Childhood Wegeners Granulomatosis Presenting with Fulminant Pulmonary Renal Syndrome and its Treatment with B Cell Depletion

Childhood Wegener’s granulomatosis presenting with fulminant pulmonary-renal syndrome Claas H. Hinze M.D. Fellow Division of Rheumatology Cincinnati Children’s Hospital Medical Center Case Presentation • A previously healthy 15 year old Caucasian boy presents with respiratory distress and acute renal failure • • • • • Well until one month before presentation Migratory arthralgias in ankles, right knee, shoulders Sore throat, nasal congestion Low grade fevers, weight loss On day of admission to outside hospital (11/12/2006): – – – – – – Fever 38.3°C, breathing difficulties, severe abdominal pain, vomiting CXR with right lower lobe infiltrate WBC 7,100/mm3, Hgb 11.0 g/dL, CRP 19.8 mg/dL, ESR > 140 mm/hr BUN 36 mg/dL, creatinine 2.3 mg/dL Presumptive diagnoses: pneumonia, prerenal azotemia Admitted to the hospital, started on IVF and cefuroxime Outside hospital course • Day 3 – Increasing creatinine, active urine sediment, large proteinuria – Hemoglobin 7.1 g/dL  Blood transfusion required – Palpable purpura • • • Day 6 – Daily cyclophosphamide begun Day 7 – Worsening respiratory status – CPAP requirement Day 9 – Endotracheal intubation, mechanical ventilation • Day 4 – Worsening respiratory distress, “pulmonary-renal syndrome” – pulse methylprednisolone therapy • Day 10 – Worsening oxygenation – High-frequency oscillatory ventilation – Plasma exchange therapy begun – Transfer to Cincinnati Children’s Hospital • Day 5 – Bronchoscopy/BAL: • Bloody secretions • Mucosal hemorrhagic lesions Imaging Day 1 Day 4 Day 9 Day 4 Day 4 Pathology Skin and Lung Biopsy (Day 5) Skin: small artery, segmental necrosis Crescent formation, segmental necrosis Normal glomeruli present IgG Segmental necrosis Nonspecific IgG staining Silver stain Disrupted basement membrane Photomicrographs provided by David P. Witte, M.D. Pertinent laboratory findings • c-ANCA 1:640 • Anti-PR3 > 100 units/mL (normal <3) • Rheumatoid factor 227 units/mL (normal <60) • Anti-TPO >1300 units/mL (normal <60) • ANA, anti-dsDNA, -RNP, -Sm, -Ro, -La negative • Anti-GBM negative • C3 92 mg/dL, C4 5.9 mg/dL () Cincinnati Children’s Hospital Medical Center Hospital Course • • • • • • • • • • • Daily cyclophosphamide IV, later PO Daily plasma exchange x 14 High-dose corticosteroids Recombinant FVIIa on three occasions for increased pulmonary hemorrhage Rituximab begun on Day 15 (375 mg/m2 once weekly x 4) Trimethoprim/sulfamethoxazole, ganciclovir Intermittent hemodialysis (HD) Day 14-23 Extubated on Day 19 Transfer to floor on Day 26 Discharged to home on Day 35 Currently (at 3 months) clinically doing well 140 BUN 120 100 mg/dL 80 60 40 20 0 6 HD Creatinine HD 5 4 mg/dL 3 2 1 0 11/9/06 HD 11/19/06 11/29/06 12/9/06 12/19/06 12/29/06 1/8/07 HD Other laboratory parameters Day 12 Day 14** 444 (43%)  279 (27%)  Day 35 * * Day 41 * * Day 48 CD3/mm3 CD4/mm3 CD8/mm3 CD19/mm3 144 (14%)  557 (54%)  * * * * CD16/mm3 Lymphs/mm3 BAFF 41 (4%)  1040 * 280 * 160 3.01 ng/mL  170 CRP Anti-PR3 2.0 mg/dL < 0.3 mg/dL >100 U/mL 61 U/mL 39 U/mL *Too few events ** Before rituximab therapy Wegener’s granulomatosis Overview • Multisystem disorder – systemic vasculitis • • Extremely rare in childhood Classic triad: 1. Granulomatous, necrotizing inflammation of the upper and lower respiratory tract 2. Necrotizing granulomatous vasculitis 3. Focal glomerulonephritis • Closely related small vessel vasculitides: – – Microscopic polyangiitis (MPA) - no granulomas Churg-Strauss syndrome - plus asthma and eosinophilia Vasculitis Preferred sites of vascular involvement Jennette JC, Falk RJ. N Engl J Med 1997; 337(21):1512-23 Wegener’s granulomatosis Two major phenomena • Vasculitis Bacon PA. N Engl J Med 2005;352(4):330-2 Clinical manifestations • Granulomatous manifestations – Upper airway involvement (sinus, ear, naso-/oropharynx, trachea) • Vasculitic manifestations – Lung involvement • Diffuse alveolar hemorrhage – Renal involvement • Focal segmental, pauciimmune glomerulonephritis • Rapidly progressive GN – Pulmonary-renal syndrome – Tracheobronchial involvement (tracheitis, stenosis) – Lung involvement • Nodular disease, parenchymal disease – Ocular involvement – Skin involvement – Neurologic disease – Musculoskeletal disease – Neurologic disease – Musculoskeletal disease Frosch M, Foell D. Eur J Pediatr 2004;163(8):425-34 Antineutrophil cytoplasmic antibody (ANCA) • Indirect