Polyarteritis Nodosa

PAN has mulitsystem involvement and progresses within few weeks to months [13]. It may affect a single organ or lead to visceral failure. Symptoms depend on the affected organs

• Musculoskeletal involvement – patients with musculoskeletal involvement present with common symptoms like fever, malaise, myalgia, arthralgia, anorexia, and weight loss
• Central nervous system involvement – when CNS is involved, temporary monocular blindness, cerebral ischemia, and subarachnoid hemorrhage may result. Lesions in CNS usually happen 2-3 years after the onset of PAN. Stroke, seizure, and focal deficits also present with CNS involvement. 
• Peripheral nervous system involvement – about 60% of the patients present peripheral neuropathy. Mononeuritis multiplex, distal polyneuropathy, and cutaneous neuropathy are also reported. 
• Skin involvement – this is one of the most common symptoms of PAN and is more common in legs. Rash, gangrene, cutaneous infarcts, nodules and livedo reticularis may be seen as manifestations of skin involvement. 
• Gastrointestinal involvement – most of the symptoms of GI involvement are nonspecific like abdominal pain, nausea and vomiting. In serious cases of PAN, pancreatic infarction, cholecystitis, and intestinal perforation may be noted. 
• Renal involvement – vasculitis of arteries in the kidney may result in renal failure and/or hypertension. Many patients complain of flank pain. 
• Other organ involvement – when other organs and organ systems like genitourinary system are affected, additional symptoms may be presented. Pain in testicular or ovarian area, chest pain, congestive heart failure, myocardial infarction, blurred vision, headache, psychosis and depression also may be seen depending on the organ affected. 

PAN is an uncommon disease with many clinical manifestations that make diagnosis difficult. Many diseases that affect the vascular integrity or result in vascular occlusion may present PAN-like symptoms. Certain drugs are also known to cause manifestations similar to that of vasculitis. Thus, it is important to distinguish the different causes for better treatment and prognosis.
Among the different imaging techniques for diagnosis, angiography is suggested when the affected tissue is inaccessible. This is preferred for aneurysms and stenosis in medium-sized blood vessels. It is also useful in case of gastrointestinal involvement, particularly when liver and kidney functions are affected. Microaneurysms in small arteries can be revealed using arteriograms. CT scan and MRI are other imaging methods that are used to check varied manifestations of PAN. These imaging techniques may be used in case of nonspecific presentations like thickening in the wall of intestine, obstruction in bowel movement, and thickening of mucosal folds. MRI is also suggested in CNS involvement where intracranial hemorrhage is suspected. Electromyography facilitates the detection of peripheral neuropathy, one of the most common complication associated with PAN.
When the affected tissue is accessible, biopsy is recommended. This includes skin, skeletal muscle and testes. Biopsy of muscles and arteries enables identification of inflammation. Histology of the affected tissue will show the presence of cellular infiltration within the wall of the vessel. In nerve cells, axonal degeneration is seen with loss of fibrous tissue. Laboratory studies are helpful in finding the systemic nature of PAN. Some of the common finding include elevated ESR, hepatitis B surface antigen, leukocytosis, proteinuria, elevated levels of liver enzymes and hypergammaglobulinemia. HBV-related PAN have increased levels of cryoglobulins.
Thus for a definitive diagnosis of the condition there should be one of the following findings: 1) histological proof of vasculitis, 2) positive serology of anti-neutrophil cytoplasmic antibodies (ANCA), 3) angiography or biopsy findings suggestive of vasculitis, and 4) elevated ESR [14].

The main component of treatment for PAN is corticosteroids. If any of the major organs are involved or if the patient is steroid refractory, cyclophosphamide is also added to the treatment. The normal course suggested is high-dose of oral prednisone at 1mg/kg/day. Once the symptoms improve and ESR normalize, prednisone dose can be lowered gradually over a period of time. Those who are receiving steroid treatment for a long-term should be given calcium and vitamin D supplementation to overcome the risk of osteoporosis.
For those with HBV-related PAN, corticosteroids are recommended with antivirals and plasmapheresis. Antiviral medication is started after steroid withdrawal. Along with antivirals, plasma exchange is recommended 3 times a week for 3 weeks. This is gradually reduced and can be stopped once seroconversion occurs. The same treatment modality is being followed for PAN related to HCV infection. For cutaneous involvement in PAN, agents like NSAIDs, colchicine, and dapone are used. In severe cases of skin involvement, steroids and additional cyclophosphamide are recommended. Those with PAN induced by streptococcal infection, penicillin is recommended. These patients may need long-tern prophylaxis and this is particularly true of children. Further consultations depend on the organ affected.
Patients with PAN should be monitored carefully to look out for relapse or symptoms of a new organ being affected. Dosage of cyclophosphamide should be adjusted based on immunosuppression.

Prognosis of PAN is related to the amount of damage to the organs. The chances of mortality increases with factors including renal insufficiency, proteinuria, gastrointestinal complications, cardiomyopathy, and involvement of central nervous system [11]. A prospective study on 342 patients showed that when none of the factors are present, the mortality rate is 11.9% in five years. If left untreated, the survival rate in 5 years is 13%. But treatment with corticosteroids may improve the survival rate which might go up to 50-60%. In general, relapse of PAN is rare. Worst prognosis is seen in the case of central nervous system involvement [12]. Those who have abdominal syndromes tend to have poor prognosis. If there is no systemic involvement, the outcome is better. It is uncommon for patients to have permanent morbidity. Death occurs with untreated and serious vasculitis, as a result of complications that arise from immunosuppression, myocardial infarction and stroke.

