Harris JP, Weisman MH, Derebery JM, Espeland MA, Gantz BJ, Gulya AJ, Hammerschlag PE, Hannley M, Hughes GB, Moscicki R, Nelson RA, Niparko JK, Rauch SD, Telian SA, Brookhouser PE. Treatment of Corticosteroid-Responsive Autoimmune Inner Ear Disease With MethotrexateA Randomized Controlled Trial. JAMA. 2003;290(14):1875-1883. doi:10.1001/jama.290.14.1875
Author Affiliations: Division of Otolaryngology–Head & Neck Surgery, University of California, San Diego (Dr Harris); Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, Calif (Dr Weisman); House Ear Institute, Los Angeles, Calif (Drs Derebery and Nelson); Department of Public Health Sciences, Wake Forest University, Winston-Salem, NC (Dr Espeland); Department of Otolaryngology–Head & Neck Surgery, University of Iowa, Iowa City (Dr Gantz); National Institute on Deafness and Other Communication Disorders, Bethesda, Md (Dr Gulya); Department of Otolaryngology–Head & Neck Surgery, New York University, New York (Dr Hammerschlag); Research Development, American Academy of Otolaryngology–Head & Neck Surgery, Alexandria, Va (Dr Hannley); Otolaryngology and Communicative Disorders, The Cleveland Clinic, Cleveland, Ohio (Dr Hughes); Department of Allergy and Immunology, Massachusetts General Hospital, Boston (Dr Moscicki); Department of Otolaryngology, Johns Hopkins University, Baltimore, Md (Dr Niparko); Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston (Dr Rauch); Department of Otolaryngology–Head & Neck Surgery, University of Michigan, Ann Arbor (Dr Telian); and Boystown National Research Hospital, Omaha, Neb (Dr Brookhouser).
Context A number of therapies have been proposed for the long-term management
of corticosteroid-responsive, rapidly progressive, bilateral sensorineural
hearing loss (autoimmune inner ear disease [AIED]). Methotrexate has emerged
as the benchmark agent but has not been rigorously evaluated for hearing improvement
in patients with AIED.
Objective To assess the efficacy of long-term methotrexate in maintaining hearing
improvements achieved with glucocorticoid (prednisone) therapy in patients
Design, Setting, and Participants A randomized, double-blind, placebo-controlled trial conducted from
February 3, 1998, to November 5, 2001, of 67 patients with rapidly progressive,
bilateral sensorineural hearing loss at 10 tertiary care centers in the United
Intervention Randomization to either oral methotrexate (15 to 20 mg/wk; n = 33) or
placebo (n = 34), in combination with an 18-week prednisone taper. Follow-up
examinations, including audiometric evaluation, were performed at 4, 8, 12,
24, 36, 48, and 52 weeks, or until hearing loss was documented.
Main Outcome Measure Maintenance of hearing improvement achieved from prednisone treatment.
Results Sixty-seven patients (57.8%) enrolled in the prednisone challenge experienced
hearing improvement. Twenty-five patients (37%) experienced hearing improvements
in both ears. Of the individuals who reached study end points, 24 (80%) of
30 end points were because of measured hearing loss in the methotrexate group
and 29 (93.5%) of 31 end points were because of measured hearing loss in the
placebo group (P = .15). Methotrexate was no more
effective than placebo in maintaining the hearing improvement achieved with
prednisone treatment (hazard ratio, 1.31; 95% confidence interval, 0.79-2.17; P = .30).
Conclusion Methotrexate does not appear to be effective in maintaining the hearing
improvement achieved with prednisone therapy in patients with AIED.
Prior reports suggested that rapidly progressive, bilateral, asymmetric
inner ear dysfunction may be caused by immunological attack or may be associated
with autoimmune disorders.1- 3 McCabe4 renewed interest in this disorder as a distinct clinical
entity and motivated investigators to identify the most efficacious treatment
regimens for management of this potentially reversible form of deafness. Initial
experience with this disorder has underscored the risk of developing bilateral
profound deafness and vestibulopathy if patients are left untreated or treated
On empirical grounds, glucocorticoids and cytotoxic agents were initially
proposed as treatments. In a follow-up report, McCabe5 recommended
high-dose prednisone with the addition of cyclophosphamide for prolonged periods.
