Acrodermatitis chronica atrophicans overview

# Overview
First record of acrodermatitis chronica atrophicans was made in 1883 in Breslau, Germany, where a physician named Alfred Buchwald first delineated it. Acrodermatitis chronica atrophicans is one of the tertiary presentations of European lyme borreliosis with Borrelia afzelii known as the most predominant responsible microorganism. Transmission of this infection probably occur via ixodes tick (such as Ixodes ricinus), mosquito and horsefly bite. These vectors themselves get infected by feeding on an infected animal reservoir. Immune reaction against borrelia leads to infiltration of CD3+ and CD4+ cells in the dermis. Some conditions such as lymphocytic meningoradiculitis, lichen sclerosus et atrophicus, morphea and other tick borne diseases have been associated with acrodermatitis chronica atrophicans. Thinning of skin, visible veins, swelling and wrinkles are some of the features can be noticed on gross pathology. Light and electron microscopic study of the skin biopsy shows degeneration of the elastica and collagen fibers. Acrodermatitis chronica atrophicans must be differentiated from chronic venous insufficiency, chronic arterial insufficiency, superficial thrombophlebitis, frostbite, morphea, and granuloma annulare. Acrodermatitis chronica atrophicans is a rare disease. The prevalence of acrodermatitis chronica atrophicans is estimated to include 10% of cases with lyme disease in Europe. The incidence of acrodermatitis chronica atrophicans increases with age. Acrodermatitis chronica atrophicans affects women more than men and the majority of acrodermatitis chronica atrophicans cases are reported in northern, central and eastern Europe. Common risk factors in the development of acrodermatitis chronica atrophicans include tick exposure, female gender and residents of northern, central and eastern Europe. The course of acrodermatitis chronica atrophicans is chronic and could lasts for several years and it can progress slowly overtime. In first phase (the inflammatory phase) skin changes appear as blue and red discoloration with boggy infiltration. These inflammatory skin lesions can become atrophic without treatment (atrophic phase). Superimposed bacterial infection, sclerotic skin changes, malignancies, arthropathy and peripheral neuropathy are some of the common complications of acrodermatitis chronica atrophicansis. The general pognosis is good with proper and rapid treatment in acute inflammatory stage of acrodermatitis chronica atrophicans, nevertheless late treatment can cause some irreversible changes. Skin examination of acrodermatitis chronica atrophicans's patients include blue, red or brown discoloration, hypopigmentation, indurated plaques and wrinkles. High anti-spirochetal antibody levels (such as IgG, IgM and IgA) has been detected at indirect immunofluorescence and enzyme linked immunosorbent assay (ELISA). Antibiotic therapy is recommended in patients with acrodermatitis chronica atrophicans. Up to four weeks treatment with antibiotics such as amoxicillin, doxycycline, ceftriaxone, cefotaxime and penicillin G has been recommended for acrodermatitis chronica atrophicans's treatment. Since transmission of borrelia infection occurs by ticks, mosquitos and horse flies bites, primary prevention could be achieved by bite avoidance.

# Historical Perspective
- The First record of acrodermatitis chronica atrophicans was made in 1883 in Breslau, Germany, where a physician named Alfred Buchwald first delineated it.
- Later in 1902 Herxheimer and Hartmann described it as a "tissue paper" like cutaneous atrophy and there were first physicians that came up with acrodermatitis chronica atrophicans's name. They described the biphasic manner of this disease by demonstrating both inflammatory and atrophic phases of it.
- In 1950s the possibility of human to human transmission was discussed. For the first time in 1984, borrelia was discovered as the responsible etiology of acrodermatitis chronica atrophicans.