The actual cause of PAN is still elusive. There are some cases in which infections, particularly viral, are involved in the development of this condition. There is a strong relationship between hepatitis B infection and development of PAN. It was one of the most common causes of this condition. Vasculitis may occur at any stage but is usually seen within 6 months of HBV infection, irrespective of its course [4]. PAN linked to hepatitis infection is induced by immune complex. As the use of hepatitis vaccines increased, the incidence of HBV-related PAN decreased considerably.
Although it is not a very important etiological factor, hepatitis C infection is also found to be related to PAN in some cases. Other viral infections including HIV, herpes zoster, and herpesvirus 68 are possibly involved in the development of this vasculitis. PAN is also known to be associated with some cancers, rheumatic diseases and blood diseases. There is an increased association of PAN with rheumatoid arthritis. Group A streptococcal infections are known to cause a flare-up of this disease, particularly in children. Many other infectious organisms cause PAN-like diseases which include the species of Klebsiella, Pseudomonas, and Yersinia [5]. Exposure to Isotretinoin is reported to be related to the occurrence of vasculitis [6]. PAN is also found to occur at an increased frequency with ulcerative colitis which is probably due to exposure to immune complexes or altered permeability of the gut. A study reports increased incidence of this vasculitis with familial Mediterranean fever [7].

Reports of incidence of this disease varies in different countries. It is relatively uncommon, with about 1.6 cases in a million in Sweden. In England the estimated incidence rate is 4.6 cases in one million, while in U.S it is 3-4.5 cases in comparable populations. Among adults, about 30.7 cases in a million are reported in Paris [8]. It occurs in all age groups, from children to adults. The incidence of PAN is more among 10 year old children, while among adults the most commonly affected age group is 40 to 65 years [9]. All ethnic groups are affected by this condition but is more prevalent in regions where hepatitis B infection is endemic. Studies report that PAN is found to be more prevalent among men when compared to women.

Vascular lesions characteristic of PAN are more commonly found in the bifurcation point and branching regions of arteries. Inflammation affects the entire wall with the laminae often destroyed and replaced with a fibrin-like, amorphous eosinophilic material. Inflammation of the vessel wall is characterized by necrosis of media with cellular infiltration, particularly by neutrophils, lymphocytes and eosinophils. Aneurysms and thrombi may occur at the site of lesion as walls are weak. Aneurysms may lead to hemorrhage. With the progression of lesions on vessels, intimal may proliferate into the lesion leading to ischemia or infarction [10]. Necrotizing vasculitis may co-exist with a healed lesion in different tissues. This co-existence may also be noted in different parts of the same tissue. Lesions are found in medium-sized arteries and are rare in large and small blood vessels.

A definitive method to prevent PAN is not known yet. Prompt treatment and close monitoring are the best ways to avoid complications and help remission.

Polyarteritis nodosa or PAN, is a rare form of vasculitis that affects small and medium-sized arteries. Inflammation of the blood vessels may affect skin and many other organs including kidney, gut and nerves [1]. This condition, first described by Kussumaul and Maier, may develop in any age group. It is found to occur in association with infections like hepatitis B and streptococcal infections [2]. If the condition affects internal organs significantly, it may be life threatening and immunosuppression may be needed. Cases where inflammation is restricted to skin are mild and need only minimal therapy. Based on the size of the blood vessel affected, PAN is subdivided into two groups: 1) Classical PAN, when it affects medium-sized blood vessels and 2) Microscopic polyangiitis, when inflammation affects the small-sized vessels [3]. PAN is a progressive disease and may be sub-acute, acute or chronic.

Polyarteritis nodosa or PAN is a rare form of autoimmune disease characterized by inflammation of small and medium-sized arteries. Inflammation of the blood vessels may affect different organs including intestine, heart, kidney and nerves, and may be life threatening in certain cases. It is found to occur in all age groups but it is more common among men than in women. The actual cause of PAN is not yet known. It may occur as a part of many viral and bacterial infections, malignancies and other diseases. It is more commonly seen in people with hepatitis B infection.
Since many organs are affected by the condition, a variety of symptoms may be presented in PAN. Some of the common nonspecific symptoms include fever, muscle pain, tiredness, and loss of appetite. Symptom depend on the organ affected. Skin sores, ulcers, and nodules are seen when skin is affected. When the condition affects gastrointestinal tract, abdominal pain and blood in stools are common symptoms. Shortness of breath and chest pain is common when inflammation affects heart. Inflammation of arteries in kidneys may cause high blood pressure. When nerves are affected, it may result in stroke, seizure, and loss of strength.
A variety of sources are used for definitive diagnosis of PAN. A complete medical history helps in checking for presence of symptoms of PAN. Physical examination helps to identify the organ affected by the disease, and also to rule out the possibility of other diseases that mimic symptoms of PAN. Blood tests are also used to identify the affected organ or site of inflammation. Imaging techniques like CT scan and MRI are useful in identifying the site of vasculitis. A definitive diagnosis can be done with angiogram and biopsy of affected tissue sample.
The cornerstone for the treatment of PAN is corticosteroids and medications that suppress immune system. This helps to improve the symptoms caused by inflammation of the blood vessel. Once the symptoms improve, dosage of corticosteroids can be reduced gradually and then stopped completely. The treatment duration and dose varies with the severity of the condition. PAN related to hepatitis and other infections are treated similarly but with an addition of antiviral medications. Outcome of this condition depends on the severity and the organ involved. But studies show that over 80% of the people survive the effects of PAN with early treatment. Prompt treatment and close monitoring help in remission.

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