Apoptosis of Fashigh CD4+ synovial T cells by borrelia-reactive Fas-ligand(high) gamma delta T cells in Lyme arthritis.

The function of the minor subset of T lymphocytes bearing the gamma delta T cell antigen receptor is uncertain. Although some gamma delta T cells react to microbial products, responsiveness has only rarely been demonstrated toward a bacterial antigen from a naturally occurring human infection. Synovial fluid lymphocytes from patients with Lyme arthritis contain a large proportion of gamma delta cells that proliferate in response to the causative spirochete, Borrelia burgdorferi. Furthermore, synovial gamma delta T cell clones express elevated and sustained levels of the ligand for Fas (APO-1, CD95) compared to alpha beta T cells, and induce apoptosis of Fashigh CD4+ synovial lymphocytes. The findings suggest that gamma delta T cells contribute to defense in human infections, as well as manifest an immunoregulatory function at inflammatory sites by a Fas-dependent process.

Molecular mimicry in Lyme disease: monoclonal antibody H9724 to B. burgdorferi flagellin specifically detects chaperonin-HSP60.

A monoclonal antibody (H9724), specific for the 41-kDa flagellar protein of the Lyme disease pathogen Borrelia burgdorferi, cross-reacts with human axons and detects one major protein in human neuroblastoma cell extracts. The homologous cross-reacting protein has now been isolated from calf adrenal and identified as chaperonin-HSP60 by N-terminal sequencing.

The Lyme disease controversy. Social and financial costs of misdiagnosis and mismanagement.

Since it was first described, Lyme disease has emerged as a major public health concern, complicated by an emerging body of beliefs often at odds with scientifically established facts. Disagreement between the belief systems has led to confusion and anxiety, resulting in an alternative, but unproved, approach to management. When Lyme disease is incorrectly diagnosed, the debility related to the true, underlying problems remains unaddressed. The financial cost of the overdiagnosis and overtreatment of Lyme disease includes expenses related to testing and therapy and those of side effects and toxic effects of these treatments. Harder to estimate are the emotional costs to society of incorrectly burdening patients with the diagnosis of a chronic, incurable illness, with attendant assumption of a sick role and a disabled self-image. Better education is a major component of the solution to the problems of misdiagnosis and mistreatment of Lyme disease.

Renal cell carcinoma presenting as polymyalgia rheumatica. Resolution after nephrectomy.

Renal cell carcinoma can present as a variety of paraneoplastic, nonmetastatic conditions, including vasculitis. We describe a patient who presented with the polymyalgia rheumatica syndrome but did not respond to a trial of prednisone. An asymptomatic, nonmetastatic renal cell carcinoma was found during this patient's evaluation. Nephrectomy led to resolution of the systemic complaints. Malignancy, in this case, renal cell carcinoma, can present as polymyalgia rheumatica and resolve after surgical removal of the underlying tumor.

The neurologic presentation of vasculitic and rheumatologic syndromes. A review.

Most rheumatologic and vasculitic syndromes can affect the central nervous system (CNS). In the vast majority of cases, however, the systemic disease is present at the time of first CNS manifestations. Certain of these diseases, including SLE, PSS, Behçet syndrome, cryoglobulinemia and lymphomatoid granulomatoses can present with CNS findings in the absence of any peripheral evidence of the underlying process. The CNS presentations of these and the other rheumatologic and vasculitic syndromes which may affect the CNS are discussed. Isolated CNS vasculitis may be due to granulomatous angiitis of the nervous system (GANS) or delayed contralateral hemiplegia following HZO. These are distinct clinical entities which can be differentiated by clinical and angiographic findings. The former is often severe and diffuse in nature, whereas the latter is usually milder and more focal. There are few if any peripheral findings in either syndrome. The cause of GANS is unknown, but the hemiplegia following HZO is clearly due to a virus-induced vasculitis spread from the overlying Gasserian nucleus; the history of preceding herpes zoster ophthalmicus strongly suggests the diagnosis. The collected evidence suggests that an aggressive evaluation, including meningeal biopsy, and early therapy with steroids (and perhaps cytotoxic agents) can alter the prognosis in GANS. It is not clear that hemiplegia following HZO requires treatment. GANS and HZO-associated CNS damage should be considered in the differential diagnosis of isolated CNS dysfunction in the absence of history, signs, or laboratory abnormalities suggestive of systemic disease.

Lyme disease patients' serum contains IgM antibodies to Borrelia burgdorferi that cross-react with neuronal antigens.

Serum from patients with neurologic manifestations of Lyme disease had serum IgM antibodies that bound to normal human axons, whereas binding was absent or weak in patients without neurologic findings. Antiaxonal binding could be eliminated by absorption with Borrelia burgdorferi. A murine monoclonal antibody to the borrelial flagellin also bound to human axons.

