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Largest Lyme Disease Trial Finds No Benefit with Long-Term Antibiotics

ARTICLE IN BRIEF

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THE ERYTHEMA MIGRANS RASH seen in 80 percent of cases of proven Lyme disease. Multiple studies have shown that long-term antibiotics use is ineffective for treatment, but experts say there remains a misperception that continued long-term antibiotics are needed.

Investigators reported that longer treatment with antibiotics proved ineffective in Lyme disease patients who complained of ongoing symptoms after an initial course of treatment treatment.

Longer treatment with antibiotics proved ineffective in Lyme disease patients who complained of ongoing symptoms after an initial course of treatment treatment, according to the largest clinical trial to address the issue.

The study, published in the March 31 issue of the New England Journal of Medicine, included patients with persistent symptoms using a single antibiotic or a combination.

The Persistent Lyme Empiric Antibiotic Study Europe (PLEASE), a randomized, double-blind, placebo-controlled trial included 280 subjects with proven disease or positive antibodies for Borrelia burgdorferi, the bacteria that causes Lyme.

Patients first received an open-label intravenous course of 2000 mg of ceftriaxone each day for two weeks before being randomized. A total of 86 patients received a 12-week oral course of doxycycline (100 mg twice daily combined with placebo twice daily), clarithromycin plus hydroxychloroquine (500 mg clarithromycin twice daily combined with 200 mg hydroxychloroquine twice daily), or placebo.

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DR. BART JAN KULLBERG: “This is the largest trial ever done on patients with persistent musculoskeletal pain, fatigue and cognitive symptoms. But we found that scores did not differ significantly among the three study groups.”

The primary outcome was health-related quality of life (HRQL) assessed using the physical summary score of the RAND Health Status Inventory (RAND SF-36), which ranges from 15 to 61 (highest). Patients' scores were taken before randomization and again at 26, 40 and 52 weeks.

“Most patients are cured after initial antibiotic therapy but as many as 20 percent report persistent symptoms,” said principal investigator Bart Jan Kullberg, MD, PhD, professor of medicine at Radboud University's Center for Infectious Diseases in Nijmegen. “But we found that scores did not differ significantly among the three study groups.”

“This is the largest trial ever done on patients with persistent musculoskeletal pain, fatigue and cognitive symptoms,” Dr. Kullberg told Neurology Today. “It is important to note however that the results are not applicable to patients with other manifestations of Lyme disease, such as active meningoradiculitis or arthritis.”

The mean score was 35.0 percent in the doxycycline group, 35.6 percent in the combination group, and 34.8 percent in patients who received placebo. The scores did not differ at subsequent time points but increased significantly in each group from baseline throughout the study. Adverse events were similar in all groups, with four serious events thought to be drug-related during the two-week open-label ceftriaxone phase. No serious events occurred during the 12-week randomized phase.

A number of patients complained of symptoms after initial therapy, a condition known as persistent post-treatment Lyme disease syndrome, or PTLDS, including fatigue, arthralgia, myalgia, or impaired cognition, and they were often severe. Yet, there are little data to support additional antibiotic treatment, and most professional guidelines do not recommend such an approach. Nonetheless, the issue remains controversial, and some physicians continue to prescribe additional regimens when patients continue to experience physical problems.

Guidelines for Lyme disease have been published by a number of independent US and European medical societies. The Infectious Disease Society of America (IDSA) recommends only initial treatment for two to four weeks, as does the Centers for Disease Control and Prevention, but the International Lyme and Associated Diseases Society (ILADS) leaves such decisions to the discretion of individual physicians, based on patient symptoms.

ARE THE FINDINGS APPLICABLE?

In an accompanying editorial, two infectious disease experts at Johns Hopkins University School of Medicine's division of infectious diseases in Baltimore made several observations about the trial.

Paul G. Auwaerter, MD, clinical director of the division, and Michael T. Melia, MD, assistant professor of medicine, first noted that the species of B. burgdorferi bacteria found in Europe are different from those that circulate in North America, including a longer initial duration of illness, they wrote.

They also said that only 96 of 280 participants, or 34 percent, had objective evidence of Lyme disease. “This means that nearly two thirds of their study population had nonspecific symptoms that were attributed to Lyme disease solely on the basis of positive IgM or IgG (or both) immunoblot assays for B. burgdorferi,” they wrote.

“Such laboratory findings do not necessarily imply causation and could represent either false positive results or remote infection, since antibody titers can remain elevated for decades,” according to the authors.

“[This] means that there was no true placebo component [and] the two active oral study regimens ... are both known to produce anti-inflammatory effects in addition to their antimicrobial properties.”

Dr. Kullberg said the editorial provided additional perspective. “The authors are correct that the patients' symptoms were not necessarily causally related to their prior Lyme disease, however all of them had a B. burgdorferi infection in their past.”

