What is the recommended initial treatment regimen for a patient with polyarteritis nodosa (PAN)?

Initial Treatment Regimen for Polyarteritis Nodosa

For newly diagnosed severe PAN, initiate combination therapy with cyclophosphamide and high-dose glucocorticoids, preferably starting with IV pulse glucocorticoids; for nonsevere PAN (including cutaneous disease), use non-glucocorticoid immunosuppressive agents (azathioprine or methotrexate) combined with moderate-dose glucocorticoids. 1

Disease Severity Classification Determines Treatment Intensity

The first critical step is determining disease severity, as this dictates the treatment regimen:

Severe PAN includes life- or organ-threatening manifestations such as:

• Renal disease
• Mononeuritis multiplex
• Muscle disease with significant weakness
• Mesenteric ischemia
• Coronary involvement
• Limb/digit ischemia 1

Nonsevere PAN presents without organ-threatening features:

• Mild systemic symptoms (fever, weight loss, fatigue)
• Uncomplicated cutaneous disease (nodules, livedo reticularis, ulcerations)
• Mild inflammatory arthritis 1, 2

Treatment Algorithm for Severe PAN

Initial Induction Therapy

Glucocorticoid Component:

• Start with IV pulse methylprednisolone 500-1,000 mg/day for adults (or 30 mg/kg/day for children, maximum 1,000 mg/day) for 3-5 days 1
• This is preferred over high-dose oral glucocorticoids because pulse dosing provides rapid suppression of inflammation through non-genomic mechanisms once glucocorticoid receptors are saturated 1
• After pulse therapy, transition to high-dose oral prednisone 1 mg/kg/day (adults, generally up to 80 mg/day) or 1-2 mg/kg/day (children, up to 60 mg/day) 1

Immunosuppressive Component:

• Cyclophosphamide is the preferred agent over rituximab or glucocorticoids alone 1
• Cyclophosphamide can be given as either oral or IV formulations with similar efficacy 1
• The combination of cyclophosphamide with glucocorticoids is superior to glucocorticoids alone, with observational data showing better outcomes and the added benefit of reducing cumulative steroid exposure 1
• Additional cyclophosphamide cycles may provide medium-term protection (3 years) against relapse 1

Alternative Agents for Cyclophosphamide Intolerance

If cyclophosphamide cannot be tolerated:

• Use azathioprine or methotrexate combined with glucocorticoids rather than glucocorticoids alone 1
• Mycophenolate mofetil has not been well studied in PAN and should be avoided 1, 2
• These alternatives are inferior to cyclophosphamide for severe disease but superior to steroid monotherapy 1

Important Contraindication

Do not add plasmapheresis to cyclophosphamide and glucocorticoids—this combination offers no benefit over cyclophosphamide and glucocorticoids alone 1

Treatment Algorithm for Nonsevere PAN

Initial Combination Therapy

Glucocorticoid Component:

• Start with moderate-dose oral prednisone 0.25-0.5 mg/kg/day (adults, generally 10-40 mg/day) or approximately 0.5 mg/kg/day (children, 10-30 mg/day) 1, 2

Immunosuppressive Component:

• Azathioprine is the preferred first-line agent 2
• Methotrexate is an acceptable alternative first-line agent 2
• Combination therapy is recommended over glucocorticoids alone, even though this contradicts older Five-Factor Score recommendations that suggested glucocorticoids alone for patients without poor prognostic factors 1

Rationale for Combination Therapy in Nonsevere Disease

The American College of Rheumatology guidelines favor upfront combination therapy because:

• A substantial number of patients initially treated with glucocorticoids alone ultimately require additional immunosuppressive therapy 1, 2
• Adding non-glucocorticoid agents minimizes cumulative steroid toxicity, which is particularly important in pediatric populations 1, 2
• The glucocorticoid-sparing effect improves long-term safety without compromising disease control 2

Special Considerations for Cutaneous PAN

For isolated cutaneous PAN (a nonsevere variant):

• Use the nonsevere PAN regimen: azathioprine or methotrexate plus moderate-dose glucocorticoids 2
• Do not use cyclophosphamide unless the disease progresses to severe systemic involvement with organ-threatening manifestations—cyclophosphamide exposes patients to unnecessary toxicity for isolated cutaneous disease 2
• Ensure proper diagnosis with deep-skin biopsy reaching medium-sized vessels of the dermis; superficial punch biopsies miss the pathology and should be avoided 2, 3

Maintenance and Duration of Therapy

Transitioning from Induction

• After achieving remission with cyclophosphamide, transition to another non-glucocorticoid immunosuppressive agent (azathioprine or methotrexate) rather than continuing cyclophosphamide indefinitely 1

Duration of Immunosuppression

• Discontinue non-glucocorticoid immunosuppressive therapy after 18 months of sustained remission rather than continuing indefinitely 1, 2
• This balances relapse risk against cumulative toxicity of prolonged immunosuppression 2

Glucocorticoid Tapering

• The optimal duration of glucocorticoid therapy is not well established 1
• Tapering should be guided by clinical response, but the goal is to reach low-dose prednisone ≤10 mg/day (adults) or ≤0.2 mg/kg/day (children, maximum 10 mg/day) 1

Management of Refractory Disease

If severe PAN remains refractory to glucocorticoids and non-cyclophosphamide immunosuppressive agents:

• Switch to cyclophosphamide rather than simply increasing glucocorticoid doses 1

For disease refractory to multiple conventional agents including cyclophosphamide:

• Case reports suggest TNF inhibitors (infliximab) may be effective 4, 5
• Tocilizumab (IL-6 inhibitor) has shown success in small case series of refractory PAN 6
• These biologics remain off-guideline options reserved for truly refractory cases 4, 5, 6

Critical Diagnostic Considerations Before Treatment

Exclude Hepatitis B-Associated PAN

• Hepatitis B-associated PAN requires antiviral therapy combined with plasma exchange rather than standard immunosuppression 5
• This is a distinct treatment paradigm from idiopathic PAN

Exclude DADA2 (Deficiency of Adenosine Deaminase 2)

• If clinical manifestations suggest DADA2 (often presents in children with early-onset systemic PAN), strongly recommend TNF inhibitors over glucocorticoids alone 1
• This represents a genetic form of PAN requiring different management

Obtain Proper Tissue Diagnosis

• For suspected skin involvement: deep-skin biopsy reaching medium-sized vessels of the dermis, not superficial punch biopsy 1, 3
• For peripheral neuropathy: combined nerve and muscle biopsy over nerve biopsy alone 1
• For suspected abdominal involvement: abdominal vascular imaging to establish diagnosis and determine extent 1

Common Pitfalls to Avoid

• Do not use glucocorticoids alone for severe PAN—combination with cyclophosphamide is essential for optimal outcomes 1
• Do not use cyclophosphamide for isolated cutaneous PAN—this exposes patients to unnecessary toxicity 2
• Do not continue cyclophosphamide indefinitely—transition to maintenance therapy after remission 1
• Do not rely on superficial skin biopsies—they miss the medium-sized vessel pathology 2, 3
• Do not add plasmapheresis to cyclophosphamide and steroids—no additional benefit 1

Adjunctive Therapies

• For patients with nerve and/or muscle involvement: physical therapy is recommended to maintain mobility and function 1
• Monitor for glucocorticoid-related adverse effects throughout treatment 2