (etanercept) are indicated in the treatment of rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis and have shown a good safety and eﬃcacy proﬁle. Elevated TNF-α levels (both in serum and biopsy) have been described in other vasculitis entities [11–13], so anti-TNF-α drugs may present a new therapeutic option for some patients with CPAN refractory to the usual treatment strategies, preventing possible relapses and/or transition to systemic disease [5, 14, 15]. Although the use of TNF-α blockade to treat panarteritis has been the focus of some works in the literature, very little information is available about pediatric patients. There is only one previous report on the pediatric use of etanercept in panarteritis from Feinstein and Arroyo, who used the compound in a 14-year-old child . These authors also report success and clinical remission. The signiﬁcant improvement observed in this second case, reported here, suggests that etanercept could be an eﬀective alternative treatment for CPAN. Although some authors have suggested that etanercept may be less eﬀective than chimeric
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