Acrodermatitis Chronica Atrophicans

Background: Acrodermatitis chronica atrophicans (ACA) is the third or late stage of European Lyme borreliosis (LB). This unusual, progressive, fibrosing skin process is due to the effect of continuing active infection with Borrelia afzelii. Buchwald first delineated it in 1883; Herxheimer and Hartmann described it in 1902 as a tissue paper–like cutaneous atrophy. It is evident on the extremities, particularly on the extensor surfaces, beginning with an inflammatory stage with bluish red discoloration and cutaneous swelling and concluding several months or years later with an atrophic phase. Sclerotic skin plaques may also develop. Physicians should use serologic and histologic examination to confirm this diagnosis.

Pathophysiology: B afzelii is the predominant, but may not be the exclusive, etiologic agent of ACA. Another genospecies of the Borrelia burgdorferi sensu lato complex, Borrelia garinii, has also been detected.

ACA is the only form of LB in which no spontaneous remission occurs. Its pathophysiology is not yet fully understood. ACA appears to be associated with long-term persistence of Borrelia organisms in the skin; several nonspecific reactions together with a specific immune response may contribute to its manifestations.

The persistence of the spirochetes despite a marked cutaneous T-cell infiltration and high serum antibody titers may be connected with resistance of the pathogen to the complement system; the ability to escape to immunologically protected sites (eg, endothelial cells, fibroblasts); and the ability to change antigens, which may lead to an inappropriate immune response. Lack of protective antibodies, with a narrow antibody spectrum and a weak cellular response with down-regulation of major histocompatibility system class II molecules on Langerhans cells, has been observed in patients with LB.

A restricted pattern of cytokine expression in ACA, including the lack of interferon-gamma, may contribute to its chronicity. Cross-reactive antibody responses could take part in autoimmune damage, but whether autoimmune reactions play any role in the pathogenesis of the disease is unclear. The pathogenic mechanism of atrophic skin changes has also not been clarified. Perhaps periarticular regions are favorite sites because of reduced acral skin temperatures or reduced oxygen pressure.

Frequency:

• In the US: The occurrence of ACA is connected with the ecology of LB, which varies in different geographical regions of the world.

  Despite a high incidence of LB in the United States (varying from 95 cases per 100,000 population in Connecticut to 1250 cases per 100,000 population in Nantucket County, Massachusetts [1996 data]), ACA is not seen in the United States, except in a few European immigrants.

• Internationally: The occurrence of ACA is connected with the ecology of LB, which varies in different geographical regions of the world.

  Ixodes scapularis, Ixodes pacificus, and 4 other tick species distributed in North America transmit B burgdorferi sensu stricto, causing EM and LB arthritis.

  Tick vectors of B afzelii, the main etiologic agent of ACA (and erythema migrans [EM]), are Ixodes ricinus, Ixodes hexagonus, and Ixodes persulcatus distributed in western and central Europe and in far eastern Europe and Asia. Almost all of these hard tick species may also transmit B garinii, a causative agent of EM and neurologic symptoms of LB.

  In Europe, LB with all its dermatologic manifestations occurs in almost all countries, predominantly in the central part of the continent. The annual incidence per 100,000 population varies from 16 cases in France to 120 cases in northeastern Poland and Slovenia and to 130 cases in Austria (1995 data).

  The frequency of ACA is about 1-10% of all European patients with LB, varying according to the region of the population sampled. Among the group of patients with skin manifestations of LB observed in Vienna, the ratio of the number of EM cases to ACA cases and to Borrelia lymphocytoma (BL) cases was 30:3:1. This ratio is 170:5:1 in the authors' as-yet-unpublished studies (provided in the group of patients with LB in northeastern Poland).

  Because the clinical diagnosis of ACA is much more difficult than that of EM or BL, the condition is often underdiagnosed, and, in fact, the ratio of EM cases to ACA cases may be higher. The total number of cases could increase with increasing frequency of untreated European LB. ACA is probably the most common late and chronic manifestation of the borreliosis in European patients with Lyme disease.

  A Bulgarian survey found that borrelial lymphocytoma and ACA were rare (0.3%) (Christova, 2004).

Mortality/Morbidity: The course of ACA is long-standing, lasting from a few to several years, and it leads to extensive flaccid atrophy of the skin and, in some patients, to the limitation of upper and lower limb joint mobility.

• Chronic, difficult-to-treat ulcerations of atrophic skin may develop after minor trauma. Malignant degeneration has rarely been observed; one should not consider ACA to be a precancerous disorder.

• The general status of patients with ACA remains good, though they may experience neurologic and/or rheumatologic signs and symptoms.

Race: ACA is not limited to any one nationality or race. It is much more frequent in whites than in other races, probably because of a far higher exposure to ticks transmitting B afzelii.

Sex: More than two thirds of patients with ACA are women. Among the authors' 19 patients, only 5 were men (Flisiak, 1999).

Age: The disease can occur in any age group, but it is most frequent in adults, usually in their 40s or 50s.

• The youngest of the authors' patients was 26 years; the oldest was 73 years (Flisiak, 1999).

