Polyarteritis nodosa

pan

1. Polyarteritis Nodosa Dr.Bhargav kiran General Medicine Post Graduate

2. Classic polyarteritis nodosa It is a systemic vasculitis characterized by necrotizing inflammatory lesions that affect medium-sized and small muscular arteries. Preferentially at vessel bifurcations, resulting in microaneurysm formation, aneurysmal rupture with hemorrhage, thrombosis, and, consequently, organ ischemia or infarction.

3. History Kussmaul and Maier first described PAN in 1866. The autopsy of a patient with fever, weight loss, abdominal pain, and polyneuropathy revealed areas of focal inflammatory exudations that gave rise to palpable nodules along the course of medium-sized arteries

4. Epidemiology Polyarteritis nodosa (PAN) is a rare disease with an incidence of about 3-4.5 cases per 100,000 population annually Sex- and age-related demographics PAN affects men more frequently than women (male-to-female ratio 1.6-2:1). it is predominantly observed in individuals aged approximately 45-65 years.

5. Pathophysiology Vascular lesions in medium-sized muscular arteries occur mainly at bifurcations and branch points. Inflammation may start in the vessel intima and progress to include the entire arterial wall, destroying the internal and external elastic lamina, resulting in fibrinoid necrosis .   Aneurysms develop in the weakened vessel, carrying a subsequent risk for rupture and hemorrhage. Thrombi may develop at the site of the lesions As lesions progress, proliferation of the intima or media may result in obstruction and subsequent tissue ischemia or infarction.   It spares large vessels (the aorta and its major branches), the smallest vessels (capillaries and small arterioles), and the venous system.

6. Etiology Hepatitis B and PAN The pathogenesis of polyarteritis nodosa (PAN) is unknown, H epatitis B virus  (HBV) infection is strongly linked with PAN. Evidence for immune complex–induced disease is confined to HBV-related PAN; the role of immune complexes in non-HBV-related PAN remains unclear .   Impaired function of endothelial cells may be part of idiopathic PAN or a consequence of it; in HBV-PAN, virus replication may directly injure the vessel wall.   Endothelial dysfunction can perpetuate the inflammation through cytokine and adhesion molecule production.   HBV was once the cause of up to 30% of PAN cases.     Widespread use of the hepatitis B vaccine has significantly decreased the incidence of HBV-PAN, which is now estimated to account for less than 8% of all PAN cases

7. Genetic associations Loss-of-function mutations in  CECR1,  the gene that encodes adenosine deaminase 2 (ADA2), have been associated with a spectrum of vascular and inflammatory phenotypes that includes polyarteritis nodosa Possible roles of ADA2 include regulation of the proliferation of activated T cells and macrophages and the differentiation of monocytes to macrophages. Reduction in ADA2 activity  may affect the adenosine inflammatory-response pathway

8. Polyarteritis Nodosa Association with Hepatitis B (surface antigen) Classic PAN is NOT associated with ANCA ANCA

9. OTHER the potential association of hepatitis C virus (HCV) with PAN. INFECTIOUS organisms include varicella-zoster virus , parvovirus B-19, cytomegalovirus , human T-cell leukemia virus, Streptococcal species ,  Klebsiella  species, Pseudomonas species, Yersinia species, Toxoplasma gondii , Rickettsiae , trichinosis, and sarcosporidiosis Recently , reports of associations with PAN and human immunodeficiency virus   and cutaneous PAN and tuberculosis ed to cutaneous PAN, a benign, limited form of PAN Rheumatoid arthritis and  Sjögren syndrome have been associated with PAN.  Hematologic malignancies, such as hairy cell leukemia and, in one case, angioimmunoblastic T cell lymphoma, have been associated with PAN-like vasculitides

10. CLINICAL FEAUTURES Polyarteritis nodosa (PAN) is an acute multisystem disease with a relatively short prodrome ( ie , weeks to months ). The spectrum of disease ranges from single-organ involvement to fulminant polyvisceral failure. Pertinent and common historical features of PAN include the following : Constitutional and musculoskeletal symptoms of PAN include the following: Fever Malaise Fatigue Anorexia and weight loss Myalgia Arthralgia in large joints or, less commonly, arthritis

11. Renal symptoms About 60% of patients with PAN have renal involvement. Flank pain may be present. Ischemic changes in the glomeruli and renal artery vasculitis can cause renal failure, hypertension, or both . A small percentage of patients may require dialysis . Renal symptoms include the following: Hypertension Costophrenic tenderness Retroperitoneal or intraperitoneal hemorrhage Renal failure

12. Cutaneous symptoms Dermatologic symptoms are very common in PAN, and about 40% of patients manifest with skin lesions including rash , Purpura Gangrene Nodules cutaneous infarcts livido reticularis Raynaud phenomenon. Skin involvement, which can be painful, occurs most frequently on the legs

13. Cutaneous symptoms in PAN include the following   Livedo reticularis that does not blanch with active pressure Ulcerations - Especially on the lower extremities, near the malleoli and on the calf Digital ischemia - May be accompanied by splinter hemorrhages and, sometimes, gangrene Nodules - Usually on the lower extremities (like ulcers); nodules are the least common skin manifestation of PAN

14. Central nervous system symptoms Transient symptoms of cerebral ischemia, including typical spells of transient monocular blindness , are the most common presenting CNS deficits of PAN . Cerebral arteritis usually presents late in the course of the disease, usually in the second to third year of the vasculitis. Cerebral arteritis may cause arterial thrombosis with cerebral ischemia or intraparenchymal or subarachnoid hemorrhage. Global CNS dysfunction with encephalopathy and seizures results from metabolic derangements secondary to multiple organ failure Acute or subacute myelopathy with paraparesis can occur at any cord level. Myelopathy may result, although rarely, from cord compression by an extramedullary hematoma secondary to a ruptured spinal aneurysm.