Although this regimen appeared to be effective, the potential adverse effects
and long-term morbidity and mortality risks of cyclophosphamide limited its
use, especially in younger patients.
Subsequently, several reports proposed the use of less toxic agents
for autoimmune inner ear disease (AIED), including methotrexate,6,7 plasmapheresis,8 azathioprine,9- 11 and
intravenous gamma globulin.12 Low-dose oral
methotrexate (7.5 to 20 mg/wk) was reported to improve hearing and balance
in patients with AIED and Meniere disease.6,7 Furthermore,
methotrexate is currently regarded as the gold standard of care for patients
with rheumatoid arthritis.13 In view of its
tolerability, efficacy, and ease of use, methotrexate has emerged as the benchmark
agent to which other agents are compared in clinical trials.14 Its
introduction in the 1980s as a once-weekly agent in the treatment of patients
with rheumatoid arthritis has led to its acceptance as the most widely prescribed
agent for rheumatoid arthritis; adherence to guidelines for careful monitoring
of hematologic, renal, hepatic, and pulmonary adverse reactions produces a
very low incidence of potential serious adverse effects.15
Although many physicians have thought that high-dose prednisone (60
mg/d) was effective in reversing hearing loss and maintaining hearing at improved,
albeit diminished levels, this treatment effect was not maintained once the
prednisone was tapered. The appeal of methotrexate was its potential prednisone-sparing
effects and long-term safety. Prior studies of methotrexate in patients with
AIED have been small, open-labeled, and uncontrolled.
In this article, we report the results of a prospective, multi-institutional,
double-blind, placebo-controlled study designed to assess the efficacy of
long-term methotrexate in the maintenance of initial hearing improvement in
patients with AIED.
The AIED study population was defined by inclusion and exclusion criteria
designed to limit enrollment to individuals with idiopathic, progressive,
bilateral sensorineural hearing loss; to ensure appropriate candidates for
treatment with study medications; and to identify those with a high likelihood
of complying with the study protocol. The sensorineural hearing loss had to
be 30 dB or more in both ears at 1 or more frequencies (250, 500, 1000, 2000,
3000, 4000, 6000, or 8000 Hz). Hearing must have actively deteriorated in
at least 1 ear within 3 months of entering the study and the hearing loss
had to be determined by the study otologists to be idiopathic based on clinical
evaluation, blood tests, or radiographic imaging.
All patients underwent a retrocochlear evaluation that included a brainstem
evoked response audiogram and a computed tomographic scan or magnetic resonance
imaging. By protocol, participants were aged 18 to 70 years, had no more than
30 days of prednisone treatment (at therapeutic doses) in the previous 3 months,
and had no more than 30 days of methotrexate therapy for AIED at any time
in their history.
Patients with the following conditions were excluded: insulin-dependent
or brittle diabetes; history of tuberculosis or prophylactic isoniazid treatment
for a positive tuberculin skin test result; serious psychiatric disease; history
of psychiatric reaction to corticosteroids; active malignancy within the past
5 years (excluding nonmelanomatous skin cancer); prior treatment with chemotherapy
agents, immunosuppressive drugs, or cyclosporine; pancreatitis or active peptic
ulcer disease; positive result for human immunodeficiency virus or hepatitis
B or C; renal insufficiency; alcohol abuse; herpes zoster; fluctuations in
hearing associated with episodic vertigo, without episodes of rapid progression;
cochlear otosclerosis defined by radiographic evidence; luetic deafness; idiopathic,
sudden sensorineural hearing loss occurring less than 24 hours as atypical
for the diagnosis of AIED; Cogan syndrome; or perilymph fistula.