immunofluorescence: – Cytoplasmic staining (c-ANCA) – Perinuclear staining (p-ANCA) • ELISA – antigens: proteinase-3, myeloperoxidase c-ANCA • Typical ANCA – Anti-proteinase 3 (usually c-ANCA) – Anti-myeloperoxidase (usually p-ANCA) p-ANCA • Evidence for role in vasculitis: – – – – Only few ANCA-negative patients with WG or MPA Increase in titer precedes relapse, decline in titer with remission Transplacental transfer of ANCA causing systemic vasculitis in neonate* Transfer of MPO-ANCA in wild-type or Rag-2 knockout mice causing necrotizing crescentic GN** Bosch X et al. Lancet 2006;368(9533):404-18 *Schlieben DJ et al. Am J Kidney Dis 45:758-761 **Xiao H et al. J Clin Invest. 2002;110:955–963 Neutrophil activation by ANCA Rarok et al. Journal of Leukocyte Biology. 2003; 74:3-15 Hypothesis: Granuloma formation and PR3 development Etiology and Pathogenesis Lamprecht P et al. J Intern Med 2006;260: 187–191 BAFF in Wegener’s granulomatosis? • B cell activating factor of the TNF family (also known as BLyS) • Crucial role in B cell development, survival, and Ig production • Krumbholz M et al. J Autoimmun 2005;25:298-302 – 46 WG patients vs. 62 controls • Transgenic mice overexpressing BAFF develop SLE-like illness** • Elevated in 10% of rheumatoid arthritis pts, in 57% of SLE pts*** *St. Clair EW, Tedder TF. Arthritis Rheum 2006;54(1):1–9 **Mackay F et al. J Exp Med 1999; 190: 1697–1710 ***Becker-Merok A et al. Lupus 2006;15, 570–576 Treatment Evolution • Natural history: mean survival 5 months, 1 yr survival 20%* • Steroid-only era: mean survival 12 months* • 1971: Daily cyclophosphamide and prednisone** – 1971 Fauci – 5 year survival 87%*** – High-rate of treatment-related morbidity • Current:  –  – – Induction with daily cyclophosphamide 1.5-2 mg/kg and prednisone Until complete remission is achieved (usually within 3-6 months) Maintenance therapy with azathioprine or methotrexate Plasma exchange therapy in diffuse alveolar hemorrhage TMP-SMX benefit questionable, but used for PCP prophylaxis *Hollander D, Manning RT. Ann Intern Med 1967;67:393–398 **Fauci A et al. N Engl J Med. 1971 Dec 30;285(27):1493-6 ***Hoffman GS et al. Ann Intern Med 1992;116:488–498 Lynch JP et al. Semin Respir Crit Care Med 2004;25(5):491-521 B cell depletion therapy with anti-CD20 monoclonal antibody (rituximab) • • • • • Chimeric anti-CD20 monoclonal antibody (rituximab) – CD20 expressed on pre-, naive, mature, and memory B cells, but not on stem cells, pro-B cell, and plasma cells B cell depletion – Via antibody-dependent cellular and complement-dependent cytotoxicity, and apoptosis B cell modulation – Interference with other B cell functions, e.g. antigen-presentation, cytokine-production, and regulatory functions Successful use in many autoimmune diseases (e.g. RA, SLE) Rationale for the use in Wegener’s granulomatosis 1. Importance of ANCAs in the pathogenesis of WG 2. Depletion of CD20 expressing precursors of ANCA-producing plasma cells 3. Short-living ANCA-producing plasma cells Tedder TF, Engel P. Immunol Today 1994;15(9):450-4 Edwards JC, et al. Best Pract Res Clin Rheumatol 2006;20(5):915-28 Sneller MC. Arthritis Rheum 2005;52(1):1-5 Rituximab • Keogh KA et al. Am J Resp Crit Care Med 2006;173:180-7 – Prospective, open-label pilot trial, monitoring for 1 yr – 10 patients with refractory WG (all anti-PR3+) – All patients with B cell depletion and complete clinical remission • Off glucocorticoids at 6 months • 5 pts were retreated for rising ANCA, 1 pt with clinical flare • Stasi R et al. Rheumatology 2006;45:1432-6 – – – – – – – Prospective, open-label study 10 patients (8 WG, 2 MPA) refractory to conventional therapy Median follow-up 33.5 months Rapid clinical improvement: 9 complete responses, 1 partial response 3 relapses – re-treatment resulting in sustained response B cell depletion 8/10 ANCA-negative after B cell depletion • 3/10 ANCA-negative even after B cell reconstitution Summary • Wegener’s granulomatosis and related ANCA-associated vasculitides are extremely rare in childhood • The etiology is unknown, even though the pathogenic effects of ANCAs are well established • The prognosis is much improved with contemporary therapy, but has a high rate of treatment-related adverse effects • B cell targeted therapy may offer further benefit without severe toxicities References 1. Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, Sanz I. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. 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