15. Neurologic symptoms in PAN include the following: Sensory and/or motor neuropathies - When these occur, they are usually asymmetrical Mononeuritis multiplex (multiple mononeuropathy ) - This is the successive ischemia or infarction of "named nerves" ( eg , ulnar, radial, peroneal , sural ). Although nerve involvement is initially asymmetrical, the development of additional nerve lesions can cause the clinical picture to resemble symmetrical polyneuropathy . CNS involvement - Although rare (≤10% of cases), encephalopathy, focal deficits, strokes, seizures, and, sometimes, brain hemorrhages can occur

16. Peripheral nervous system symptoms Peripheral neuropathy develops in as many as 60% of patients. Vasculitic neuropathy is often asymmetrical and presents as ( 1) mononeuritis multiplex (2 ) distal polyneuropathy (3) cutaneous neuropathy . It can take the form of a pure motor, pure sensory, or mixed sensorimotor polyneuropathy.

17. Gastrointestinal symptoms GI involvement usually presents as nonspecific symptoms and signs such as abdominal pain (which may be postprandial) nausea and vomiting, with or without obvious GI bleeding . Rare and more serious complications of PAN include Bowel infarction and perforation Cholecystitis Hepatic infarction Pancreatic infarction

18. Less common symptoms reported in PAN include the following: Genitourinary - Patients may develop pain over the testicular or ovarian area. In rare cases, testicular infarction may occur; testicular pain is usually unilateral Cardiac - Chest pain, dyspnea, palpitations, pericarditis, myocardial infarction, and congestive heart failure; cardiac disease affects 35% of patients with PAN, but most affected patients are asymptomatic Ophthalmologic - Blurred vision Neuropsychiatric - Headache, psychosis ,   and depression

19. Cardiac symptoms include the following: Hypertension Tachycardia out of proportion to fever Pericardial friction rub Arrhythmias Congestive heart failure Ophthalmologic symptoms of PAN include the following: Retinal vasculitis Retinal detachment Cotton-wool spots

20. Differential Diagnoses Antiphospholipid Syndrome Atrial Myxoma Cholesterol Embolism Eosinophilic Granulomatosis with Polyangiitis ( Churg -Strauss Syndrome ) Goodpasture Syndrome Granulomatosis with Polyangiitis (Wegener Granulomatosis ) Henoch-Schonlein Purpura Leukocytoclastic (small vessel) vasculitis Microscopic PolyangiitisS

21. Diagnosis Laboratory findings in PAN are nonspecific but can help to establish the systemic nature of the disease. Findings include the following: Elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein - These markers may be useful in evaluating some patients for active disease but do not correlate with activity in all patients Leukocytosis, normochromic anemia, or thrombocytosis Hepatitis B surface antigen and hepatitic C serologies Elevated creatinine level Mild proteinuria Elevated levels of liver enzymes Hypergammaglobulinemia - Found in 30% of patients with PAN Cryoglobulins , circulating immune complexes, and decreased levels of serum complement ( ie , C3, C4) may be observed in patients with HBV-related PAN but are otherwise uncharacteristic of idiopathic PAN.

22. Arthritis Rheum. 1990;33:1088 ACR Criteria (3 of 10) Wt loss > 4 kg Livedo reticularis Testicular pain Myalgias, weakness or leg tenderness Mononeuropathy or polyneuropathy Diastolic BP > 90  BUN or Creatinine Hepatitis B virus Arteriographic abnormality Biopsy of small or medium artery containing PAN

23. Treatment I mmunosuppression continues to be the standard therapy for polyarteritis nodosa (PAN ). Corticosteroids plus cyclophosphamide (in the case of steroid-refractory disease or major organ involvement) can prolong survival for patients with idiopathic PAN . In contrast, for hepatitis B–related PAN, treatment consists of corticosteroids for early, initial control followed by plasmapheresis and antiviral agents. Stronger immunosuppression using a combinations of steroids and cyclophosphamide is typically avoided in these cases as it can enhance viral replication

24. Prognosis Idiopathic (non–HBV-related) PAN Traditionally, it has been taught that relapses of polyarteritis nodosa (PAN) are rare in individuals who completely recover Recovery from neurologic deficits due to PAN can take up to 18 months. Central nervous system (CNS) involvement carries a worse prognosis than does peripheral nerve involvement.   The prognosis is markedly worse in patients with acute abdominal syndromes characterized by extensive bowel involvement.   Multiple perforations may be found, relapses are common, and the postoperative course is complicated by infections and delayed healing. The prognosis is better in patients with cutaneous PAN without systemic involvement. This disease is benign but tends to relapse

25. HBV-related PAN Patients who seroconvert usually recover. Once HBV-PAN goes into remission, the risk of recurrence is very low HCV-related PAN One study found that in patients with HCV-related vasculitis, HCV-PAN exhibits a more severe clinical presentation but a higher rate of clinical remission.  

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