Acrodermatitis chronica atrophicans L90.4

The first description was given by Buchwald in Breslau in 1883 under the title: Diffuse idiopathic skin atrophy. Further reports followed in 1886 by Touton, in the same year by Pospelow, in 1895 by Pick (erythromelia) and by I.v.Neumann (erythema neoparalyticum). The term acrodermatitis chonica atrophicans comes from Herxheimer and Hartmann (1902).

An eminently chronic (bacterial) multisystemic disease caused by an infection with Borrelia bacteria, leading to pronounced skin atrophy (cigarette paper phenomenon) with extensive livid red erythema on the trunk and extremities.

Borrelia afzelii more rarely Borrelia burgdorferi.

Incidence (Europe): about 10/100,000 inhabitants/year. More frequent in Borrelia endemic areas, especially in some wooded areas of Austria, Poland and Eastern Europe.

Acrodermatitis chronica atrophicans (ACA) mainly affects women aged 40-70 years. In the pediatric population, ACA is rare and only a few cases have been reported in children. ACA is more common in Europe due to untreated infection with Borrelia afzelii and is rare in the United States. The overall prevalence of ACA in patients with Lyme disease in Europe is approximately 10%.

The cause is borrelia belonging to the Spirochaetacea family. There are about 20 different genospecies, but only five pose a significant pathogenic risk to humans (Hubálek Z et al. 1997):

• B. afzelii
• B. garinii
• B. bavariensis
• B. burgdorferi sensu stricto
• B. spielmanii

Acrodermatitis chronica atrophicans is mainly caused by a bacterial infection with B. afzelii. However, it can also be caused by European B. burgdorferi sensu stricto or B. garinii.

In ACA, there is a chronic, T-cell-mediated immune response against Borrelia with the presence of CD3+ and CD4+ cells in the skin infiltrate (Kempf W et al. 2015). Borrelia bind to extracellular matrix proteins, including glycosaminoglycan-binding protein, fibronectin-binding protein and decorin proteoglycan (Brissette CA et al. 2009). Borrelia have a high affinity for collagen fibers, which has been demonstrated by electron microscopy. They activate metalloproteases and thereby cause the degradation of the extracellular matrix. The damage to the connective tissue with the destruction of collagen leads to fibrosis and skin atrophy (Müller KE 2012).

Acrodermatitis chronica atrophicans is the most common late and chronic manifestation of Lyme borreliosis. Around 20% of patients with ACA have a history of spontaneously healed erythema chronicum migrans, usually on an extremity on which the signs of acrodermatitis chronica atrophicans (ACA) developed 6 months to 8 years later - stage 3 of Lyme borreliosis (Moniuszko-Malinowska A et al. 2018). Acrodermatitis chronica atrophicans is primarily due to infection with B. afzelii, but can also be caused by B. garinii or European B. burgdorferi infections. Occurrence is possible at any age, especially in the 5th-6th decade of life; women are preferentially affected (Strle F et al. 2013).

Distal extremities (Strle F et al. 2013) and acra, rarely trunk. Face is almost always left out. Finger end phalanges and toes also remain free. Often asymmetrical onset. After years of infestation, either both arms or both legs are more frequently affected.

Infiltrative (oedematous) stage: months to years after the primary stage, circumscribed, rather discrete, palm-sized, not very sharply defined, non-symptomatic, brownish-red, succulent, non-scaling erythema and plaques form when first diagnosed (if they are recognized as a Borrelia infection). These are often misinterpreted as "chronic venous insufficiency" on the lower extremity. If left untreated, the lesions gradually spread to form large, oedematous, blurred, livid red plaques with a shiny surface, often covering an entire part of the body.

