Urticaria vasculitisM31.8

McDuffie, 1973

Chronic inflammatory disease with recurrent course, clinically characterized by urticarial papules or plaques, sometimes also by deep-lying pruritic or variably painful nodules, and by angioedema. A distinction is made between 2 forms:

• Urticarial vasculitis with hypocomplementemia (HUVS)
• Urticariavasculitis with normocomplementemia (C1q vasculitis).

Urticariavasculitis with hypocomplementemia (HUVS) is associated with lupus erythematosus up to 50%.

Note: Urticarial vasculitis (UV) wrongly carries its name "urticaria" because the primary florescence is not a wheal but a urticarial papule or plaque. In contrast to the wheal (persistence of hours), the urticarial papule persists for several days!

Incidence and prevalence are unknown. Approximately 2-20% of inpatient cases admitted for urticaria suffer from urticarial vasculitis, of which again 20% suffer from HUV. In Germany about 20,000- 50,000 patients are affected (source Charité).

Autoantibodies against C1q are suspected;

Associations have been described with:

• Autoimmune diseases: SLE, Sjögren's syndrome, autoimmune thyroiditis (Cherrez-Ojeda I et al. 2019)
• Infections: Viral infections(hepatitis B, hepatitis C, Epstein-Barr virus infections)
• Neoplasms: IgA myeloma, IgM gammopathies (see MGUS below), colon carcinoma
• Medication intake: non-steroidal anti-inflammatory drugs, fluoxetine.
• Mutations in the DNASE1L3 gene (DNASE1L3 stands for "Deoxyribonuclease 1 Like 3"/chromosome: 3p14.3) have been described for urticarial vasculitis with hypocomplementemia (HUVS).

• In patients with recurrent urticarial plaques associated with signs of systemic inflammation including fever and elevated inflammatory markers (C-reactive protein/serum amyloid A, leukocytosis and negative connective tissue serologies), autoinflammatory diseases should be considered, such as cryopyrin-associated periodic syndrome, Schnitzler syndrome and familial autoinflammatory cold syndrome 2.

Women are affected twice as often as men. Illness peak is the 5th decade of life. Hypocomplementaemic urticarial vasculitis is found almost exclusively in women.

Exanthema accompanied by fever attacks, small spots, maculo-papular, itchy or painful, reminiscent of urticaria. A purple component is usually detectable. Arthralgias and arthritides are frequent, large and small joints are affected. The course is intermittent, possibly with abdominal pain and membranoproliferative glomerulonephritis. Often swelling of the lymph nodes. Patients with hypocomplementary urticarial vasculitis are more prone to systemic complaints (involvement of joints 70%, kidneys 50%, GIT 30%, lungs 20%, eyes 10%). ANA and signs of systemic lupus erythematosus are more frequent in these patients.

There are no pioneering laboratory constellations. Increase in acute-phase proteins. Hypocomplementation (_C3 and_C4 significantly reduced) is detectable in about 50% of patients. Often the detection of anti C1q-Ak is successful. The detection of ANA is not uncommon (usually no ENA or antiphospholipid-Ak).

Inconspicuous surface epithelium. Interstitial edema in the upper and middle dermis. A proportion of patients show features of leukocytoclastic vasculitis.

In the majority of patients, predominantly superficial and profound interstitial infiltrates of neutrophilic granulocytes are found, usually (but not obligatorily) with marked leukocytoclasia. Not infrequently, the vascularity that is prominent in classic leukocytoclastic vasculitis is lost. Round cell infiltrates as well as eosinophilic granulocytes in different densities are admixed to the neutrophil infiltrate.

Clinical differential diagnosis:

• Acute urticaria (efflorescences persist for max. 12 hours; no evidence of leukocytoclastic vasculitis)
• Sweet syndrome (painful, succulent, papular or plaque skin changes; leukocytosis with neutrophilia)
• Drug exanthema (anamnesis; otherwise a urticarial exanthema is also possible there)
• viral exanthema (usually signs of infection are detectable; often general symptoms)

Histological differential diagnoses:

• Urticaria (no evidence of leukocytoclastic vasculitis)
• Sweet syndrome (diffuse, neutrophilic, non-vasculitic dermatitis)
• eosinophilic cellulite (diffuse dermal infiltrate eosinophilic granulocytes; flame figures)
• Arthropod sting reaction (epidermal puncture site with focal spongiosis; wedge-shaped mixed cell infiltrate with eosinophilic granulocytes of varying density)
• Erythema anulare centrifugum (focal or absent spongiosis; strictly perivascular infiltrate sheaths with varying admixture of eosinophil granulocytes).

Initially symptomatic therapy. Antihistamines are not very effective. Combinations of H1-blockers with H2-blockers can be tried.

Itch-killing, cooling lotio alba, possibly with addition of 2-5% polidocanol R200.

Alternatively: 1% menthol solution.

Alternative: Gels containing antihistamines (e.g. Soventol, Fenistil, Tavegil; Remark: only moderate success) or mild lotions containing glucocorticoids R123.

Glucocorticoids have a beneficial effect in the hypocomplementary form of urticarial vasculitis. Start therapy in medium to high dosages such as prednisolone (e.g. Solu Decortin H) 60-100 mg/day. Reduction according to clinic, maintenance dose preferably below the Cushing's threshold. If resistant to therapy, attempt to reduce glucocorticoid levels by combining with azathioprine (e.g. Imurek) 50-100 mg/day p.o. or mucophenolate mofetil (2.0 g/day p.o.). Cave! Regular laboratory checks are required.

Alternatively: Chloroquine (e.g. Resochin) initial 1-2 Tbl./day, dose reduction according to clinic.

Alternative: DADPS (e.g. Dapson Fatol) as monotherapy 50-100 mg/day or in combination with Pentoxifyllin (e.g. Trental) 2-3 times/day 400 mg or Colchicin (e.g. Colchicum-Dispert Drg.) 0,5-1,5 mg/day can be tried.

Alternative: Successes are also described with systemic interferon alpha therapy(e.g. Roferon) 3 times/week 3 million IU s.c.

Further alternatives:

• Methotrexate (e.g. MTX) or cyclophosphamide (e.g. endoxane), if necessary in combination with glucocorticoids (see above) or the use of plasmapheresis for complicated systemic manifestations.
• IVIG (2g/kgKG).
• In the case of concomitant arthralgia, non-steroidal anti-inflammatory drugs such as indomethacin (e.g. Amuno Kps.) have proven to be effective 2-3 times/day 25 mg in individual doses. No influence on skin symptoms!

Very persistent, chronic recurrent course.

Less frequent are life-threatening courses with signs of systemic vasculitis (kidney, heart, lung, stomach and intestinal involvement and neurological symptoms with pseudotumour cerebri, aseptic meningitis and paresis of central or peripheral nerves).

The following differently accentuated syndromes are regarded as "special forms" of hypocomplementary urticarial vasculitis:

• AHA syndrome (arthritis, urticarial vasculitis, angioedema)
• Schnitzler syndrome
• Cogan syndrome (urticarial vasculitis, interstitial keratitis, possibly also scleritis, uveitis and hypacusis, tinnitus, dizziness, neurological symptoms such as polyneuropathy, mononeuritis multiplex with encephalitis episodes and myelopathies, CNS vasculitis)
• Muckle-Wells Syndrome

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2. Al-Mayouf SM et al (2011) Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nature Genet 43: 1186-1188.
3. Cherrez-Ojeda I et al. (2019) Autoimmune thyroid disease and urticarial vasculitis: is there a significant
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