Long term treatment of chronic Lyme arthritis with benzathine penicillin.

The cases are reported of two patients with chronic Lyme arthritis resistant to the recommended antibiotic regimens who were cured by long term treatment with benzathine penicillin. It is suggested that the sustained therapeutic levels of penicillin were effective either by the inhibition of germ replication or by lysis of the spirochaetes when they were leaving their sanctuaries.     

Borrelia burgdorferi in joint fluid in chronic Lyme arthritis

Although indirect evidence suggests that chronic Lyme arthritis is caused by persistent infection with Borrelia burgdorferi, direct visualization has been lacking. We report the demonstration of B. burgdorferi from synovial fluid aspirated from the right knee of a 31-year-old man with Lyme arthritis for more than 1 year. After 6 days, culture medium inoculated with synovial fluid showed one motile and several nonmotile spirochetes. Direct immunofluorescence staining showed reactivity with anti-B. burgdorferi serum. Spirochetes were not seen in subcultured material. The patient's arthritis improved with high-dose intravenous penicillin. Identification of B. burgdorferi from the joint fluid of a patient with long-standing arthritis supports the concept that the arthritis is due to persistent infection.     

Host metalloproteinases in Lyme arthritis.

OBJECTIVE: To assess the role of matrix metalloproteinases (MMPs) in cartilage and bone erosions in Lyme arthritis METHODS: We examined synovial fluid from 10 patients with Lyme arthritis for the presence of MMP-2, MMP-3, MMP-9, and "aggrecanase" activity using gelatinolytic zymography and immunoblot analysis. We developed an in vitro model of Lyme arthritis using cartilage explants and observed changes in cartilage degradation in the presence of Borrelia burgdorferi and/or various protease inhibitors. RESULTS: Synovial fluid from patients with Lyme arthritis was found to contain at least 3 MMPs: gelatinase A (MMP-2), stromelysin (MMP-3), and gelatinase B (MMP-9). In addition, there was evidence in 2 patients of "aggrecanase" activity not accounted for by the above enzymes. Infection of cartilage explants with B. burgdorferi resulted in induction of MMP-3, MMP-9, and "aggrecanase" activity. Increased induction of these enzymes by B. burgdorferi alone was not sufficient to cause cartilage destruction in the explants as measured by glycosaminoglycan (GAG) and hydroxyproline release. However, addition of plasminogen, which can act as an MMP activator, to cultures resulted in significant GAG and hydroxyproline release in the presence of B. burgdorferi. The MMP inhibitor batimastat significantly reduced the GAG release and completely inhibited the collagen degradation. CONCLUSION: MMPs are found in synovial fluids from patients with Lyme arthritis and are induced from cartilage tissue by the presence of B. burgdorferi. Inhibition of MMP activity prevents B. burgdorferi-induced cartilage degradation in vitro.     

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.     

Lyme arthritis

Lyme borreliosis continues to be a significant public health problem. Because of good public education, the incidence of Lyme arthritis and other late-stage symptoms has not increased in tandem with the increases in early infection. There have been major advances in the understanding of the pathogenesis of Lyme arthritis. The understanding of mechanisms of arthritis in Lyme borreliosis may also shed light on the mechanisms of disease in other infectious and noninfectious arthritides.     

Seronegative Lyme arthritis

We present a 10-year-old girl who had been diagnosed with juvenile idiopathic arthritis 5 years before and who experienced a flare of arthritis affecting one knee while she was off medication for almost 3 years. Seronegative Lyme arthritis had to be diagnosed based on the detection of Borrelia burgdorferi DNA in synovial fluid. No humoral immune response to Borrelia burgdorferi was detectable before, at the time of diagnosis and up to 3 years later.     

