Granulomatosis with polyangiitis M31.3

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.

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

Granulomatous vasculitis and disturbances of leukocyte function are discussed.

Autoimmune mechanisms: Evidence of autoimmune disease by detection of antibodies against cytoplasmic structures in neutrophil granulocytes and monocytes(ANCAs) has been described.

Genetics: Association with HLA-B8 and HLA-DR2 indicates the importance of genetic factors.

Environmental factors (silicosis): This group of individuals has been found to have a more than 24-fold risk of systemic scleroderma and ANCA+ vasculitides) (Makol A et al. 2011).

Pathogenesis: It is discussed that there is activation of endothelial cells and granulocytes by cytokines (interleukin-1, tumor necrosis factor alpha) in the setting 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 granulocyte activation process is not fully understood, but there is evidence 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.

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

Classic triad of ENT involvement, pulmonary manifestation and renal 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
• Involvement of the lungs with hemoptysis.
• Renal involvement in the form of immune complex-negative, often necrotizing, extracapillary proliferative glomerulonephritis(Rapid Progressive Glomerulonephritis) with the clinical picture of rapidlyprogressive loss of function. Mostly interstitial inflammatory signs detectable in the kidney.
• Involvement of eyes (clinical: "red eye"- episcleritis or scleritis), salivary glands, pleura, heart, genital tract, spleen, gastrointestinal tract.
• Involvement of the skin (greasy ulcerations).
• Joint involvement (polyarticular arthralgias) and central nervous system involvement have been described with varying frequency.
• Clinical signs may include rhinitis, otitis, hearing loss, anosmia, jaw pain (gingivitis), uveitis, retinitis, orchitis, arthralgias, and neurologic symptoms such as mononeuritis multiplex.

Multiphasic course (EUVAS definition):

1. Localized stage: Initially lasting months to years, lavage localized stage with no or mild systemic signs.
2. Early systemic stage: Any manifestation without organ or vital threat.
3. Generalization stage: Renal involvement or other organ-threatening manifestation. Mostly abrupt transition to a generalized stage with severe systemic signs (see above).
   • Skin and mucosal lesions (in 40-50% of cases): Ulcerative or granulomatous changes on lips, tongue, buccal mucosa, palate, pharynx, possibly perforations. Vesicular, papulonecrotic, also urticarial, ulcerative skin changes, especially over the extensor surfaces of large joints.
4. Severe, vital-threatening generalization stage with renal failure or failure of another vital organ.
5. Refractory stage: Progressive disease without response to corticosteroids or cyclophosphamide.

Leukocytosis (10,000-20,000 leukocytes/μl) (sometimes eosinophilia in blood and tissues) Thrombocytosis, anemia, and hypergammaglobulinemia in Bl

Usually excessive elevation of ESR 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 renal involvement, frequent detection of antibodies against LAMP-2.

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.

• 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.

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

1. Borchers T et al (2004) Nodular pulmonary vasculitis in a twelve-year-old boy. Pediatr 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) Initial manifestations of Wegener's disease on the skin. Dermatologist 54: 986-988
10. Klinger H (1931) Borderline forms of periarteritis nodosa. Frankfurter Zeitschrift für Pathologie (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. Makol A et al (2011) Prevalence of connective tissue disease in silicosis (1985-2006)-a report from the state of Michigan surveillance system for silicosis. Am J Ind Med 54:255-262.
13. Popa ER et al (2003) The relation between Staphylococcus aureus and Wegener's granulomatosis: current knowledge and future directions. Intern Med 42: 771-780
14. Ratzinger G et al (2015) The vasculitis wheel-an algorithmic approach to cutaneous vasculitides. JDDG 1092-1118
15. 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
16. 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
17. Wegener F (1936) On generalized septic vascular disease. Verh Dtsch Path Ges 29: 202
18. Wegener F (1939) On a peculiar rhinogenous granulomatosis with special involvement of the arterial system and kidneys. Contributions to pathological anatomy and general pathology (Jena) 102: 36-38.
19. Wright AC et al (2015) Cutaneous manifestations of pediatric granulomatosis with polyangiitis: a clinicopathologic and immunopathologic analysis. J Am Acad Dermatol 72: 859-867.