Antigen-specific proliferation of CSF lymphocytes in Lyme disease.

The neurologic manifestations of Lyme disease include meningitis, radiculoneuritis, and cranial neuritis. In two patients, we investigated the proliferative response of CSF and peripheral blood lymphocytes to protein antigens derived from the Lyme disease spirochete. The response of CSF lymphocytes was 5 to 10 times greater than that of peripheral blood lymphocytes. In contrast, in the one patient studied, lectin-induced proliferation was less in CSF than in peripheral blood. These findings show that the CSF of patients with Lyme meningitis is an enriched source of antigen-specific proliferative lymphocytes.

Multi-well ELISA based on independent peptide antigens for antibody capture. Application to Lyme disease serodiagnosis.

Novel procedures for the use of peptides as antibody-capture reagents in the ELISA format have been investigated. Epitope sequences from known immunodominant antigens of Borrelia burgdorferi were selected by screening peptide libraries with sera from patients with Lyme disease. Several epitope peptides were synthesized and immobilized, separately, on the ELISA plate as haptens on bovine serum albumin. Based on a comparative analysis of serum samples, it appears that peptide antigens can be used as effectively as a whole cell lysate to discriminate between Lyme disease and non-Lyme disease sera, thus avoiding dependence on bacterial sonicates which vary from passage to passage. Further improvements in epitope design for enhancement of accuracy in serodiagnosis are discussed.

Persisting complaints attributed to chronic Lyme disease: possible mechanisms and implications for management.

A better understanding of the natural history of Lyme disease and of possible causes for persisting symptoms other than active infection is needed to optimize management of patients with persistent symptoms. Review of patients seen at a Lyme disease referral center and of the immunologic and clinical literature on Lyme disease suggests most symptoms that persist after therapy can be explained by one or more of seven proposed pathogenetic mechanisms, only one of which includes active ongoing infection. Individualization of care and reanalysis of patients problems are crucial if misdiagnosis and overtreatment of Lyme disease are to be avoided.

Early disseminated Lyme disease: cardiac manifestations.

The cardiac features of Lyme disease usually occur within weeks to months of the infecting tick bite; the result may be disruption of the conduction system, leading to heart block and muscle dysfunction, causing a mild myopericarditis. Lyme carditis is usually mild, although permanent heart block and a few fatalities claimed to be due to Lyme carditis have been reported, the latter usually with poor documentation. In general, Lyme carditis is treatable and curable with antibiotic regimens in current use. Recent reports have suggested that Lyme disease may be a cause of chronic congestive cardiomyopathy. Lyme carditis should be considered in the proper clinical setting with appropriate use of diagnostic tests, recalling that patients with carditis early in Lyme disease may be seronegative and that all patients who are seropositive do not necessarily have Lyme disease.

Anxiety and persistence of Lyme disease.

Lyme disease has become a major concern in endemic areas, in large measure because of fears that it does not respond to current antibiotic regimens. This anxiety has led to the use of untested drugs and longer courses of therapy than have been demonstrated to be necessary, with attendant increase in cost and toxicity. Concern about the lack of response to such therapy has convinced many patients that they have a permanent disease, with profound effects on their lives and those of their families. A better understanding of the natural history of Lyme disease and of possible causes for persisting symptoms other than active infection is needed to optimize management of such patients. Most symptoms persisting after adequate therapy can be explained by a small number of pathogenic mechanisms, only one of which is ongoing infection. Individualization of care and prudent analysis are crucial if overdiagnosis and overtreatment of Lyme disease are to be avoided.

Summary of the first 100 patients seen at a Lyme disease referral center.

PURPOSE AND PATIENTS AND METHODS: Lyme disease is a major clinical problem in a number of endemic areas in the United States. In areas where anxiety about the disease is high, patients and physicians often ascribe clinical concerns to Lyme disease. Incorrect diagnosis often leads to unnecessary antibiotic treatment (often prolonged or repeated intravenous therapy). This report summarizes the cases of the first 100 patients referred to the Lyme Disease Center at Robert Wood Johnson Medical School. RESULTS: In only 37 of the patients referred was Lyme disease, either current or preceding, the explanation for the complaints. Many of the patients had another definable arthropathy. Twenty-five of the patients had fibromyalgia, which has not previously been reported in Lyme disease. Three of these patients had active Lyme disease at the time of evaluation, and 17 had a history suggesting preceding Lyme disease. Approximately half of the 91 courses of antibiotic therapy given to these 100 patients before referral were probably unwarranted. CONCLUSIONS: Anxiety about possible late manifestations of Lyme disease has made Lyme disease a "diagnosis of exclusion" in many endemic areas. Persistence of mild to moderate symptoms after adequate therapy and misdiagnosis of fibromyalgia and fatigue may incorrectly suggest persistence of infection, leading to further antibiotic therapy. Attention to patient anxiety and increased awareness of these musculoskeletal problems after therapy should decrease unnecessary therapy of previously treated Lyme disease.

