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Clinical outcomes and documentation of partial beneficial effects of immunotherapy for multiple sclerosis.

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Clinical Outcomes and Documentation of
Partial Beneficial Effects of Immunotherapy
for Multiple Sclerosis
Multiple sclerosis (MS) is a chronic disease that usually
worsens or progresses over years or decades. Except
for primary chronic progressive (CP) MS, the other
common disease patterns-relapsing-remitting, relapsing-progressive, and secondary CP-are typified in the
early stages of MS by relapses followed by some degree of remission. Progression, or the failure of remission, is the element of MS that is the major cause of
disability and decline of quality of life in MS. In spite
of the prevalence of C P MS, evaluation of new therapeutic agents in this disease form has been difficult,
partially due to its long and variable course.
With the goals of determining success (often referred to as fewer treatment failures) and safety of a
treatment, the performance of therapeutic trials in MS
is a learning process. A recent workshop dealt with
the critical issues that must be considered for a valid
outcome of clinical trials in MS [l}. Goodkin, Rudick,
and coworkers [2] followed the prevailing guidelines
in conducting a carefully crafted study while being willing to take on the tough task of investigating treatment
for CP MS. In a randomized, double-blind, placebocontrolled study of 60 ambulatory CP MS patients,
they present evidence, derived from a “composite” of
clinical scales, that weekly oral methotrexate (MTX)
was significantly more effective, notably for upper extremity function, than placebo in slowing the pace of
worsening. Although there was a 15%’ dropout in
treatment and control groups over the 2 years of the
study, MTX appeared to be safe at the dosage used.
MTX is one of the more broadly acting immunosuppressants that have been tested in MS. Prior to the
study by Goodkin and colleagues, MTX had received
only minimal attention for the treatment of MS {31,
and results had been negative or inconclusive 141. Usually viewed as exerting its effect as an antimetabolite
because it inhibits dihydrofolate reductase and blocks
folic acid conversion [ 5 } , MTX is also an antiinflammatory agent {GI. It inhibits the synthesis of interleukin-1 and possibly other cytokines; interferes with the
generation of prostaglandins; and enhances the release
of adenosine, which, in turn, suppresses inflammation
16, 71. MTX has shown benefit in patients with rheumatoid arthritis treated prospectively and openly for as
long as 7 years even though by that time less than 50%
of the patients starting treatment remained on the drug
IS}. As an indication of MTX’s apparent safety, only
11.5%: of patients with rheumatoid arthritis treated
with an average weekly dose of MTX of approximately
10 mg withdrew after 7 years of treatment [8}.
The reported benefit of MTX in this trial
places
emphasis on the importance of selecting a primary
end point in study design. Goodkin and coworkers 121
used a composite battery of measures, specifically the
Kurtzke Expanded Disability Status Scale (EDSS) [7],
the Ambulation Index (AI) [lo), the Box and Block
Test (BBT), and the 9-Hole Peg Test (7HPT) [l 11.
Failure of therapy was defined as a designated change
that was sustained for more than 2 months in one or
more of the components of the composite measure.
The EDSS and A1 are heavily weighted for lower extremity impairment and have been the customary clinical scales used in clinical trials of agents in CP MS that
failed to evidence benefit [12, 131. Similarly, MTX did
not significantly affect C P MS when judged by the
EDSS or A1 in this study. But it did when assessed by
the BBT and 9HET, both of which are tests for upper
extremity function. Thus, is the documentation of a
benefit of MTX in C P MS, a phase whose natural history heretofore has not been significantly betc-ered by
any treatment, the unique effects of MTX or the improved outcome measures of upper extremity func.
.
tion! It is conceivable that other agents, such as
cyclosporine, cyclophosphamide, and azatl-ioprine,
presently viewed as having no or limited beneficial effect in C P MS, might have also had a documentable
desired effect if the composite measure, with emphasis
on measures other than the EDSS and AI, had been
used to determine their effectiveness.
