ANTIBIOTIC THERAPY A clinical study on the efficacy of antibiotic therapy for treating chronic Lyme disease was completed in late 2000. It was funded through a contract awarded to the New England Medical Center (NEMC) in Boston and involved randomized, double-blind, placebo-controlled multicenter studies to examine the safety and efficacy of ceftriaxone and doxycycline for treating patients with either seropositive or seronegative chronic Lyme disease. The clinical protocols for these studies, which have been posted on the NIAID Web site, were developed with extensive review and input from Lyme disease research experts as well as an NIAID Lyme Disease Advisory Panel. The panel is composed of patients with Lyme disease, members of patient advocate groups, practicing physicians who treat patients with Lyme disease, and basic research scientists with expertise in either infectious diseases or Lyme disease. The panel provided input on implementing the protocols selected for use in this as well as in intramural clinical studies. Since all of these clinical studies include an extensive research component, they represent the most comprehensive and thorough characterization of Lyme disease extant. They already have provided—and will continue to generate—a wealth of new information that can be used to devise more effective therapeutic approaches. On November 14, 2000, the Data and Safety Monitoring Board (DSMB) for NEMC clinical trials on the efficacy of antibiotic therapy for the treatment of chronic Lyme disease reviewed a planned interim analysis of the data obtained. These trials involved testing the safety and efficacy of intensive antibiotic treatment in people with Lyme disease who had developed chronic symptoms, despite earlier treatments with antibiotics. The trials compared treatment with 30 days of intravenous ceftriaxone followed by 60 days of oral doxycycline to treatment with intravenous placebo followed by oral placebo for the same duration, using patients who were either seropositive or seronegative at the time of enrollment. Both trials enrolled patients with a well-documented history of prior Lyme disease and used the same regimen. After its review, the DSMB unanimously recommended that NIAID terminate the treatment component of these studies. Their preliminary analysis showed that after 90 days of continuous antibiotic therapy there were no significant differences in the percentage of patients who felt that their symptoms had improved, gotten worse, or stayed the same between the antibiotic treatment and placebo groups in either trial. DSMB’s review suggested there was only a slight chance that a difference between the placebo- and antibiotic-treated groups would be found even with continued accrual of another 131 patients, the number needed to reach full enrollment. Therefore, the Board recommended that the treatment component of the studies stop enrolling new patients and that those currently receiving treatment discontinue that therapy. It further recommended that the investigators continue to follow the study patients to monitor their longer-term safety and to obtain additional information that might have value in determining the underlying basis of chronic Lyme disease and in suggesting more effective therapeutic approaches. These rather extensive follow-up studies are still in progress. No new therapeutic studies are contemplated until they have been completed and the results analyzed. The results of the NEMC clinical trials were published in The New England Journal of Medicine (NEJM 345:85-93, 2001). In another placebo-controlled study conducted at the State University of New York (SUNY) at Stony Brook, 55 patients with post-treatment chronic Lyme disease (PTCLD) were given either ceftriaxone or placebo (intravenous) for 28 days. They were then evaluated to determine whether there was significant improvement with respect to fatigue, cognitive function, and the clearance of OspA antigen that was present in the spinal fluid of only 16 percent of all enrolled patients. Ceftriaxone therapy was associated with improvement in fatigue but not with other primary outcome markers considered (Neurology 60:1923, 2003). It is noteworthy that in both the NEMC and SUNY clinical trials cited above, 40 percent of patients given placebo alone reported improvement in their symptoms (placebo effect). Also, aside from their ability to eliminate persisting infection, several antibiotics have beneficial effects that can alleviate some of the musculoskeletal and neurological symptoms generally associated with chronic Lyme disease. For example, the anti-inflammatory properties of doxycycline and tetracyclines are well-known, and several beta lactam and cephalosporin antibiotics—including ceftriaxone which is commonly used to treat chronic Lyme disease—have neuroprotective properties that can positively influence various neurological disorders (Nature 433: 73-77, 2005). In view of these considerations, valid conclusions on the efficacy of any proposed therapy for treating chronic Lyme disease can be achieved only by conducting carefully designed, placebo-controlled clinical trials in which sufficient numbers of patients are enrolled to permit rigorous statistical analysis. Because fatigue, which is a non-specific symptom, was the only primary outcome measure affected and because the treatment examined was associated with adverse events, the results of this study do not support the use of additional antibiotic therapy with parenteral ceftriaxone in post-treatment, persistently fatigued PLS patients. We do not know whether the benefit observed for fatigue is due to antibacterial effects or some other mechanism. Additional follow-up studies on patients enrolled in both the NIAID-supported NEMC and SUNY studies revealed that 28 to 90 days of antibiotic therapy had no beneficial effect with respect to several measures of cognitive function (Neurology 60:1916, 2003). Both the intramural and extramural studies mentioned above involve data collection as well as the maintenance of specimen repositories. Such specimens have been made available to other investigators working on Lyme disease and thus have contributed significantly to the development of improved and/or novel diagnostic procedures. Appropriate animal models also have provided considerable information on