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Progressive systemic sclerosis: Management. Part
IV: Colchicine
Alarcon-Segovia D.
Dept. Immunol. Rheumatol., Inst. Nac. Nutric., Mexico City
Mexico
Clinics in Rheumatic Diseases (United States) 1979, 5/1
(294-302)
Our studies indicate that colchicine appears to halt the
progression of PSS, and probably of the localized forms of
scleroderma as well, and causes improvement in a substantial
proportion of patients. Such improvement takes place mainly in
the skin and has been significant enough to be corroborated by
the histological examination of skin biopsies evaluated
without knowledge of the clinical situation. Some improvement
has also occurred at sites of involvement other than the skin,
particularly in regard to dysphagia and Raynaud's phenomenon.
The nature of our study did not allow us to determine if
treatment with colchicine may prevent the development of renal
or lung involvement. Patients who were begun on treatment with
colchicine earlier in the course of their disease had
significantly greater improvement than those who were first
treated after disease of longer duration. Long-term treatment
appeared to be required as evaluated by the correlation
between improvement and total colchicine dose received. The
apparent innocuity of long-term treatment with colchicine and
the beneficial effects which have been observed warrant the
use of this agent in the treatment of PSS. Early and prolonged
use appear particularly desirable.
Fish - oil dietary supplementation in patients with
Raynaud's phenomenon: a double-blind, controlled, prospective
study.
DiGiacomo RA; Kremer JM; Shah DM
Division of Rheumatology, Albany Medical College, New York
12208.
Am J Med (United States) Feb 1989, 86 (2)
p158-64
PURPOSE: The ingestion of omega -3 fatty acids could
benefit patients with Raynaud's phenomenon because, among
other effects, these fatty acids induce a favorable vascular
response to ischemia. The aim of our study was to investigate,
in a double-blind, placebo-controlled manner, the effects of
fish - oil fatty-acid dietary therapy in patients with
rheumatic disease.
PATIENTS AND METHODS: Thirty-two patients with primary or
secondary Raynaud's phenomenon were randomly assigned to
olive-oil placebo or fish - oil groups. Patients ingested 12
fish -oil capsules daily containing a total of 3.96 g
eicosapentaenoic acid and 2.64 g docosahexaenoic acid or 12
olive-oil capsules and were evaluated at baseline and after
six, 12, and 17 weeks. All patients ingested olive oil between
Weeks 12 to 17. Digital systolic blood pressures and blood
flow were measured at room air and water baths of 40 degrees
C, 25 degrees C, 15 degrees C, and 10 degrees C using strain
gauge plethysmography. Onset of Raynaud's phenomenon was timed
with a stop watch and defined as plethysmographic evidence of
cessation of blood flow and blood pressure in the study
finger.
RESULTS: In the fish -oil group, the median time interval
before the onset of Raynaud's phenomenon increased from 31.3
+/- 1.3 minutes baseline to 46.5 +/- 2.1 minutes at six weeks
(p = 0.04). Patients with primary Raynaud's phenomenon
ingesting fish oil had the greatest increase in the time
interval before the onset of the condition. Five of 11
patients (45.5 percent) with primary Raynaud's phenomenon
ingesting fish oil in whom the phenomenon was induced at
baseline could not be induced to develop Raynaud's at the six-
or 12-week visit compared with one of nine patients (11
percent) with primary Raynaud's ingesting olive oil (p =
0.05). The mean digital systolic pressures were higher in the
patients with primary Raynaud's phenomenon ingesting fish oil
than in patients with primary Raynaud's ingesting olive oil in
the 10 degrees C water bath (+32 mm Hg, p = 0.02).
CONCLUSION: We conclude that the ingestion of fish oil
improves tolerance to cold exposure and delays the onset of
vasospasm in patients with primary, but not secondary,
Raynaud's phenomenon. These improvements are associated with
significantly increased digital systolic blood pressures in
cold temperatures.
Retrospective studies in scleroderma : effect of
potassium para-aminobenzoate on survival.
Zarafonetis CJ; Dabich L; Negri D; Skovronski JJ; DeVol EB;
Wolfe R
Department of Internal Medicine, University of Michigan
Medical School, Ann Arbor.