The study protocol and consent forms were approved by institutional
review boards at each of the 10 clinical sites and the coordinating center.
The study involved 2 phases (Figure
1); all participants were fully informed and provided separate signed
consent before entering each phase. In the prednisone challenge phase, all
enrolled participants were prescribed a 1-month open-label regimen of prednisone
therapy (60 mg/d). The primary goal of this phase was to identify participants
who were responsive to therapy according to the following: pure-tone air conduction
thresholds at 8 frequencies (250, 500, 1000, 200, 3000, 4000, 6000, and 8000
Hz) and word identification scores at 40-dB sensation level. Participants
were recruited to the randomized trial of methotrexate vs placebo if they
demonstrated improved hearing, defined as (1) an improvement of sensorineural
hearing from baseline, in at least 1 ear, of 15 dB or more in the pure-tone
air conduction thresholds at any of the 8 frequencies, or of 10 dB at 2 consecutive
frequencies; or an increase of more than 12% in word identification score;
and (2) no significant additional pure-tone air conduction threshold loss
at any frequency and no significant additional loss in word identification
score in either ear.
Improvement could have taken place in either ear (ie, not necessarily
the ear in which the rapid hearing loss was demonstrated in order for the
participant to enter the study) but there could be no further hearing loss
in either ear.
In phase 2, participants whose hearing stabilized in response to prednisone
therapy were tapered from prednisone and followed up by study personnel. Participants
who experienced further hearing loss were also followed up by study personnel
but their treatment was organized by their own physicians and not governed
by study protocol. Participants and study personnel were blinded to which
group the participants were assigned. Audiologists were also blinded to previous
audiological results obtained on each participant.
Of the 959 volunteers who were screened, 681 were found to be ineligible.
The major reasons for ineligibility were audiologic criteria (n = 329), medical
history (n = 199), and age (n = 125); however, an additional 28 were excluded
for other reasons (eg, refusal to accept randomization and factors judged
by clinic staff to compromise adherence). An additional 162 individuals declined
further participation at some time during the screening process.
Of the 116 patients who enrolled in the prednisone challenge, 18 refused
further participation in the study. Of the remaining 98 individuals, 67 responded
to prednisone and accepted randomization into the methotrexate clinical trial.
Randomization was governed by a masked variable-length blocking scheme (block
lengths 2 or 4), which was stratified by clinical site to promote balance
within each center, and administered by computer and maintained at the coordinating
center that automatically checked all eligibility criteria.
At the end of the prednisone challenge and at the beginning of the prednisone
taper, participants were randomly assigned, with equal probability, to either
methotrexate at 7.5 mg/wk or placebo. An oral methotrexate regimen was used
in which 2.5-mg tablets of methotrexate or placebo were given at 12-hour intervals
for 3 doses. If no toxicity had occurred after the first 4 weeks, dosage for
both was escalated to 6 tablets or 15 mg/wk for the second 4 weeks. After
8 weeks, the dosage for both was increased to 8 tablets or 20 mg/wk and remained
at this level for the remainder of the trial. The dosage of the blinded medication
could be adjusted to 15 mg/wk for the remainder of the trial in response to
symptoms of intolerance. All participants took 1 mg/d of folic acid for prevention
of folate depletion and prophylactic avoidance of adverse effects associated
with chronic methotrexate administration.
Prednisone taper, at the end of 1 month at 60 mg/d, was accomplished
by a dose reduction to 40 mg for 1 month, reduction of 10 mg for 2 successive
months each, and then by 5 mg every 2 weeks (× 3) until the goal of
no prednisone was reached after an 18-week taper. Participant follow-up consisted
of regularly scheduled clinic visits to assess current medication use, symptoms,
and safety. Adherence to study medication was monitored through pill counts
at each clinic visit. Audiometric examinations were performed at 4, 8, 12,
24, 36, 48, and 52 weeks into follow-up to identify study end points. All
patients were given prescriptions for ranitidine to be used for gastrointestinal
symptoms associated with chronic prednisone therapy.