He emphasized that the main conclusion of the study was that long-term antibiotic treatment had no additional beneficial effects on health-related quality of life.

“The strength of the study is that the patients themselves have reported multiple aspects of their health status, including physical and mental health, daily activities, pain, and fatigue, over a one-year follow-up period, and consistently reported that they did not experience any benefit from prolonged therapy compared to controls.”

EXPERTS COMMENT

Commenting on the paper, Andrew R. Pachner, MD, the Murray B. Bornstein professor of neurology at Dartmouth University Geisel School of Medicine, in Lebanon, NH, said the study confirms a large body of evidence against prolonged treatment with antibiotics. But, he added, it may not change how some practitioners approach persistent symptoms.

“There continues to be the perception, among a small number of practitioners, and certainly some patients, that these symptoms are being caused by persistent infection. But the data against it [are] quite strong,” he told Neurology Today.

“This study is helpful and hopefully will change the practice of prescribing long-term antibiotics for patients who have been initially treated for Lyme disease by a small number of physicians.”

He added that it is possible that some patients with symptoms have in fact become infected again. “A number of persons who are bitten by ticks and become infected undergo initial treatment and their symptoms are resolved, but then work or live in areas where reinfection can occur.”

Many patients may also be misdiagnosed, he added. Although the ILADS guidelines allow physicians to continue treating patients if they continue to have symptoms, European doctors tend to be conservative in treatment.

“They tend to not be very aggressive, in general,” Dr. Pachner said, adding that “strains of Lyme disease in Europe are more toxic and neurotropic than those in the US.”

The standard of care in Europe is two weeks of antibiotics, and most patients who continue to have symptoms get better over time, Dr. Pachner noted. Nonetheless, the ongoing debate over treatment is unlikely to be resolved any time soon, he told Neurology Today. “As long as there are people out there fanning the flames this is going to continue, but I believe that it will change in time.”

Lauren Krupp, MD, professor of neurology at New York University Langone Medical Center, said that in addition to being perhaps the largest study of its kind, it reflects what most physicians encounter in their practice, where Lyme disease may not always manifest as typical symptoms, such as erythema migrans rash.

“Even if patients did not meet the CDC's definition of Lyme disease this is a good study, and the researchers did some interesting things by also including patients with probable disease based on antibodies and chronic symptoms,” she told Neurology Today.

“The results were very clear. There was no group difference with treatment or placebo, and I think this sends a clear message.”

All of the subjects were initially in the low range for QOL, yet all of them improved. “In the community this is what happens — people tend to get better with any intervention, so the placebo effect is possible,” she said. “I think this will change the practice for most physicians, but not all. People like an explanation for why they feel symptoms, even if the data does not support longer treatment.”

EXPERTS: ON LONG-TERM ANTIBIOTICS FOR LYME DISEASE TREATMENT

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DR. ANDREW R. PACHNER: “There continues to be the perception, among a small number of practitioners, and certainly some patients, that these symptoms are being caused by persistent infection. But the data against it [are] quite strong. This study is helpful and hopefully will change the practice of prescribing long-term antibiotics for patients who have been initially treated for Lyme disease by a small number of physicians.”

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DR. LAUREN KRUPP: “In the community this is what happens — people tend to get better with any intervention, so the placebo effect is possible. I think this will change the practice for most physicians, but not all. People like an explanation for why they feel symptoms, even if the data do not support longer treatment.”

LINK UP FOR MORE INFORMATION:

•. Berende A, Hadewych JM, Kullberg BJ, et al. Randomized trial of longer-term therapy for symptoms attributed to Lyme disease http://www.nejm.org/doi/full/10.1056/NEJMoa1505425. N Eng J Med 2016;374:1209–1220.
    •. Melia MT, Auwaeter PG. Time for a different approach to Lyme disease and long-term symptoms http://www.nejm.org/doi/full/10.1056/NEJMe1502350. N Eng J Med 2016;374:1277–1278.
      •. Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline Recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease http://www.ncbi.nlm.nih.gov/pubmed/25077519. Expert Rev Anti Infect Ther 2014;12:1103–1135.
        •. Seriburi V, Ndukwe N, Chang Z, et al. High frequency of false positive IgM immunoblots for Borrelia burgdorferi in clinical practice http://www.ncbi.nlm.nih.gov/pubmed/22369185. Clin Microbiol Infect 2012;18:1236–1240.
          •. Mygland A, Ljøstad U, Fingerless V, et al. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis http://www.ncbi.nlm.nih.gov/pubmed/19930447. Eur J Neurol 2010;17:8–16.
            •. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America http://www.ncbi.nlm.nih.gov/pubmed/17029130. Clin Infect Dis 2006;43:1089–1134.