J Clin Epidemiol (England) 1988, 41 (2) p193-205
Demographic and survival data are presented for 390
patients with scleroderma . For the entire group an estimated
81.4% survived 5 years from diagnosis and 69.4% survived 10
years. Life-table analyses revealed that adequate treatment
with potassium para-aminobenzoate (Potaba KPAB) was associated
with improved survival (p less than 0.01); 88.5% 5 year
survival rate and 76.6% 10 year survival rate for adequately
treated patients. Five and ten year survival rates for
patients never treated with KPAB were 69.8 and 56.6%,
respectively. Similar findings were obtained by comparing
observed to expected mortality for these patients; again, KPAB
therapy showed prolongation of survival. The Cox proportional
hazards model was also applied to this retrospective study
adjusting for baseline clinical involvement, demographics and
KPAB treatment. There were some interesting results including
a high significance for skin involvement per se as a
prognostic indicator: the greater the extent of skin
involvement the poorer prognosis. Time from first diagnosis to
first University Hospital visit or admission when included as
a covariate did not influence survival.
Lipodermatosclerosis is characterized by elevated
expression and activation of matrix metalloproteinases:
implications for venous ulcer formation.
Herouy Y; May AE; Pornschlegel G; Stetter C; Grenz H;
Preissner KT; Schopf E; Norgauer J; Vanscheidt W
Department of Dermatology, University-Hospital, Freiburg,
Germany.
J Invest Dermatol (United States) Nov 1998, 111 (5)
p822-7
Lipodermatosclerosis refers to skin induration of the lower
extremities and is associated with patients preceding venous
ulcerations. To better understand the pathogenesis of ulcer
formation we investigated the expression of matrix
metalloproteinases (MMP) and tissue inhibitors of
metalloproteinases (TIMP) in lipodermatosclerosis. By
preparing biopsies from healthy skin and liposclerotic
lesions, MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were analyzed
by using reverse transcriptase-polymerase chain reaction,
western blot, zymography, hydrolysis of [3H]labeled collagens,
and immunohistochemistry. Our investigations provide evidence
that mRNA and protein expression of MMP-1, MMP-2, and TIMP-1
were significantly increased in lipodermatosclerosis, whereas
the total amount of MMP-9 and TIMP-2 mRNA and protein was not
altered. Western blot of liposclerotic lesions revealed an
inactive proMMP-1-TIMP-1 complex, whereas MMP-2 was prominent
as an active 66 kDa band. Increased proteolytic activity of
MMP-2 could be proven in lesional in comparison with healthy
skin by zymography and [3H] collagen degradation. Increased
diffuse staining was found for MMP-1 in the epidermis and
dermis in comparison with controls. In lipodermatosclerosis,
MMP-2 was predominantly localized in the basal and suprabasal
layers of the epidermis, in perivascular regions, and in the
reticular part of the dermis. Furthermore, MMP-2 was
imbalanced by locally reduced expression of TIMP-2 in the
basement membrane zone of lesional skin. Our findings indicate
lipodermatosclerosis to be characterized by elevated matrix
turnover.
Pathogenesis of scleroderma (systemic
sclerosis).
LeRoy EC
J Invest Dermatol (United States) Jul 1982, 79 Suppl 1
p87s-89s
Increasing interest in the vascular features of scleroderma
has led to the hypothesis that the blood vessel is the major
target tissue and that the endothelial cell is the principal
cell target. Useful observations stemming from the vascular
hypothesis include the use of microvascular abnormalities in
the early detection of the patient destined to develop
classical scleroderma, the discovery of a serum protease
selectively cytotoxic to endothelial cells, and the study of a
serum mitogenic activity for fibroblasts in scleroderma
patients. Immune events related to the vascular lesions are
under active study but have not as yet provided a unique
immunological lesion in scleroderma patients. The possibility
that immunity to basement membrane (type IV) collagen may be
selective for scleroderma patients deserves further study.
