Erythema elevatum diutinum L95.1

Hutchinson 1888; Bury 1889; Radcliffe-Crocker & Williams 1894. Erythema elevatum et diutinum (EED) was first described in the 1880s. The term "erythema elevatum diutinum" was first used by Henry Radcliffe-Crocker (1845-1909) in 1894.

Relatively rare (less than 1000 cases have been described in the literature worldwide), benign, albeit eminently chronic (diutinum!), reactive-inflammatory disease of the skin with the characteristic histologic picture of leukocytoclastic "small vessel" vasculitis with consecutive angiocentric and storiform fibrosis (Sandhu JK et al. 2019).

Relatively rare, epidemiology figures are not available.

Unexplained, probably "immune-triggered" vasculitis of small vessels; occasional detection of monoclonal immunoglobulins, most frequently in the context of IgA gammopathy (more rarely IgG gammopathy/multiplemyeloma), possibly also in cryoglobulinemia.

It is assumed that the clinical symptoms are due to the deposition of immune complexes in the blood vessels of the skin, which leads to complement fixation, activation of the complement system, an influx of neutrophils and the release of destructive enzymes.

Apparently, antineutrophil cytoplasmic antibodies (ANCAs) are pathogenetically effective in EED. They are detected in a high percentage of patients (Ayoub N et al. 2004). Furthermore, EED can be triggered by the activation of cytokines (interleukin-8), which cause a selective recruitment of leukocytes into the blood vessels. This leads to repeated damage to the vessels, which eventually develops into fibrosis.

Associations with infections (e.g. HIV, hepatitis B, hepatitis C, HIV), with autoimmune diseases, in particular rheumatoid arthritis, as well as Crohn's disease, ulcerative colitis, Wegener's granulomatosis have been described; furthermore with myelodysplasia. The occurrence of EED after COVID vaccination has been reported several times (Fiorillo G et al. 2022).

The presence of extracutaneous manifestations (see below) in patients with erythema elevatum diutinum (EED) suggests that EED may be a multiorgan vasculitic systemic disease.

Mainly over the extensor sides of the extremity joints (fingers, hands, knees), also buttocks, genitals, face and neck.

Subacute development of symmetrically arranged, initially soft, later firm, roundish, also anular or polycyclic, blue-red or red-brown, also hemorrhagic, succulent plaques over a large area (Note: A purpuric component is not always clearly evident, since the small focal hemorrhages occur episodically). In the course of weeks and months, blue-red-brown, surface-smooth, firm, broad-based, several centimeter large nodules may develop. Central indentation can be frequently detected, possibly also stabbing pain, burning or itching. Early lesions tend to be bright red, whereas older lesions tend to be livid red to brownish red. EED in dark skin presents a particular clinical challenge because the initial red tones are now completely obscured and only the slightly darker tinged, plaque or nodular contouring is recognizable.

Plate-like, keloid lesions are also described. These are apparently completely resistant to therapy, so that surgical methods also become necessary (Awan BE et al. 2021/s.Fig.).

Possible syntropias exist with gout, arthralgias, scleritis, panuveitis, peripheral ulcerative keratitis, with Sjögren's syndrome (Shimizu S et al 2008), oral and penile ulcers (Sandhu JK et al 2019). Evidence suggests early indications of non-Hodgkin's lymphoma (Hatzitolios A et al 2008). The extent to which pathogenetic links exist to the clinical picture of "pulmonary hyaline granulomatosis" is currently unclear (see Rodríguez-Muguruza S et al. 2015; see also Müller CSL et al. 2009). The skin lesions may heal after years (periods of 5-35 years are reported) leaving hyperpigmented scars.

At an early stage, the signs of leukocytoclastic vasculitis can be detected with perivascular oriented neutrophilic leukocytes and nuclear dust as well as fibrin in the vessel walls.

In "full-blown" lesions, a dense, diffuse infiltrate is found in the upper and middle dermis. Vascular orientation is then usually not (or no longer) detectable. Epidermis and skin appendages remain uninvolved. The infiltrates consist of lymphocytes, neutrophilic leukocytes and nuclear dust, eosinophilic leukocytes, histiocytes and plasma cells. In addition, proliferation of fibrocytes as well as collagen fibers. Concentric fibrosis may dominate the fine tissue picture in older lesions, possibly with a "pseudotumorous" aspect. Also in older lesions, lipid deposits can be detected in the connective tissue, which gave the clinical picture the name "extracellular cholesterolosis" at that time (Herzberg JJ 1958; Wolff HH et al. 1978). Their pathogenetic significance is unclear.

Schematizingly, the following algorithm can be established:

Granuloma anulare: the greatest clinical analogies exist with this clinical picture. However, the EED shows a stronger inflammation. Histological clarification may be necessary.

Granuloma facale: the classic granuloma faciale has to be excluded due to its localization. The rare extrafacial granuloma "faciale" has to be excluded histologically.

Erythema anulare centrifugum: anular truncal red plaques; no nodularity;

Erythema multiforme: the clinical acuity of EEM speaks absolutely against the protracted course of EED; typical clinical picture with the cocard lesions.

Acute febrile neutrophilic dermatosis (Sweet's sndrome): acute exanthematous, febrile, papulo-pustular clinical picture, laboratory with inflammatory parameters.

Rheumatoid nodules: nodules and nodules belonging to the so-called rheumatism nodosus, occurring in 20% of patients with chronic polyarthritis (rheumatoid arthritis), mostly in severe courses. Rheumatoid factor positive.

Multicentric reticulohistiocytosis: Symmetrically distributed, multiple, pinhead- to pea-sized, mostly derb-consistent, skin-colored but also copper-brown, sometimes slowly growing, sometimes eruptively exanthematous, solitary, also confluent papules and nodules, possibly with atrophic, possibly also excoriated, mostly smooth surface. Typical (>50% of cases) is a pearl cord-like involvement of the nail folds of the fingers (coral bead sign). In 25% of the cases, xanthelasma are present at the same time.

If necessary, treatment of the underlying disease.

The best results are described with DADPS. Patients respond to varying doses (50-150 mg/day). Improvement is immediate in some patients within days, in others skin lesions take months to heal. Treatment failures are known.

Local therapy with a 5% dapsone gel (ACZONE; Allergan Inc, Irvine, CA/Frieling GW et al. 2013) also appears to be effective in isolated cases.

The clinical picture is usually less responsive to glucocorticoids. However, a therapy cycle over 4-6 weeks is recommended (initially 50mg prednisolone /day; gradual reduction over the indicated period) .

The use of nicotinamide (e.g. Nicobion 1 tbl./day) is described as successful in individual cases.

Symptomatic therapy of itching with H ₁ antagonists, e.g. desloratadine (Aerius) 1 tablet/day p.o. or levocetirizine (Xusal) 1 tablet/day p.o..

Chronic course. Spontaneous healing is possible after years, leaving a hypo- or hyperpigmented scar.

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