Acrodermatitis Chronica Atrophicans Patients Research Articles

Pathogenetic implications of the age at time of diagnosis and skin location for acrodermatitis chronica atrophicans

BackgroundThe pathogenesis of acrodermatitis chronica atrophicans (ACA) is not well understood. ObjectiveThe purpose of this study was to gain a better understanding of ACA by utilizing a large data set of adult Slovenian patients with Lyme borreliosis. MethodsThe age of 590 ACA patients was compared with that of patients with other manifestations of Lyme borreliosis. The location of the ACA lesion on the body was compared with that of erythema migrans (EM). ResultsPatients diagnosed with ACA were on average 14.3 years older than patients with EM (p<0.001). ACA patients were also significantly older than patients with Lyme neuroborreliosis or Lyme arthritis (p<0.001). The average delay in diagnosis of ACA was 1.6 years (range 0.1–20 years). For 572 (96.9%) of the ACA patients, the site of the skin lesion(s) was confined to an extremity vs. 79.6% for patients with EM, p<0.001. For the 20 ACA patients who reported a preceding untreated EM lesion at the same body site, the mean time between the development of the EM and the onset of ACA was 3.0±4.4 (median 1.3, range 0.1–15.0) years. ConclusionsACA is more likely to be diagnosed in older individuals than any other manifestation of Lyme borreliosis. ACA is more likely than EM to be localized anatomically to the extremities. Available data favor the hypothesis that ACA occurs most often on the extremities of older individuals because of predisposing age-related anatomic or physiologic changes, but more data are needed to define the latency period and other aspects of the pathogenesis of this skin condition.

Gender Disparity between Cutaneous and Non-Cutaneous Manifestations of Lyme Borreliosis

Cutaneous manifestations of Lyme borreliosis in Europe include erythema migrans (EM) and acrodermatitis chronica atrophicans (ACA); the most common non-cutaneous manifestations are Lyme neuroborreliosis (LNB) and Lyme arthritis. The purpose of this study was to evaluate the gender distribution of patients with these clinical manifestations of Lyme borreliosis. Data on gender were obtained from the clinical records of patients with Lyme borreliosis aged ≥15 years who had been evaluated at the University Medical Center Ljubljana, Ljubljana, Slovenia.Among 10,539 patients diagnosed with EM, 6,245 (59.3%) were female and among 506 ACA patients 347 (68.6%) were female. In contrast, among the 60 patients with Lyme arthritis only 15 (25%) were female (p<0.0001 for the comparison of gender with EM or ACA) and among the 130 patients with LNB only 51 (39.2%) were females (p<0.0001for the comparison of gender with EM or ACA). Although the proportion that was female in the LNB group was greater than that of patients with Lyme arthritis, this difference did not reach statistical significance (p = 0.10). Although older individuals are more likely to be female in the general Slovenian population, the age of patients with cutaneous versus non-cutaneous manifestations was not the explanation for the observed differences in gender.In conclusion, patients with cutaneous manifestations of Lyme borreliosis were predominantly female, whereas those with non-cutaneous manifestations were predominantly male. This provocative finding is unexplained but may have direct relevance to the pathogenesis of Lyme borreliosis.

Diagnostic value of PCR for detection of Borrelia burgdorferi in skin biopsy and urine samples from patients with skin borreliosis.

Skin biopsies of 36 patients with erythema migrans and acrodermatitis chronica atrophicans (ACA) before therapy and those of 8 patients after therapy were examined for Borrelia burgdorferi DNA by PCR. Skin biopsies of 27 patients with dermatological diseases other than Lyme borreliosis and those of 10 healthy persons were examined as controls. Two different primer sets targeting 23S rRNA (PCR I) and 66-kDa protein (PCR II) genes were used. PCR was performed with freshly frozen tissue (FFT) and paraffin-embedded tissue (PET). For FFT specimens of erythema migrans, 73% were positive by PCR I, 79% were positive by PCR II, and 88% were positive by combining PCR I and II. For PET specimens, PCR was less sensitive (PCR I, 44%; PCR II, 52%). For FFT specimens of ACA, PCR I was positive for two of five patients and PCR II was positive for four of five patients. B. burgdorferi was cultured from 79% of the erythema migrans specimens but not from any of the ACA lesions. Elevated B. burgdorferi antibodies were detected in sera of 74% of erythema migrans patients and 100% of ACA patients. All urine samples were negative by PCR II, whereas PCR I was positive for 27%. However, hybridization of these amplicons was negative. Sequencing of three amplicons identified nonborrelial DNA. In conclusion, urine PCR is not suitable for the diagnosis of skin borreliosis. A combination of two different primer sets achieves high sensitivity with skin biopsies. In early erythema migrans infection, culture and PCR are more sensitive than serology.

Detection of Borrelia afzelii, Borrelia burgdorferi sensu stricto, Borrelia garinii and group VS116 by PCR in skin biopsies of patients with erythema migrans and acrodermatitis chronica atrophicans.

