What are the differential diagnoses and treatment options if a patient does not have Granulomatosis with Polyangiitis (GPA)?

Differential Diagnosis When GPA is Excluded

If GPA is ruled out in a patient presenting with systemic vasculitis, granulomatous disease, or ANCA-associated features, the primary differential diagnoses include microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), sarcoidosis, and other granulomatous/eosinophilic disorders, each requiring distinct diagnostic approaches and treatment strategies. 1

Key Differential Diagnoses

ANCA-Associated Vasculitides (Non-GPA)

Microscopic Polyangiitis (MPA)

• Presents with systemic necrotizing small-vessel vasculitis without granulomatous inflammation 1
• Typically associated with MPO-ANCA (perinuclear pattern) rather than PR3-ANCA 1
• Commonly manifests as pulmonary-renal syndrome with alveolar hemorrhage and rapidly progressive glomerulonephritis 2
• Lacks the upper respiratory tract involvement and granulomatous features characteristic of GPA 3, 2

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

• Distinguished by the triad of asthma, eosinophilia, and systemic vasculitis 1, 4
• Only 30-40% are ANCA-positive, predominantly MPO-ANCA 1
• MPO-ANCA-positive patients more frequently show glomerulonephritis, peripheral neuropathy, and purpura 1
• ANCA-negative patients more commonly manifest cardiomyopathy and lung infiltrates 1
• Chronic rhinosinusitis with nasal polyps is typical 1
• Peripheral neuropathy (particularly mononeuritis multiplex) and eosinophilic cardiomyopathy are characteristic features 1, 4

Non-ANCA Granulomatous Diseases

Sarcoidosis

• Presents with non-caseating granulomas affecting multiple organ systems 1
• Nasal involvement shows nodular mucosal thickening on CT, with mean Lund-Mackay score of 6.2 1
• Serum angiotensin-converting enzyme (SACE) elevated in many cases (sensitivity 60%, specificity 70%) 1
• Nasal biopsy positive in 91% when mucosa appears macroscopically abnormal 1
• Chest imaging typically shows bilateral hilar lymphadenopathy and pulmonary nodules 1
• Stage 1 disease often undergoes spontaneous remission within two years without treatment 1

Other Granulomatous Conditions

• Tuberculosis, syphilis, rhinoscleroma, fungal infections, and leprosy must be excluded 1
• IgG4-related disease can present with overlapping features 1
• Drug-induced vasculitis (hydralazine, propylthiouracil, levamisole-adulterated cocaine) characterized by high-titer MPO-ANCA, dual MPO/PR3 positivity, and positive ANA/antihistone antibodies 1

Hematologic Eosinophilic Disorders

• Lymphocytic and myeloproliferative hypereosinophilic syndromes (the latter characterized by FIP1L1 fusion genes) 1
• Allergic bronchopulmonary aspergillosis 1
• Parasitic infections 1

Diagnostic Approach

Essential Laboratory Testing

ANCA Testing

• MPO-ANCA by ELISA is the reference standard for AAV diagnosis 1
• PR3-ANCA positivity (with C-ANCA pattern) makes EGPA less likely (scored -3 points in ACR-EULAR criteria) 1
• Isolated P-ANCA without MPO-ANCA can occur in non-vasculitic inflammatory conditions like inflammatory bowel disease 1

Additional Serologic Studies

• Absolute eosinophil count (≥1 × 10⁹/L supports EGPA diagnosis) 1
• Serum angiotensin-converting enzyme for sarcoidosis 1
• ANA and antihistone antibodies for drug-induced vasculitis 1
• Complement levels (C3, C4) to evaluate for immune complex-mediated vasculitides 5

Histopathologic Evaluation

Tissue Biopsy Strategy

• Kidney biopsy shows crescentic necrotizing glomerulonephritis in AAV; immune deposits suggest alternative diagnoses (IgA vasculitis, cryoglobulinemia) 1
• EGPA kidney tissue may show eosinophilic infiltrates, granulomatous changes, and eosinophil-rich necrotizing vasculitis 1
• Skin biopsy in EGPA reveals necrotizing vasculitis with vascular, perivascular, or interstitial dermal eosinophil distribution 1
• Sarcoidosis shows non-caseating granulomas; nasal biopsy has 91% positivity when mucosa appears abnormal 1
• Sino-nasal biopsies often non-diagnostic in EGPA despite structured histopathological evaluation 1

Imaging Studies

Chest Imaging

• Sarcoidosis: bilateral hilar lymphadenopathy, multiple nodules, or nodular infiltration 1
• EGPA: pulmonary infiltrates, often fleeting and migratory 1
• MPA: alveolar hemorrhage pattern 2

Sinus Imaging

• Sarcoidosis: generalized opacification with turbinate/septal nodularity (21%), osteoneogenesis (15%), bone erosion (8%) 1
• EGPA: chronic rhinosinusitis changes with nasal polyps 1

Treatment Algorithms

EGPA Management

Remission Induction

• Severe disease with organ-threatening manifestations: high-dose glucocorticoids plus cyclophosphamide or rituximab 1, 4
• Non-organ-threatening disease: glucocorticoids plus methotrexate or azathioprine 1
• Cardiac involvement (most common cause of death) requires aggressive immunosuppression 4

Maintenance Therapy

• Prolonged corticosteroid therapy often necessary for asthma control 4
• Disease relapses common, requiring vigilant monitoring 4

Microscopic Polyangiitis Treatment

• Follows same treatment paradigm as GPA: glucocorticoids plus cyclophosphamide or rituximab for induction 1
• Azathioprine or low-dose rituximab for maintenance 1
• Urgent treatment initiation critical in rapidly progressive glomerulonephritis 1

Sarcoidosis Management

Observation vs. Treatment

• Stage 1 disease: 75% managed symptomatically with NSAIDs; spontaneous remission common 1
• Stage 2 disease: 65% spontaneously regress 1
• Erythema nodosum with acute arthritis: 85% remit spontaneously 1

Immunosuppression Indications

• Oral corticosteroids for Stage II/III pulmonary disease and extrapulmonary critical organ involvement 1
• Hydroxychloroquine/chloroquine for cutaneous, bone, and neurologic sarcoidosis (monitor for retinal toxicity) 1
• Steroid-sparing agents (methotrexate, cyclophosphamide, azathioprine) for refractory disease 1
• TNF-alpha antagonists (infliximab) for refractory cutaneous, ophthalmic, hepatic, and neurosarcoidosis 1

C3 Glomerulopathy (If Renal-Limited Disease)

• Moderate-to-severe disease without monoclonal gammopathy: mycophenolate mofetil plus glucocorticoids initially 1
• If treatment fails: consider eculizumab (complement C5 inhibitor) 1
• Clinical trial enrollment strongly encouraged given limited evidence base 1

Critical Diagnostic Pitfalls

• Drug-induced vasculitis: Always obtain detailed medication history; discontinuation of offending agent is critical to prevent relapses 1
• ANCA-negative EGPA: Absence of ANCA does not exclude diagnosis; focus on clinical phenotype (asthma, eosinophilia, organ involvement) 1
• Isolated P-ANCA positivity: Requires MPO-ANCA confirmation by ELISA to distinguish true vasculitis from inflammatory mimics 1
• Biopsy timing in AAV: Do not delay immunosuppressive therapy while awaiting biopsy in rapidly deteriorating patients with compatible clinical presentation and positive ANCA 1