Vasculitis leukocytoclastic (non-iga-associated) D69.0; M31.0

Heberden, 1802; Schönlein, 1832; Henoch, 1868

Inflammation of small vessels (small vessel vasculitis), which is caused by deposition of circulating immune complexes or bacterial endotoxins in vessel walls with subsequent complement activation and is histologically presented as leukocytic vasculitis of post-capillary venules with fibrinoid swelling of the vessel wall and/or thrombi in the lumina (the synonyms usually describe only partial aspects). In contrast to the purpura Schönlein-Henoch, primary IgG/IgM vasculitis does not detect IgA immune complexes in the vessel walls.

It seems to be emerging that in IgA-negative leukocytoclastic vasculitis a clinical classification is useful according to:

• Leukocytoclastic vasculitiS (LcV) with systemic involvement.
• Leukocytoclastic vasculitiS (LcV) without systemic involvement (cutaneous LcV).

Both variants have an analogous etiology.

The classical cutaneous immune complex vasculitis (including the "IgA-associated vasculitides e.g. the Purpura Schönlein) is a disease frequently occurring in large dermatological collectives. Its incidence is estimated at 10-20/100,000 per year.

Circulating immune complexes can be detected in a large proportion of patients. They are of great etiopathological importance.

• Triggered by:
  • Drugs (e.g., allopurinol, thiazides, sulfonamides, gold, nonsteroidal anti-inflammatory drugs, ketoconazole, tetracyclines, penicillins).
  • Bacterial and viral infections (e.g., streptococci, staphylococci, N. meningitidis, N. gonorrhoeae, Escherichia coli, mycoplasma, M. tuberculosis, hepatitis B virus, herpes virus, influenza virus, cytomegalovirus)
  • vaccinations (e.g. after COVid-19 vaccination/Wollina U et al. 2022)
  • Fungal infections (Candida albicans)
  • Protozoa (trypanosomes, Plasmodium malariae)
  • Helminths
  • Interaction of infection and drugs
  • Autoantigens: e.g. in primary chronic polyarthritis (rheumatoid arthritis), systemic lupus erythematosus. Note: LcV in collagenoses is listed as a special form by some authors!
  • Malignancies (e.g. lymphomas, hairy cell leukemia, rarely solid tumors)
  • Food and food additives ( food intolerance)
  • Idiopathic/unexplained (up to 50%).

Occurrence both in adulthood (average 39.-49. LJ) and in childhood. Women are 2-3 times more frequently affected than men.

Due to stasis phenomena, the lower legs are preferentially affected; in the case of higher acuity, also on the thighs or on the trunk at fixed clothing contact points. The probability of systemic involvement increases as soon as the skin symptoms appear above the belt line.

The clinical picture corresponds to an acute chronic inflammatory systemic disease with different organ involvement. The leading clinical and dermatological symptom of "small vessel vasculitis of the leukocytoclastic type" is " purpura". The clinical picture depends, among other things, on the stage of development, the acute nature of the disease and the extent of organ manifestation (monorganic or polyorganic in about 50% of patients).

At the beginning there are often vague general symptoms with fever, uncharacteristic rheumatic complaints with (poly)arthralgias, arthritides or myalgias, more rarely myositides. The characteristic clinical-dermatological picture of leukocytoclastic vasculitis is purpura with lesions ranging from 0.1 cm to several centimeters. Depending on the acuity and the stage of development of the vasculitis, the purpura appears as hemorrhagic spots or papules (palpable purpura), accompanied by itching, pain or burning. In further stages of development, hemorrhagic vesicles or blisters, hemorrhagic plaques and consecutive pustules, erosions or ulcers may form.

Acute-phase reactions (high BSG, CRP, leuko- and thrombocytosis) go parallel with the acuteity of vasculitis. Circulating immune complexes (lowered complement: CH50,_C3, Ced,_C4), possibly pathological urine sediment (the urine status should be done at least 3 times in a row), blood in stool (the haemocult test should be done at least 3 times in a row) . Activity parameters are the soluble sIl-2 and factor VIII-associated antigen (extent of endothelial damage). In addition: smear test of the pharynx and tonsils. There is no diagnostic evidence of any parameter in the laboratory. In addition, immunological and molecular biological techniques should be used to exclude hepatitis C/B. Possible autoantibodies such as ANCA and ANA are both activity and diagnosis associated.

In early stages edema of the papillary dermis. Sparse, superficial, intramural and sleeve-shaped perivascularly oriented inflammatory infiltrate of lymphocytes, histiocytes and apoptotically decomposing neutrophil leukocytes (leukocytoclasia, nuclear dust) and, to varying degrees, eosinophilic leukocytes. Endothelial cells appear epitheloid swollen and protruding into the lumen. Fibrin is found in the vessel wall of post-capillary venules. At the same time there are perivascular accentuated erythrocyte extravasations of varying density. The exudation can lead to subepidermal blistering or even pustular formation. Vascular occlusion clinically results in a grey shade in the centre of the lesion and, depending on its extent, can lead to tissue necrosis, recognisable by spongiosis and fading keratinocytes. There seems to be a correlation between tissue eosinophilia and drug-induced vasculitis.

The following algorithm can be schematized:

Perivascular IgG and/or IgM deposits (in contrast to the Purpura Schönlein-Henoch in which perivascular IgA deposits occur)

Clinical presentation: papulonecrotic tuberculide, pityriasis lichenoides et varioliformis acuta; erythema exsudativum multiforme; Purpura pigmentosa; Purpura jaune d'ocre.

Histological: Erythema exsudativum multiforme; Septic vasculitis; Urticaria; Livedo racemosa.

For all severe leukocytoclastic vasculitis that do not show a self-limiting course:

• Predominant or exclusive affection of the skin: glucocorticoids ( prednisone, 60-100 mg/day) as monotherapy, in case of resistance to therapy in combination with azathioprine (100-150 mg/day), reduction after clinical treatment to the lowest possible maintenance dose.
• Alternatively, if resistant to therapy, high-dose IVIG therapy(e.g. Intratect) 0.5-1.0 g/kg bw every 28 days i.v.
• System involvement: glucocorticoids (prednisone 60-150 mg/day), possibly in combination with cyclophosphamide (100 mg/day), possibly cyclophosphamide as shock therapy (1 g as short infusion + 3 l liquid/day + mesna (uromitexane) 200 mg i.v. or orally. A total of 3 cycles in 2-4 weeks intervals).
• In severe cases, plasmapheresis may be added.

I.A.'s prognosis is favourable. It depends on the acuteity and extent of internal organ involvement. In larger statistics, deaths have been reported in 2-3% of patients. Chronic recurrent course may indicate cryoglobulinemia or a persistent infection (e.g. hepatitis C).

• Absence of IgA deposits
• Age > 20 years
• Occurrence of eosinophilic leukocytes in the infiltrate
• Lower involvement of the intestinal tract.

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17. Wollina U et al. (2022) Severe leukocytoclastivc vasculitis after COVID-19 vaccination-cause or coincidence? Case reprot and literature review. Georgian Med News 324:134-139.