Granulomatosis with polyangiitis M31.3

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 10.05.2022

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Synonym(s)

Angiitis malignant granulomatous; GPA; Granulomatosis with polyangiitis; Malignant granulomatous angiitis; Rhinogenic granulomatosis; Wegener-Klinger-Churg-Strauss Syndrome; Wegener's granulomatosis

History
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McBride, 1897; Klinger, 1931; Wegener, 1936

Definition
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Rare, necrotizing systemic vasculitis with predominant infestation of small and medium-sized vessels. Non-cheesy granulomas develop in the area of the nose, mouth, throat and lungs. Renal involvement is found in about 80% of cases.

Occurrence/Epidemiology
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Incidence: 0.5-3/100,000 population/year. Prevalence: 5/100,000 population/year. Panethnic, predominantly in light-skinned population.

Etiopathogenesis
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  • Granulomatous vasculitis and leukocyte dysfunction are discussed.
  • Evidence of autoimmune disease by detection of antibodies against cytoplasmic structures in neutrophil granulocytes and monocytes(ANCAs) has been described.
  • The association with HLA-B8 and HLA-DR2 points to the importance of genetic factors.
  • Pathogenetically, it is discussed that cytokines (interleukin-1, tumor necrosis factor α) lead to activation of endothelial cells and granulocytes in the context of an infection, resulting in increased adhesion of inflammatory cells to vessel wall endothelia. Tissue toxic mediators (proteases, reactive oxygen species) synthesized and released by granulocytes and monocytes then lead to necrotizing changes in the vessels.
  • The role of ANCAs in the activation process of granulocytes is not yet fully understood, but there are indications that the antibodies may increase the formation of oxygen radicals. A molecular mimicry between the ANCA target antigens and certain adhesion proteins of granulocytes is discussed. Adhesion proteins of bacteria.

Manifestation
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Possible at any age, mostly 40th-50th LJ; no sex preference.

Clinical features
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  • Classic triad of ENT involvement, lung manifestation and kidney involvement!
    • Initial usually development of painful or painless, oral or nasal or paranasal ulcers with purulent or bloody sinusitis and rhinitis(Carnevale C et al. 2019)
    • Otitis media or mastoiditis
    • Poor general condition with fever
    • Lung involvement with hemoptoe.
    • Renal involvement in the form of immunocomplex-negative, often necrotizing, extracapillary proliferative glomerulonephritis(Rapid Progressive Glomerulonephritis) with the clinical picture of a rapidly progressive loss of function. Mostly interstitial signs of inflammation in the kidney can be detected.
    • Involvement of the eyes (clinically: "red eye" episcleritis or scleritis), salivary glands, pleura, heart, genital tract, spleen, gastrointestinal tract.
    • Skin (greasy ulcerations)
    • Joint infestation (polyarticular arthralgia) and infestation of the central nervous system are described with varying frequency.
    • Clinical signs may include rhinitis, otitis, hearing loss, anosmia, jaw pain (gingivitis), uveitis, retinitis, orchitis, arthralgias and neurological symptoms such as mononeuritis multiplex.

Multiphase course (EUVAS definition):

  1. Localized stage: Initially months to years lasting, lavated localized stage without or with mild system signs.
  2. Early systemic stage: Any manifestation without organ or vital threat.
  3. Generalization stage: Renal involvement or other organ-threatening manifestation. Mostly sudden transition to a generalized stage with severe system signs (see above).
    • Skin and mucous membrane changes (in 40-50% of cases): ulcerous or granulomatous changes in the lips, tongue, buccal mucous membrane, palate, throat, possibly perforations. Vesicular, papulonecrotic, also urticarial, ulcerative skin changes, especially over the extensor sides of large joints
  4. Severe, vital-threatening generalization stage with kidney failure or failure of another vital organ.
  5. Refractory stage: Progressive disease without response to corticosteroids or cyclophosphamide.

Laboratory
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  • Leukocytosis (10,000-20,000 leukocytes/μl) (sometimes eosinophilia in blood and tissue) Thrombocytosis, anemia and hypergammaglobulinemia in blood
  • mostly excessive increase of BSG and C-reactive protein
  • Detection of circulating immune complexes
  • Detection of antineutrophil cytoplasmic antibodies (in 90%) with cytoplasmic fluorescence pattern: c-ANCA; PR3-ANCA (most frequently positive), MPO-ANCA (10-20%).
  • In case of kidney involvement, frequent detection of antibodies against LAMP-2.

Histology
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Histopathological algorithm of granulomatosis with polyangiitis (lowest common denominator:italics, leading symptoms:bold) varies according to Ratzinger et al. 2105
Accentuates around post-capillary venules and larger vessels in the skin and subcutis
Capillaries omitted or less strongly involved
perivascular leukocytoclasia
Damage to endothelial cells
Fibrin in/around vessel walls
Perivascular extravasation of erythrocytes
No/mild edema in the papillary dermis
Collagen degeneration with basophilic necrotic lesions of variable extent surrounded by palisade granulomas
No significant number of eosinophils
Plasma cells or fibrosclerosis
Reorganisation due to lymphocytic vasculitis

Indirect immunofluorescence
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ANCA (antineutrophilic cytoplasmic autoantibodies) in 90% of cases, highly specific, correlation with disease acuteity.

Diagnosis
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The detection of anti-neutrophilic cytoplasmic antibodies (ANCA) in serum against different antigens, most frequently against serine protease-3-PR3 in the ELISA, is diagnostic with high sensitivity and specificity. ANA negative. Obtaining biopsies from skin or mucosa.

