What is the treatment approach for polyarteritis nodosa (PAN)?

Polyarteritis Nodosa: Pathophysiology, Presentation, Diagnosis, and Treatment

Pathophysiology

Polyarteritis nodosa is characterized by necrotizing inflammation of medium-sized arteries, leading to arterial wall weakening, aneurysm formation, stenosis, and potential rupture with resultant tissue ischemia. 1, 2

• The disease involves necrotizing vasculitis that spares small vessels (arterioles, capillaries, venules) and does not cause glomerulonephritis, distinguishing it from ANCA-associated vasculitides 2
• Vascular inflammation causes alternating areas of arterial narrowing and aneurysmal dilation, particularly affecting mesenteric, hepatic, and renal arteries 3, 4
• Different etiopathogenetic variants exist, including idiopathic PAN, hepatitis B-associated PAN (now classified as secondary vasculitis), and monogenic disorders like adenosine deaminase-2 deficiency (DADA2) 1, 5

Clinical Presentation

Fever, weight loss, and abdominal pain are the most common constitutional symptoms, while peripheral neuropathy represents the most frequent organ-specific manifestation. 3, 2

Constitutional Symptoms

• Fever and weight loss occur commonly at presentation 3
• Fatigue and chills are frequent systemic manifestations 6

Organ-Specific Manifestations

• Neurologic: Mononeuritis multiplex and peripheral neuropathy (motor and/or sensory) are among the most frequent clinical features 3, 2
• Cutaneous: Skin nodules, livedo reticularis, and subcutaneous nodules occur frequently 3
• Gastrointestinal: Abdominal pain from mesenteric ischemia is common and can present as acute abdomen if aneurysm rupture occurs 3, 6
• Renal: Renal insufficiency develops from renal artery involvement (not glomerulonephritis) and renovascular hypertension 3, 2
• Musculoskeletal: Myopathy and osteoarticular symptoms are frequent 2
• Cardiac: Coronary artery involvement can occur 7
• Pulmonary: The lungs are characteristically spared in classic PAN 2

Severity Classification

• Severe disease includes life- or organ-threatening manifestations: renal insufficiency, mononeuritis multiplex, muscle disease, mesenteric ischemia, coronary involvement, limb/digit ischemia 7
• Non-severe disease includes mild systemic symptoms, uncomplicated cutaneous disease, and mild inflammatory arthritis without organ-threatening features 7

Diagnosis

Diagnosis requires a combination of clinical findings, vascular imaging showing characteristic aneurysms and stenoses, and tissue biopsy when accessible organs are involved. 7, 3

Vascular Imaging

• Abdominal vascular imaging (CT angiography, MR angiography, or conventional angiography) should be obtained to establish diagnosis and determine disease extent 7, 3
• Characteristic findings include saccular or fusiform aneurysms and stenotic lesions in mesenteric, hepatic, and renal arteries 3
• Conventional catheter-based angiography provides better resolution but carries low complication risk; non-invasive CT or MR angiography are acceptable alternatives 7
• Imaging may not be warranted if patients present with isolated mononeuritis multiplex or myopathy without gastrointestinal or genitourinary symptoms 7

Tissue Biopsy

• For suspected cutaneous PAN, obtain a deep-skin biopsy reaching medium-sized vessels of the dermis rather than superficial punch biopsy 7, 3, 8
• For suspected PAN with peripheral neuropathy, obtain combined nerve and muscle biopsy rather than nerve biopsy alone 7
• Deep tissue sampling is critical as superficial biopsies frequently miss the medium-sized vessel involvement 8

Laboratory Evaluation

• Elevated ESR and CRP are common but non-specific 4
• ANCA testing is typically negative (helps distinguish from microscopic polyangiitis) 2
• Hepatitis B serology must be obtained to identify HBV-associated PAN, which requires different treatment 1, 2
• Consider ADA2 sequencing or functional assays if DADA2 is suspected (recurrent strokes, early-onset disease) 7

Treatment

Severe PAN (Life- or Organ-Threatening Disease)

For newly diagnosed active, severe PAN, initiate cyclophosphamide combined with high-dose glucocorticoids rather than glucocorticoids alone. 7, 3, 9