Treatment of Lyme arthritis

Summary The efficacy of different therapeutic regimens for Lyme arthritis is reviewed. The first treatment for Lyme arthritis, intramuscular benzathine penicillin 2.4 million units weekly for 3 weeks, had a success rate of 35%. Another study employed intravenous penicillin G at a dosage of 20 million units daily for 10 days, which cured 55% of patients. Intravenous ceftriaxone has been shown to be superior to penicillin with a response rate of 94%. However, these results have been challenged in recent reports. Oral doxycycline or amoxicillin in association with probenecid seems to work equally well although neuroborreliosis was more frequent following treatment with amoxicillin. An anecdotal report indicates the usefulness of long-term benzathine penicillin for chronic Lyme arthritis. Long-term antibiotic therapy, which is recommended also for Reiter's syndrome, may be useful for eradicating the sanctuaries ofBorrelia burgdorferi. Disease-modifying drugs such as hydroxychloroquine or sulphasalazine, a drug which is commonly used in reactive arthritis following enteric infections, may be of value in Lyme arthritis resistant to antibiotics but have not been tested to date. The role of intraarticular injections of steroids or synovectomy is still controversial. Antibiotic treatment is the cornerstone of Lyme arthritis treatment. Additional interventions should be studied for patients with Lyme arthritis resistant to antibiotics.

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Behandlung der Lyme-Arthritis

Zusammenfassung Die Wirksamkeit verschiedener Therapieregime für die Behandlung der Lyme-Arthritis wird in einer Übersicht dargestellt. Als erster Behandlungsmodus für die Lyme-Arthritis wurde intramuskulär appliziertes Benzathinpenicillin in einer Dosierung von 2,4 Mio IE wöchentlich für drei Wochen eingesetzt. Die Erfolgrate lag bei 35%. Mit Penicillin G in einer Dosierung von 20 Mio IE i.v. täglich für 10 Tage wurden 55% der Patienten geheilt. Ceftriaxon i.v. verbesserte die Ansprechrate im Vergleich zu Penicillin auf 94%. Neuere Berichte stellen allerdings diese Ergebnisse in Frage. Vergleichbar gute Ergebnisse wurden mit oralem Doxycyclin und Amoxicillin in Kombination mit Probenecid beschrieben, doch trat nach Behandlung mit Amoxicillin häufiger eine Neuroborreliose auf. Einzelfallberichte weisen auf die Wirkung einer Langzeitbehandlung mit Benzathinpenicillin bei chronischer Lyme-Arthritis hin. Möglicherweise läßt sich durch Langzeitbehandlung mit Antibiotika wie beim Reiter-Syndrom auch eine Ausrottung vonBorrelia burgdorferi aus seinen Schlupfwinkeln erreichen. Medikamente, die den Krankheitsverlauf beeinflussen wie Hydroxychloroquin oder Sulphazalasin, das häufig zur Behandlung von reaktiven Arthritiden nach Darminfektionen eingesetzt wird, sind möglicherweise bei antibiotikaresistenter Lyme-Arthritis von Wert, doch liegen bisher keine Studien vor. Die intraartikuläre Injektion von Kortikosteroiden wird nach wie vor kontrovers diskutiert. Die Antibiotikatherapie ist der Eckstein der Behandlung der Lyme-Arthritis. Weitergehende Maßnahmen sollten bei Patienten mit antibiotikaresistenter Lyme-Arthritis geprüft werden.

     

Lyme arthritis in Belgium. Report of three cases

Summary Three cases of lyme arthritis are reported. The clinical manifestations of lyme disease and the literature are discussed.     

Chronic Lyme arthritis. Clinical and immunogenetic differentiation from rheumatoid arthritis.

Ten patients with Lyme arthritis have developed chronic involvement of one or both knees. Lyme arthritis was diagnosed by onset with erythema chronicum migrans (six patients); residence in Lyme, Connecticut (eight); seasonal onset in summer and early fall (nine); early periods of short recurrent attacks (nine); absence of rheumatoid factor (nine); and absence of symmetrical polyarthritis, morning stiffness, subcutaneous nodules, or antinuclear antibodies (in all). Five patients had synovectomies; pannus formation and underlying cartilage erosion were present in all. Seven of the 10 patients had the same B-cell alloantigen, DRw2 (frequency in normal control subjects, 22% [P less than 0.005]), but did not have an increased frequency of the alloantigens associated with rheumatoid arthritis. Chronic Lyme arthritis, the result of an apparent tick-transmitted infection, resembles rheumatoid arthritis pathologically but generally differs from it in both prearticular and immunogenetic characteristics.     

