Berende A, ter Hofstede HJ, Vos FJ, van Middendorp H, Vogelaar ML, Tromp M, van den Hoogen FH, Donders AR, Evers AW, Kullberg BJ. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med. 2016 Mar 31;374(13):1209-20.
The treatment of persistent symptoms attributed to Lyme disease remains controversial. We assessed whether longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment.
In a randomized, double-blind, placebo-controlled trial conducted in Europe, we assigned patients with persistent symptoms attributed to Lyme disease--either related temporally to proven Lyme disease or accompanied by a positive IgG or IgM immunoblot assay for Borrelia burgdorferi--to receive a 12-week oral course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. All study groups received open-label intravenous ceftriaxone for 2 weeks before initiating the randomized regimen. The primary outcome measure was health-related quality of life, as assessed by the physical-component summary score of the RAND-36 Health Status Inventory (RAND SF-36) (range, 15 to 61, with higher scores indicating better quality of life), at the end of the treatment period at week 14, after the 2-week course of ceftriaxone and the 12-week course of the randomized study drug or placebo had been completed.
Of the 281 patients who underwent randomization, 280 were included in the modified intention-to-treat analysis (86 patients in the doxycycline group, 96 in the clarithromycin-hydroxychloroquine group, and 98 in the placebo group). The SF-36 physical-component summary score did not differ significantly among the three study groups at the end of the treatment period, with mean scores of 35.0 (95% confidence interval [CI], 33.5 to 36.5) in the doxycycline group, 35.6 (95% CI, 34.2 to 37.1) in the clarithromycin-hydroxychloroquine group, and 34.8 (95% CI, 33.4 to 36.2) in the placebo group (P=0.69; a difference of 0.2 [95% CI, -2.4 to 2.8] in the doxycycline group vs. the placebo group and a difference of 0.9 [95% CI, -1.6 to 3.3] in the clarithromycin-hydroxychloroquine group vs. the placebo group); the score also did not differ significantly among the groups at subsequent study visits (P=0.35). In all study groups, the SF-36 physical-component summary score increased significantly from baseline to the end of the treatment period (P<0.001). The rates of adverse events were similar among the study groups. Four serious adverse events thought to be related to drug use occurred during the 2-week open-label ceftriaxone phase, and no serious drug-related adverse event 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.
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.”
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.”…
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.”