Participants who were documented at any time during the 52 weeks of
planned follow-up to have lost hearing relative to the point of randomization
into the trial (ie, after a 1-month course of prednisone therapy) were defined
to have reached end point. The primary end point for the trial was both clinically
meaningful and sensitive to medical therapy. Hearing loss criteria were based
on changes from the time of randomization in either the pure-tone air conduction
thresholds or word identification scores, in either ear, as a deterioration
in pure-tone air conduction threshold relative to randomization values, by
15 dB at an individual frequency or 10 dB at 2 consecutive frequencies; or
a worsening of word identification score of at least 12%. Word identification
score was based on the ability to repeat correctly an open set of monosyllabic
words at suprathreshold intensity. Word lists were phonetically balanced and
percentage was based on the number of words repeated correctly. End point
status was declared if these criteria were confirmed at 2 consecutive examinations,
2 to 4 weeks apart, and at least 1 criterion was met.
To control for the possibility of differential follow-up between treatment
groups, individuals who were lost to follow-up or who did not complete the
scheduled 52-week closeout visit were also declared to have reached study
end point at the time of their last visit. This approach prevented differential
rates of end points to be attributable to differential rates of follow-up.
Participants who were not scheduled to have a 52-week closeout visit because
of the early termination of the trial were censored at the time of their last
visit, unless clinic staff reported that follow-up had already been lost.
This approach allowed end point status to be defined for all participants
except those censored because of early termination of the trial.
The secondary end point evaluated hearing loss in comparison with baseline
values (before prednisone treatment) in the event of a primary end point,
which was based on hearing loss in comparison with the phase 1 closeout audiogram.
If a participant continued to exhibit some hearing gains, this additional
evaluation checked for a deterioration in pure-tone average (500 to 3000 dB)
by 5 dB or a worsening of word identification score of at least 12% (both
relative to baseline values).
In the absence of these criteria and physician approval, participants
were permitted continued treatment on blinded study medication. A secondary
end point was declared if these criteria were demonstrated on consecutive
visits, if the physician or the participant elected to discontinue treatment,
or if the participant was lost to follow-up. For a treatment failure occurring
before 52 weeks, regardless of treatment assignment, a participant was offered
an additional month of prednisone and open-label methotrexate in similar doses.
All analyses were based on the intention-to-treat principle. Times to
events were measured from the date of randomization to the date of the first
audiometric analysis that triggered end point. Although a second audiogram
was used to confirm end point 2 to 4 weeks later, it was not used for hearing
data analysis or timing the end point. Kaplan-Meier method plots were used
to portray the distribution of times until end points.16 Log-rank
tests served as the primary comparisons between treatment groups. Cox proportional
hazards regression model was used to compute hazard ratios (HRs) and 95% confidence
intervals (CIs) for participant subgroups and to identify predictors of end
points.17 The proportionality assumption inherent
in this model was supported by analysis of residuals. χ2 Test
was used to compare frequencies. Mean levels of the longitudinal audiometric
data over time between the treatment groups were compared using generalized
linear models fitted by maximum likelihood, which allowed for varying patterns
of follow-up among participants. Poisson regression was used to compare rates
of adverse events; Fisher exact test was used to compare the percentage of
individuals experiencing any adverse event. SAS statistical software version
6.06 was used for all analyses (SAS Institute Inc, Cary, NC). P<.05 was considered statistically significant.
This trial was designed to detect, with 90% statistical power, whether
methotrexate therapy might lead to a 3-fold increase (from an expected 20%
in the placebo group) in the success rates of maintaining hearing improvement
associated with prednisone therapy at 52 weeks. To accomplish this, a goal
of randomizing 130 participants was set. Trial monitoring guidelines for early
stopping for success were based on approximate O'Brien-Fleming boundaries
to control for multiple testing.18 Stopping
for futility was based on interim analyses of conditional power. These interim
power projections were developed through computer simulations in which the
current observed data were augmented with randomly imputed data generated
from probabilities for adherence, compliance, and success detailed in the
study protocol (and determined before the start of the trial) and the targeted
sample size. Each interim power was estimated by using 10 000 simulations.
