Post-Lyme-Disease Syndrome: Longer Antibiotics May Not Help

A new study has suggested that longer-term use of antibiotics does not improve health-related quality of life in patients with post–Lyme disease syndrome.

Anneleen Berende, MD, from Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues published the results of their study in the March 31 issue of the New England Journal of Medicine.

"In patients with persistent symptoms attributed to Lyme disease, longer-term antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment," the authors write.

Post–Lyme disease syndrome (or chronic Lyme disease) is a term used to describe the constellation of persistent symptoms experienced by some patients with Lyme disease, a tick-borne disease caused by infection with the bacterium Borrelia burgdorferi. These long-standing symptoms typically include musculoskeletal pain, fatigue, and cognitive complaints and may arise after resolution of early Lyme disease symptoms, such as an erythema migrans rash.

However, the treatment of these persistent symptoms remains controversial. According to the authors, "[p]revious randomized, clinical trials have not shown convincingly that prolonged antibiotic treatment has beneficial effects in patients with persistent symptoms attributed to Lyme disease." However, some guidelines do recommend prolonged antibiotic therapy.

As a consequence, the authors conducted the Persistent Lyme Empiric Antibiotic Study Europe (PLEASE) study, a double-blind, randomized, placebo-controlled trial designed to determine whether long-term antibiotic treatment leads to better patient outcomes than standard treatment does.

Patients (N = 280) were included in the trial if they had persistent symptoms attributed to Lyme disease — symptoms that were either temporally related to proven Lyme disease or accompanied by a positive immunoglobulin G or immunoglobulin M immunoblot assay for B burgdorferi.

All patients received open-label ceftriaxone for 2 weeks. They were then randomly assigned (1:1:1) to receive a 12-week oral regimen of doxycycline (n = 86), clarithromycin combined with hydroxychloroquine (n = 96), or placebo (n = 98). The mean duration of symptoms at baseline was 2.7 years in the doxycycline and clarithromycin–hydroxycholoroquine groups and 2.1 years in the placebo group.

The three groups did not differ in terms of the study's primary outcome, which was the mean health-related quality of life at the end of the 14-week treatment period, as indicated by the physical component summary (PCS) score of the RAND-36 Health Status Inventory (RAND SF-36), corrected for baseline SF-36 PCS score and sex.

Specifically, the mean scores were 35.0 (95% confidence interval [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 = .69). In addition, there were no differences at subsequent study visits (P = .35).

The authors also saw no differences in secondary outcomes, including physical and mental aspects of health-related quality of life (as indicated by the use of the RAND SF-36) and fatigue (as indicated by the use of the fatigue-severity scale of the Checklist Individual Strength).

At the end of the 14-week treatment period, the mean SF-36 PCS score had improved significantly from baseline (difference, 4.6 points; 95% CI, 3.6 - 5.5 points; P < .001) in all three groups. At weeks 26, 40, and 52, the SF-36 PCS score remained higher than the baseline score but did not change significantly from the 14-week score in any of the three groups.

Overall, 205 participants (73.2%) reported at least one adverse event (AE). During the 2-week open-label ceftriaxone phase, rash and diarrhea were the most common AEs; five serious AEs occurred, four of which were allergic reactions related to ceftriaxone use.

During the 12-week randomized phase, 134 patients (47.9%) had at least one AE; however, the rates of any-cause (P = .27) or drug-related (P = .14) AEs did not significantly differ among the three groups. Photosensitivity and nausea were the most common AEs in the doxycycline group, nausea and diarrhea were the most common AEs in the clarithromycin–hydroxychloroquine group, and rash was significantly more prevalent in the clarithromycin–hydroxychloroquine group than in either of the other two groups (P = .01). Four serious AEs occurred, none of which were judged to be drug-related.

Although the mean SF-36 PCS score improved significantly from baseline to the end of the treatment period in all groups, the authors note that participants' quality of life remained below that of the general population.

"Whether improvement in the SF-36 physical-component summary score at the end of the treatment period is a beneficial effect of shorter-term antibiotic therapy or a nonspecific effect caused by the low level of baseline functioning, expectations associated with treatment, or placebo effects remains unclear, because all the patients had received 2 weeks of open-label antibiotics before entering into the longer-term randomized study-drug or placebo phase," the authors emphasize.

They acknowledge the limitations of their study, including the use of open-label antibiotics in all participants for 2 weeks before the randomized phase. However, they chose not to include a placebo group because they considered it unethical to withhold treatment from patients who might have an infection at baseline that had not been treated.

"Although we did not identify any benefit of longer-term therapy, the question of whether a 2-week regimen of antibiotics is superior to withholding any therapy in our patient population remains unanswered," the authors conclude.

In an accompanying editorial, Michael T. Melia, MD, and Paul G. Auwaerter, MD, both from the Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, note that although critics may say that this study does not truly reflect the situation that arises in patients with bona fide Lyme disease, other studies with stricter inclusion criteria have already been performed. They also suggest that the approach used in this study reflects the situation in ambulatory care settings, in which checks for Lyme disease are performed when patients present with symptoms such as fatigue or nonspecific pain, even though evidence suggests these tests will not identify a cause or result in a treatment benefit.

Dr Melia and Dr Auwaerter highlight the importance of the results of this study: "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," they emphasize.

Because it remains unclear what type of treatment intervention is helpful for patients who have prolonged symptoms that are attributed to Lyme disease, the editorialists stress the need for innovative research to gain better insight into the biologic mechanisms underlying Lyme disease. For example, a recent study found that compared with patients with other infections, individuals with B burgdorferi infection had a differential gene expression signature and differing postinfection cytokine or metabolic changes.

"Future research efforts should continue to explore such different strategies that may lead to proven options for helping our patients," Dr Melia and Dr Auwaerter conclude.

This study was supported by a grant from the Netherlands Organization for Health Research and Development. One coauthor has reported a patent related to a cellular diagnostic test method for Lyme disease that is licensed to Oxford Immunotec. The other authors have disclosed no relevant financial relationships. One editorialist has received personal fees for medical-legal expert testimony regarding Lyme disease and personal fees from Biomerieux outside the submitted work and also serves as vice president and a member of the board of directors and executive committee of the Infectious Diseases Society of America and is a member of the society's panel for updating Lyme Disease Guideline. The other editorialist is a coinvestigator for hepatitis C clinical trials conducted at his institution; funding for these studies has been received by his institution from Merck Sharpe & Dohme, Janssen, Gilead, Bristol-Myers Squibb, and AbbVie. He has also provided medical-legal expert testimony unrelated to Lyme disease. Dr Auwaerter is a Medscape advisory board member.

N Engl J Med. 2016;374:1209-1220, 1277-1278. Article full text, Editorial full text