# Pathophysiology
- Acrodermatitis chronica atrophicans is one of the tertiary presentations of European Lyme borreliosis with Borrelia afzelii known as the most predominant responsible microorganism.
- Nevertheless other borrelia species such as borrelia garinii and borrelia burgdorferi (B. burgdorferi sensu lato) have been also detected in acrodermatitis chronica atrophicans patients.
- Transmission of this infection probably occur via ixodes tick (such as Ixodes ricinus), mosquito and horsefly bite. These vectors themselves get infected by feeding on an infected animal reservoir.
- Development of various symptoms in this disease is a result of chronic T cell mediated reaction of immune system against borrelia.
- This immune reaction leads to infiltration of CD3+ and CD4+ cells in the dermis. Borrelia is capable of attaching to the extracellular matrix proteins (such as glycosaminoglycan, fibronectin and decorin proteoglycan) which eventually leads to metalloproteases activation and extracellular matrix degradation. Pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-4, have been detected in skin biopsies.
- There is no known gene responsible in pathophysiology of acrodermatitis chronica atrophicans disease. Some conditions such as lymphocytic meningoradiculitis, lichen sclerosus et atrophicus, morphea and other tick borne diseases have been associated with acrodermatitis chronica atrophicans. Thinning of skin, visible veins, swelling and wrinkles are some of the features can be noticed on gross pathology.
- Light and electron microscopic study of the skin biopsy shows degeneration of the elastica and collagen fibers. Thinning of dermis and epidermis, pigmented stratum germinativum, dermal blood vessels dilation and perivascular plasma cell infiltration are some of the findings on microscopic pathology.

# Causes
- This progressive skin disorder is due to the effect of chronic infection with the spirochete borrelia afzelii, which is the predominant cause of acrodermatitis chronica atrophicans.
- However borrelia afzelii is not the exclusive etiologic agent of acrodermatitis chronica atrophicans and other microorganisms such as borrelia garinii and borrelia burgdorferi have also been detected.

# Differentiating Acrodermatitis Chronica Atrophicans from Other Diseases
- Acrodermatitis chronica atrophicans must be differentiated from chronic venous insufficiency, chronic arterial insufficiency, superficial thrombophlebitis, frostbite, morphea, erysipelas, acrocyanosis and granuloma annulare.

# Epidemiology and Demographics
- Acrodermatitis chronica atrophicans is a rare disease. The prevalence of acrodermatitis chronica atrophicans is estimated to include 10% of cases with lyme disease in Europe.
- The incidence of acrodermatitis chronica atrophicans increases with age and commonly affects individuals in range of 40 to 70 years old with a median of 64 years old. However there are few case reports on children who are diagnosed with acrodermatitis chronica atrophicans.
- Acrodermatitis chronica atrophicans affects women more than men.
- The majority of acrodermatitis chronica atrophicans cases are reported in northern, central and eastern Europe (most commonly in countries bordering the Baltic Sea). Lately few cases of acrodermatitis chronica atrophicans have been reported in the United States and Canada.

# Risk Factors
- Common risk factors in the development of acrodermatitis chronica atrophicans include:
Tick exposure
Female gender and residents of northern, central and eastern Europe.
- Tick exposure
- Female gender and residents of northern, central and eastern Europe.

# Natural History, Complications, and Prognosis
- The course of acrodermatitis chronica atrophicans is chronic and could last for several years and it can progress slowly over time. It has been estimated that mean duration of acrodermatitis chronica atrophicans before diagnosis is approximately 12 months, based on a study. It usually start on one extremity and can spread and involve extensor surfaces of the acral regions of limbs.
- Acrodermatitis chronica atrophicans has a biphasic manner. In the first phase (the inflammatory phase) skin changes appear as blue and red discoloration with boggy infiltration. These inflammatory skin lesions can become atrophic without treatment (atrophic phase).
- Based on two studies, 55% and 66% of patients with acrodermatitis chronica atrophicans have at least one history of tick bite, while others may never remember such an accident. One fifth of patients in a study experienced erythema migrans 6 months to 8 years before acrodermatitis chronica atrophicans development.
- Superimposed bacterial infection, sclerotic skin changes, malignancies, arthropathy and peripheral neuropathy are some of the common complications of acrodermatitis chronica atrophicansis. In contrast to other skin manifestations of borrelia infection, acrodermatitis chronica atrophicans doesn't heal without treatment and can lead to extensive atrophy of skin and limitations of upper and lower limb joint mobility.
- The general pognosis is good with proper and rapid treatment in acute inflammatory stage of acrodermatitis chronica atrophicans. Nevertheless late treatment can cause some irreversible changes.