Atrophic stage: after months of persistence, barely noticeable transition to a peculiarly shiny, thinned, hairless (follicles are destroyed), atrophic skin stage. A noticeable (and name-giving) feature is a wrinkled wrinkling of the brown-red discolored skin, with clearly translucent vessels. The superficial veins run under this atrophic skin in the form of strange, twisted strands that are otherwise only found in the withered skin of very old people. In some patients with a long-term course, small, circumscribed, "anetoderma-like" atrophies are also found. The skin is hyper- or depigmented. Particular attention should be paid to cutaneous-subcutaneous, often well-displaced, cord-like, well-displaced, also adherent band-like, reddish plaques. They are referred to as ulnar striae on the ulna (in around 25% of advanced cases) and as tibial striae on the tibia (very rarely <5% of cases).

Proliferative stage (only observedin long-term A.chr.a./veryrarely):

• Fibroid nodules: In about 25% of this long-term clientele, the so-called fibroid nodules, reddish or livid in color, are located near joints (elbows, fingers, knees). One of the unexplained peculiarities of this disease is that, in addition to the extensive atrophy of the skin and subcutis that characterizes the clinical picture (in an untreated state), they form focal connective tissue growths, so-called fibroid juxtaarticular nodules. These are up to walnut-sized, possibly calcifying nodules, especially over the elbows (see illustration).
• Plate-like dermatosclerotic plaques: Can be observed on the back of the foot, ankles and distal lower legs. The latter are described as armor-like thickened, firm, also sclerotic and shiny. There is a risk of ulceration.
• Morphea-like acrodermatitis chronica atrophicans: in this particular and rare variant, the characteristic atrophy of acrodermatitis atrophicans does not occur, but rather a reactive "morphea-like" sclerosis of the skin. Deratotic changes can occur on the trunk, but also on the distal extremities (lower leg and back of the foot). Particularly on the trunk, these foci are difficult to distinguish from the plaque type of circumscribed scleroderma (morphea) (histology with plasma cell dominance, positive Borrelia serology).

Optional concomitant symptoms:

Secondary skin changes:

• Loss of hair follicles, sebaceous and sweat glands, dry skin.
• Tendency to exsiccation eczema.
• Torpid ulcerations due to minor trauma to the lesional skin.
• Frequent pseudolymphomas of the skin (borrelia lymphocytoma), lipoma, fibroma, carcinoma, transition to malignant cutaneous B-cell lymphoma possible.

Neurological complications:

• About half of the patients may develop axonal peripheral neuropathy, usually limited to lesions, which is accompanied by numbness, tingling or allodynia, an exaggerated burning pain reaction to banal stimuli.
• Disseminated neuropathy is less common.

Strong increase in gamma globulins and BSG due to stimulation of the B-lymphocyte system with maturation of plasma cells. High antibody titres against Borrelia antigens (IgG).

In bone marrow biopsy: plasma cell and lymphoid inflammation, also eosinophilia.

Inflammatory-edematous stage: epithelium slightly widened, orthokeratosis. Edema of the dermis with vascular dilatation. Characteristic are interstitial granulomatous infiltrates(CD68 positive), with peculiarly thickened and homogenized collagen bundles, as well as a band-like infiltrate of CD4 positive T lymphocytes. Vacuolated degeneration of the basal cell layer in places. The interface changes are usually not very pronounced. Plasma cells are often but not always detectable. In a larger study (Brandt FC et al. 2017), plasma cells were absent in 9 of 22 biospies.

B. afzelii, serotype 2 is preferentially detected (see Borrelia below).

Atrophic stage: Epidermal atrophy with compact orthokeratosis; increasing loss of elastic fibers. Rather sparse, diffuse inflammatory infiltrate of lymphocytes and plasma cells.

Fibroid nodules and dermatosclerotic plaques show essentially the same structure, which is characterized by 2 superimposed layers. In the upper layers there is a parellization of the connective tissue. Plasma cell-rich infiltrates are visible between the collagenous bundles.

The diagnosis of ACA is based on clinical findings and is supported by serological tests (high concentration of specific Borrelia IgG antibodies). In the majority of chronic Lyme disease patients, serology is positive for Borrelia IgG antibodies. IgM antibodies against Borrelia are often false positive in the late stage and therefore not helpful for the diagnosis of ACA. A negative serological test excludes ACA. If the clinical picture is uncertain, further diagnosis is made by skin biopsy and histological examination. The detection of B. burgdorferi DNA by culture or PCR supports the diagnosis.

