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Granulomatosis with Polyangiitis (GPA)

last modified on: Tue, 02/27/2024 - 08:32

Note: last updated before 2018

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Case Example: Subglottic Stenosis due to Granulomatosis with Polyangitis

GENERAL CONSIDERATIONS

  1. Definitions
    1. Granulomatosis with polyangiitis - a form of systemic, necrotizing vasculitis with granulomatous inflammation. First described by Friedrich Wegener in a 1936 entitled "On generalized, septic vascular diseases" (Translated from German).
  2. Prevalence/Demographics
    1. GPA is rare. One population study in the United Kingdom showed 40 cases of WG in a district of ~500,000 persons > 15 years old over a 10 year period.
    2. GPA most commonly affects males ages 50-60, with 95% of cases being Caucasian individuals.
  3. Pathogenesis
    1. GPA is thought to be an immune-mediated condition.
    2. Tissue injury is followed by highly specific immune response to neutrophil granule proteins, including Proteinase 3 (70-80% of cases) and Myeloperoxidase (10% of cases) among others, leading to a high titer of anti-neutrophil cytoplasmic antibodies (ANCA).
    3. Type III immune-complex hypersensitivity reaction leads to vasculitis of small-to-medium arteries and veins.
    4. Matrix metalloproteinases are thought to play a role
    5. Staphylococcal infection may trigger relapse in patients in remission, a process possibly mediated by the staphylococcal toxic syndrome toxin-1.
  4. Broad Classifications
    1. Classic - systemic vasculitis with necrotizing granulomatous inflammation involving the upper and lower respiratory tract and kidneys.
      1. Classic triad includes:
        1. Granulomas of the respiratory tract
        2. Progressive glomerulonephritis
        3. Necrotizing vasculitis of small-to-medium arteries and veins
      2. Other sites of involvement may include: spleen, joints, skin, eyes, middle ear, heart, peripheral, and central nerves.
      3. Classic cases are more likely to be positive for ANCA
    2. Limited - similar to the classic form, with findings isolated to the respiratory tract (many of patients in this classification will later develop more widespread disease manifestations.
      1. Limited cases are less likely to be positive for ANCA compared to classic cases
  5. Complications and Associated Conditions
    1. Rapidly progressive glomerulonephritis leading to renal failure
    2. Sepsis
    3. Normochromic, normocytic anemia
    4. Disseminated intravascular coagulation
    5. Venous thromboembolism
    6. Alveolar hemorrhage
    7. Ophthalmologic inflammatory states including uveitis, optic neuritis, and orbital inflammatory disease
    8. Cardiac manifestations including dilated cardiomyopathy, pericarditis, and an association with ischemic heart disease

EVALUATION

  1. History
    1. Chief Complaint
      1. Upper airway and/or pulmonary involvement - nearly all patients
        1. Sinusitis, chronic nasal discharge, oral and nasal ulcers, and hemoptysis are common
        2. Cough, rhinitis, dyspnea, and pleuritic pain are also encountered
      2. Fever - 90% of cases
      3. Microscopic hematuria
      4. Hearing loss - both conductive and sensorineural
      5. Mild non-specific arthralgias 
      6. Less common presentations include glomerulonephritis, otitis, myalgias, neuritis, and weight loss
    2. Family History        
      1. May include relatives with Granulomatosis with Polyangiitis (GPA) or
      2. Related disorders including rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid disease, multiple sclerosis, or myasthenia gravis
    3. Social History
      1. Patient may have associated functional limitations with occupational or family responsibilities   
    4. Review of Systems
      1. May reveal common rheumatologic symptoms - xerostomia, uveitis, pleurisy, oral/genital ulcers, skin rash/photosensitivity, Raynaud's, etc.
      2. May also reveal peripheral neuropathy
  2. Physical Exam
    1. HEENT
      1. May have keratoconjunctivitis or proptosis
      2. Nasal cartilage destruction - "saddle-nose deformity" and septal perforation
      3. Sinusitis
      4. Mucosal ulcerations of the nasopharynx (less common)
      5. Hyperplastic gingivitis
    2. Subglottic stenosis (SGS)
      1. May be encountered as a presenting feature or late stage manifestation
      2. SGS segments may persist despite treatment and control of disease elsewhere in the body. 
      3. Patients may adjust to lesions obstructing their airway until a critical point of stenosis is reached requiring intervention.
      4. Symptoms may include cough, shortness of breath, increased work of breathing and biphasic stridor.
    3. Pulmonary
      1. May have pulmonary infiltrates
      2. Pleural effusion
    4. Musculoskeletal
      1. Mild non-specific arthritis
    5. Skin
      1. Palpable purpura
      2. Vesicular, ulcerative, and hemorrhagic lesions
      3. May have livido reticularis
  3. Imaging
    1. Chest x-ray findings may vary, but could possibly include
      1. Cavitary nodules
      2. Alveolar opacities
      3. Pleural opacities
      4. Diffuse hazy opacities possibly reflecting alveolar hemorrhage
      5. Hilar Adenopathy
    2. Chest CT may show nodular densities, interstitial infiltrates, lymph node enlargement
    3. Echocardiogram may also show abnormalities
  4. Laboratory Analysis
    1. Urine studies may show abnormal urine sediment
    2. Serum Studies
      1. C-ANCA positive in 90% of cases
      2. P-ANCA negative
      3. Routine labs (CBC, ESR, CRP) are generally non-specific, but may show normochromic, normocytic anemia
      4. RF, ANA, and hepatitis serologies may be indicated to rule out other possible conditions
      5. Note that emerging support of limited GPA (Granulomatosis with Polyangiitis) presenting as subglottic stenosis in isolation without initial laboratory abnormalities has been published (Arebro et al 2012 and Gouveris et al 2013)
  5. Tissue Biopsy
    1. Lung – must show granulomas (necrotizing but noncaseating)
    2. Kidney – FSGS with possible crescent formation
    3. Blood Vessels – monocytic infiltration with granulomas

