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Cutaneous polyarteritis nodosa
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Polyarteritis nodosa (PAN) is a necrotizing vasculitis that predominately involves medium-sized arteries. Small arteries may also be targeted, but small vessels (arterioles, capillaries, and venules) are not. Classic PAN is characterized by fever, weight loss, cutaneous ulcers, livedo reticularis, myalgias and weakness, arthralgias or arthritis, neuropathy, abdominal pain, ischemic bowel, testicular pain, hypertension, and renal failure. By contrast, cutaneous PAN (cPAN), sometimes termed benign cutaneous polyarteritis, is a localized necrotizing arteritis that does not affect internal organs and runs a chronic but benign course. It is characterized by livedo reticularis, retiform purpura, tender nodules, digital infarction, and ulceration. cPAN most often affects the legs but can appear on the arms and trunk. Extracutaneous manifestations can include fever, malaise, myalgias, arthralgias, and neuropathy. Many reports have linked cPAN to infections including group A streptococcus (most common), hepatitis B and C, parvovirus B19, Mycobacterium tuberculosis , and urinary tract pathogens. Inflammatory bowel disease, hairy cell leukemia, and minocycline exposure are also associated with cPAN. Occasional reports have linked cPAN to antiphospholipid antibodies, cryoglobulins, or antineutrophil cytoplasmic antibodies (pANCA or atypical ANCA more commonly than cANCA), but these are typically negative/normal in cPAN. One recent report has demonstrated that interleukin-6 is elevated in roughly 40% of patients. A mutation in the CERC1 gene leading to deficiency in the ADA2 protein has been identified in some patients with early cPAN and early-onset vasculopathy. cPAN is seen more commonly in women than men (ratio of 1.7:1 in one study) in contrast to PAN, which is more common in men. Age of onset is typically between ages 30 and 50 but children can also be affected.
Management Strategy
cPAN causes pain and discomfort and may ulcerate, thereby causing disability. Therapy may include local measures, for example, gradient pressure stockings, or systemic therapies, including colchicine, dapsone, pentoxifylline, hydroxychloroquine, systemic corticosteroids, methotrexate, azathioprine, cyclophosphamide, infliximab, etanercept, rituximab, and intravenous immunoglobulin (IVIG). Most of the reports are anecdotes or small case series.
Treatment is often indicated for underlying and associated conditions.
Specific Investigations
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Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases
Daoud MS, Hutton KP, Gibson LE. Br J Dermatol 1997; 136: 706–13.
In this analysis, ulceration was associated with neuropathy and a prolonged course. Most patients (60%) had no associated medical condition. Systemic PAN did not develop in any patient. Corticosteroids, azathioprine, pentoxifylline, and hydroxychloroquine appeared effective in individual patients, and patients with non-ulcerative disease responded better than those with ulcers.
Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy
Navon Elkan P, Pierce SB, Segel R, et al. N Engl J Med 2014; 370(10): 92.
This study identified recessive loss of function mutations in CECR1 , the gene encoding adenosine deaminase 2 (ADA2), in six families with multiple cases of systemic or cutaneous PAN.
Clinical and laboratory markers associated with relapse in cutaneous polyarteritis nodosa
Kato A, Hamada T, Miyake T, et al. JAMA Dermatol 2018; 154(8): 922.
In this retrospective case series of cPAN, pretreatment cutaneous ulcer, and high C-reactive protein levels, absolute neutrophil count, neutrophil-to-lymphocyte ratio, and systemic immune-inflammation indices were associated with relapse; arthropathy and neuropathy were not.
High titer of phosphatidylserine–prothrombin complex antibodies in patients with cutaneous polyarteritis nodosa
Kawakami T, Yamazaki M, Mizoguchi M, et al. Arthritis Rheum 2007; 57: 1507–13.
Antiphosphatidylserine–prothrombin complex and/or anticardiolipin antibodies were positive in all 16 cPAN patients tested compared with none in the control group.
Epidemiological, clinical and laboratory profiles of cutaneous polyarteritis nodosa patients: report of 22 cases and literature review
Criado PR, Marques GF, Morita TC, et al. Autoimmun Rev 2016; 15: 558–63.
cPAN was more prevalent in women (77%) with a mean age at time of diagnosis of 39.4 years (9–61 years). Clinical manifestations in decreasing order of frequency were ulcers, livedo racemosa, subcutaneous nodules, atrophie blanche, and purpura. Lower limbs were affected in all cases, but trunk and upper limbs were affected at equal frequency of 27%. No cases of cPAN progressed to systemic PAN. Symptoms reported were pain (64%) and paresthesias (30%). Twenty-three percent were diagnosed with mononeuritis multiplex. The most common infectious agent in this study was Mycobacterium tuberculosis .
Polyarteritis-like vasculitis in association with minocycline use: a single center case series
Kermani T, Ham E, Camilleri M, et al. Semin Arthritis Rheum 2012; 42: 213–21.
Nine cases occurring in the context of minocycline use – four with cutaneous-only disease. All had positive pANCA. Minocycline was discontinued, and six patients required immunosuppressive therapy.
Vasculitic conditions mimicking cPAN have also been reported with isotretinoin and amphetamines.
Manifestations, clinical course and prognostic markers in cutaneous polyarteritis nodosa
Munera-Campos M, Bielsa I, Martínez-Morillo M, et al. J Dtsch Dermatol Ges 2020; 18(11):1250-1259.
In a series of 31 patients, cPAN manifestations were nodules (90.3%), livedo reticularis (45.2%), ulceration (35.5 %), livedo racemosa (12.9%) and purpura (3.2%). At least one extracutaneous manifestation was reported in 67.7% of patients—myalgia (58.1%), paresthesia (45.2%) and arthralgia without arthritis (19.4%). Mononeuritis multiplex was noted in 9 of 21 patients (29%) who had electroneuromyography. The most common comorbid conditions were hypertension (22.6%), Type 2 diabetes mellitus (16.1%) and autoimmune hypothyroidism (9.68%). Relapse was seen in 17 (54.8%) of patients. Ulceration at presentation was the strongest predictor of relapse.
First-Line Therapies
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