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 leukocyte dysfunction 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: The association with HLA-B8 and HLA-DR2 indicates the importance of genetic factors.

Environmental factors (silicosis): A more than 24-fold risk of systemic scleroderma and ANCA+ vasculitis was found in this group of people) (Makol A et al. 2011).

Pathogenesis: It is discussed that cytokines (interleukin-1, tumor necrosis factor alpha) activate endothelial cells and granulocytes in the context of an infection, resulting in increased adhesion of inflammatory cells to vascular 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 lead to the release of reactive oxygen radicals and proteases, which could result in necrotizing vasculitis. The vasculitis is accompanied by the formation of granulomas. A molecular mimicry between the ANCA target antigens and certain adhesion proteins of vasculitis is being discussed. adhesion proteins of bacteria.

Possible at any age, usually in the 6th and 7th decade of life; men tend to be affected slightly more frequently.

Classic triad of ENT involvement, lung manifestation and kidney involvement!

• Initial mostly 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, often also arthralgia and arthritis.
• Involvement of the lungs with hemoptysis.
• Kidney involvement in the form of immune complex-negative, frequently necrotizing, extracapillary proliferative glomerulonephritis(rapid progressive glomerulonephritis) with the clinical picture of a rapidly progressive loss of function. Mostly interstitial signs of inflammation detectable in the kidney.
• Involvement of the eyes (clinically: "red eye" episcleritis or scleritis), salivary glands, pleura, heart, genital tract, spleen, gastrointestinal tract.
• Involvement of the skin (greasy ulcerations), paplpable purpura, acral necrosis, acneiform papules, subcutaneous nodules.
• Joint involvement (polyarticular arthralgias) and involvement of the central nervous system have been 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.

Multiphasic course (EUVAS definition):

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

In the approximately 10% of ANCA-negative cases, the localized form of GPA is found more frequently and there is less renal involvement than in PR3-ANCA- or MPO-ANCA-positive patients with comparable overall survival without recurrence (Puechal X et al. 2022).

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

Usually excessive increase in ESR and C-reactive protein

Detection of circulating immune complexes

Detection of antineutrophil cytoplasmic antibodies (in 90%) with cytoplasmic fluorescence pattern: c-ANCA; anti-protease 3 (PR3)-ANCA (most frequently positive), MPO-ANCA (10-20%).

In renal involvement often 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.

The question of differential diagnosis arises in the presence of serologically and histologically diagnosed ANCA-associated vasculitis, which represents a subgroup of primary systemic vasculitis according to the Chap Hill Consensus Conference. The following diseases come into consideration:

• Eosinophilic granulomatosis with polyangiitis (EGPA - presence of blood eosinophilia + bronchial asthma)
• Microscopic polyangiitis (MPA - no granulomatous organ infiltrates)

Furthermore:

• Leukocytoclastic vasculitis.

• Early phase/granulomatous phase/abortive form:
  • Therapy with cotrimoxazole (e.g. Eusaprim forte): 2 times/day 160 mg/800 mg p.o.
• Acute phase (standard therapy):
  • Cyclophosphamide (e.g. Endoxan) 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 within 3-6 months below the Cushing's threshold (7.5 mg/day).
    After remission (cANCA titer) bolus therapy with 15-20 mg cyclophosphamide/day every 3-4 weeks.
    Cave! Gastric protection during oral glucocorticoid administration!
    Bladder protection during cyclophosphamide therapy with Uromitexan (e.g. Mesna), generous daily drinking (balancing!), anticonception, long-term monitoring of the bladder, as there is a risk of developing bladder carcinoma.
  • Alternative:
    • Ciclosporin A (Sandimmun): 7-10 mg/kg bw/day. Check kidney values and blood pressure.
    • Methotrexate (e.g. MTX - 15-25 mg/week i.m. usually in combination with glucocorticoids. Caution! Regular creatinine and urine pH checks.
    • Rituximab+glucocorticoids
    • Avacopan (C5aR inhibitor) + glucocorticoids, combined with rituximab or ciclosporin
• Chronic phase:
  • Azathioprine (e.g. Imurek) 100-150 mg/day p.o. in combination with glucocorticoids such as prednisolone (e.g. Decortin H) 1 mg/kg bw/day. Reduce prednisolone to below the Cushing's threshold as the disease progresses. Only gradually reduce azathioprine to a maintenance dose of e.g. 50 mg/day after remission.
  • Alternatively.
    • Methotrexate (e.g. MTX) see above. + glucocorticoids
    • Rituximab + glucocorticoids
• Highly acute course:
  • Plasmapheresis in combination with the above-mentioned immunosuppressive therapy.
  • Alternative:
    • Therapy trials with application of high-dose immunoglobulins ( IVIG) with 30 g/day for 5 days i.v. or Infliximab show promising results in refractory patients.

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

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