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When ANCA is negative: Challenges in Diagnosing Granulomatosis with polyangiitis

When ANCA is negative: Challenges in Diagnosing Granulomatosis with polyangiitis. Allison J Wildin, DO Medical College of Wisconsin, Milwaukee. Overview. Brief review of granulomatosis with polyangiitis Case presentation Literature review and discussion Conclusion.

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When ANCA is negative: Challenges in Diagnosing Granulomatosis with polyangiitis

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  1. When ANCA is negative: Challenges in Diagnosing Granulomatosis with polyangiitis Allison J Wildin, DO Medical College of Wisconsin, Milwaukee

  2. Overview • Brief review of granulomatosis with polyangiitis • Case presentation • Literature review and discussion • Conclusion

  3. Features of Granulomatosis with Polyangiitis • GPA – formerly known as Wegner’s granulomatosis • Older adults, more common in Caucasians, and equal M:F ratio • Antineutrophil cytoplasmic antibody (ANCA)-associated small to medium vessel necrotizing vasculitis • Commonly perinuclear- ANCA (p-ANCA) pattern by immunofluorescence and proteinase 3 (PR3) antibody positive by enzyme immunoassay • Granulomatous inflammation of upper and lower respiratory tracts • Necrotizing, pauci-immune glomerulonephritis • “Limited” or “Localized” forms exist – most commonly upper respiratory tract Seo p, stone j. the antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117:39-50. Lutalo P, D’Cruz D. Diagnosis and classification of granulomatosis with polyangiitis (aka wegner’s granulomatosis). Journal of autoimmunity. 2014;48-49:94-98.

  4. HPI MR. J • Previously healthy 25 y/o black male with worsening bilateral pulmonary infiltrates, fever, hypoxia • Presented four months prior to his PCP complaining of dry cough and dyspnea • Negative CXR • Treated with azithromycin and given an albuterol inhaler • Subsequent multiple encounters for persistent cough and dyspnea

  5. HPI • One month ago he was seen in an emergency department with fever of 100.6 and nonproductive cough • CXR - right upper lobe infiltrate • Treated again with azithromycin • Four days later he was admitted with worsening symptoms • Febrile, tachycardic • CT - bilateral apical consolidations, scattered pulmonary nodules, and mediastinal and hilar lymphadenopathy • Unresponsive to standard antibiotic therapy for community acquired pneumonia • Extensive work-up including bronchoscopy with BAL, brush biopsy and infectious work-up was unrevealing • Empirically started on antifungal therapy with some improvement • Discharged 10 days later on amoxicillin and itraconazole

  6. HPI • One week after discharge, he was admitted with unresolved fevers, chills, dyspnea, and cough • Febrile to 101.6, tachycardic and mildly hypoxic • CT chest- progressive worsening of bilateral upper lobe infiltrates with new nodular appearing infiltrates now involving the lower lobes • Rheumatology was consulted

  7. Additional History • ROS was negative apart from fatigue, cough, fever, chills and dyspnea • MedH: Attention-deficit disorder • SurgH: None • FamH: Mother has diabetes. No known family history of autoimmune or rheumatologic disease. • Meds: amoxicillin, itraconazole, amphetamine-dextroamphetamine • Allergies: NKDA • SocH: Single and lives at home with his mother. Worked as a packer in a warehouse for the preceding 6 months, but quit 1 month ago when he got sick. Stopped smoking marijuana and tobacco products one month ago. No known occupational exposures other than dust. No recent travel or sick contacts. No pets.

  8. Physical exam • Vitals: T 98.6 BP 138/84 P 120 SpO2 95% on 1 L O2 Gen: Not in any acute distress Skin: No rashes or skin lesions HEENT: PERRL, moist oral mucosa, no lesions in nose or mouth Cardio: Tachycardic, no murmur Resp: Diminished lung sounds. Breathing unlabored and able to speak in complete sentences Abd: Active BS, soft and nontender Neuro: Strength and sensation intact without deficit MSK: No swelling, tenderness or restricted ROM

  9. Labs • WBC 32.4 • Hgb 10.4 • Plt 430 • Creatinine 0.79 • AlkPhos 179 • AST 40 • ALT 40 • Tbili 1.1 • Infectious work up including blood and respiratory cultures, coccidiodes, blastomyces, histoplasma, cryptococcal, legionella, Hepatitis panel, TB and HIV negative • ESR 128 • C3 193 C4 19 • CK 132 • RF 19 • ANCA, MPO, PR3 negative • ANA negative • UA without RBC or protein

  10. Imaging Consolidations and nodular infiltrates in the upper lobes Diffuse patchy bilateral airspace opacities

  11. Hospital Course • Differential diagnosis was broad including infectious, inflammatory and neoplastic etiologies • VATS procedure with wedge resection of right upper and lower lobes • 4 days post-operatively he developed ARDS requiring intubation and mechanical ventilation and right-sided pneumothorax requiring chest tube placement • Lung biopsy histopathology demonstrated a pattern of granulomatous inflammation, vasculitis and thrombus most consistent with GPA

