POLYARTERITIS NODOSA PROGNOSIS: WHAT PATIENTS NEED TO KNOW

Polyarteritis Nodosa (PAN) is a rare, systemic necrotizing vasculitis primarily affecting medium-sized muscular arteries. Characterized by segmental inflammation and necrosis of the arterial wall, PAN can lead to a spectrum of clinical manifestations due to the resulting microaneurysms, stenoses, thromboses, and occlusions. Unlike many other vasculitides, classic PAN is typically negative for anti-neutrophil cytoplasmic antibodies (ANCA). The disease can be idiopathic or secondary to infections such as Hepatitis B virus (HBV). If left untreated, PAN carries a high mortality rate, making early diagnosis and aggressive management critical.

Clinical Features: A Multi-Systemic Presentation

The diverse clinical features of PAN arise from ischemia, infarction, or hemorrhage in various organ systems, reflecting the widespread nature of the vasculitis. Symptoms are often non-specific initially, making diagnosis challenging.

1. Constitutional Symptoms: These are frequently the first indicators, often preceding specific organ involvement. Patients commonly experience fever (often spiking), profound fatigue, malaise, anorexia, and significant unintentional weight loss (often exceeding 10 kg).
2. Renal Involvement: This is one of the most common and serious manifestations, occurring in up to 70-80% of patients. It typically involves the renal arteries and their branches, leading to:
   • Hypertension: Often severe and rapidly progressive, primarily due to renal ischemia activating the renin-angiotensin system.
   • Renal Infarction: Resulting from occluded vessels, leading to flank pain, hematuria, and elevated lactate dehydrogenase.
   • Renal Insufficiency: Progressive decline in kidney function, though direct glomerulonephritis is less characteristic than in ANCA-associated vasculitis. Microscopic hematuria and proteinuria are common.
3. Neurological Manifestations: Occur in 50-70% of cases and can be debilitating.
   • Peripheral Neuropathy: The most common neurological symptom, presenting as mononeuritis multiplex. This involves simultaneous or sequential damage to two or more distinct nerve areas, leading to asymmetric, painful sensory and/or motor deficits (e.g., foot drop, wrist drop, paresthesias).
   • Central Nervous System (CNS) Involvement: Less common but more severe, including strokes (ischemic or hemorrhagic due to aneurysm rupture), transient ischemic attacks, seizures, encephalopathy, and subarachnoid hemorrhage.
4. Gastrointestinal Involvement: Affects 30-60% of patients and can be life-threatening.
   • Abdominal Pain: Often severe, diffuse, and worsened after meals (“abdominal angina”) due to mesenteric ischemia.
   • Gastrointestinal Bleeding: From ulcerations, erosions, or ruptured aneurysms.
   • Bowel Infarction/Perforation: A surgical emergency, leading to peritonitis and sepsis.
   • Less common symptoms include nausea, vomiting, diarrhea, cholecystitis, and pancreatitis.
5. Dermatological Features: Present in 25-50% of patients.
   • Livedo Reticularis: A mottled, purplish discoloration of the skin, particularly on the extremities, representing a net-like vascular pattern due to impaired blood flow.
   • Subcutaneous Nodules: Tender, firm nodules along blood vessels, especially on the legs.
   • Skin Ulcers/Infarcts: Painful, often “punched-out” lesions or digital gangrene from vessel occlusion.
   • Less common are palpable purpura (more typical of small vessel vasculitis) and Raynaud’s phenomenon.
6. Musculoskeletal Symptoms: Myalgias (muscle pain) and arthralgias (joint pain) are very common, affecting up to 70% of patients. Frank arthritis is less frequent and typically non-erosive.
7. Cardiovascular Involvement: Myocardial infarction, congestive heart failure, and pericarditis can occur due to vasculitis of coronary arteries or severe hypertension.
8. Testicular Pain: In men, testicular pain, tenderness, or atrophy resulting from vasculitis of the testicular arteries can be a distinctive early symptom.

Investigations: Establishing a Definitive Diagnosis

The diagnostic process for PAN is often challenging due to its varied presentation and the need for histological or angiographic confirmation.

