Cutaneous Polyarteritis Nodosa Sine Nodosa Erica Merman, Cheryl Rosen, Danny Ghazarian, Ayman Al Haheeb, and Sanjay Siddha

Background and Objective: C u ta n e o u s p o ly a rte ritis n o d o sa, a fo rm o f v a sc u litis a ffe c tin g th e s m all to m e d iu m sized a rterie s, m o s t c o m m o n ly p re s e n ts as te n d e r s u b c u ta n e o u s n o d u le s o v e r t h e lo w e r leg s an d fe e t. O th e r fe a tu re s in c lu d e liv ed o re tic u la ris , skin ulcers an d te n d e r in d u ra te d p laqu es.

Conclusion: W e re p o rt a 5 1 -y e a r o ld w o m a n w ith a p rim a rily liv ed o re tic u la ris p re s e n ta tio n o f c u ta n e o u s p o ly a rte ritis nod o sa w ith o u t a n o d u la r c o m p o n e n t.

Contexte et objectif: La p o ly a rte rite n o u eu se c u ta n e e , u ne fo rm e d e v a s c u la rite to u c h a n t les a rteres d e p e tit e t d e m o y e n calib re, se m a n ife s te s u rto u t p ar d es n o d u le s so u s-cu tan e s, sensibles, situ es le lon g d e la p a rtie in fe rie u re d e la ja m b e e t du p ied. Les a u tre s m a n ife s ta tio n s c o m p re n n e n t le liv ed o re tic u la ire , d es u lceres c u tan es , e t d es p la q u es in d u ree s, sensibles.

Conclusion: S era e x p o s e ici le cas d 'u n e fe m m e d e 51 ans, s o u ffra n t p rin c ip a le m e n t d e liv ed o re tic u la ire lie a u n e p o ly a rte rite n o u e u s e c u ta n e e m a is e x e m p te d e n odules.

51-year-old woman was seen in December 2012 with a widespread skin eruption that began 4 years prior to presentation. The lesions first developed on her lower legs and later spread proximally to her knees. They were pruritic and painful, with accompanying swelling and arthralgias in both knees. On review of symptoms, she denied any neurologic or constitutional symptoms, oral or nasal ulcers, hair loss, Raynaud phenomenon, or a malar rash. Her workup included a normal arterial duplex sonogram of the lower legs and a venous Doppler sonogram that demonstrated superficial thrombophlebitis. A previous biopsy showed unremarkable epithelium with minimal perivascular lymphocytic infiltrate. There was no evidence of vasculitis, eosinophils, or granulomatous inflammation. Her past medical history included hypothyroidism, and her line of employment required that she stand for 12 hours a day on an assembly line. Her treatment included compression stockings, hydroxychlor­ oquine (started in 2009), methotrexate (started May 2012),


From Undergraduate Medicine, University o f Toronto; Division of Dermatology, and Department of Pathology, University Health Network Hospitals, Toronto, ON. Address reprint requests to: Erica Merman, Undergraduate Medicine, University of Toronto, 1 Kings College Circle, Rm 2111 Toronto, ON M5S 1A8; e-mail: [email protected]

DOI 10.2310/7750.2014.13165 © 2014 Canadian Dermatology Association

and oral prednisone (started on 20 mg in June 2012) on an alternating tapering dose of 7.5 mg and 5 mg daily. On examination, the patient appeared well and noncachectic. She was afebrile, with stable vital signs. Livedo reticularis was noted on both legs up to the knee. The livedo was violaceous to erythematous, blanchable, and without ulceration. It was accompanied by bilateral knee swelling, left more than right. Nodular elevation was absent, with poorly circumscribed areas of swelling over the flexor surfaces of both feet (Figure 1 and Figure 2). The clinical appearance was suggestive of a livedo vasculopathy or polyarteritis nodosa (PAN), and a skin biopsy from an area of livedo on the left leg was taken. The histology showed an infiltrate of plasma cells and neutrophils suggestive of a necrotizing vasculitis (Figure 3), and the location of the vessels at the dermal subcutaneous junction was in keeping with a diagnosis of PAN. Inflammatory and coagulopathic bloodwork was also ordered. A complete blood count showed a slight leukocytosis, 13.4 X 109/L (normal range 4-10 X 109/L); neutrophilia, 10.2 X 109/L (normal range 2.5- 7.5 X 109/L); elevated erythrocyte sedimentation rate (ESR), 38 mm/hr (normal range 125 mm/hr); and elevated C-reactive protein, 31 mg/L (normal range < 10 mg/L). Antinuclear antibody (ANA), antiphospholipid antibody (APLAB), and antineutrophil cytoplasmic antibody (ANCA) were all negative, and complement levels and factor V activity were within normal limits. Other investigations, including liver func­ tion tests, serum creatinine kinase, urine microscopy,