OBJECTIVE: To evaluate the diagnostic performance of two polymerase chain reaction (PCR) procedures using skin biopsies of 20 erythema migrans (EM) and 24 acrodermatitis chronica atrophicans (ACA) patients. METHODS: One assay amplified a fragment of the outer surface protein (Osp) A gene. The second method amplified the spacer region between the 5S and 23S rRNA genes; hybridization of this fragment allowed identification of Borrelia burgdorferi sensu lato species. RESULTS: Among EM patients, both assays detected Borrelia DNA in 15 samples. Among ACA patients, the ospA PCR detected 15 positives and 10 samples were positive by 5S-23S PCR. In 19 samples one species was detected, 15 skin biopsies contained Borrelia afzelii, and Borrelia garinii was found in two patients. Group VS116 was detected in two EM patients, and therefore this group has pathogenic potential. Mixed infections of B. afzelii and B. garinii, group VS116 or B. burgdorferi sensu stricto were found in three EM and three ACA patients. CONCLUSIONS: Diagnosis of EM and ACA by PCR is useful and knowledge of the presence of species may be used to predict the course of disease or the need for further antibiotics.

Polymerase chain reaction control of antibiotic treatment in dermatoborreliosis

Assessment of the efficacy of an antibiotic drug used in patients with various manifestations of dermatoborreliosis is crucial. Clinical judgement alone (resolution of the present dermatologic lesion, prevention of later major or minor sequelae) is not sufficient in erythema migrans and acrodermatitis chronica atrophicans. Thus, laboratory tests are desirable to prove the benefit of an antimicrobial agent. It was intended to establish a constant parameter--besides the clinical picture--for assessing the efficacy of antibiotic treatment in patients with dermatoborreliosis in terms of eradication of Borrelia burgdorferi from the site of infection. Polymerase chain reaction (PCR) was therefore performed from pretreatment biopsy specimens from lesional skin of 36 erythema migrans patients (m:f = 15:21, mean age 49 years) and seven acrodermatitis chronica atrophicans patients (m:f = 0:7, mean age 59 years), respectively. After antibiotic therapy with minocycline (100 mg, orally twice daily, 14 days) for erythema migrans, and ceftriaxone (2 g, intravenously once daily, 14 days) for acrodermatitis chronica atrophicans another punch biopsy was obtained and analysed by PCR. In pretreatment specimens, B. burgdorferi-specific DNA was amplified by PCR in 23/36 erythema migrans patients (69%), and in 5/7 acrodermatitis chronica atrophicans patients (71%). After antibiotic therapy, PCR yielded negative results in all of these cases. Clinically, all patients showed complete recovery or at least marked improvement of lesions at this time. PCR appears to be a reliable parameter for the assessment of the efficacy of antibiotic treatment in dermatoborreliosis.

Establishment of enzyme-linked immunosorbent assay using purified recombinant 83-kilodalton antigen of Borrelia burgdorferi sensu stricto and Borrelia afzelii for serodiagnosis of Lyme disease

The 83-kDa antigen of Borrelia burgdorferi was expressed as a recombinant protein in Escherichia coli and purified for use in an enzyme-linked immunosorbent assay (p83-ELISA). Antibodies to the 83-kDa antigen of both the immunoglobulin G (IgG) and IgM isotypes could be detected in all stages of Lyme disease. Sensitivity varied, depending on the clinical stage of illness. In early stages, as defined for 118 patients with erythema migrans, it was found to be 20% (24 of 118 patients: 7 with IgM, 16 with IgG, and 1 with IgM and IgG). Of the patients with late-stage Lyme arthritis and acrodermatitis chronica atrophicans, 94% (16 of 17:2 with IgM and IgG and 14 with IgG) and 86% (36 of 42:2 with IgG and IgM and 34 with IgG) revealed positive results in the p83-ELISA, respectively. p83 displays sequence heterogeneity according to the genomospecies, but when the reactions of serum specimens from acrodermatitis chronica atrophicans patients and arthritis patients with p83 derived from representative strains of B. burgdorferi sensu stricto and Borrelia afzelii in ELISAs were compared, no differences in specificity and sensitivity were seen. When 82 serum specimens from healthy controls were tested, none had IgG and only 3 (4%) had IgM antibodies, indicating a high specificity. Positive reactions with antibodies against Treponema pallidum (1 of 37 patients; IgG) and Epstein-Barr virus (1 of 44 patients; IgM) and with autoantibodies of various specificities (1 of 53 patients; IgG) were seen with < 3% of the serum samples te11111111111111111111 high speficicity for B. burgdorferi.2+ 13% for IgM antibodies, the IgM p83-ELISA provided little diagnostic information for Lyme disease, whereas the IgG p83-ELISA appears to be a suita ;e test for serodiagnosis of advanced-stage Lyme disease.