Results from these simulations were accumulated and the proportion of times
a significant result was achieved based on the primary analysis described
in the protocol was computed. This size of simulation approach was sufficient
to yield an SE for estimated power of ≤.005.
Trial monitoring for early stopping was conducted semi-annually by an
independent data and safety monitoring committee charged to protect the safety
of the participants and the integrity of data. Each clinical site underwent
an audit for compliance with the study protocol by members of the data coordinating
center, a physician member of the study steering committee, and/or a member
of the National Institutes of Health clinical trials staff.
Enrollment of the trial began February 3, 1998, with formal monitoring
of the trial in November 1998. Assignment to methotrexate therapy was associated
with an increased rate of study end points (relative to placebo) at every
interim analysis. On October 31, 2001, the data and safety monitoring committee
recommended termination of recruitment and the orderly closure of the trial,
based on no apparent benefit of methotrexate over placebo and projections
indicating that continuation would be unlikely to alter this finding. At that
time, the probability of detecting a significant benefit for methotrexate
(should the trial continue to its planned completion) was 0.016 at the current
estimated HR for methotrexate therapy and 0.146 at the lower bound of a 95%
CI for this HR. It was thus quite unlikely that the unfavorable trend observed
for methotrexate would be reversed. Study data were collected up to November
Figure 1 illustrates that
116 (12%) of 959 patients screened were entered into the trial and participated
in the prednisone challenge. Table 1 describes
the 67 participants who qualified and enrolled in the trial. The randomization
process yielded similar distributions of these characteristics between the
trial groups. Twenty-five participants (37%) experienced hearing improvements
in both ears. In their most responsive ears, the mean (SD) change in air conduction
threshold across the 8 measured frequencies was 10.0 (9.5) and in word identification
scores was 20.5 (18.4).
Figure 2 shows the distribution
of times until study end points by treatment assignment. Differences between
these distributions did not reach statistical significance (log rank P = .29). Table 2 provides
a breakdown of the reasons for study end points. Of the 30 individuals who
reached study end points in the methotrexate group, 24 end points (80%) were
because of measured hearing loss; of those assigned to placebo therapy, 29
(93.5%) of 31 end points were because of measured hearing loss. These 2 rates
did not differ significantly (P = .15). The percentage
of audiometric end points occurring among ears that initially responded to
prednisone therapy was similar between groups: 22 (91.7%) of 24 in the methotrexate
group and 27 (93.1%) of 29 in the placebo group.
Of the 61 patients who reached criteria for a primary end point, 51
(83.6%) also reached secondary end point status, 9 (14.8%) did not reach secondary
end point status by 52 weeks, and 1 (1.6%) was censored because of the early
termination of the trial. Of the 51 secondary end points, 15 (29.4%) were
because of audiologic criteria, 24 (47.1%) were because of drug discontinuation
by the AIED physician, and 12 (23.5%) were because of participant dropout
or refusal. There were no statistically significant differences in times until
secondary end point status between individuals assigned to methotrexate vs
placebo (log rank P = .51) (Figure 3).
Table 3 lists results from
Cox proportional hazards regression model to identify predictors of primary
end points. Patients assigned to methotrexate were at slightly, but not significantly,
higher risk for end points than those assigned to placebo (fitted HR, 1.31;
95% CI, 0.79-2.17; P = .30). The rates of end points
were similar across sexes and age groups and were not significantly related
to the response to prednisone therapy (all P>.10).
Figure 4 shows the mean changes
in pure-tone air conduction thresholds and word identification scores by treatment
assignment. These are limited to ears that initially responded to prednisone
and to examinations through primary end point determination. There were no
significant differences between treatment groups with respect to these measures
(P = .21 and P = .59, respectively).
