Treatment of early Lyme disease

http://www.annals.org/cgi/reprint/140/7/577.pdf

*Treatment of early Lyme disease*

TO THE EDITOR: Wormser and colleagues (1) reported the results of
very short-term (10-day) versus short-term (20-day) antibiotic treatment
for patients with early Lyme disease who presented with an
erythema migrans rash. Using an on-study analysis, the authors
claimed that 84% to 90% of patients had a complete response to one
or the other treatment after 30 months of follow-up. These results
represent “creative mismanagement” of the study data (2).

Although the study enrolled 180 patients in 3 treatment groups,
only 99 patients were evaluable after 30 months of observation,
yielding a dropout-plus-exclusion rate of 45% (25% of patients were
excluded, and 20% dropped out). Since almost half of the patients
were not included in the final analysis of this observational trial, the
on-study results are virtually meaningless because the uncounted participants
must be considered potential treatment failures (2). Furthermore,
an exclusion rate of 25% invalidates the study randomization,
and a dropout rate of 20% invalidates the overall study results (2).

In the more appropriate intention-to-treat analysis, which we
present in the Table, the least stringent response rates (complete
response plus partial response) ranged from 49% to 62%, while the
most stringent response rates (complete response only) ranged from
44% to 53% at 30 months of follow-up. These results are a far cry
from the response rates trumpeted by the authors, and they indicate
potential failure of both the short-term and very short-term regimens
in a significant number of patients.

An illustrative problem with the analysis was the exclusion of
the 5% to 10% of patients who developed a recurrent erythema
migrans rash. Although the authors excluded these patients because
of the possibility of a new spirochetal infection, a more likely explanation
is that the patients had recurrent rashes because of failure of
their initial treatment and persistent Lyme disease (3). Thus, manipulation
of the study results turned an intention-to-treat failure into
an on-study success, and this outcome highlights the problematic
data interpretation embraced by the authors. Furthermore, by conservative
estimate, at least 41% of patients with early Lyme disease
never develop an erythema migrans rash (4). Thus, the study by
Wormser and colleagues included only patients whose conditions
were easiest to diagnose, making the poor treatment results of shortterm
therapy even more disappointing.

Over the past 3 years, undertreatment of Lyme disease has become
institutionalized in the United States. This unfortunate trend
has evolved on the heels of a highly flawed study of chronic Lyme
disease therapy (5) and publication of manipulated data from early
Lyme disease treatment, as seen in the report by Wormser and colleagues
and elsewhere (6). It is time to start using well-designed
studies and more appropriate statistics in the analysis of Lyme disease
therapy in order to assess the gravity and risk of this protean illness.
In contrast to the current national trend, we need to examine longer
courses of antibiotics to treat persistent spirochetal infection and
obtain better clinical outcomes for patients with Lyme disease (6).

Raphael B. Stricker, MD
California Pacific Medical Center
San Francisco, CA 94108

Andrea Gaito, MD
Morristown Memorial Hospital
Morristown, NJ 07962

Nick S. Harris, PhD
IGeneX Laboratory
Palo Alto, CA 94303

Joseph J. Burrascano, MD
East End Medical Associates
East Hampton, NY 11937

References
1. Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer
P, et al. Duration of antibiotic therapy for early Lyme disease. A randomized,
double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:697-704. [PMID:
12729423]
2. Schulz KF, Grimes DA. Sample size slippages in randomised trials: exclusions and
the lost and wayward. Lancet. 2002;359:781-5. [PMID: 11888606]
3. Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L. Recurrent
erythema migrans despite extended antibiotic treatment with minocycline in a patient
with persisting Borrelia burgdorferi infection. J Am Acad Dermatol. 1993;28:312-4.
[PMID: 8436647]
4. Stricker RB, Lautin A. The Lyme Wars: time to listen. Expert Opin Investig Drugs.
2003;12:1609-14. [PMID: 14519082]
5. Phillips S, Bransfield R, Sherr V, Brand S, Smith H, Dickson K, et al. Evaluation of
antibiotic treatment in patients with persistent symptoms of Lyme disease: an ILADS
position paper. Accessed at www.ilads.org/position2.htm on 9 May 2003.
6. Stricker RB, Phillips SE. Lyme disease without erythema migrans: cause for concern?
[Letter]. Am J Med. 2003;115:72-3; author reply 73-4. [PMID: 12867241]

IN RESPONSE: Stricker and colleagues have “creatively” misread our
study, in which 10 days and 20 days of doxycycline treatment were
demonstrated to have similar efficacy in patients with erythema migrans.
Efficacy was evaluated at 4 different, specific time points (20
days, 3 months, 12 months, and 30 months), as well as at the time of
the last visit with the patient, in both an on-study and an intentionto-
treat analysis. The sample size estimates were based, as explicitly
stated in the manuscript, on the 12-month time point, and were met.

At last patient contact in our intention-to-treat analysis, the
complete response rates for the 10-day and 20-day doxycycline
groups were nearly identical (83.3% and 86.2%, respectively). The
patients who were classified as partial responders had usually mild
subjective symptoms, such as intermittent fatigue or arthralgias.
“Healthy” control groups of adults without a history of Lyme disease
have been found to have similar symptoms at comparable frequencies
(1), suggesting that Lyme disease is one of a number of triggers of
such symptoms or that our patients’ symptoms were unrelated to
their episode of Lyme disease. In either case, the take-home message
is that symptoms in early Lyme disease sometimes resolve slowly but
will do so at the same rate regardless of whether antibiotic therapy is
extended beyond 10 days.

Stricker and colleagues suggest that patients who developed erythema
migrans at a different skin location during a subsequent
summer, as well as those who did not return for a particular study
visit, should have been considered treatment failures. This would not
have affected the study findings because the frequency of these events
was similar across treatment groups. Erythema migrans, which is
found in more than 90% of patients who meet the Centers for
Disease Control and Prevention’s case definition of Lyme disease if a
complete skin examination is performed (2), is, however, not a manifestation
of late Lyme disease; it can be recognized as a reinfection
because the site of the new tick bite is usually readily identifiable.

There is no scientific evidence to justify prolonged antibiotic
therapy for patients with any manifestation of Lyme disease, and our
study and that of others (3) should further help to discourage such
practice. In addition, antibiotics are no better than placebo in treating
patients who carry the label of “chronic Lyme disease,” probably
because evidence indicates that this entity is not infectious (4).
Shorter courses of antibiotic therapy are more convenient for the
patient, less expensive, potentially safer, and less likely to promote
the emergence of resistant bacteria in the community.

Gary P. Wormser, MD
John Nowakowski, MD
Robert B. Nadelman, MD
New York Medical College
Valhalla, NY 10595

References
1. Nowakowski J, Nadelman RB, Sell R, McKenna D, Cavaliere LF, Holmgren D, et
al. Long-term follow-up of patients with culture-confirmed Lyme disease. Am J Med.
2003;115:91-6. [PMID: 12893393]
2. Steere AC, Sikand VK, Meurice F, Parenti DL, Fikrig E, Schoen RT, et al. Vaccination
against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein
A with adjuvant. Lyme Disease Vaccine Study Group. N Engl J Med.
1998;339:209-15. [PMID: 9673298]
3. Wormser GP, Nadelman RB, Dattwyler RJ, Dennis DT, Shapiro ED, Steere AC, et
al. Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society
of America. Clin Infect Dis. 2000;31 Suppl 1:1-14. [PMID: 10982743]
4. Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, et al. Two
controlled trials of antibiotic treatment in patients with persistent symptoms and a
history of Lyme disease. N Engl J Med. 2001;345:85-92. [PMID: 11450676]
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