# Diagnosis

## History and Symptoms
- History of tick bite, erythema migrans or other symptoms of lyme disease, and rheumatological symptoms have been presented in patients with acrodermatitis chronica atrophicans. Since there could be several years between the tick bite and development of skin lesions, absence of tick bite in patients' history never exclude the diagnosis.
- Symptoms and different forms of skin involvement in acrodermatitis chronica atrophicans are dependent to duration of the disease. Symptoms, such as sclerotic skin changes, pain and burning, edema and constitutional symptoms have been observed in acrodermatitis chronica atrophicans.
- Half of patients with acrodermatitis chronica atrophicans experience symptoms of peripheral neuropathy, such as paresthesia and hypesthesia. Symptoms of peripheral neuropathy can occur at the exact site of acrodermatitis chronica atrophicans's lesion or at other sites.
- Involvement of lower limb is more common compared to the upper limb. In some cases episodic knee joint effusion has been observed.

## Physical Examination
- Skin examination of acrodermatitis chronica atrophicans's patients include blue, red or brown discoloration, hypopigmentation, indurated plaques and wrinkles, thinning and shining of involved skin.
- Readily visible veins, edema, ulcers and peeling are usually found. Although the most common location of these skin changes are observed on limbs, there are some cases with facial and abdominal involvement.
- Peripheral neuropathy develops in 50% of patients. Physical examination of some patients may reveal ulnar bands. Moreover fibrotic nodules could be seen on bony prominences, such as tibia or ulna.

## Laboratory Findings
- High anti-spirochetal antibody levels (such as IgG, IgM and IgA) has been detected at indirect immunofluorescence and enzyme linked immunosorbent assay (ELISA).
- Among various antigens in borrelia burgdorferi, flagellum antigen is one of the recommended serologic evaluation in acrodermatitis chronica atrophicans patients. Diagnosis of acrodermatitis chronica atrophicans can be excluded if the serologic evaluataion is negative.
- Borrelia itself has been found in some of the skin samples. When clinical presentations are not clear enough, biopsy and histological evaluation can assist. Findings such as plasma cells, histiocytes and lymphocytic infiltration plus telangiectasia and thinning of dermis and epidermis are commonly found in skin biopsies.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with acrodermatitis chronica atrophicans.

# Treatment

## Medical Therapy
- Antibiotic therapy is recommended in patients with acrodermatitis chronica atrophicans.
- Up to four weeks treatment with antibiotics such as amoxicillin, doxycycline, ceftriaxone, cefotaxime and penicillin G has been recommended for acrodermatitis chronica atrophicans's treatment.
Preferred regimen (1): Amoxicillin 500 to 1000 mg three times daily for 14 to 28 days
Preferred regimen (2): Doxycycline 100 mg twice daily or 200 mg once daily for 14 to 28 days
Preferred regimen (3): Ceftriaxone (IV) 2000 mg every 24 hours for 14 to 28 days
Preferred regimen (4): Cefotaxime (IV) 2000 mg every 8 hours for 14 to 28 days
Preferred regimen (5): Penicillin G (IV) 3 to 4 MU every 4 hours for 14 to 28 days
- Preferred regimen (1): Amoxicillin 500 to 1000 mg three times daily for 14 to 28 days
- Preferred regimen (2): Doxycycline 100 mg twice daily or 200 mg once daily for 14 to 28 days
- Preferred regimen (3): Ceftriaxone (IV) 2000 mg every 24 hours for 14 to 28 days
- Preferred regimen (4): Cefotaxime (IV) 2000 mg every 8 hours for 14 to 28 days
- Preferred regimen (5): Penicillin G (IV) 3 to 4 MU every 4 hours for 14 to 28 days

## Primary Prevention
- Since transmission of borrelia infection occurs by ticks, mosquitos and horse flies bites, primary prevention could be achieved by bite avoidance.
- Instructions such as using insect repellants, avoiding tick-infested regions or wearing long sleeves and pants when necessary can help.

## Secondary Prevention
- Proper antibiotic treatment of a patient who has been diagnosed with lyme disease can reduce the probability of acrodermatitis chronica atrophicans.