Table 4 lists serious and
other adverse events that occurred during the prednisone challenge and trial,
and provides rates per 100 person-years. Very few adverse events occurred.
Two patients (1 in each group) experienced severe adverse events; the most
serious included the patient in the placebo group diagnosed with lung cancer
at the beginning of the blinded portion of the trial. Most of the other adverse
events were predictable based on exposure to prednisone and methotrexate,
elevated blood glucose levels and weight gain (prednisone), and abnormal liver
function (methotrexate). In total, 10 (14.9%) of 67 patients discontinued
participation in the trial for adverse events.
This study demonstrated that methotrexate was no more effective than
placebo in maintaining hearing improvement in patients with AIED, who demonstrated
initial benefit from high-dose corticosteroids. The study was halted when
conditional power calculations and analyses revealed that further recruitment
of patients would be futile given the decline in hearing that was observed
in both groups.
An early reported clinical trial on the use of methotrexate in immune-mediated
inner ear disease was retrospective and uncontrolled.6 In
that study of 25 participants treated with methotrexate, 69.6% were reported
to have improved hearing and 80% showed improvement of vestibular symptoms.
In a subsequent retrospective clinical trial19 of
methotrexate for treatment of bilateral immune-mediated Meniere disease (N
= 18), hearing improvement was observed in 5 participants (28%) and stabilization
of hearing was observed in 7 participants (39%). The major benefit appeared
to be resolution of vertigo observed in 14 participants (78%).19
In a prospective open-label study, 25 individuals with several forms
of presumed immune-mediated sensorineural hearing loss (bilateral Meniere
disease, Cogan syndrome, and progressive sensorineural hearing loss responsive
to prednisone) were treated with a 3-week high-dose prednisone taper; 18 participants
responded with partial improvement in at least 1 ear (72%).20 This
compares to 57.8% in our study, although participants with Cogan syndrome
and typical Meniere disease were specifically excluded.
Allowing for a larger hearing loss change than permitted in our study
and only using a single audiological evaluation at 52 weeks, Matteson et al20 found at the end of the 12-month study period that
11 (65%) of 17 participants improved, 2 participants (12%) had worse hearing,
and 4 participants (23%) remained the same compared with the pretreatment
values. Both pure-tone and speech discrimination improved in at least 1 ear
in only 4 (23%) of 17 participants. In our study, however, the comparisons
were made with postprednisone levels to determine if hearing improvements
could be maintained. Matteson et al20 used
baseline levels before any treatment, which means that they also incorporated
the effect of prednisone in their analysis. When data from our study was reexamined
adopting the end point definition used by Matteson et al,20 there
were still no detectable significant differences associated with the addition
of methotrexate with prednisone therapy (P = .32).
Several factors may have influenced these findings. Strict audiologic
and clinical criteria were necessary to confirm AIED and protect patient safety
but clearly resulted in a low enrollment rate of 12% of those screened. Despite
this, it is possible that our study cohort contained individuals who did not
have an autoimmune or an immunological cause of deafness. Prednisone responsiveness,
the primary diagnostic criterion for entry into our study, likely did not
offer complete specificity in identifying patients with an autoimmune basis
for their hearing loss. In addition, entry criteria required all participants
to have experienced hearing loss within the previous 3 months.