Cellular immune findings in Lyme disease. Correlation with serum IgM and disease activity.

Cellular immune findings were studied in 48 patients with various stages of Lyme disease. At each stage, some patients, particularly those with neuritis or carditis, had elevated serum IgM levels and lymphopenia. During early disease, mononuclear cells tended to respond normally to phytohemagglutinin, and spontaneous suppressor cell activity was greater than normal. Later, during active neuritis, carditis, or arthritis, the trend was toward heightened phytohemagglutinin responsiveness and less suppression than normal. By multiple regression analysis, serum IgM levels correlated directly with disease activity (p = 0.025) and inversely with the number of T cells (p = 0.02); during acute disease only, elevated IgM levels correlated with increased phytohemagglutinin responsiveness (p = 0.004) and decreased suppressor cell activity (p = 0.03). Decreased suppression, observed later in the disease, may permit damage to host tissues because of either autoimmune phenomena or a heightened response to the Lyme spirochete.

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."

Current recommendations for the treatment of Lyme disease.

Lyme disease is a multisystem inflammatory disease caused by infection with Borrelia burgdorferi. Soon after the tick bite which transmits the infection, the pathognomonic skin rash erythema chronicum migrans occurs in 50 to 70% of patients, often with associated symptoms resembling a 'summer cold' or viral infection. Therapy for this stage of disease consists of 3 to 4 weeks of oral therapy. The agents currently used are: amoxicillin (500 mg 3 or 4 times daily) with or without probenecid 500 mg 3 times daily, doxycycline (100 mg twice daily), or tetracycline (500 mg 4 times daily). Longer duration therapy has never been evaluated and therefore is not currently indicated. Even patients with severe early manifestations of Lyme disease should be treated orally. Later features of Lyme disease include carditis and neurological disease, which can occur days to approximately 9 months after the onset of illness, and arthritis and neurological disease which can occur weeks to years after the onset of the illness. Treatment at this stage is with 2 to 3 weeks of intravenous antibiotics, currently cefotaxime (3 g every 12 hours), ceftriaxone (1 g every 12 hours or 2 g every day) and benzylpenicillin (14 g in divided doses). There is no evidence that longer duration therapy is indicated or more efficacious. The exception to this suggestion is the patient with isolated facial seventh cranial nerve palsy; if such a patient has no other signs or symptoms to suggest Lyme disease and has normal spinal fluid, oral therapy is usually sufficient, although some physicians will give concomitant corticosteroids to hasten the resolution of the palsy. Of major consequence to the practitioner and patient is the possibility that persistent symptoms (e.g. fibromyalgia) may be caused by a process which is no longer antibiotic-sensitive. Special care in the management of so-called 'chronic Lyme disease' is crucial lest the clinician prescribes prolonged or unending courses of antibiotics for such noninfectious problems.

Dapsone in rheumatoid arthritis.

Dapsone, a synthetic sulfone with chemical similarities to sulfapyridine, has been used for a number of years to treat leprosy and dermatitis herpetiformis. Recently, a number of prospective, randomized, double-blind trials have shown their success in the management of rheumatoid arthritis, with dapsone being superior to placebo and comparable to chloroquine and hydroxychloroquine. Its mode of anti-inflammatory actions in rheumatoid arthritis is not clearly understood, but modulation of neutrophil activity or inhibition of neutrophil inflammatory product formation or release appear to play a role. The major limiting side effect is hemolytic anemia, which may be mitigated through careful patient selection, conservative drug dosing, close monitoring, and possibly, concurrent administration of antioxidants or cytochrome P450 inhibitors. Methemoglobinemia is another common finding among patients receiving dapsone therapy, but rarely does it result in prominent symptoms other than transient pallor. Less common adverse events to dapsone include the idiosyncratic reactions of leukopenia and agranulocytosis, cutaneous eruptions, peripheral neuropathy, psychosis, toxic hepatitis, cholestatic jaundice, nephrotic syndrome, renal papillary necrosis, severe hypoalbuminemia without proteinuria, an infectious mononucleosis-like syndrome, and minor neurological and gastrointestinal complaints. In this report, two patients with advanced rheumatoid arthritis, who were safely and effectively treated with dapsone after failure with other second-line agents, are described and the literature is reviewed. We suggest that dapsone is an effective second-line agent in the treatment of rheumatoid arthritis.