DECKER^ C anadian D erm atology A ssociation I Journal o f Cutaneous Medicine and Surgery, Vol 18, N o 6 (November/December), 2014: pp 420-423

Cutaneous Polyarteritis Nodosa Sine Nodosa



Figure 1. Livedo reticularis on initial presentation.

hepatitis B surface antigen (HBsAg), anti-hepatitis B core antibody (anti-HBc) IgM, chest radiography, and electro­ cardiography, were all negative or within normal ranges. The patient was instructed to continue on her current regimen of prednisone (5 mg/7.5 mg alternating days), hydroxychloroquine (400 mg five times/week), and methotrexate (20 mg weekly). She was also started on pentoxifylline 400 mg three times daily. When seen 1 month later, her skin lesions had improved. The livedo pattern appeared faded, with minimal swelling on both feet. The patient was instructed to continue with her current medication regimen. At the next visit, her rash continued to fade, and the swelling had largely subsided. She was asked to increase the dose of prednisone to 20 mg with a gradual taper to follow, in an attempt to prevent future eruptions.

Figure 3. Infiltrate of plasma cells and neutrophils at the dermal subcuta­ neous junction (hematolxylin and eosin stain; X 100 original magnification).

Discussion Cutaneous polyarteritis nodosa (CPAN) is a rare form of vasculitis affecting the small to medium-sized arteries in the dermis and subcutaneous tissue.1 Although the etiology of CPAN remains unclear, an immune complexmediated pathogenesis has been proposed, involving IgM and C3 deposition in affected tissue.1 Whereas juvenile CPAN is often a reaction to an infection and self-limited, adult CPAN is often a chronic, persistent condition. CPAN is characterized clinically by tender subcutaneous nodules, infarcts in the form of black or purple patches, and livedo reticularis with or without ulceration.2 The lesions are mostly found over the legs and feet, and although systemic involvement is rare, there can be extracutaneous features, including arthralgias, arthritis, neuropathy, and myopa­ thy.3 CPAN has a chronic and relapsing course and should be distinguished from PAN, which presents with systemic involvement of the kidneys, liver, heart, or gastrointestinal tract and has a different clinical course, management, and prognosis.4 In a recent vasculitis classification system, CPAN is considered a “single-organ vasculitis” and termed

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Merman et al

“cutaneous arteritis” to separate it from classic PAN.5 Although systemic PAN is rare, CPAN is even more so, and its true incidence is unknown.6 Skin biopsy is the basis for diagnosis as there are no specific serologic tests for CPAN. A biopsy of a cutaneous lesion may show segmentary leukocytoclastic vasculitis involving the arteries of the deep dermis and/or hypodermis with lymphocytic infiltrates within and around the arterial wall. Treatment is not definitive, but symptoms are controlled with the use of steroids and immunosuppressants.

Clinical Presentation In CPAN, the primary site of involvement is the legs, with > 95% of lesions located in this region/ An extensive retrospective study analyzing 79 cases of CPAN found that painful nodules on the lower extremities with associated swelling and edema were the most common clinical findings, found in 80% of the reported cases/ Other notable findings include livedo reticularis in 56%, skin ulcers in 49%, and tender indurated plaques in 10% of cases.8 A subset of CPAN patients have also been described as presenting with atrophie blanche as the predominant skin finding in the absence of venous insufficiency.9 In our patient, the classic nodular presentation was absent, with only minimal swollen and firm areas over the feet. The predominant feature was diffuse livedo reticularis that was violaceous to erythematous and blanchable. The livedo reticularis was diffuse and not limited to the swollen areas. Our patient did have some extracutaneous symptoms, as reported in the literature, including myalgias and arthral­ gias of the knees. Patients with CPAN can also present with neurologic symptoms, including numbness, paresthesia, and areflexia, which were all absent in our patient. Due to the lack of distinct nodules, the presence of livedo reticularis, and the nonspecific extracutaneous symptoms, a skin biopsy was essential in elucidating the final diagnosis.

