Long-Term Antibiotics Fail Again in Lyme Disease

03.30.2016

Focus on Lyme and antibiotics for persistent symptoms called unhelpful

by Nancy Walsh
Senior Staff Writer, MedPage Today

Lengthy antibiotic treatment failed to improve quality of life among patients with symptoms attributed to persistent Lyme disease, a randomized Dutch study found.

Following a 2-week course of ceftriaxone, patients were randomly assigned to one of three treatments extending for 12 weeks: doxycycline, a combination of clarithromycin and hydroxychloroquine, or placebo. At the end of treatment, no differences were seen between the three groups on the Short Form (SF)-36 physical component summary scores, according to Bart-Jan Kullberg, MD, PhD, of Radboud University Medical Center in Nijmegen, and colleagues.

At 14 weeks, the SF-36 was 35 (95% CI 33.5-36.5) in the doxycycline group, 35.6 (95% CI 34.2-37.1) in the clarithromycin-hydroxychloroquine group, and 34.8 (95% CI 33.4-36.2) in the placebo group (P=0.69), the researchers reported Wednesday in the New England Journal of Medicine.

And even though these scores at week 14 represented significant improvements of 4.6 points over baseline, quality of life was still considerably lower than in the general population, where the average SF-36 score is around 50, they noted.

In an accompanying editorial, Michael T. Melia, MD, and Paul G. Auwaerter, MD, of Johns Hopkins University, stated that the study “is an important contribution and contains a simple message.”

“Patients with subjective, vexing symptoms attributed to Lyme disease should not anticipate that even longer courses of antibiotics will produce relief, a finding that is in concert with results from previous trials,” Melia and Auwaerter wrote.

Those previous trials included two evaluating intravenous ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or intravenous and oral placebos. Those studies were discontinued early when an interim analysis suggested that it was “highly unlikely” that a significant difference would be seen between the active treatment and placebo groups.

The PLEASE Study

Some 10% to 20% of patients with infections caused by Borrelia burgdorferi experience long-lasting symptoms of pain, fatigue, and cognitive or neurologic difficulties.

Most treatment guidelines recommend antibiotic treatment for 2 to 4 weeks, but controversy has persisted for years as to whether longer treatment could be beneficial.

To address this in an adequately powered, blinded study, Kullberg and colleagues enrolled 280 patients in what they called the Persistent Lyme Empiric Antibiotic Study Europe (PLEASE). Participants were recruited from 2010 to 2013, with persistent symptoms that were temporally associated with the typical erythema migrans rash, were an “otherwise proven case of symptomatic Lyme disease,” or who had evidence of antibodies to B. burgdorferi IgG or IgM.

The median duration of symptoms was about 2.5 years. Slightly over half of the patients had a history of tick bite, 28% reported the erythema migrans rash, and fewer than 10% had meningoradiculitis.

Baseline SF-36 physical component scores were 30.3, 32.7, and 31.8 in the doxycycline, clarithromycin-hydroxychloroquine, and placebo groups, respectively.

A total of 89% had previously received courses of antibiotics, with a median number of two courses per patient.

Treatment in PLEASE consisted of 2,000 mg intravenous ceftriaxone per day for 14 days, followed by 3 months of doxycycline, 100 mg twice per day; 500 mg clarithromycin twice daily plus 200 mg hydroxychloroquine twice daily; or placebo.

As with the primary endpoint of SF-36 physical component, no differences were seen between the three groups on secondary endpoints such as the SF-36 mental health component, global health composite, general health scale, or bodily pain and vitality scales.

During the 14 weeks of the study, 73.2% of patients experienced at least one adverse event, with 3.2% having a serious event and 6.8% withdrawing because of an adverse event.

During the initial ceftriaxone phase, 46.8% reported adverse events, which most often were diarrhea and rash. During the subsequent randomized phase, 47.9% of patients reported adverse events, most commonly nausea and photosensitivity for patients receiving doxycycline and nausea and diarrhea predominating in the clarithromycin-hydroxychloroquine group.

Critique of the Study

In their editorial, Melia and Auwaerter described the study as “well performed,” but pointed out several features of PLEASE that they felt needed consideration. For example, most of the previous studies of antibiotic therapy had been conducted in the U.S., and the species of B. burgdorferi found in Europe differ from those in the U.S. “The infections associated with these species can manifest differently than do infections from North American species, such as with a longer initial duration of illness.”

They also pointed out that only 34% of study participants had objective findings of Lyme disease such as the rash, and that in the remaining two-thirds, the assumption of infection was based on immunoblot assays for IgG or IgM, which might represent false-positive results or resolved infection long in the past.

In addition, because patients in all treatment groups showed improvements exceeding the minimal clinically important difference of 2 to 5 points on the SF-36 physical component, some of the treatment effects may have reflected the fact that 11% of the participants had not been given any previous antibiotic treatment.

The editorialists also pointed out some encouraging factors, such as that in a long-term follow-up study of 100 patients with culture-confirmed Lyme disease, SF-36 physical and mental health scores were similar to those typical of the wider population 11 to 20 years after the infection.

Another recent study they cited involved comparisons of gene expression signatures in patients at the time of acute Lyme infection and then 6 months later. In this study, researchers found differential expression from what is seen in other infections, and proposed that changes in the cytokine or metabolic milieu may result from B. burgdorferiinfection.

That study also found downregulation of the eIF2 signaling pathway in both early and late Lyme disease. “Notably, Lyme disease at 6 months post-treatment had 60% and 31% of their predicted pathways overall in common with [systemic lupus erythematosus] and [rheumatoid arthritis], respectively,” the authors wrote.

The researchers also noted that inhibitors of that pathway have been suggested as having a therapeutic role in inflammatory bowel disease, “and further studies are needed to assess whether eIF2 inhibitors may constitute potential targets for inflammatory sequelae of Lyme disease.”

Another View

MedPage Today spoke with Gary P. Wormser, MD, chief of the Division of Infectious Diseases and director of the Lyme Disease Diagnostic Center at New York Medical College in Valhalla, N.Y., about the PLEASE study and his own experiences.

“The fundamental issue is that there are many patients in the general population with medically unexplained symptoms, and the majority of patients I see who have these unexplained symptoms don’t have a history of actually having Lyme disease. So what is going on?” he asked.

“These medically unexplained symptoms such as chronic joint pain and fatigue need to be more of a priority in terms of research in this country,” he said. Research programs need to focus on what causes these symptoms and to identify sophisticated techniques such as molecular signatures that would help differentiate subgroups of patients, and to find new and useful ways to help. The mechanisms involved in post-infectious persistent symptoms also need to be explored, he said.

“The symptoms definitely impact quality of life and function, and these patients don’t seem to get much attention,” he said.

“One of the problems has been the focus on antibiotics, with all the randomized studies in the literature evaluating antibiotics for post-Lyme symptoms. That means that all the research resources are going toward the question that’s been repeatedly asked — should we give more antibiotics — and not looking for another approach that might actually work,” he said.

“These people are really suffering, and I think most mainstream doctors feel frustrated that they can’t do more for these patients. That doesn’t mean, however, that we should misrepresent the role of antibiotics in treatment,” Wormser said.

Lead author Kullberg has received support from the Netherlands Organization for Health Research and Development and holds a patent for a cellular diagnostic test for Lyme disease.

Editorialist Auwaerter has received fees for medical-legal expert testimony regarding Lyme disease and from BioMerieux.

  • Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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