Coexistent minocycline-induced systemic lupus erythematosus and autoimmune hepatitis.

OBJECTIVES: This study was performed to raise awareness among rheumatologists about two autoimmune disorders associated with long-term minocycline therapy that can coexist in the same patient. We provide an update on the occurrence of these disorders, their main characteristics, and the current knowledge of potential pathogenic mechanisms. METHODS: We searched the medical literature in English indexed in MEDLINE from 1966 through April 1998 for the term minocycline combined with each of the following: autoimmune hepatitis (AIH), chronic hepatitis, lupus, systemic lupus erythematosus (SLE), anti-myeloperoxidase (anti-MPO), arthritis, vasculitis, and toxicity. We also reviewed relevant references cited in the articles our search uncovered. RESULTS: We identified over 60 minocycline-induced cases of SLE and 24 cases of minocycline-induced AIH. Both autoimmune disorders coexisted in the same patient in 12 cases reported in the literature and in one case seen at our clinic. These 13 patients were characterized by symmetrical polyarthralgias/polyarthritis, elevated liver enzymes, and positive antinuclear antibodies (ANA); they also were generally anti-histone-negative, and only two patients had perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). After withdrawal of minocycline, their symptoms resolved, and abnormal laboratory results normalized or markedly improved. CONCLUSIONS: Although data on the actual prevalence of autoimmune disorders induced by minocycline are not available, numerous case reports or small series deal with such disorders. Probable pathogenic mechanisms for each of these conditions are discussed.

Polyamine-fas interactions: inhibition of polyamine biosynthesis in MRL-lpr/lpr mice is associated with the up-regulation of fas mRNA in thymocytes.

MRL-lpr/lpr is a strain of mice that develops spontaneous signs of the autoimmune disease, systemic lupus erythematosus (SLE or lupus). The lpr (lymphoproliferation) defect has been identified as an insertion of an early transposon (ETn) derived sequence into the fas apoptosis gene. We studied the in vivo effects of difluoromethylornithine (DFMO), an irreversible inhibitor of the polyamine biosynthetic enzyme, ornithine decarboxylase (ODC), on the expression of fas in MRL-lpr/lpr mice as well as in congenic MRL- + / + and autoimmune NZB/W strains. Using Northern blot hybridization and reverse transcription polymerase chain reaction (RT-PCR), we found that DFMO treatment resulted in an increase in the expression of fas mRNA in the thymus of MRL-lpr/lpr mice. Using RT-PCR, we further found that the increased expression of fas was associated with the suppression of chimeric ETn/fas mRNA. With fractionated CD4 + and CD8 + T cells, we found a cell-specific effect of DFMO on chimeric ETn/fas expression in CD8 + cells. ETn/fas expression was detected in CD8+ T cells from untreated mice, but it was eliminated after DFMO treatment. HPLC analysis of polyamines showed depletion of putrescine and partial reduction of spermidine (35%) in DFMO-treated mice compared to controls. These results indicate that DFMO-mediated polyamine depletion is linked to the regulation of fas and chimeric ETn/fas in MRL-lpr/lpr mice. Elevated levels of polyamines in this strain, as found in earlier studies, may be associated with the progression of the autoimmune disease by altering the expression of fas gene or by facilitating the expression of chimeric ETn/fas. Our data also provide new mechanistic insights into the beneficial effects of DFMO on these mice.

Management of Lyme disease refractory to antibiotic therapy.

Lyme disease has become a major public health problem. One result of this anxiety is over-diagnosis and over-treatment in many endemic and near-to-endemic areas. The diagnosis of Lyme disease is often made solely on the basis of often misinterpreted serologic tests. Therefore, a major reason for inadequate response to antibiotic therapy is initial misdiagnosis. Persisting inflammation and tissue damage following treated Lyme disease does occur but is probably an uncommon cause of refractory symptoms and long-term debility post-Lyme disease.

Lyme disease: testing and treatment. Who should be tested and treated for Lyme disease and how?

LD can mimic a number of other disease, and vice versa. It is imperative that clinicians understand LD and be able to use serologic diagnostic techniques appropriately. LD is not a diagnosis that can be made on the basis of serologic testing. By this is meant that vague symptoms plus a positive serologic test do not assure that the patient has LD. On the other hand, a patient with ECM or other manifestations of LD may still be seronegative. In addition, therapy for LD must be tailored to the clinical problems of the individual patient. Especially in patients with chronic or persisting complaints, it is important to be precise in making the correct diagnosis and in understanding the underlying pathogenetic mechanisms at work so that an appropriate and ultimately successful therapeutic plan can be made.