Differential Diagnosis The following conditions should be considered part of a thorough differential diagnosis of CPAN10: 1. Systemic PAN 2. Erythema nodosum 3. ANCA-associated vasculitides: Churg-Strauss syn­ drome, microscopic polyangiitis, and granulomatosis with polyangiitis 4. Cryoglobinemic vasculitis

5. Livedo vasculopathy: systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, and scleroderma 6. Erythema induratum 7. Urticarial vasculitis

Diagnosis Skin biopsies are required for the diagnosis of CPAN and are guided by clinical suspicion. Biopsy specimens will reveal a leukocytoclastic vasculitis in the small and medium-sized vessels of the dermis or subcutaneous tissue. Four specific stages of histologic findings in CPAN have been reported, each with a characteristic appearance.4 The degenerative stage will show deposition of fibrinoid material with destruction of the elastic laminae of the vessel.5 The acute inflammatory stage will show a neutrophilic infiltrate with some eosinophils in and around the arterial wall.11 In the granulation stage, the infiltrate is made up of lymphocytes and macrophages along with proliferation of the intima and thrombosis of the artery. The end stage will show fibroblastic proliferation extending perivascularly,12 as was the case with the biopsy specimen from our patient. Some literature also suggests that two skin biopsies with consecutive deeper sections are required to establish an accurate diagnosis of CPAN.13 However, the presence of vasculitis in the small to medium-sized arteries on histology is not enough to diagnose CPAN. Further investigations should include baseline blood pressure, complete blood count, ESR, liver and renal function tests, cryoglobulins, ANA, ANCA, rheumatoid factor, and complement levels to rule out other vasculitides and to distinguish CPAN from systemic PAN.4 Further evaluation should be based on specific symptoms. The cause for the onset of the vasculitis should also be investigated using ASO titers or throat culture, viral hepatitis serology, tuberculin skin testing, and evaluation for other medical conditions.4

Management The mainstay of treatment for CPAN involves high-dose systemic corticosteroids.14 However, in mild cases of CPAN, primarily consisting of nodules and livedo reticularis, nonsteroidal antiinflammatory drugs (NSAIDs) may suffice.10 Topical corticosteroids, such as 0.1% mometasone furoate cream, may also be effective in minor cases presenting with erythema alone, reported in one case to result in complete regression of cutaneous lesions in less than 1 month.15

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As was the case with our patient, individuals who do not respond to NSAIDs or topical treatments should be started on high-dose systemic corticosteroids. Prednisolone is often effective for controlling acute exacerbations of CPAN, but a dosage of 1 mg/kg/day might be required.1,5 Due to the side effects associated with long-term steroid use and the occurrence of acute exacerbations during cortico­ steroid taper, an additional medication is often required to control the disease. Such medications include cyclopho­ sphamide,14 methotrexate,16,17 sulfapyridine,11 nicotinic acid/ and pentoxifylline.18'19 These agents are used in conjunction with corticosteroids and can be effective in treating CP AN resistant to high-dose corticosteroids alone. In our case, the patient was treated with a corticoster­ oid and methotrexate without sufficient relief of her symptoms. Pentoxifylline, a synthetic xanthine derivative, which has been shown anecdotally to be efficacious in the treatment of CPAN,18,19 was added to the treatment regimen. Pentoxifylline increases erythrocyte deformability, reduces blood viscosity, and inhibits platelet aggregation and thrombosis;18 however, its mechanism of action in the treatment of CPAN remain unclear.10 The course of CPAN is chronic, with relapses and remissions that may occur spontaneously or following treatment. Despite this, the prognosis of the disease is favorable, with no known mortality from the disease itself.10 Treatment with medication targets not only the cutaneous lesions but may also lead to the resolution of extracutaneous symptoms, including myalgias, arthralgias, and paresthesias. Follow-up should continue biannually during asymptomatic periods to monitor for the development of systemic PAN.10

Conclusion Although nodules of the lower extremity are typically the most prominent feature of CPAN, a more unusual pattern of presentation with livedo reticularis and swelling without distinct nodules can be seen. A high index of clinical suspicion is important in making the diagnosis and initiating successful treatment. Although there is no specific serologic testing, skin biopsy is the current gold standard for diagnosis of CPAN. The mainstay of treat­ ment is oral corticosteroids and immunosuppressants; however, additional medications, including pentoxyfylline, may be considered in refractory cases.

