Chronic Lyme Arthritis Research Articles

An ospA frame shift, identified from DNA in Lyme arthritis synovial fluid, results in an outer surface protein A that does not bind protective antibodies.

Passive immunization with murine or human Abs to outer surface protein A (OspA) can protect mice against Borrelia burgdorferi, but OspA Abs elicited during natural infection in mice or humans are unable to clear the spirochete from the infected host. To examine Ab binding by OspA during the course of human infection, we amplified the operon encoding full-length ospA and ospB from synovial fluids of a patient with chronic Lyme arthritis, the first such recoveries from human material, at four separate time points over 4.5 mo, and expressed OspA in Escherichia coli. OspA mAbs that passively protected mice from infection did not bind one of the expressed OspAs, because of a deletion in ospA that resulted in a frame shift and premature stop codon near the carboxyl terminus. However, expressed OspA from a later synovial fluid sample did not contain this deletion. Thus, although altered forms of OspA, which potentially can influence host immune effectiveness, do occur in the human host, they cannot be the only factors responsible for microbial persistence.

Lyme Disease in Human DR4Dw4-Transgenic Mice

The evolution of Lyme arthritis in DR4-transgenic mice infected with Borrelia burgdorferi was studied because chronic Lyme arthritis in humans is associated with an increased frequency of the HLA-DR4 allele. B10 nontransgenic and DR4-transgenic mice expressing chimeric human-mouse major histocompatibility complex class II genes in which the human alpha 1 and beta 1 domains of DR4Dw4 replaced the corresponding domains of the mouse I-E(d) were inoculated with B. burgdorferi and examined at up to 180 days for infection and disease. All mice were infected throughout the 180 days, and arthritis evolved to equal severity in transgenic and control mice within 30 days and resolved by day 120. Both groups of mice developed high antibody titers to B. burgdorferi, but antibodies to outer surface proteins A and B were not readily detectable. The DR4Dw4 transgene did not predispose mice to the development of chronic Lyme arthritis.

Successful treatment of a patient with chronic Lyme arthritis with extracorporeal photochemotherapy

We report the use of photopheresis in a patient with chronic Lyme arthritis with apparent resolution of the signs and symptoms. Further controlled trials will be required to determine whether there is a therapeutic role for photopheresis in this disease.

A NEW DIAGNOSTIC TEST FOR LYME ARTHRITIS.

When chronic Lyme arthritis develops in patients who have received adequate antibacterial therapy, it raises the question of whether Borrelia

Chronic Septic Arthritis Caused

Chronic arthritis occurs in 10% of Lyme disease patients. A patient had chronic septic Lyme arthritis of the knee for seven years despite multiple antibiotic trials and multiple arthroscopic and open synovectomies. Spirochetes were documented in synovium and synovial fluid (SF). Polymerase chain reaction (PCR) analysis of the SF was consistent with Borrelia infection. Persistent infection should be excluded with silver stains and cultures in any patient with chronic monoarticular arthritis and a history of Lyme disease.

Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi

Chronic Lyme arthritis that is unresponsive to antibiotic therapy is associated with an increased frequency of the HLA-DR4 specificity. To determine whether the immune response to a particular polypeptide of Borrelia burgdorferi may be associated with treatment-resistant chronic Lyme arthritis, we correlated the clinical courses and HLA-DR specificities of 128 patients with Lyme disease with their antibody responses to spirochetal polypeptides. Antibody reactivity was determined by Western blotting (immunoblotting) with sonicated whole B. burgdorferi and recombinant forms of its outer surface proteins, OspA and OspB, as the antigen preparations. Of 15 patients monitored for 4 to 12 years, 11 (73%) developed strong immunoglobulin G responses to both OspA and OspB near the beginning of prolonged episodes of arthritis, from 5 months to 7 years after disease onset. When single serum samples from 80 patients with Lyme arthritis, were tested, 57 (71%) showed antibody reactivity to recombinant Osp proteins; in contrast, none of 43 patients who had erythema migrans or Lyme meningitis (P < 0.00001) and 1 of 5 patients who had chronic neuroborreliosis but who never had arthritis (P = 0.03) showed antibody reactivity to these proteins. Among the 60 antibiotic-treated patients with Lyme arthritis, those with the HLA-DR4 specificity and Osp reactivity had arthritis for a significantly longer time after treatment than those who lacked Osp reactivity (median duration, 9.5 versus 4 months; P = 0.009); a similar trend was found for the HLA-DR2 specificity. For other HLA-DR specificities, arthritis resolved within a median duration of 2 months in both Osp-reactive and nonreactive patients. We conclude that the combination of the HLA-DR4 specificity and OspA or OspB reactivity is associated with chronic arthritis and the lack of a response to antibiotic therapy.

Preferential usage of T cell antigen receptor V region gene segment V beta 5.1 by Borrelia burgdorferi antigen-reactive T cell clones isolated from a patient with Lyme disease.