Additional issues should be considered as other investigators seek to confirm the findings of Goodkin
and coworkers 12). First, in the absence of an independent, assessable marker, such as serial cranial magnetic
resonance imaging (MRI), the demand for “blinding”
of assessment must be very strong. Subtle unlilinding
effects could have resulted from EDSS score s :ratification of patients by the study coordinator who made
the treatment assignments, evaluations by a consultative study advisory committee, and the careful observations of the treating neurologist. Second, of greater
concern is the inclusion of both patients with primary
and those with secondary CP MS in the study. While
the distinction between these two forms of ICP MS
may not have been fully appreciated at the onset of
this trial, there is steadily mounting evidence that primary C P MS differs from secondary CP MS, especially
Copyright 0 1995 by the American Neurological Assocktion
5
in regard to the extent of inflammation 1141. In the
MTX study, 11 of 29 of the placebo control group and
7 of 31 of the MTX-treated group had primary C P
MS. While it is true that this difference in the arms of
the study is not statistically significant, it could be of
importance. This small study would have been more
persuasive had primary CP MS patients been excluded
altogether rather than relying on statistical support for
lack of effect of the unequal distribution of 30% (18
of 60) of the population investigated. Third, a decision
must be reserved on the adequacy of validation and
analysis of the composite measure. Goodkin, Rudick,
and colleagues are clearly established as clinical investigators of MS. However, scales that have not received
widespread use in MS trials and derivative outcome
measures, such as the composite battery, will require
more experience. Fourth, the concordance of the serial
cranial MRI with the clinical outcome of the MTX
effect is important. As was shown by the trial of interferon beta-1 b C151, the stabilization of disease burden
as determined by cranial MRI furnishes additional confidence for an effective treatment in MS since tissue
damage is often clinically silent. In specific reference to
MTX, its beneficial effect on symptoms in rheumatoid
arthritis may be discordant with the usual continued
erosion of bone seen radiographically [8].
The unlabeled or unapproved new use of medications is common in the United States and permits the
physician, even in the absence of specific approval from
the Food and Drug Administration (FDA), to prescribe
a drug already recommended for another purpose.
MTX has been approved previously for the treatment
of certain forms of leukemia and carcinoma, severe
psoriasis, and severe rheumatoid arthritis in adults. I t
has also been tried in a variety of autoimmune diseases
through unlabeled new use. Although recommendations have been proposed to expand the availability of
experimental treatments for MS while they are still
under controlled clinical study { l b ] ,there is no uniform and acceptable policy for the unapproved new
utilization of drugs for MS. The decision by a qualified
physician to administer medicines through unlabeled
new use often rests on the lack of other therapeutic
options for a patient's condition and publications, such
as the present one on MTX C21, in peer-reviewed medical journals. Through the mechanism of peer review,
a critical analysis of collected data by investigators,
manuscript reviewers, and a journal editor constitutes
the informal acceptance of a new use of medications
even though such use did not result from FDA approval. Goodkin, Rudick, and colleagues have given
MTX a careful study in CP MS, but follow-up studies
and additional documentation, possibly with different
drug doses and even a pivotal trial Cl], will be required
before the beneficial, partial effect they note can be
clarified and the appropriate role of MTX in the management of CP MS defined. In the meantime, physicians caring for C P MS patients may elect to treat them
with MTX through a judicious and cautious application
of the unlabeled new use of a drug.
John N . Whitaker, MD't
Galeri W . Mitchell. MD*
Gary R. Cutter, Pt5Df.O'
* Departmeiit of Neurology and
Cerzter for Neuroinimunology of the
Uniuersity of Alubamu at Birmingham
Birmingham. A L
i' Neurology and Research SewiceJ
of the Birmingham Veteruns Medical Center
B imiinghani A L
~
f Dit'ision of Biostatistics
AMC Cancer ReJearch Ceriter
Denrer. CO
Q'Pythagaros.1mDetiiler. CO
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outcomes, effect, beneficial, documentation, clinical, immunotherapy, partial, sclerosis, multiple
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