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Childhood Wegener’s granulomatosis

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					  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                                   •   Day 6
    – Increasing creatinine, active urine       – Daily cyclophosphamide begun
      sediment, large proteinuria           •   Day 7
    – Hemoglobin 7.1 g/dL  Blood               – Worsening respiratory status
      transfusion required                      – CPAP requirement
    – Palpable purpura                      •   Day 9
•   Day 4                                       – Endotracheal intubation,
    – Worsening respiratory distress,             mechanical ventilation
      “pulmonary-renal syndrome”            •   Day 10
    – pulse methylprednisolone therapy          – Worsening oxygenation
                                                – High-frequency oscillatory
•   Day 5                                         ventilation
    – Bronchoscopy/BAL:                         – Plasma exchange therapy begun
        • Bloody secretions                     – Transfer to Cincinnati Children’s
        • Mucosal hemorrhagic lesions             Hospital
            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
                                                                                   Disrupted basement membrane
          Segmental necrosis                     Nonspecific IgG staining
                                             Silver stain


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                140
                                                                   BUN
                                                        120


•    Daily plasma exchange x 14                         100



•    High-dose corticosteroids                              80




                                                mg/dL
•    Recombinant FVIIa on three occasions for
                                                            60




     increased pulmonary hemorrhage
                                                            40


                                                            20
                                                                                        HD
•    Rituximab begun on Day 15 (375 mg/m2                    0
                                                                                  HD

     once weekly x 4)
                                                             6
                                                                       Creatinine
                                                             5


•    Trimethoprim/sulfamethoxazole,                          4


     ganciclovir




                                                    mg/dL
                                                             3



•    Intermittent hemodialysis (HD) Day 14-23                2




•    Extubated on Day 19                                     1


                                                                                  HD
•    Transfer to floor on Day 26
                                                             0
                                                             11/9/06         11/19/06   11/29/06   12/9/06   12/19/06   12/29/06   1/8/07



                                                                                        HD
•    Discharged to home on Day 35
•    Currently (at 3 months) clinically doing
     well
                  Other laboratory parameters

                    Day 12     Day 14**      Day 35      Day 41       Day 48
    CD3/mm3                    444 (43%)      *            *

    CD4/mm3                    279 (27%)      *            *

    CD8/mm3                    144 (14%)      *            *

    CD19/mm3                   557 (54%)      *            *

    CD16/mm3                   41 (4%)        *            *

   Lymphs/mm3                     1040        280          160         170

       BAFF                                            3.01 ng/mL 
       CRP         2.0 mg/dL                           < 0.3 mg/dL
     Anti-PR3     >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                  •   Vasculitic manifestations
          – Upper airway involvement (sinus,              – Lung involvement
            ear, naso-/oropharynx, trachea)                   • Diffuse alveolar hemorrhage
          – Tracheobronchial involvement                  – Renal involvement
            (tracheitis, stenosis)                            • Focal segmental, pauci-
          – Lung involvement                                    immune glomerulonephritis
                                                              • Rapidly progressive GN
               • Nodular disease, parenchymal
                 disease                                  – Pulmonary-renal syndrome
                                                          – Skin involvement
          – Ocular involvement
                                                          – Neurologic disease
          – Neurologic disease
                                                          – Musculoskeletal 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                                                        c-ANCA

          – antigens: proteinase-3, myeloperoxidase
    • 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
                         Etiology and Pathogenesis
        Hypothesis: Granuloma formation and PR3 development




Lamprecht P et al. J Intern Med 2006;260: 187–191
              BAFF in Wegener’s granulomatosis?
    • B cell activating factor of the TNF                  • Krumbholz M et al. J Autoimmun
      family (also known as BLyS)                            2005;25:298-302
    • Crucial role in B cell development,                     – 46 WG patients vs. 62 controls
      survival, and Ig production




    • 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. Arthritis Rheum 2004;50(11):3580-90.
2. Bacon PA. The spectrum of Wegener's granulomatosis and disease relapse. N Engl J Med
   2005;352(4):330-2.
3. Becker-Merok A, Nikolaisen C, Nossent HC. B-lymphocyte activating factor in systemic
   lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease
   measures and time. Lupus 2006;15(9):570-6.
4. Bosch X, Guilabert A, Font J. Antineutrophil cytoplasmic antibodies. Lancet
   2006;368(9533):404-18.
5. Edwards JC, Cambridge G, Leandro MJ. B cell depletion therapy in rheumatic disease.
   Best Pract Res Clin Rheumatol 2006;20(5):915-28.
6. Fauci AS, Wolff SM, Johnson JS. Effect of cyclophosphamide upon the immune response
   in Wegener's granulomatosis. N Engl J Med 1971;285(27):1493-6.
7. Frosch M, Foell D. Wegener granulomatosis in childhood and adolescence. Eur J Pediatr
   2004;163(8):425-34.
8. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci
   AS. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med
   1992;116(6):488-98.
9. Hollander D, Manning RT. The use of alkylating agents in the treatment of Wegener's
   granulomatosis. Ann Intern Med 1967;67(2):393-8.
                                    References
10. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, Ekstrand A,
    Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert
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    2003;349(1):36-44.
11. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337(21):1512-23.
12. Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, Specks U. Rituximab for
    refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial. Am J
    Respir Crit Care Med 2006;173(2):180-7.
13. Krumbholz M, Specks U, Wick M, Kalled SL, Jenne D, Meinl E. BAFF is elevated in serum of
    patients with Wegener's granulomatosis. J Autoimmun 2005;25(4):298-302.
14. Lamprecht P, Csernok E, Gross WL. Effector memory T cells as driving force of granuloma
    formation and autoimmunity in Wegener's granulomatosis. J Intern Med 2006;260(3):187-
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15. Lynch JP, 3rd, White E, Tazelaar H, Langford CA. Wegener's granulomatosis: evolving
    concepts in treatment. Semin Respir Crit Care Med 2004;25(5):491-521.
16. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J,
    Browning JL. Mice transgenic for BAFF develop lymphocytic disorders along with
    autoimmune manifestations. J Exp Med 1999;190(11):1697-710.
17. Rarok AA, Limburg PC, Kallenberg CG. Neutrophil-activating potential of antineutrophil
    cytoplasm autoantibodies. J Leukoc Biol 2003;74(1):3-15.
18. Schlieben DJ, Korbet SM, Kimura RE, Schwartz MM, Lewis EJ. Pulmonary-renal syndrome
    in a newborn with placental transmission of ANCAs. Am J Kidney Dis 2005;45(4):758-61.
                                    References
19. Sneller MC. Rituximab and Wegener's granulomatosis: are B cells a target in vasculitis
    treatment? Arthritis Rheum 2005;52(1):1-5.
20. Specks U. Methotrexate for Wegener's granulomatosis: what is the evidence? Arthritis
    Rheum 2005;52(8):2237-42.
21. St Clair EW, Tedder TF. New prospects for autoimmune disease therapy: B cells on
    deathwatch. Arthritis Rheum 2006;54(1):1-9.
22. Stasi R, Stipa E, Del Poeta G, Amadori S, Newland AC, Provan D. Long-term observation of
    patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with
    rituximab. Rheumatology (Oxford) 2006;45(11):1432-6.
23. Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol
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24. Wegener F. On generalised septic vessel diseases. By Friedrich Wegener, 1937 (translation).
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25. Wegener F. Wegener's granulomatosis. Thoughts and observations of a pathologist. Eur
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26. Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y, Maeda N, Falk RJ, Jennette JC.
    Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause
    glomerulonephritis and vasculitis in mice. J Clin Invest 2002;110(7):955-63.

				
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