Host metalloproteinases in Lyme arthritis

Objective

: To assess the role of matrix metalloproteinases (MMPs) in cartilage and bone erosions in Lyme arthritis

Methods

We examined synovial fluid from 10 patients with Lyme arthritis for the presence of MMP‐2, MMP‐3, MMP‐9, and “aggrecanase” activity using gelatinolytic zymography and immunoblot analysis. We developed an in vitro model of Lyme arthritis using cartilage explants and observed changes in cartilage degradation in the presence of Borrelia burgdorferi and/or various protease inhibitors.

Results

Synovial fluid from patients with Lyme arthritis was found to contain at least 3 MMPs: gelatinase A (MMP‐2), stromelysin (MMP‐3), and gelatinase B (MMP‐9). In addition, there was evidence in 2 patients of “aggrecanase” activity not accounted for by the above enzymes. Infection of cartilage explants with B burgdorferi resulted in induction of MMP‐3, MMP‐9, and “aggrecanase” activity. Increased induction of these enzymes by B burgdorferi alone was not sufficient to cause cartilage destruction in the explants as measured by glycosaminoglycan (GAG) and hydroxyproline release. However, addition of plasminogen, which can act as an MMP activator, to cultures resulted in significant GAG and hydroxyproline release in the presence of B burgdorferi. The MMP inhibitor batimastat significantly reduced the GAG release and completely inhibited the collagen degradation.

Conclusion

MMPs are found in synovial fluids from patients with Lyme arthritis and are induced from cartilage tissue by the presence of B burgdorferi. Inhibition of MMP activity prevents B burgdorferi–induced cartilage degradation in vitro.

     

Development of autoimmunity in Lyme arthritis

Treatment-resistant Lyme arthritis (TRLA) develops in 10% of Lyme arthritis patients and is characterized by continuous joint inflammation that does not resolve with antibiotic therapy. TRLA is associated with HLA-DRB1*0401 and related alleles, as well as with an immune response to the Borrelia burgdorferi (Bb) outer surface protein A (OspA). The immunodominant epitope of OspA in the context of HLA-DRB1*0401 corresponds to amino acids 165-173 (OspA165-173). The human Lymphocyte Function Antigen-1 (hLFA1alpha) contains a peptide with homology to OspA165-173. Treatment-resistant Lyme arthritis patients' T cells, cloned based on their ability to bind OspA165-173-loaded HLA-DRB1*0401 tetramers, respond to OspA and hLFA1alpha with a different cytokine profile, suggesting that hLFA1alpha acts as a partial agonist with a potential role in the perpetuation of joint inflammation.     

A case of pacemaker-dependent Lyme carditis

It is reported on a case of lyme-borreliosis with cardiac participation. Here the case in question were disturbances of the transmission of impulses in form of a third-degree atrioventricular block, which temporarily underwent a cardiac pacemaker treatment. By means of the antibiotic treatment recommended in the literature a restitutio ad integrum was achieved.     

Post-yersinial arthritis in Cleveland, England.

Four cases of post-yersinial reactive arthritis are described. All patients presented with an acute lower limb arthropathy with features of an associated enthesopathy. Two patients had restriction of axial skeletal movements. Systemic features were prominent in three, including weight loss and malaise. Mean age of onset was 34 years. Three patients gave a history of antecedent diarrhoea within the previous month. Three patients had raised titres to Y enterocolitica type 0:3 (ranging from 1 in 320 to 1 in 2560) and one had raised titres to Y pseudotuberculosis type 2 at 1 in 640. Two of the three patients with Y enterocolitica reactive arthritis ran a chronic course with low grade arthropathy of lower limbs and back stiffness. One patient developed radiological sacroiliitis at two years, and two patients had an increased sacroiliac index, though x rays of the sacroiliac joints were normal. The patient with Y pseudotuberculosis reactive arthritis had a self limiting disease with spontaneous resolution over six months.     

