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Multiclinic study of DMSO for systemic sclerosis.

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LETTERS
muscle strength gradually increased during the following
months. Two months after initiation of treatment, the serum
muscle enzyme levels had returned to normal. The dose of
cyclosporine was reduced to 5 mg/kg/day after 4 weeks of
treatment, because of upper gastrointestinal complaints and
elevated serum creatinine levels. These side effects subsided
after dose reduction, and the creatinine level returned to
pretreatment values. Prednisone dosage was reduced to 10
mgld ay .
At this time, almost a year after initiation of treatment, the patient’s polymyositis is in complete remission;
she receives a maintenance dosage of 5 mgikg of body
weightiday of cyclosporin A. Moreover, from her original
bedridden state, she has returned to performing light housework.
We agree with Zabel et a1 (2) and Bendtzen et a1 (3),
that carefully monitored treatment with cyclosporine should
be considered in patients with intractable polymyositis,
since the results of such treatment in our patient proved to
be quite favorable.
Henk Simon Goei The, MD
Piet Jacobs, MD
Harry Houben, MD
Department of Rheumatology
De Wever Ziekenhuis
Heerlen, The Netherlands
1. Bohan A, Peter JB: Polymyositis and dermatomyositis. N Engl J
Med 292:344-347, 1975
2. Zabel P, Leimenstoll G, Gross WL: Cyclosporin for acute
de:rmatomyositis (letter). Lancet i:343, 1984
3. Bendtzen K, Tvede N, Andersen V, Bendixen G: Cyclosporin
for polymyositis (letter). Lancet i:792-793, 1984
4. Eingel WK, Richter AS, Gakdi AP: Polymyositis: remarkable
response to total body irradiation (letter). Lancet i:658, 1981
5 . Hubbard WW, Walport MJ, Halnan KE: Remission from polymyositis after total body irradiation. Br Med J 284:1915-1916,
19182
Multiclinic study of DMSO for systemic sclerosis
To tihe Editor:
After reading about the multiclinic statistical study
by VJilliams et a1 on the comparative effects of high and low
concentration DMSO and normal saline on the healing of
scleroderma ulcers (l), I must congratulate the investigators,
statisticians, and the Food and Drug Administration (FDA)
for their combined efforts. However, there are some controversial issues that I do not believe have been adequately
addressed.
It is my understanding that the original NIH protocol, which was designed at the request of the FDA, called for
a 6-month study which included a 3-month double-blind
study using placebo, 2% DMSO, and 70% DMSO followed
by a 3-month, open-label crossover study for all participants
to immerse their hands and wrists in 70% DMSO. However,
the article does not include data from the last 3 months of the
study.
The statistical data for the first 3 months of the study
1437
show DMSO to be of questionable value except in the area of
pain reduction. The authors state that DMSO efficacy could
have been overlooked because fewer patients than expected
were using in 70% DMSO. This was the result of a 29%
dropout due to adverse skin reactions. Therefore, the low
number of patients completing the study allowed the possibility of a Type I1 error. To illustrate the statistical burden
imposed by this sample size limitation, only if the 70%
DMSO group had 100% improvement, while the control
group had become at least 10% worse, would it have been
possible to offer even a 90% chance of finding a significant
difference. The results, which are less than definitive because of the low statistical power calculation, do not prove
lack of DMSO efficacy; rather, the results obtained when
utilizing this statistical technique are inclusive. Nonetheless,
despite sample size limitations, when all patients who were
previously treated with normal saline or 2% DMSO were
crossed over to 70% DMSO, a trend toward decreased
numbers of ulcers and of open ulcers soon became evident.
The trend analyses showed statistically significant positive
trends for 3 variables which included pain, total number of
ulcers (P = 0.059 by one-way analysis of variance), and
reduction in number of open ulcers (P = 0.086).