For classification, 2 of 4 criteria of the ACR criteria (1990) should apply:

  1. Inflammation of nose and mouth with ulcers and purulent secretion
  2. Nodes, infiltrations or cavern detection in the Rö thorax
  3. Nephritic urine sediment (erythrocyturia > 5 erythrocytes/visual field or erythrocyte cylinder)
  4. Bioptically proven granulomatous inflammation in arterial vessel walls or perivascular.

Differential diagnosis
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Complication(s)
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Haemorrhagic cystitis (increased risk of developing bladder cancer) when treated with cyclophosphamide.

Internal therapy
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  • Early phase/granulomatous phase/abortive form:
    • Therapy with Cotrimoxazol (e.g. Eusaprim forte): 2 times/day 160 mg/800 mg p.o.
  • Acute phase (standard therapy):
    • Cyclophosphamide (e.g. endoxane) and prednisolone (e.g. Decortin H) according to the FAUCI scheme: Cyclophosphamide 2-(4) mg/kg bw/day and prednisolone 0.5-1 mg/kg bw/day. Reduction of prednisolone below the Cushing's threshold (7.5 mg/day) within 3-6 months.
      After remission (cANCA titre) bolus therapy with 15-20 mg cyclophosphamide/day every 3-4 weeks.
      Cave! Gastric protection with oral glucocorticoid administration!
      Bladder protection with cyclophosphamide therapy with uromitexane (e.g. Mesna), generous daily drinking amount (balancing!), anti-conception, long-term bladder control, as there is a risk of developing bladder carcinoma.
    • Alternative: Ciclosporin A (sand immune): 7-10 mg/kg bw/day. Control of kidney values and blood pressure.
      Methotrexate (e.g. MTX) 15-25 mg/week i.m. Cave! Regular creatinine and urine pH checks.
  • Chronic phase:
    • Azathioprine (e.g. Imurek) 100-150 mg/day p.o. in combination with glucocorticoids like prednisolone (e.g. Decortin H) 1 mg/kg bw/day. Reduce Prednisolon further below the Cushing's threshold. Azathioprine should only be gradually reduced after remission to a maintenance dose of e.g. 50 mg/day. Alternatively methotrexate (e.g. MTX) see above.
  • Highly acute course:
    • Plasmapheresis in combination with the above mentioned immunosuppressive therapy.
  • Alternatively:
    • Therapy trials with the application of high-dose immunoglobulins ( IVIG) with 30 g/day for 5 days i.v. or Infliximab show promising results in refractory patients in the new literature.

Progression/forecast
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Untreated, GPA shows a mortality of 80% within 2 years. Recurrences in 50-70% of all patients in a period of 10-15 years.

Literature
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  1. Borchers T et al (2004) Nodular pulmonary vasculitis in a twelve-year-old boy. Pediatric Pulmonol 37: 181-185
  2. Carnevale C et al (2019) Head and Neck Manifestations of Granulomatosis with Polyangiitis: A Retrospective analysis of 19 Patients and Review of the Literature. Int Arch Otorhinolaryngol 23:165-171.
  3. Douglas G et al (2003) Wegener's granulomatosis in patients with rheumatoid arthritis. J Rheumatol 30: 2064-2069
  4. Esca SA et al (1984) Wegener's granulomatosis. Dermatologist 35: 379-382
  5. Falk RJ et al (2011) Granulomatosis with polyangiitis (Wegener's): an alternative name for Wegener's granulomatosis.arthritis rheum 63:863-864
  6. Del Porto Fet al. (2014) Granuloma annularis revealing Wegener's granulomatosis. Int J Immunopathol Pharmacol 27:273-278
  7. Godman GC Churg J (1954) Wegener's granulomatosis. Pathology and review of the literature. Arch Pathol (Chicago) 58: 533
  8. Hoffmann GS et al (1992) Wegner granulomatosis: an analysis of 158 patients. Ann Int Med 117: 619-621
  9. Klammer M et al (2003) First manifestations of Wegener's disease on the skin. dermatologist 54: 986-988
  10. Klinger H (1931) Limit forms of periarteritis nodosa. Frankfurt Journal of Pathology (Wiesbaden) 42: 455-480
  11. McBride P (1897) Photographs of a case of rapid destruction of the nose and face. J Laryngol Rhinol Otol (London) 12: 64-66
  12. Popa ER et al (2003) The relation between Staphylococcus aureus and Wegener's granulomatosis: current knowledge and future directions. Internal med 42: 771-780
  13. Ratzinger G et al. (2015) The Vasculitis Wheel-an algorithmic approach to cutaneous vasculitis. JDDG 1092-1118
  14. Richter C et al (1995) Treatment of anti-neutrophil cytoplasmic antibody (ANCA)- associated systemic vasculitis with high-dose intravenous immunoglobulin. Clin Exper Immunol 101: 2-7
  15. Van der Woude FJ, Lobatto S, Permin H et al (1985) Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet 1: 425
  16. Wegener F (1936) On generalized septic vascular diseases. Verh Dtsch Path Ges 29: 202
  17. Wegener F (1939) On a peculiar rhinogenic granulomatosis with particular involvement of the arterial system and kidneys. Contributions to pathological anatomy and general pathology (Jena) 102: 36-38
  18. Wright AC et al (2015) Cutaneous manifestations of pediatric granulomatosis with polyangiitis: a clinicopathologic and immunopathologic analysis. J Am Acad Dermatol 72: 859-867

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Last updated on: 10.05.2022