Acknowledgment Financial disclosure of authors and reviewers: None reported.

References 1. Khoo BP, Ng SK. Cutaneous polyarteritis nodosa: a case report and literature review. Ann Acad Med Singapore 1998;27:868-72. 2. Gupta S, Duggal L, Jain N. Cutaneous polyarteritis nodosa - a rare benign vasculitis. J Indian Acad Clin Med 2006;7:159-60. 3. Praveen KS, Singh NV, Swaminathan RP. Cutaneous polyarteritis nodosa: a rare isolated cutaneous vasculitis. Indian Dermatol Online J 2012;3(l):21-4, doi: 10.4103/2229-5178.93488. 4. Bauza A, Espana A, Idoate M. Cutaneous polyarteritis nodosa. Br I Dermatol 2002;146:694-9, doi: 10.1046/j. 1365-2133.2002. 04624.x. 5. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;651:1-11, doi:10.1002/art.37715. 6. Borrie P. Cutaneous polyarteritis nodosa. Br J Dermatol 1972;87: 87-95, doi:10.1111/j. 1365-2133.1972,tbl6181.x. 7. Diaz-Perez JL, Winkelmann RK. Cutaneous periarteritis nodosa: a study of 33 cases. Mahor Probl Dermatol 1980;10:273-84. 8. Daoud MS, Hutton KP, Gibson LE. Cutaneous polyarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol 1997;136:706-13, doi:10.1111/j.l365-2133.1997.tb03656.x. 9. Mimouni D, Ng PP, Rencic A, et al. Cutaneous polyarteritis nodosa in patients presenting with atrophie blanche. Br J Dermatol 2003;148:789-94, doi: 10.1046/j. 1365-2133.2003.05176.x. 10. Morgan HJ, Schwartz RA. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol 2010;49:750-6. 11. Diaz-Perez JL, Winkelman RK. Cutaneous periarteritis nodosa. Arch Dermatol 1974;110:407-14, doi:10.1001/archderm. 1974,016 30090045009. 12. Chen KR. Cutaneous polyarteritis nodosa: a clinical and histopathological study of 20 cases. J Dermatol 1989;16:429-42. 13. Kawakami T, Kimura S, Takeuchi S, Soma Y. Significance of two skin biopsy performances with consecutive deeper sections in the differential diagnosis between cutaneous polyarteritis nodosa and livedo vasculopathy. Acta Derm Venereol 2014;94:84-5, doi:10. 2340/00015555-1603. 14. Kawakami T, Okudaira A, Okano T, et al. Treatment for cutaneous arteritis patients with mononeuritis multiplex and elevated Creactive protein. J Dermatol 2013;40:1004-7, doi:10.1111/13468138.12302. 15. Rogalski C, Sticherling M. Panarteritis cutanea benigna - an entity limited to the skin or cutaneous presentation of a systemic necrotizing vasculitis? Report of seven cases and review of the literature. Int J Dermatol 2007;46:817-21, doi: 10.1111/j, 1365-4632.2007.02975.X. 16. Mitchell MS, Gifford RH, Bertino JR. The treatment of disseminated vasculitis with methotrexate. Inflammation 1976; 1: 285-95, doi: 10.1007/BF00917868. 17. Tannenbaum H. Combined therapy with methotrexate and prednisolone in polyarteritis nodosa. Can Med Assoc J 1980;123: 893-4. 18. Calderon MJ, Landa N, Aguirre A, Diaz-Perez JL. Successful treatment of cutaneous PAN with pentoxifylline. Br J Dermatol 1993;128:706-8, doi:10.1111/i.l365-2133.1993.tb00276.x. 19. Kluger N, Guillot B, Bessis D. Ulcerative cutaneous polyarteritis nodosa treated with mycophenolate mofetil and pentoxifylline. J Dermatolog Treat 2011;22:175-7, doi:10.3109/0954663100363 6809.

Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol IS, No 6 (November/December), 2014: pp 420-423


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Cutaneous polyarteritis nodosa sine nodosa.

Cutaneous polyarteritis nodosa, a form of vasculitis affecting the small to medium sized arteries, most commonly presents as tender subcutaneous nodul...
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