I question the use of an arbitrary 3-month end point
for evaluation of ulcer healing (1). It is well known that the
healing time of ulcers is highly variable, and may range from
a few weeks to a year or longer. If the vascular supply to the
ulcer site is only temporarily occluded, ulcer healing will
occur more rapidly, with minimal loss of tissue, than the
ulcer which is associated with extensive and permanent
obliteration of digital arteries.
In my opinion, DMSO does not promote ulcer healing by specific pharmacologic activity. Rather, healing is
improved because DMSO rapidly penetrates damaged tissues, allows oxygen and nutrients to enter, and then becomes an effective scavenger of hydroxyl radicals (2), toxins, and other waste products that delay the healing process.
These DMSO actions allow for natural tissue healing to take
place. It is unlikely that this complex process of tissue repair
can be accomplished within 3 months in a random sample of
patients.
I also question the method used in this study for hand
immersion in 70% DMSO. Percutaneous administration of
DMSO is a more complex process than was originally
anticipated. Topical application or immersion with high
concentration DMSO is likely to cause skin irritation (3).
These adverse skin reactions are minimized when DMSO is
applied in low concentration during the initial phase of
treatment (3). The concentration of DMSO is then gradually
increased weekly, until the desired concentration can be
used without serious discomfort (3). Williams and colleagues
reported a 29% dropout rate because of adverse skin reactions that occurred with constant use of 70% DMSO
throughout the study.
The skin changes involving the hand, shown in
Figure 1 of Williams et al’s article (11, are not as serious as
portrayed. My colleagues and I have reported similar
changes (3). Several patients treated with prolonged daily
hand soaks for 12-14 months showed marked wrinkling and
shedding of sclerodermatous skin. Patients wore soft white
gloves between DMSO soaks. After soaking was discontin-
LETTERS
ued. the skin became soft, pliable, and normal-appearing.
The new skin did not become hide-bound during the 2-year
followup after completion of the study.
In my study on the treatment of scleroderma ulcers
by DMSO immersion (4), improvement in ulcer healing
occurred during the first 3 months of the study ( I extremity
was treated). During the second 3 months, improvement did
not continue as rapidly. However, the best ulcer healing
appeared during the last 6 months of the study (both extremities treated). In some patients, continuation of treatment
was necessary in order to maintain the improved state.
DMSO exerts a palliative, therapeutic effect on ulcer healing. However, it is a worthwhile supplemental therapeutic
agent, provided the limitations of therapy are understood.
Arthur L. Scherbel, MD
St. Luke’s Medical Center
Phoenix, AZ
and Cleveland Clinic Foundation
Cleveland, OH
1. Williams HJ, Furst DE, Dahl SL, Steen VD, Marks C, Alpert EJ,
Henderson AM, Samuelson CO Jr, Dreyfus JN, Weinstein A,
MacLaughlin EJ, Alarcon GS, Kaplan SB, Guttadauria M,
Luggen ME, Reading JC, Egger MJ, Ward JR: Double-blind,
multicenter controlled trial comparing topical dimethyl sulfoxide
and normal saline for treatment of hand ulcers in patients with
systemic sclerosis. Arthritis Rheum 28:308-314, 1985
2. Fox RB, Fox WK: Dimethyl sulfoxide prevents hydroxyl radicalmediated depolymerization of hyaluronic acid. Ann NY Acad Sci
41 1:14-18, 1983
3. Scherbel AL, McCormack LJ, Layle JK: Further observations
on the effect of dimethyl sulfoxide in patients with generalized
scleroderma (progressive systemic sclero , I S ) . Ann NY Acad Sci
141:613-629, 1967
4. Scherbel AL: The effect of percutaneous dimethyl sulfoxide on
cutaneous manifestations of systemic sclerosis. Ann NY Acad
Sci 411:120-130, 1983
Reply
To the Editor:
We appreciate Dr. Scherbel’s comments regarding
our paper (1) and we wish to respond to several of the issues
he raised.