• Clinical differential diagnoses:
  • Acrocyanosis: no atrophy of the skin; preferably acral localization; Borrelia serology negative (also applies to all other DD).
  • Perniones: circumscribed plaques or nodules, no skin atrophy, variable course.
  • Stasis dermatitis in chronic venous insufficiency: CVI sign, only lower extremity affected, almost exclusively bilateral, brown color, possibly ulcer formation.
  • Erysipelas: Acute course, fever, painfulness, painful lymphadenitis, leukocytosis, CRP significantly elevated.
  • Erythromelalgia: typical reproducible pain symptoms, positive cold water test.
  • Circumscribed scleroderma type atrophodermia idiopathica et progressiva: stem localization, negative serology and PCR.
• Histologic differential diagnoses:
  • Lichen planus: marked interface dermatitis with pronounced vacuolization of the basal keratinocytes; no plasma cells.
  • Lichenoid drug reaction: usually marked dermal edema; often eosinophilia, no plasma cells.
  • Mycosis fungoides: typical halo formation around polymorphic lymphocytes, hardly any plasma cells, marked epidermotropy with vacuolized epidermal cells; eosinophilia is possible.
  • PLEVA: no histiocytes, no plasma cells.
  • Syphilitic exanthema: interface dermatitis with high infiltrate density, psoriasiform epidermal reaction, numerous plasma cells.
  • Atrophodermia idiopathica et progressiva: rather sparse, lympho-histiocytic infiltrate, clumped collagen fiber bundles in the deep dermis; atrophic, hyperpigmented surface epithelium.

Bacterial superinfections;

ACA is considered a risk factor for malignancies, including B-cell lymphoma, basal cell carcinoma and squamous cell carcinoma.

The treatment of first choice is ceftriaxone (e.g. Rocephin), even in the case of concomitant extracutaneous manifestations such as arthritis or CNS involvement (see Table 1). The antibiotic cycles should be repeated at 3-month intervals depending on the clinical situation and last 21-28 days due to the generation times.

Adults receive ceftriaxone 1 time/day 2 g i.v., in severe, refractory cases up to 4 g/day for 3 weeks. Children receive 50 mg/kg bw once/day up to a maximum dose of 2 g/day for 21 days. In premature infants and newborns up to 2 weeks, do not exceed doses of 50 mg/day/kg bw.

The duration of therapy depends on the clinical findings; cycles may need to be repeated.

Antibody titer controls are only of limited value for the course of the healing process. However, a drop in titres can be observed with sufficient therapy. Atrophies are not reversible.

Alternative: Oral amoxicillin 500 to 1000 mg three times a day for 14 to 28 days

Alternative: Doxycycline orally 100 mg twice daily or 200 mg once daily for 14 to 28 days

Alternative: Cefotaxime 2000 mg intravenously every 8 hours for 14 to 28 days

Alternative: Penicillin G intravenously 3 to 4 MU every 4 hours for 14 to 28 days

Children/pregnancy (risk of diaplacental transmission!)

• Amoxicillin 50 mg/kg bw/day p.o. (2-3 times/day 500 mg/day p.o.)
• Alternative: Cefuroxime juice 20-30 mg/kg bw/day for 21 days
• Alternative: Erythromycin 3-4 times/day 500 mg p.o. or i.v. over 21 days

The clinical prognosis is favorable if the acute inflammatory stage is treated appropriately. For the chronic atrophic phase, the clinical outcome is difficult to predict as the changes are only partially reversible. One study showed that 28 days of treatment with third-generation cephalosporins led to a partial to complete regression of the skin lesions. If ACA remains untreated, it usually does not regress spontaneously. This results in fibrosis and increasing atrophy. In general, antibiotic therapy cannot reverse existing polyneuropathic symptoms!

Therapy options for acrodermatitis chronica atrophicans

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