1. Laboratory Tests:
   • Inflammatory Markers: Elevated Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP) are almost universally present, indicating systemic inflammation, but are non-specific.
   • Complete Blood Count (CBC): Often shows leukocytosis (elevated white blood cells), normocytic normochromic anemia (anemia of chronic disease), and thrombocytosis (elevated platelets).
   • Renal Function Tests: Elevated serum creatinine and urea indicate kidney impairment. Urinalysis may reveal microscopic hematuria and mild proteinuria.
   • Liver Function Tests: May be abnormal, particularly in cases of HBV-associated PAN.
   • Serology:
     • ANCA: Crucially, ANCA tests (both p-ANCA and c-ANCA) are typically negative in classic PAN, distinguishing it from ANCA-associated vasculitides (e.g., microscopic polyangiitis, granulomatosis with polyangiitis).
     • Hepatitis B Serology: Essential to screen for current or past Hepatitis B infection (HBsAg, HBeAg, anti-HBc, anti-HBs), as HBV is a known trigger for PAN.
     • Other Autoimmune Markers: Antinuclear antibodies (ANA), rheumatoid factor (RF), and complement levels are usually negative or non-contributory, helping to exclude other connective tissue diseases.
2. Imaging Studies:
   • Angiography (Conventional or CT Angiography): This is a cornerstone for diagnosis, particularly when biopsy of an affected organ is difficult or negative. It visualizes the characteristic changes in medium-sized arteries. Renal, mesenteric, and hepatic arteries are common targets. Findings include:
     • Microaneurysms: Multiple, small (1-5 mm) dilatations of arteries, often at bifurcations, giving a “string of beads” appearance. These can rupture or thrombose.
     • Stenoses and Occlusions: Narrowing or blockage of vessels.
     • Irregular luminal contours.
     • Digital Subtraction Angiography (DSA) remains the gold standard for many, but CT Angiography (CTA) or MR Angiography (MRA) can also be highly informative and less invasive.
   • MRI/MRA: Useful for assessing CNS involvement (identifying infarcts, hemorrhages), and can sometimes detect vasculitic changes in peripheral nerves or muscles.
   • PET/CT: May assist in identifying metabolically active lesions, guiding biopsy sites, or assessing disease extent, though not routinely used for primary diagnosis.
3. Biopsy (Definitive Diagnosis):
   • The most definitive diagnostic method involves obtaining a tissue sample from an affected organ exhibiting clinical or angiographic evidence of vasculitis.
   • Common Biopsy Sites: Sural nerve (for peripheral neuropathy), muscle (if myalgia is prominent), skin (subcutaneous nodules or ulcers), kidney (renal biopsy), liver, or gastrointestinal tract (during endoscopy or exploratory laparotomy).
   • Histopathological Findings: Show characteristic transmural inflammation of medium-sized arteries, with fibrinoid necrosis, infiltration by neutrophils and mononuclear cells, disruption of the internal elastic lamina, and frequently, evidence of thrombosis or aneurysm formation. The lesions are segmental, meaning normal and inflamed areas can coexist, necessitating adequate sampling to avoid false negatives.

Management: A Phased Approach to Disease Control

Treatment aims to induce remission, prevent organ damage, and minimize treatment-related toxicity. It typically involves high-dose corticosteroids combined with immunosuppressants.

1. Induction Therapy (Acute Phase):
   • Corticosteroids: High-dose glucocorticoids are the cornerstone of initial therapy. Oral prednisone/prednisolone (e.g., 1 mg/kg/day, maximum 60-80 mg/day) is standard. For severe, life-threatening organ involvement (e.g., rapidly progressive renal failure, severe GI or CNS involvement), intravenous methylprednisolone pulse therapy (e.g., 500-1000 mg/day for 3-5 days) may be used before transitioning to oral corticosteroids.
   • Cyclophosphamide: For patients with severe or organ-threatening disease, cyclophosphamide is added to corticosteroids. It can be given orally or, more commonly, as intravenous pulse therapy (e.g., 0.6 g/m² body surface area every 3-4 weeks). IV pulse cyclophosphamide is often preferred due to a lower cumulative dose and reduced risk of side effects like hemorrhagic cystitis and gonadal toxicity, while maintaining efficacy.
   • Rituximab: While primarily used in ANCA-associated vasculitis, rituximab (an anti-CD20 monoclonal antibody) has an emerging role in refractory PAN or as an alternative in specific circumstances, though it is less established than cyclophosphamide for classic PAN.
2. Maintenance Therapy (Long-Term Remission):
   • Once remission is achieved (typically after 3-6 months of induction therapy), cyclophosphamide is usually discontinued and replaced with less toxic immunosuppressants to maintain remission and allow for further corticosteroid tapering.
   • Azathioprine: Often the first-line maintenance agent (e.g., 1.5-2 mg/kg/day), continued for at least 1-2 years, sometimes longer.
   • Methotrexate: Another option for maintenance (e.g., 15-25 mg/week), particularly for less severe cases or as an alternative to azathioprine.
   • Mycophenolate Mofetil: May be used as an alternative maintenance agent.
   • Corticosteroids are slowly tapered to the lowest effective dose or discontinued if possible, to minimize long-term side effects.
3. Management of Hepatitis B-associated PAN:
   • This subtype requires a distinct approach. Antiviral therapy (e.g., lamivudine, entecavir, tenofovir) is paramount to suppress HBV replication.
   • Corticosteroids: Used cautiously and typically briefly, in conjunction with antivirals, as immunosuppression can exacerbate HBV replication.
   • Plasma Exchange: May be considered in severe cases, often in combination with antivirals and low-dose corticosteroids.
4. Supportive Care and Management of Complications:
   • Blood Pressure Control: Aggressive management of hypertension to prevent further cardiovascular and renal damage.
   • Pain Management: For neuropathy, arthralgia.
   • Surgery: May be required for acute complications such as bowel perforation, ruptured aneurysms, or severe organ ischemia.
   • Physical Therapy: For neurological deficits to improve function.
   • Prevention of Opportunistic Infections: Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) is crucial for patients receiving high-dose corticosteroids and cyclophosphamide. Bone protection (calcium, vitamin D, bisphosphonates) against corticosteroid-induced osteoporosis.

