Cutaneous polyarteritis nodosa
Cutaneous polyarteritis nodosa (PAN) is a rare form of vasculitis (inflammation of blood vessels) that involves small and medium-sized arteries of the dermis and subcutaneous tissue i.e. the deeper layers of the skin. It is sometimes called periarteritis nodosa.
Although identical skin lesions are common in systemic PAN, cutaneous PAN should be considered a separate disease and distinguished from systemic PAN as the clinical course and management of these conditions differ from each other. PAN is a vasculitis that causes destructive inflammation of medium-sized muscular arteries of multiple systems including the liver, kidney, heart, lung, gastrointestinal tract, musculoskeletal and nervous systems. Systemic PAN is a potentially life-threatening form of vasculitis whereas cutaneous PAN usually runs a chronic but benign course.
What is the cause of cutaneous PAN?
Cutaneous PAN results from a complex interaction of autoinflammatory and autoimmune factors, and immunodeficiency.
Autosomal recessive mutations in the CERC1 gene have been implicated in some patients with cutaneous polyarteritis nodosa. This genetic abnormality results in deficiency in the ADA2 protein (DADA2). DADA2 can also cause immunodeficiency. ADA2 is a plasma protein essential for development of endothelial cells (these line the blood vessel wall), and leucocytes (white blood cells). DADA2 leads to uncontrolled, chronic activity of neutrophils and damages endothelial cells.
In most cases of cutaneous PAN, the disease is triggered by certain infections, particularly Group A streptococcus, hepatitis B, Hepatitis C, Human Immunodeficiency virus, Parvovirus B19 (Fifth disease). Genetic defects lead to over-reaction to the infection.
What are the signs and symptoms of cutaneous PAN?
- Tender lumps appear under the skin, especially on the thighs and lower legs. These usually measure between 4-15 mm in diameter and follow along the course of medium-sized arteries.
- Larger inflammatory plaques may be seen. These tend to have nodules along the edges. As the plaques heal, they leave patches of postinflammatory pigmentation.
- Infarcts in the skin present as purple or black patches or blood-filled blisters. They are dead areas of skin due to blocked blood vessels.
- Blistering and ulceration may occur.
- Livedo reticularis can be seen as lesions radiate out in a
Lesions are most often found on the legs and feet. Other areas that may be affected include the arms, trunk, buttocks, and head and neck. They are most likely on pressure points such as the knees, back of the foot and lower leg.
In addition to the skin problems, patients may also have generalised symptoms such as malaise, fever, sore throat, and joint and muscle aches and pains. Neurological symptoms may also be present and include numbness, tingling, sensory disturbances, weakness, and absent reflexes.
Diagnosis of cutaneous PAN
Skin biopsy of a typical lesion is often performed to make an accurate diagnosis of cutaneous PAN. A specimen showing panarteritis (inflammation of all blood vessels in the skin sample) is the only definitive proof of PAN.
Laboratory tests of blood samples are generally unhelpful in diagnosing or monitoring cutaneous PAN, as blood counts and chemistry are often normal. They are initially required to determine the cause of vasculitis or to exclude other organ involvement as occurs in systemic PAN.
Levels of ADA2 protein and/or CERC1can be measured in some centres.
What is the treatment of cutaneous PAN?
Cutaneous PAN usually runs a chronic course lasting from months to years with exacerbations and remissions. Neurological symptoms and muscular aches and pains usually resolve over a matter of months whilst skin lesions take longer to heal.
Remissions may occur spontaneously or after treatment with oral corticosteroids , cyclophosphamide or other immunosuppressive medications used to control the acute exacerbation and relieve pain. They can be stopped as symptoms become less severe or subside. Intravenous immunoglobulin has been used successfully.
Non-steroidal anti-inflammatory drugs are also used and are suitable alternative first-line agents in patients when corticosteroids are contraindicated. Colchicine may also be used.
Ulcerating skin lesions may be treated with bland topical preparations such as active manuka honey and covered with special dressings to improve healing. Occasionally skin grafts are advised but they may fail because of the damage to the blood vessels supplying nutrition to the skin.
Warfarin (with a international normalised ratio [INR] of 3) has been reported to be effective in 3 cases of cutaneous polyarteritis nodosa with improvement in livedo reticularis and healing of ulcers.
New therapies are being developed for patients with cutaneous PAN that have DADA2. These unproven treatments include:
- Recombinant ADA2 protein
- Fresh frozen plasma
- Haematopoietic cell transplantation
- Anti-TNFα biologics (if TNFα is elevated)
- Anti-interleukin 6-blocking agents (eg, tocilizumab)
- Book: Textbook of Dermatology. Ed Rook A, Wilkinson DS, Ebling FJB, Champion RH, Burton JL. Fourth edition. Blackwell Scientific Publications.
- Khoo BP and Ng SK. Cutaneous Polyarteritis Nodosa: A Case Report and Literature Review. Ann Acad Med Singapore 1998; 27:868-72.
- Kawakami T, Soma Y. Use of warfarin therapy at a target international normalized ratio of 3.0 for cutaneous polyarteritis nodosa. J Am Acad Dermatol. 2010 Oct;63(4):602-6. Epub 2010 Aug 2.
- Marie I, Miranda S, Girszyn N, Soubrane J-C, Vandhuick T, Levesque H. Intravenous immunoglobulins as treatment of severe cutaneous polyarteritis nodosa. Internal Medicine Journal 2012;42:459-462.
- Gonzalez Santiago TM, Zavialov A, Saarela J, Seppanen M, Reed AM, Abraham RS, Gibson LE. Dermatologic Features of ADA2 Deficiency in Cutaneous Polyarteritis Nodosa. JAMA Dermatol. 2015 Jul 1. doi: 10.1001/jamadermatol.2015.1635. [Epub ahead of print] PubMed PMID: 26131734.
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