the transmission and pathogenesis of Lyme borreliosis, as well as on the mechanisms involved in the development of protective immunity. NIAID, in collaboration with NINDS, has broadened these efforts to include comprehensive studies on non-human primate animal models for experimental research on the neuropathology associated with chronic Lyme borreliosis. A major goal of these studies is to optimize the Rhesus model of Lyme borreliosis as well as to determine the pathogenesis of the disease with a focus on the neurological manifestations. We anticipate these studies, which were undertaken at the urging of several Lyme disease patient advocates, will expand our knowledge of those factors that contribute to the pathology associated with persistent infection of the central nervous system by B. burgdorferi and ultimately will enable us to devise more effective clinical approaches for treating chronic Lyme borreliosis in humans. They also will supplement and enhance the results of current clinical studies on the efficacy of antibiotic therapies for treating chronic Lyme disease and provide precedents for use in designing future clinical studies. Other studies have shown that B. burgdorferi can be detected in mice for at least 3 months after treatment with therapeutic doses of various antibiotics (ceftriaxone, doxycycline, or azithromycin). These surviving spirochetes could not be transmitted to healthy mice and some lacked plasmid genes associated with infectivity. By 6 months, antibiotic-treated mice no longer tested positive for the presence of B. burgdorferi, and even cortisone immunosuppression failed to alter this result; that is, it failed to activate infection. Nine months after antibiotic treatment, low levels of Borrelia DNA still could be detected in some—but not all—of the mice. These findings indicate that noninfectious B. burgdorferi can persist in mice for a limited period of time after antibiotic therapy. The implications of these findings to persistent infection and the nature of chronic Lyme disease in humans remain to be assessed. Since various published reports suggested the possibility that B. burgdorferi may play a role in the etiology of Alzheimer’s disease, NIAID intramural scientists examined this issue in greater detail. The results of a recent study, using a very sensitive PCR assay capable of amplifying a Borrelia-specific DNA target sequence from all strains of B. burgdorferi sensu lato species known to cause disease in humans, provided no evidence to indicate the presence of Borrelia in the brains of deceased patients with Alzheimer’s disease. Although the Lyme Urinary Antigen Test (LUAT) is one of several diagnostic tests used routinely in NIAID’s clinical studies on chronic Lyme disease, the results of independent quality control assessments of tests conducted by extramural and intramural scientists showed the LUAT to be unreliable because it yields an unacceptably high percentage of false positive reactions. By contrast, the similar assessments confirmed a high degree of reproducibility and concordance (virtually 100 percent) for the results obtained using ELISA and Western blot assays. NIAID expects to sustain a high level of activity in research on Lyme disease in the coming years. It will continue to encourage research on alternative modes of therapy as well as the development of animal models that mimic human infection to enhance or supplement ongoing clinical studies. NIAID investigators conducting controlled clinical studies on therapeutic approaches for treating chronic Lyme disease participated in an NINDS-sponsored conference on neuroborreliosis to facilitate the exchange and application of new knowledge as well as to foster collaborative interactions. Since the complete genome of B. burgdorferi has been sequenced by scientists at The Institute for Genomic Research (TIGR), the widespread application of this information will play a significant role in increasing our understanding of the pathogenesis of Lyme disease at the molecular and cellular levels, as well as to accelerate the development of improved diagnostic tests. Researchers already are applying microarray technology to this end. THE ROLE OF AUTOIMMUNE REACTIVITY The results of recent studies conducted by NIAID and NINDS intramural scientists indicate that T cells from patients with chronic Lyme disease are reactive not only against B. burgdorferi -specific antigens but also against various host (self) antigens. Such antigenic mimicry has the potential to generate autoimmune inflammatory reactions that could be responsible for arthritic as well as some neurological symptoms associated with chronic Lyme disease. Intramural and extramural scientists are exploring the implications of this finding. In other clinical studies conducted by NIAID-supported extramural scientists, case subject patients with symptoms persisting after treatment for acute Lyme disease (patients with PTCLD) and control subjects without such symptoms after the same treatment were compared for the presence of several human leukocyte antigen (HLA) class II (DRB1 and DQB1) genetic markers, some of which are known to be associated with the expression of autoimmune reactivity. The results obtained did not support the involvement of an autoimmune mechanism in PTCLD. However, it is noteworthy that because not all autoimmune diseases are associated with specific HLA haplotypes, these findings do not necessarily exclude that possibility. Definitive proof clearly would involve demonstrating the presence of significant levels of relevant autoimmune antibodies and/or autoreactive T cells in patients with PTCLD but not in treated control subjects without such symptoms. Interesting to note the anti-inflammatory properties of doxycycline and tetracycline. Could explain why patients feel better when they are on these antibiotics long term. The jury seems to be out though on whether long term antibiotic therapy for chronic lyme disease is effective and no studies that I could find on the effects on the body of long-term treatment with doxycycline. And the autoimmune inflammatory reactions that could be responsible for the arthritic and neurological symptoms associated with chronic lyme disease are an interesting sideline. I will try to dig up more current research, but I recommend a visit to the NIH site.