Forty-three CD3+4+8- TCR alpha beta+ Borrelia burgdorferi-reactive T cell clones isolated from the peripheral blood of a single patient with clinically active chronic Lyme arthritis were characterized. The spirochetal Ag recognized by 16 of these T cell clones was determined by reactivity with a panel of recombinant spirochetal Ag, which included the OspA, OspB, flagellin, Hsp60 and Hsp70 proteins. All three T cell clones reactive with heat shock proteins recognized a non-cross-reactive epitope unique to the spirochetal Ag. Analysis of the TCR V regions revealed preferential usage of V beta 5.1; 5 of 15 T cell clones that recognized an unidentified spirochetal Ag utilized this V beta gene segment. Most of the T cell clones recognized a given spirochetal Ag exclusively within the context of one HLA class II allele. However, two T cell clones, which recognized an unidentified Ag in the spirochetal lysate within the context of different HLA class II alleles, were both TCR V beta 5.1+, although each displayed a distinct alpha-chain. Moreover, in vitro incubation of this patient's PBMC with B. burgdorferi Ag resulted in a specific increase in the percentage of T cells expressing TCR V beta 5.1. These results indicate that B. burgdorferi has a V beta-selective factor influencing the cellular immune response in a patient with clinically active Lyme disease.

Lyme Arthritis as the Incorrect Diagnosis in Pediatric and Adolescent Fibromyalgia

In areas endemic for Lyme disease there is increasing concern and anxiety about possible chronic and untreatable manifestations of the disease. The authors have diagnosed fibromyalgia in many patients with chronic musculoskeletal complaints in whom chronic Lyme arthritis had previously been diagnosed as the cause of their joint pains. Fibromyalgia is a common disorder, causing arthralgia (not true arthritis), fatigue, and debility. The repeated and/or long-term antibiotic therapy prescribed for "chronic Lyme disease" is not successful in curing the symptoms of fibromyalgia. Especially in areas where anxiety about Lyme disease is great, it is important to be careful in diagnosing chronic Lyme disease. Fibromyalgia is a potentially treatable and curable cause of chronic complaints and should be considered in the differential diagnosis of "refractory Lyme arthritis."

Chronic Lyme disease arthritis: Review of the literature and report of a case of wrist arthritis

A case of Lyme arthritis with advanced degenerative changes localized to the midcarpal joint was treated with a limited wrist arthrodesis with relief of pain and improved function. Chronic Lyme arthritis occurs as the third stage of Lyme disease. Serologic testing and a history of a characteristic rash may be helpful in the diagnosis. Radiographic and histopathologic findings are nonspecific, with both degenerative and inflammatory characteristics. Intravenous antibiotics provide an effective treatment of chronic Lyme arthritis.

Lyme Arthritis With Subarticular Cyst Formation in Metacarpal and Metatarsal Bones

A young woman was treated for seronegative rheumatoid arthritis for more than 9 years, without clinical improvement, before the diagnosis of chronic Lyme arthritis of the metacarpal and metatarsal phalangeal joints was made. Roentgenograms showed subarticular cyst formation in the metacarpal and metatarsal bones. The patient's response to treatment with a 2-week course of ceftriaxone was dramatic.

Borrelia burgdorferi activates a T helper type 1-like T cell subset in Lyme arthritis.

18 cloned T cell lines reactive with Borrelia burgdorferi proteins, all CD3+4+8-TCR-alpha/beta+ and restricted by HLA class II proteins, were isolated from four patients with chronic Lyme arthritis. Analysis of these T cell clones indicated that the T cell response to the Lyme disease spirochete is not oligoclonally restricted; yet all produced the same pattern of lymphokines, resembling that of murine type 1 T helper cells, after antigen-specific or nonspecific stimulation. Therefore, a subset of human CD4+ T cells, with a distinct profile of lymphokine secretion, is selectively activated by the pathogen inciting this chronic inflammatory disease.

Treatment of refractory chronic Lyme arthritis with arthroscopic synovectomy

Of 20 patients who underwent arthroscopic synovectomy for refractory chronic Lyme arthritis of the knee, 16 (80%) had resolution of joint inflammation during the first month after surgery or soon thereafter, and they have remained well during the 3-8-year followup period. Three of these 16 patients who were more disabled preoperatively, still had mild functional limitation at long-term followup. The remaining 4 patients (20%) had persistent or recurrent synovitis. We conclude that arthroscopic synovectomy is effective in treating chronic Lyme arthritis in patients in whom the disease does not respond to antibiotic therapy.

T cell and antibody reactivity with the Borrelia burgdorferi 60-kDa heat shock protein in Lyme arthritis.

The reactivity of cloned T cells and serum antibodies, obtained from patients with chronic Lyme arthritis, with expressed recombinant B. burgdorferi 60-kDa heat shock protein homologue (HSP60) was analyzed. The expressed recombinant Borrelia burgdorferi HSP60 was bound by antibodies in the sera of patients with Lyme arthritis, but not by control sera. A T cell clone (CR253), isolated from one of four patients examined, exhibited an HLA-DR2 restricted proliferative response to the expressed recombinant B. burgdorferi HSP60. This T cell clone specifically recognized the HSP60 of B. burgdorferi and did not proliferate in response to the human, mycobacterial, or Escherichia coli HSP60 homologues. The epitope recognized by this cloned T cell, located between amino acids 260 and 274, is in a region of the spirochetal HSP60 that is not conserved between bacteria and eukaryotes.