• The mean age of the female group was 54.3 ± 12.8 years; the mean age of the male group was 46.2 ± 6.5 years.

• ACA is rare in adolescents; however, it has been observed in children. A case in a 15-year-old girl was reported by Zalaudek et al in 2005.

Treatment
Medical Care: The choice of treatment depends on the coexistence of other signs or symptoms of LB with ACA. The authors also consider the value of the titer of serologic tests.

• If the extracutaneous LB signs are absent and the level of specific antibodies is low, the authors usually recommend oral doxycycline or oral amoxicillin, over 3 weeks.

• If organic or systemic physical or laboratory signs of LB are present or if the antibody titer is high, the appropriate treatment should be introduced mainly with ceftriaxone or cefotaxime or aqueous penicillin G given intravenously for 21-28 days.

Consultations: Seek the appropriate consultations (ie, neurologist, ophthalmologist, rheumatologist, cardiologist) if extracutaneous signs and symptoms exist.

Medication
The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.
Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.

Drug Name	Amoxicillin (Amoxil, Trimox) -- Bactericidal against Borrelia species. Semisynthetic penicillin of aminopenicillins group demonstrating wide spectrum of bactericidal activity related to gram-positive and gram-negative bacteria. Mechanism of action involves bacterial cell wall synthesis inhibition.
Adult Dose	500 mg PO q6h or 1000 mg PO q12h for 21-28 d
Pediatric Dose	2-3 years: 40-60 mg/kg/d PO bid/tid >4 years: 375-750 mg/d PO tid
Contraindications	Documented hypersensitivity; infectious mononucleosis; lymphatic leukemia
Interactions	Neomycin decreases its absorption; allopurinol increases rash development; reduces efficacy of oral contraceptives
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; may cause dyspepsia or rash

Drug Name	Doxycycline (Vibramycin) -- Tetracycline antibiotic that inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Used for antibacterial and anti-inflammatory effect and for concern about possible coexistent infection.
Adult Dose	100-200 mg PO qd for 21-28 d
Pediatric Dose	<8> >8 years: Administer as in adults
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Ceftriaxone (Rocephin) -- Bactericidal against Borrelia species. Third-generation cephalosporin with broad-spectrum, gram-negative activity. Lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.
Adult Dose	2 g IV q24h for 14-21 d 1-2 g IV/IM q12-24h
Pediatric Dose	50-100 mg/kg IV/IM; not to exceed 4 g/d
Contraindications	Documented hypersensitivity
Interactions	High doses of probenecid may increase clearance by blocking biliary secretion and displacement of ceftriaxone; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; caution in women who are breastfeeding and allergy to penicillin; caution in children who are hyperbilirubinemic because of its ability to displace bilirubin; adverse effects include headaches, dizziness, pseudomembranous colitis, nausea, vomiting, and diarrhea

Drug Name	Cefotaxime (Claforan) -- Third-generation of semisynthetic cephalosporin with board-spectrum bactericidal activity against gram-negative bacteria and Staphylococcus and Streptococcus species. Resistant to beta-lactamases. Mechanism of action is related to inhibition of bacteria cellular wall component synthesis.
Adult Dose	1-2 g IV q8h for 14-21d
Pediatric Dose	<12> >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Synergic with aminoglycosides, vancomycin, and anticoagulants; may cause false-positive Coombs reaction
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause hypersensitivity reaction, headaches, dizziness, pseudomembranous colitis, nausea, and vomiting; neutropenia and biochemical signs of liver injury are seldom

Drug Name	Penicillin G (Pfizerpen) -- Beta-lactam antibiotic. The mechanism of action is related to bacterial cell wall synthesis inhibition in the growth phase as a result of penicillin and bacterial transpeptidase binding.
Adult Dose	4.5-6 million U IV q6h or 3-4 million U IV q4h (18-24 million U/d) for 21 d
Pediatric Dose	50,000-80,000 U/kg/d IV divided q6h
Contraindications	Documented hypersensitivity; caution in patients with bronchial asthma, renal insufficiency, or circulatory insufficiency; caution in those receiving potassium and diuretics
Interactions	Probenecid and NSAIDs increase blood concentration and extend time of action; penicillin benzathine demonstrates in vivo synergism with aminoglycoside antibiotics, but, in vitro, it causes their inactivation; not to be administered in the same syringe with vancomycin, cephalothin, amphotericin B, or metronidazole; antagonism toward tetracycline, chloramphenicol, and mucolytic drugs; high doses given with digoxin increase toxicity; combination with beta-adrenergic blocking drugs increases risk of anaphylaxis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not contraindicated in pregnancy but can lead to fetal hypersensitization, particularly in the second or third trimester; can induce anaphylactic shock, hypersensitivity reactions, arthralgia, fever, eosinophilia, lymphadenopathy, and kidney interstitial inflammation; high doses can lead to hemolytic anemia, leukopenia, and electrolytic disturbances; neurotoxicity; can induce Jarisch-Herxheimer reaction in patients with spirochetosis