Remission Induction

• IV pulse glucocorticoids (methylprednisolone 500-1000 mg/day for 3-5 days) are preferred over high-dose oral glucocorticoids for initial treatment 7, 9
• High-dose oral glucocorticoids (prednisone 1 mg/kg/day, maximum 80 mg/day in adults) are an alternative 7
• Cyclophosphamide plus glucocorticoids is preferred over rituximab plus glucocorticoids 7
• For patients unable to tolerate cyclophosphamide, use alternative non-glucocorticoid immunosuppressive agents (methotrexate, azathioprine, mycophenolate) with glucocorticoids rather than glucocorticoids alone 7, 9
• Plasmapheresis combined with cyclophosphamide and glucocorticoids is NOT recommended over cyclophosphamide and glucocorticoids alone for idiopathic PAN 7 (Note: plasmapheresis IS used for HBV-associated PAN with antiviral therapy 2)

Remission Maintenance

• Cyclophosphamide should be limited to 3-6 months per course due to toxicity concerns 9
• After achieving remission with cyclophosphamide, transition to another less toxic immunosuppressive agent (methotrexate or azathioprine) rather than continuing cyclophosphamide 7, 3, 9
• Discontinue non-glucocorticoid immunosuppressive agents after 18 months of remission rather than continuing indefinitely 7, 9
• Glucocorticoid taper duration is not well-established and should be guided by clinical response; tapering off by 6 months versus longer is acceptable 7, 9

Non-Severe PAN

For newly diagnosed active, non-severe PAN, use non-glucocorticoid immunosuppressive agents (methotrexate or azathioprine) plus glucocorticoids rather than glucocorticoids alone. 7, 9

• This approach minimizes glucocorticoid exposure and associated toxicity 9
• Maintenance therapy follows the same 18-month duration recommendation 9

Refractory Disease

For severe PAN refractory to glucocorticoids and non-cyclophosphamide immunosuppressive agents, switch to cyclophosphamide rather than increasing glucocorticoids alone. 7, 9

Special Populations

DADA2-Associated PAN

• For patients with clinical manifestations of DADA2 (recurrent strokes, early-onset PAN), tumor necrosis factor inhibitors are STRONGLY recommended over glucocorticoids alone 7
• This is a strong recommendation despite limited case series data because TNF inhibitors prevent strokes, a severe and potentially fatal complication 7
• Consider DADA2 testing in any PAN patient with stroke history 7, 9

Hepatitis B-Associated PAN

• Treatment consists of antiviral therapy combined with plasmapheresis, NOT the immunosuppressive regimens used for idiopathic PAN 1, 2

Adjunctive Therapies

• Physical therapy is recommended for patients with nerve and/or muscle involvement 7

Monitoring

Disease Activity Assessment

• Serial neurologic examinations are preferred over repeated electromyography/nerve conduction studies (e.g., every 6 months) for monitoring peripheral motor neuropathy 7, 3
• Follow-up abdominal vascular imaging is recommended for patients with severe PAN and abdominal involvement who become clinically asymptomatic 7
• Avoid indefinite routine vascular imaging if abdominal disease is shown to be quiescent 9

Prognosis

Untreated severe PAN has a mortality rate of approximately 40% at 5 years, but prognosis has improved significantly with early diagnosis and combination immunosuppressive therapy. 3, 9, 1

• The combination of cyclophosphamide and glucocorticoids has dramatically improved survival in severe disease 2, 6
• Early recognition and treatment are critical to prevent irreversible organ damage and death 1

Critical Pitfalls to Avoid

• Do not perform superficial skin biopsies when deep-skin biopsy is needed - this frequently misses the diagnosis 8
• Do not use plasmapheresis for idiopathic PAN (only for HBV-associated PAN) 7
• Do not continue cyclophosphamide indefinitely - transition to less toxic agents after remission 7, 9
• Do not miss DADA2 - consider testing in young patients or those with strokes, as they require TNF inhibitors rather than conventional therapy 7, 9
• Do not forget to test for hepatitis B - HBV-associated PAN requires antiviral therapy, not immunosuppression 1, 2