ASSOCIATION OF CHRONIC LYME ARTHRITIS WITH HLA-DR4 and HLA-DR2 ALLELES

ASSOCIATION OF CHRONIC LYME ARTHRITIS WITH HLA-DR4 and HLA-DR2 ALLELES

A case of chronic Lyme arthritis in England.

A case of chronic Lyme arthritis in England.

Roxithromycin + cotrimoxazole resolves chronic Lyme arthritis

Roxithromycin + cotrimoxazole resolves chronic Lyme arthritis

Chronic Lyme Arthritis and HLA Alleles

Chronic Lyme Arthritis and HLA Alleles

Association of Chronic Lyme Arthritis with HLA-DR4 and HLA-DR2 Alleles

A small percentage of patients infected with Borrelia burgdorferi have chronic Lyme arthritis that does not respond to antibiotic therapy. To learn whether genetically determined variations in the host immune response might account for such outcomes, we determined the immunogenetic profiles of 130 patients with various manifestations of Lyme disease. Of the 80 patients with arthritis, 57 percent of those with chronic arthritis (12 to 48 months in duration) had the HLA-DR4 specificity; only 23 percent of those with arthritis of moderate duration (6 to 11 months) and only 9 percent of those with arthritis of short duration (1 to 5 months) had this specificity (P = 0.003). After the HLA-DR4-positive patients were excluded from each group, a secondary association was noted with HLA-DR2, which was found in 75 percent of the remaining patients with chronic arthritis and in 50 percent of those with arthritis of moderate duration, but in only 20 percent of those with arthritis of short duration (P = 0.023). Altogether, 25 of the 28 patients with chronic arthritis (89 percent) had HLA-DR2 or HLA-DR4, or both, as compared with 27 percent of those with arthritis of short duration (relative risk, 22; P = 0.00006). These HLA specificities appeared to act as independent, dominant markers of susceptibility. Nucleotide-sequence typing, performed in five patients with chronic arthritis, identified the HLA-DR2 allele as Dw2 (DR beta 1*1501), and the HLA-DR4 alleles as Dw4, Dw14, and Dw13 (DR beta 1*0401, DR beta 1*0404, and DR beta 1*0403, respectively). The presence of HLA-DR4 in patients with arthritis was associated with a lack of response to antibiotic therapy (P = 0.01). Particular Class II major histocompatibility genes determine a host immune response to B. burgdorferi that results in chronic arthritis and lack of response to antibiotic therapy.

Immunogenic integral membrane proteins of Borrelia burgdorferi are lipoproteins

The pathogenic spirochete Borrelia burgdorferi contains a set of integral membrane proteins which were selectively extracted into the detergent phase upon solubilization of intact B. burgdorferi with the nonionic detergent Triton X-114. Virtually all of these hydrophobic proteins were recognized by antibodies in pooled sera from patients with chronic Lyme arthritis, demonstrating that proteins partitioning into the detergent phase of Triton X-114 encompass the major B. burgdorferi immunogens. Furthermore, most of these immunogenic proteins, including the previously characterized OspA and OspB membrane antigens, could be biosynthetically labeled when B. burgdorferi was incubated in vitro with [3H]palmitate. The OspA and OspB antigens were radioimmunoprecipitated from [3H]palmitate-labeled detergent-phase proteins with monoclonal antibodies, and [3H]palmitate was recovered unaltered from these proteins after sequential alkaline and acid hydrolyses. The combined results provide formal confirmation that the major B. burgdorferi immunogens extracted by Triton X-114 are lipoproteins. The demonstration that B. burgdorferi integral membrane antigens are lipoproteins may explain the basis of their immunogenicity and may help to improve our understanding of the surface topology of B. burgdorferi.

Analysis of T lymphocytes cloned from the synovial fluid and blood of a patient with lyme arthritis

Cloned T lymphocytes reactive with Borrelia burgdorferi proteins were isolated from a patient with chronic Lyme arthritis. All of the T cell clones which proliferated in response to Borrelia proteins were CD3 + CD4 + CD8 - TCR alpha beta + and HLA-DR restricted. One T cell clone (GN30) exhibited HLA-DR-restricted cytotoxic activity against antigen-presenting cells pulsed with Borrelia antigen. In response to Borrelia antigen, the T cell clones produced TNF-alpha, INF-gamma, and GM-CSF. There are at least three distinct spirochetal proteins recognized by the four T cell clones analyzed. Purified Borrelia proteins triggered the HLA-DR-restricted proliferative and cytotoxic responses, as well as lymphokine secretion by two of the T cell clones. The spirochetal protein which triggered the HLA-DR-restricted proliferative and cytotoxic activities of the T cell clone (GN30) isolated from synovial fluid is the 41 kd flagellar protein.