This study was conducted independent of FDA direction. As stated in our article, the protocol was developed
at the Coordinating Center, Cooperative Systematic Studies
of Rheumatic Diseases Program, with the assistance and
approval of the member clinics and under the direction and
guidance of our Advisory Committee.
The protocol was a 3-month, double-blind study,
with an optional additional unblinded 3-month period with all
patients using the 70% dimethyl sulfoxide (DMSO) solution.
It was not a crossover design, and the latter 3-month period
was instituted to allow continued therapy without revealing
to either the patient or the observer the treatment used in the
double-blind trial. It also helped in the recruitment of
patients, since all patients could be assured at least 3 months
of treatment with 70% DMSO, even if initially randomly
placed in the placebo group. Forty-three patients entered,
but only 26 patients completed the open phase. Data were
collected on the last 3-month period but were uncontrolled
and have not been analyzed or presented.
Dr. Scherbel is correct that a Type 11 error was
possible and could lead to the conclusion that no differences
were present between the treatments when one did exist. If
our discussion in the paper which addressed this point was
unclear, we apologize. However, we do not understand Dr.
Scherbel’s calculations used to determine the “statistical
burden imposed by the sample size limitation.” To detect a
difference between an improvement rate of 5% in the control
group and 95% in a treatment group with 90% power at an a
of 0.05 would only require 6 patients per group (2). Large
differences among treatment groups were not apparent in our
study. While it is statistically possible that small differences
were not detected as explained in our paper, the differences
observed were very small, and Type I1 error was unlikely.
We selected 3 months for our double-blind trial based
on reports by Scherbel and coworkers that response was
rapid (3,4). In one study (3), 12 patients were treated with
topical DMSO in varying concentrations, with the result that
in 6 patients, ulcers healed within 3 weeks, and in the 3
others, within 6 weeks. Two of the 3 patients whose ulcers
were initially unresponsive were subsequently treated with
immersion therapy and their ulcers healed in 1 week. It was
reported that immersion therapy resulted in more rapid
healing than did topical application. In a later study (4),
Scherbel reported healing in 73% of ulcers within 3 months.
It is possible that a gradual increase in concentration
might moderate the skin reactions, but is not likely to
improve the efficacy. Seventy percent DMSO is the concentration commonly used and has been recommended as an
appropriate therapeutic dose (5). The skin reactions reported
were not simply peeling of the skin, but were painful,
erythematous blistering eruptions that could even crack and
bleed. The reactions were severe enough to require discontinuation of the drug.
H. James Williams, MD
John R. Ward, MD
James C. Reading, PhD
Cooperative Systematic Studies
of Rheumatic Diseases
Salt Lake City, UT
1. Williams HJ, Furst DE, Dahl SL, Steen VD, Marks C, Alpert EJ,
Henderson AM, Samuelson CO Jr, Dreyfus JN, Weinstein A,
MacLaughlin EJ, Alarcon GS, Kaplan SB, Guttadauria M,
Luggen ME, Reading JC, Egger MJ, Ward JR: Double-blind
multicenter controlled trial comparing topical dimethyl sulfoxide
and normal saline for treatment of hand ulcers in patients with
systemic sclerosis. Arthritis Rheum 28:308-314, 1985
2. Fleiss JL: Statistical Methods for Rates and Proportions. Second
edition. New York, John Wiley & Sons, 1981
3. Scherbel AL, McCormack LJ, Layle JK: Further observations
on the effect of dimethyl sulfoxide in patients with generalized
scleroderma (progressive systemic sclerosis). Ann NY Acad Sci
I4 1 :6 13-629, 1967
4. Scherbel AL: The effect of percutaneous dimethyl sulfoxide on
cutaneous manifestations of systemic sclerosis. Ann NY Acad
Sci 411:120-130, 1983
5. Fleischmajer R: Discussion paper: methodology and techniques
in the evaluation of dimethyl sulfoxide for connective tissue
disorders. Ann NY Acad Sci 243:393-394, 1975
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