Expression of public idiotypes in patients with Lyme arthritis.

OBJECTIVE: Joints are often affected in Lyme disease and in some instances this may be due to immune autoreactivity. To characterise further the immune response in this disease investigations were carried out to determine the expression of three public idiotypes on serum immunoglobulins in patients with Lyme disease during the development of varying degrees of arthritis. METHODS: The expression of idiotypes (Ids) 16/6, BEG2, and PR4, first identified on monoclonal antibodies to DNA, was determined by an enzyme linked immunosorbent assay (ELISA) in serial blood samples from 12 patients with Lyme disease over a mean period of six years during the development of a variety of arthritic symptoms, and in serum samples from healthy control subjects and control subjects with systemic lupus erythematosus. RESULTS: Expression of serum IgM or IgG public Ids 16/6 and BEG2 was significantly increased in patients with Lyme disease. IgA Id 16/6 expression, in contrast, was significantly increased only during episodes of arthritis and was also related to its severity. IgM and IgG Id 16/6 expression was related to their respective total immunoglobulin concentration and, in the case of IgM, to the level of IgM antibodies to Borrelia burgdorferi, whereas similar findings were not apparent with IgA antibodies. This may indicate that the IgA response is related to the pathogenesis of arthritis, especially as total IgA and IgA Id 16/6 levels were found to increase over the duration of disease. Sequential analysis of antibodies also showed restriction in the expression of Id 16/6 as it was never found on all immunoglobulin isotypes at the same time, and Id PR4 was never expressed. Ids 16/6 and BEG2 expression, however, may be associated as seven patients expressed these idiotypes simultaneously. CONCLUSIONS: These data indicate the use of public idiotypes in the immune response against B burgdorferi, which may be restricted in terms of idiotype class and isotype expression, and a possible association between IgA antibodies bearing Id 16/6 with arthritis.     

A case of active chronic hepatitis with painless erosive arthritis

True arthritis is very much less common than arthralgia in patients suffering from active chronic hepatitis and only scanty information is available about the joint changes in this disease. We report here the case of a young woman with active chronic hepatitis complicated by a painless, erosive small joint arthropathy.     

Prominent expression of mRNA for proinflammatory cytokines in synovium in patients with juvenile rheumatoid arthritis or chronic Lyme arthritis

OBJECTIVE: To examine the cytokine profiles in synovium of patients with juvenile rheumatoid arthritis (JRA) or Lyme arthritis, 2 chronic inflammatory arthritides that affect children. METHODS: We used in situ hybridization with specific riboprobes to determine the expression of mRNA for proinflammatory or antiinflammatory cytokines in synovial samples from 5 patients with early, untreated JRA, 15 patients with late, treated JRA, and 9 patients with chronic Lyme arthritis. For comparison, synovia were examined from 6 patients with rheumatoid or psoriatic arthritis, and from 9 patients with various orthopedic conditions. RESULTS: Among the children with early, untreated JRA, a median of 3 to 8% of inflammatory cells in synovial samples expressed mRNA for the proinflammatory cytokines interleukin 1beta (IL-1beta), tumor necrosis factor-alpha(TNF-alpha), or interferon-gamma (IFN-gamma). Although a median of 3.9% of the cells expressed mRNA for the antiinflammatory cytokine IL-10, none had IL-4 mRNA. Most of the patients with late, treated JRA, chronic Lyme arthritis, rheumatoid, or psoriatic arthritis had mRNA for each of these proinflammatory cytokines in about 1% of the cells, whereas mRNA for the antiinflammatory cytokines was less frequent. The inflammatory cell density was much less in the synovium of patients with various orthopedic conditions, but about 1% of the infiltrating cells expressed mRNA for at least one of the proinflammatory cytokines. CONCLUSION: Patients with early or late JRA or chronic Lyme arthritis have expression of mRNA in synovial tissue primarily for proinflammatory cytokines, with less expression of antiinflammatory cytokines.