Appropriate selection of participants was further addressed by excluding
those individuals in whom a nonimmunological etiology could be established
(eg, a strong familial/genetic history of hearing loss, chronic otitis media,
otosclerosis), and by including individuals with a coexisting autoimmune condition
and with rapidly progressive hearing loss. As a result of these selection
criteria, 57.8% of the participants enrolled in the prednisone challenge experienced
It is also possible that our study design did not allow for sufficient
methotrexate treatment, either in terms of dose or duration, to achieve therapeutic
benefit. Although the exact mechanism of its beneficial effect in rheumatoid
arthritis is not completely known, methotrexate appears to affect a variety
of intracellular pathways that are of potential importance in the pathogenesis
of not only rheumatoid arthritis but other related diseases of immune dysregulation.21 Methotrexate appears to provide initial improvement
in most patients with rheumatoid arthritis within a few weeks and maximal
benefit is noted at 6 months.22,23 When
methotrexate was initially approved by the Food and Drug Administration for
treatment of rheumatoid arthritis, the dosages used in the initial trials
were 7.5 to 15 mg/wk.24 As experience has been
gained with long-term use of the drug, current recommended dosages have nearly
doubled to 15 to 25 mg/wk.13,14,25
The appropriateness of the 20 mg dosage is affirmed by recent trials
of new agents for rheumatoid arthritis (entanercept), in which the methotrexate
regimen, viewed as standard therapy, is 20 mg/wk.26- 28
In our study, the choice of 20 mg/wk should have been sufficient to
achieve a treatment effect as suggested by companion data in other autoimmune
states. The methotrexate dose was escalated rapidly while participants were
maintained when receiving high-dose prednisone, keeping mindful of the fact
that the safety of this drug had not been established in AIED. Participants
received at least 15 mg/wk of methotrexate with a goal of 20 mg/wk if adverse
effects did not develop. The most common dose of methotrexate was 15 mg/wk.
Furthermore, to determine if reaching end point was a consequence of inadequate
methotrexate dosage, our study reviewed the future status of participants
who were end point free at the time they reached their full methotrexate dose
and compared this with the future status of participants in the placebo group
who were end point free at comparable times. The rates of future end point
were very similar between the 2 groups: 7 (78%) of 9 for participants in the
methotrexate group and 7 (70%) of 10 for participants in the placebo group.
The failure to detect a positive methotrexate effect does not appear to be
because of failure in reaching full methotrexate dose.
Another possible explanation is that the study end point definition
was overly sensitive to minor changes in audiometric results, which required
confirmation according to study protocol. To address the possibility that
a treatment effect was not measured by the primary end point, secondary end
points were defined that required more changes in clinical status. No difference
was found between methotrexate and placebo with respect to more conservative
One of the potential benefits of methotrexate might have been stabilization
of hearing levels with fewer fluctuations over time. Many patients with AIED
experience large swings in their hearing thresholds or speech discrimination
that greatly impacts their function. Unfortunately, our study was unable to
assess this. It was clear, however, that methotrexate was not able to maintain
the significant hearing improvements obtained by high-dose prednisone over
time any better than placebo.
The participants enrolled in our trial showed very acceptable complication
rates and anticipated adverse events. There were no deaths or severe morbidities.
The adverse events associated with prednisone included glucosuria and elevated
blood glucose levels. No participants were admitted for drug-induced diabetes,
although 1 participant required an oral hypoglycemic on a temporary basis.
One participant was discovered to have a mild developing cataract. No participant
developed clinically evident avascular necrosis of the hip or symptomatic
osteoporotic fractures. Given the dosages of corticosteroids used in the study,
osteoporosis probably developed in many participants. For this reason, study
personnel required every participant to be cared for by a primary care physician
with full knowledge of the risks of the experimental treatment disclosed to
that physician. Several participants required discontinuation of study medication
(n = 2 in the placebo group and n = 2 in the methotrexate group) or open-label
methotrexate (n = 5) during treatment for abnormal blood data. All resolved
without further intervention. Based on these results and with proper informed
consent, the use of prolonged and high-dose corticosteroids in patients with
AIED may be safe, despite the inherent risks.
The results of our study clearly underscore the need for more effective
and less toxic therapy for AIED, and that randomized controlled trials are
necessary to establish benefit. Methotrexate is not effective in maintaining
hearing after patients are tapered down from high-dose prednisone treatment.
Despite prolonged high-dose prednisone and a slow taper treatment, the patients
once again began to lose their hearing.