  12. Pathology Multinucleated giant cells and lung necrosis with neutrophilic infiltration Granulomatous inflammation of the lung

  13. pathology Magnified view of vasculitic vessel showing intraluminal irregularity Vessel demonstrating dense neutrophilic infiltration consistent with vasculitis

  14. Treatment • Due to disease severity he was started on pulse dose steroids 1 GM solumedrol x 3 days followed by prednisone1 mg/kg with plasmapheresis and IV cyclophosphamide • Responded well to treatment and extubated a week later • Post-discharge he received pulse IV cyclophosphamide every 2 weeks for 3 months and his steroids were tapered with plan to use Rituxan as maintenance therapy

  15. Case Summary ANCA negative GPA localized to the lower respiratory tract in a young black male presenting as worsening bilateral pulmonary infiltrates A challenging diagnosis to make Atypical patient Disease limited to a single organ without other “classic” features Negative serologic studies

  16. Literature Review and discussion • One other case report of ANCA-negative GPA isolated to the lower respiratory tract in a Japanese journal • 53 y/o F with nodular lung lesions and negative ANCA serologies diagnosed by thorascopic lung biopsy • ANCA serologies • Role in pathogenesis • Methods of testing • Utility in diagnosis • Implications of serology for disease manifestations and course Tomizawa, H, Enomoto K, Kurokawa H, et al. [Antineutrophil cytoplasmic antibody (ANCA) negative Limited-form granulomatosis with polyangiitis of the lung diagnosed by the thorascopic lung biopsy]. Kyobugeka. 2018; 71(9):680-684.

  17. ANCA and disease Pathogenesis • ANCA are directed against proteins found in azurophile (primary) granules of polymorphonuclear cells and monocytes and can be present on the cell surface or secreted into the extracellular environment in response to inflammatory stimuli • Proteinase 3 (PR3) • Myeloperoxidase (MPO) • ANCA may increase neutrophil-endothelial interactions and activate neutrophils leading to release of reactive oxygen species, lytic enzymes and pro-inflammatory cytokines • Triggered by environmental or infectious triggers in genetically pre-disposed individuals Gomez-peurta J, Hernandez-Rodriguez J, Lopez-soto A, et al antineutrophil cytoplasmic antibody-associated vasculitidtes and respiratory disease. Chest. 2009;136(4):1101-1111. Lutalo P, D’Cruz D. Diagnosis and classification of granulomatosis with polyangiitis (aka wegner’s granulomatosis). Journal of autoimmunity. 2014;48-49:94-98.

  18. ANCA testing • Two commonly used assays for ANCA • Indirect Immunofluorescence Assay (IIFA) • Patterns: c-ANCA, p-ANCA, atypical ANCA • Enzyme-linked Immunosorbent Assay (ELISA) • PR3 or MPO antibodies • Newer forms of this assay including capture-ELISA, chemiluminescence enzyme immunoassay, and fluoro-enzyme immunoassay • ANCA biochip Radice, A, Bianchi L, Sinica R. Anti-neutrophil cytoplasmic antibodies methodologic aspects and clinical significance in systemic vasculitis. Autoimmunity reviews. 2013;12:487-495. Tateyama K, Kodama S, Kishibe K, etal. A novel strategy with combined assays for detection of anti-neutrophil cytoplasmic antibody (ANCA) in clinically anca-negative granulomatosis with polyangiitis patients. Auris Nasus Larynx. 2017;44:735-741.

  19. ANCA in Diagnosis • IFA is a more sensitive marker, while ELISA is more specific • Combined use of IFA and ELISA give a reported Sensitivity of 96% and Specificity of 98.5% • Positive ANCA needs to be interpreted in the context of clinical setting and histopathology • Negative ANCA does not rule-out diagnosis Seo p, stone j. the antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117:39-50. Lutalo P, D’Cruz D. Diagnosis and classification of granulomatosis with polyangiitis (aka wegner’s granulomatosis). Journal of autoimmunity. 2014;48-49:94-98. Radice, A, Bianchi L, Sinica R. Anti-neutrophil cytoplasmic antibodies methodologic aspects and clinical significance in systemic vasculitis. Autoimmunity reviews. 2013;12:487-495.

  20. Classification and diagnostic criteria • Classification criteria and definitions, but no universally accepted and tested diagnostic criteria • American College of Rheumatology 1990 classification criteria • Chapel Hill Consensus Conference criteria • European Medicines Agency (EMA) Algorithm • Only the EMA algorithm includes ANCA as a diagnostic criterion Lutalo P, D’Cruz D. Diagnosis and classification of granulomatosis with polyangiitis (aka wegner’s granulomatosis). Journal of autoimmunity. 2014;48-49:94-98. Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides ad polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007;66(2):222.