Prognosis: Factors Influencing Outcome

The prognosis of PAN has dramatically improved with modern immunosuppressive therapy.

• Untreated: Historically, PAN was associated with an extremely poor prognosis, with 5-year survival rates estimated to be less than 10-20%.
• Treated: With the advent of corticosteroids and cyclophosphamide, 5-year survival rates now exceed 70-80%, and 10-year survival rates are around 60%.

Factors influencing prognosis (poor prognostic indicators):

• Five-Factor Score (FFS): Developed by the French Vasculitis Study Group, helps stratify risk. Poor prognostic factors include:
  • Proteinuria >1 g/24 hours or serum creatinine >1.58 mg/dL (140 µmol/L) at diagnosis.
  • Gastrointestinal involvement (bleeding, perforation, infarction).
  • Cardiac involvement (cardiomyopathy, congestive heart failure).
  • Central nervous system involvement (stroke, seizures).
  • Absence of ear, nose, and throat (ENT) manifestations (though ENT involvement is rare in PAN).
• Other factors: Age older than 65 years at diagnosis, persistent hypertension, severe weight loss, and persistent disease activity.
• Relapses: Can occur in 10-20% of patients, often within the first few years of treatment, and may necessitate repeating induction therapy. Cumulative organ damage from relapses can worsen long-term outcomes.

Complications: Long-Term Sequelae and Acute Crises

PAN and its treatment can lead to a range of severe complications:

1. Organ Damage and Failure:
   • Renal Failure: Chronic kidney disease progressing to end-stage renal disease (ESRD) due to repeated ischemic insults or severe hypertension.
   • Bowel Infarction/Perforation: Acute, life-threatening abdominal crisis requiring emergency surgery and carrying high morbidity and mortality.
   • Stroke and Myocardial Infarction: Due to vasculitic occlusion of cerebral or coronary arteries, or as a consequence of severe hypertension.
   • Peripheral Neuropathy: Chronic pain, weakness, and functional impairment, often irreversible.
2. Aneurysm Rupture: Especially in cerebral, renal, or mesenteric arteries, leading to hemorrhage (e.g., intracranial hemorrhage, retroperitoneal bleed), which can be fatal.
3. Hypertension: Chronic, often severe hypertension, which can further damage kidneys, heart, and brain, increasing the risk of cardiovascular events.
4. Treatment-Related Complications:
   • Immunosuppression: Increased risk of severe and opportunistic infections (e.g., PJP, viral infections), and malignancy (especially bladder cancer with long-term oral cyclophosphamide use).
   • Corticosteroids: Numerous side effects including osteoporosis, diabetes mellitus, hypertension, cataracts, glaucoma, avascular necrosis, muscle weakness, and Cushingoid features.
   • Cyclophosphamide: Bone marrow suppression (leukopenia, anemia, thrombocytopenia), hemorrhagic cystitis, infertility, and increased risk of secondary malignancies (leukemia, bladder cancer).
5. Relapses: Recurrent episodes of disease activity can lead to cumulative organ damage and further treatment-related complications.

In conclusion, Polyarteritis Nodosa is a severe systemic vasculitis requiring prompt diagnosis and aggressive, individualized treatment. A high index of suspicion based on the multi-systemic clinical features, coupled with confirmatory angiography or biopsy, is essential. While prognosis has significantly improved with modern immunosuppressive regimens, careful monitoring for disease activity and treatment-related complications remains vital for optimizing long-term outcomes for affected patients.

References:

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