Intrathecally produced antibodies to Borrelia burgdorferi measured by IgG-capture ELISA

An IgG-capture enzyme-linked immunosorbent assay (ELISA) which directly measures the intrathecal production of Borrelia burgdorferi-specific IgG in neuroborreliosis is described. The method is based on the simultaneous measurement of IgG-specific antibodies in paired cerebrospinal fluid (CSF) and serum samples. Sixty-nine paired CSF/serum samples from 64 patients with neuroborreliosis or other neurological disorders and six samples from acrodermatitis chronica atrophicans (ACA) patients were analysed by IgG-capture ELISA. Of 12 samples from patients with early neuroborreliosis, intrathecal production of B. burgdorferi-specific IgG could be demonstrated in 11 samples. Of 56 patients with other neurological disorders of known or unknown etiology, intrathecal production of B. burgdorferi-specific IgG was demonstrated in one patient who had a history compatible with a previous neuroborreliosis. No intrathecal production was found in the samples from ACA patients in spite of high Borrelia titres in their CSF as measured by indirect ELISA. In conclusion, the B. burgdorferi IgG-capture ELISA is a sensitive and reliable method for the detection of intrathecal production of IgG antibodies to B. burgdorferi. It is advantageous in comparison to the indirect ELISA as it does not require correction for leakage across the blood/CSF barrier.

Frequencies of Borrelia burgdorferi-reactive T lymphocytes in Lyme arthritis.

Using a limiting dilution system, frequencies of Borrelia burgdorferi-reactive T cells were determined in the blood and synovial fluid of four patients with chronic Lyme arthritis (LA), one patient with acrodermatitis chronica atrophicans (ACA), two patients with other inflammatory joint diseases, and two healthy individuals. B. burgdorferi-reactive precursor T cells ranged from 1/750 to 1/8220 in case of LA and ACA patients and from 1/820 to 1/31 400 in case of controls. In vivo activated B. burgdorferi-reactive T cells were almost absent in control subjects. With one exception, they were detected in LA patients at frequencies ranging from 1/1 300 to 1/15 400. Interestingly, even after successful antibiotic therapy of LA patients, similar frequencies of in vivo activated B. burgdorferi-reactive T cells were observed in the peripheral blood, provided that low cell concentrations were used for culture. At higher cell numbers, the fraction of B. burgdorferi-reactive T cells apparently dropped, suggesting regulatory phenomena.

Immunochemische analyse der immunantwort bei spätmanifestationen der Lyme Borreliose: Immunochemical analysis of the immune response in late manifestations of Lyme Borreliosis

Compared to American strains, European Borrelia burgdorferi strains revealed considerable heterogeneity of major proteins. Four strains isolated from ticks, human skin and human CSF were selected from our 23 Borrelia burgdorferi isolates. These strains and the American type strain B31 were characterized by SDS-PAGE (Coomassie Blue staining) and Western blots (using rabbit immune sera against two of the strains and two monoclonal antibodies (H5323 and H3TS) against a major outer surface protein (OspA)). The strains showed considerable differences in SDS-PAGE pattern. Corroborating the results of a previous study, we could demonstrate that the OspA (31/32K) can change from a minor to a major protein and in reverse the pC (21/22K) from a major to a minor protein during subculturing. Moreover, European strains can antigenically differ in OspA, pC and also in a further low molecular weight protein of 17/18K. To examine whether the antigenic heterogeneity of European isolates is reflected in the immune response of European patients we examined sera from patients with late manifestations of Lyme Borreliosis by Western blot using the five strains as antigens. Sera from seven patients with acrodermatitis chronica atrophicans (ACA) showed a surprisingly strong reactivity with the skin isolate. All sera had antibodies against the 17/18K protein of the skin isolate, but none was reactive with the analogous 17/18K of the other strains. On the other hand a comparable predominance of one strain was not found testing sera from patients with Lyme arthritis. One patient even had antibodies against OspA and OspB proteins of strain B31. Contrary to findings in American Lyme Disease antibodies against the OspA were rarely observed in the sera of our patients (only one patient had such antibodies) although we tested the patients sera with five different strains. Only two patients had stronger reactions with the skin isolate. These findings suggest that ACA is caused by antigenically closely related Borreliae. This could explain the finding that ACA is rarely observed in the US (US strains are antigenically closely related to strain B31). Our findings in patients with Lyme Arthritis — on the other hand — suggest that “different serotypes” can cause Lyme Arthritis. This does not exclude the possibility that Borrelia proteins are an important factor in the pathogenesis of Lyme arthritis. Finally the differences in reactivity of sera with different strains in the Western blot led us to examine whether such differences are also found in serodiagnostic tests using different strains as antigens. Except in two ACA sera (which reacted stronger with the skin isolate) no significant differences were found using the five strains as antigens in the IgG immunofluorescent assay (we tested four sera from ACA patients, four sera from patients with neurological manifestations, four sera from Lyme arthritis patients and five sera from control persons without Lyme Borreliosis). These findings suggest that the IgG IFT can be performed by using only one strain as antigen. But in some cases antigen-dependent differences have been observed and we do not know whether different results occur using different antigens in other serodiagnostic tests (i.e. ELISA, IgM IFT).