  21. 1990 ACR Criteria • Nasal or oral inflammation • Abnormal chest radiograph • Abnormal urinary sediment • Granulomatous inflammation on biopsy • Presence of 2 or more criteria yielded a sensitivity of 88% and specificity of 92% • Criteria pre-date ANCA testing • Does not discriminate GPA from microscopic polyangiitis or mimickers of GPA • Criteria have not performed well in some clinical studies Leavitt R, Fauci A, Bloch D, et al. The American College of rheumatology 1990 criteria fir the classification of Wegner’s granulomatosis. Arthritis Rheum. 1990;33(8):1101. Lutalo P, D’Cruz D. Diagnosis and classification of granulomatosis with polyangiitis (aka wegner’s granulomatosis). Journal of autoimmunity. 2014;48-49:94-98. Rao, J. Allen N, Pincus T. Limitations of the 1990 American College of Rheumatology classification criteria in the diagnosis of vasculitis. Ann Intern Med. 1998;129(5):345.

  22. Chapel Hill Consensus Conference criteria • Originally proposed in 1994 and revised in 2012 • Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vascultitis affecting predominately small to medium vessels (e.g. capillaries, venules, arterioles, arteries, and veins. Necrotizing glomerulonephritis is common. Jeanette J, Falk R, Bacon P, et al. 2012 revised international chapel hill consensus conference nomenclature of vasculitides. Arthritis Rheum.2013:65(1):1-11.

  23. European Medicines Agency algorithm • Uses criteria for EGPA, ACR Criteria, and Chapel Hill Consensus definition in a stepwise algorithm to categorize patients Watts R, Lane S, Hanslik T, et AL. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007:66(2):222.

  24. Anca IN diagnosis • Use of ANCA in diagnosis is challenging • ANCA can be positive in the absence of autoimmune vasculitis • Presence of ANCA can help increase suspicion and support the diagnosis in the right clinical scenario • 10-20% of patients with GPA are ANCA negative • 5-30% with localized GPA are ANCA negative • One Japanese study reported approximately 50% of limited GPA defined as GPA localized to the upper respiratory tract were ANCA negative • Some of these studies did not use combined assays Seo p, stone j. the antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117:39-50. Lutalo P, D’Cruz D. Diagnosis and classification of granulomatosis with polyangiitis (aka wegner’s granulomatosis). Journal of autoimmunity. 2014;48-49:94-98. Radice, A, Bianchi L, Sinica R. Anti-neutrophil cytoplasmic antibodies methodologic aspects and clinical significance in systemic vasculitis. Autoimmunity reviews. 2013;12:487-495. Tateyama K, Kodama S, Kishibe K, etal. A novel strategy with combined assays for detection of anti-neutrophil cytoplasmic antibody (ANCA) in clinically anca-negative granulomatosis with polyangiitis patients. Auris Nasus Larynx. 2017;44:735-741.

  25. Theories about negative ANCA • Tateyama et al proposed that some patients might have ANCA that is not able to be detected by current methods or that alternate pathogenic mechanisms exist • Minor antigens and antibodies (azurocidin, bactericidal permeability increasing protein, cathepsin G, elastase, lactoferrin, and lysozyme (LAMP-2)) • T-cell dependent mechanisms Tateyama K, Kodama S, Kishibe K, etal. A novel strategy with combined assays for detection of anti-neutrophil cytoplasmic antibody (ANCA) in clinically anca-negative granulomatosis with polyangiitis patients. Auris Nasus Larynx. 2017;44:735-741. Gomez-peurta J, Hernandez-Rodriguez J, Lopez-soto A, et al antineutrophil cytoplasmic antibody-associated vasculitidtes and respiratory disease. Chest. 2009;136(4):1101-1111.

  26. ANCA status implications on disease course • ANCA negative disease is more likely to be “limited” or “localized,” and less severe • Patients with ANCA-negative disease may be at higher risk for relapse and progression to systemic disease • In cases of progressive disease, ANCA may subsequently become positive Miloslavsky E, Lu N, Unizony S, et al. Myeloperoxidase-antineutrophil cytoplasmic antibody (anca)-positive and anca-negative patients with granulomatosis with polyangiitis (Wegner’s): distinct patient subsets. Arthritis Rheumatol. 2016;68:2945-2952. Gomez-peurta J, Hernandez-Rodriguez J, Lopez-soto A, et al antineutrophil cytoplasmic antibody-associated vasculitidtes and respiratory disease. Chest. 2009;136(4):1101-1111.

  27. Conclusion • Localized forms of GPA with negative ANCA can be difficult to diagnose • Negative ANCA cannot be used to definitively rule-out autoimmune vasculitis • High level of suspicion and tissue diagnosis is essential

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