MANAGEMENT

  1. High-dose corticosteroids plus cyclophosphamide (1-3 mg/kg/day PO or IV pulsed) or methotrexate (Azothioprine if Cr >2) to induce remission. 
    1. Steroid dosing:
      1. 1mg/kg/day for 1 month
      2. Taper by 10 mg/day to target 20 mg/day by weeks 8-10
      3. Plateau 20 mg/day for 2 weeks
      4. Taper by 2.5 mg/day each week to target 10 mg/day
      5. Taper by 1 mg/day each week until discontinued
    2. Rituximab may be used instead of IV cyclophosphamide and may be more effective in patients with relapsing disease
    3. Pulsed IV cyclophosphamide has been associated with lower risk of leukopenia, lower infectious side effects, lower toxicity, and lower mortality than daily oral administration, but high rates of relapse
    4. Pulsed IV cyclophosphamide may increase remission vs. continuous dosing
  2. Methotrexate 20-25 mg/week (progressively increased from 0.3 mg/kg/week) or AZT 2mg/kg/day for 12-18 months for maintenance (less toxic than cyclophosphamide)
  3. Adjuvant Therapies
    1. Limited evidence suggests trimethoprim-sulfamethoxazole 160/800 BID for 24 months reduces relapse rate
    2. IVIG currently being evaluated as a possible adjuvant to systemic corticosteroids and immunosuppressants - evidence is insufficient
      1. One small trial noted that IVIG may reduce persistent disease activity for up to 3 months
    3. Plasma exchange and plasmapheresis in patients with renal vasculitis may reduce progression to end-stage renal disease requiring dialysis and increase renal survival compared to high dose methylprednisolone, respectively
    4. Etanercept appears ineffective in maintenance of remission
  4. Serial ANCA titers to may be useful to predict relapse but may not be useful to to predict clinical exacerbation.

REFERENCES

Hoffman GS, et al. "Wegener Granulomatosis: An Analysis of 158 Patients." Annals of Internal Medicine 1992; 116(6):488-498

Wegener F. Über generalisierte, septische Gefässerkrankungen [On generalized, septic vascular diseases]. Verhandlungen der Deutschen Pathologischen Gesselschaft 1936; 29: 202.10. © Expired. Original article available at http://www.grandrounds-e-med.com/articles/gr10L001-Wegener-original.pdf  Translation available at http://www.grandrounds-e-med.com/articles/gr10L001-Translation.pdf'

Stegeman, CA, Cohen Tervaert, JW, Sluiter, WJ, et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 1994; 120:12.

Popa, ER, Tervaert, JW. The relation between Staphylococcus aureus and Wegener's granulomatosis: current knowledge and future directions. Intern Med 2003; 42:771.

Faurschou M, et al. Increased morbidity from ischemic heart disease in patients with Wegener's granulomatosis. Arthritis Rheum. 2009 Apr;60(4):1187-92.

de Groot K, et al. Standardized neurologic evaluations of 128 patients with Wegener granulomatosis. Arch Neurol. 2001 Aug;58(8):1215-21.

Stone JH, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32.

Jones RB, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20.

Fortin, et al. Intravenous immunoglobulin as adjuvant therapy for Wegener's granulomatosis. Cochrane Database Syst Rev 2009 Jul 8;(3):CD007057

Jayne DR, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM. 2000 Jul;93(7):433-9.

Walters G, Willis NS, Craig JC. Interventions for renal vasculitis in adults. Cochrane Database Syst Rev 2008 Jul 16;(3):CD003232

Jayne DR. et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007 Jul;18(7):2180-8.

Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005 Jan 27;352(4):351-61.

Boomsma MM, et al. Prediction of relapses in Wegener's granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum. 2000 Sep;43(9):2025-33.

Kerr GS, et al. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener's granulomatosis. Arthritis Rheum. 1993 Mar;36(3):365-71.

Solans-Laqué R, Bosch-Gil J, Canela M, Lorente J, Pallisa E, Vilardell-Tarrés M. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis. Lupus. 2008 Sep;17(9):832-6.

Gouveris H, Karaiskaki N, Koutsimpelas D, Chongolwatana C, and Mann W: Treatment for adult idiopathic and Wegener-associated subglottic stenosis. Eur Arch Otorhinolaryngol (2013) 270:989-993

Arebro J, Henriksson G, Macchiarini P, and Juto J: New Treatment of subglottic stenosis due to Wegener's granulomatosis. Acta Oto-Laryngologica, 2012;132: 995-1001