Persistent immunity to endothelial basement membrane
structures would provide a basis for continued endothelial
injury. Techniques to quantify endothelial injury are useful
to assess activity of the vascular lesions and to monitor
therapies designed to block further vascular injury. The
definition of pre-fibrotic vascular lesions may have future
therapeutic and preventive implications for scleroderma .
Cutaneous vitamin D3 formation in progressive
systemic sclerosis.
Matsuoka LY; Dannenberg MJ; Wortsman J; Hollis BW; Jimenez
SA; Varga J
Department of Dermatology, Jefferson Medical College,
Philadelphia, PA 19107.
J Rheumatol (Canada) Aug 1991, 18 (8) p1196-8
Progressive systemic sclerosis (PSS) is a predominantly
dermal disorder which may be associated with epidermal
atrophy. We investigated epidermal function in 8 patients with
PSS and their healthy controls matched for age, sex and racial
group. We measured the vitamin D3 photosynthetic response to
whole body irradiation with ultraviolet light B (UVB). There
were no significant differences in basal serum vitamin D3
levels (mean +/- SEM: PSS 1.2 +/- 0.2 ng/ml; controls 0.8 +/-
0.1 ng/ml; p greater than 0.1) or post UVB blood values (PSS
5.2 +/- 1.4 ng/ml; controls 6.9 +/- 1.1 ng/ml; p greater than
0.1); although the increases post-UVB were significant in both
groups (p less than 0.01). In an additional group of 19
patients with PSS and their corresponding matched healthy
controls, we performed determination of random levels of the
active vitamin D metabolites, 25-hydroxyvitamin D (25-OH-D)
and 1,25-dihydroxyvitamin D [1,25-(OH)2-D]. Similar levels
were observed in both groups: 25-OH-D PSS 28 +/- 3 ng/ml,
controls 29 +/- 3 ng/ml; 1,25-(OH)2-D PSS 27 +/- 2 pg/ml,
controls 31 +/- 2 pg/ml (p greater than 0.1). None of the
correlations between skin area involved and vitamin D3
formation or active circulating metabolites reached
statistical significance (p greater than 0.1). We conclude
that global epidermal synthesis of vitamin D is retained in
PSS and, that the hepatic and renal vitamin D hydroxylating
mechanisms function normally in that condition.
Treatment of scleroderma with oral 1, 25-
dihydroxyvitamin D3: evaluation of skin involvement using
non-invasive techniques. Results of an open prospective
trial.
Humbert P; Dupond JL; Agache P; Laurent R; Rochefort A;
Drobacheff C; de Wazieres B; Aubin F
Department of Dermatology and Vascular Diseases, Hopital St
Jacques, Besancon, France.
Acta Derm Venereol (Sweden) Dec 1993, 73 (6)
p449-51
1,25-dihydroxycholecalciferol (1,25 (OH)2 D3) causes
dose-dependent inhibition of fibroblast growth and collagen
synthesis and has numerous immunoregulatory activities. We
assessed the effects of oral 1,25 (OH)2 D3 in the treatment of
patients with systemic sclerosis (SS). Eleven patients with SS
entered an open prospective study. Oral 1,25(OH)2 D3 was given
at a mean dose of 1.75 micrograms/day. The effects of the
treatment were evaluated using clinical examination and
physical measurements. After the treatment period (6 months to
3 years), a significant improvement, as compared with baseline
values, was observed. No serious side-effects were observed.
These results suggest that high-dose 1,25 (OH)2 D3 may be a
useful therapeutic agent for scleroderma .
Localized scleroderma--response to 1, 25-
dihydroxyvitamin D3.
Humbert PG; Dupond JL; Rochefort A; Vasselet R; Lucas A;
Laurent R; Agache P
Department of Dermatology, Centre Hospitalier Universitaire
St-Jacques, Besancon, France.
Clin Exp Dermatol (England) Sep 1990, 15 (5)
p396-8
1, 25 - Dihydroxyvitamin D3 [1,25(OH)2 D3] may be an
immunomodulatory drug which could have a role in controlling
collagen deposition, and inducing reversal of fibrosis in some
tissues. These observations prompted a study of the possible
use of this hormone for the treatment of scleroderma . A
35-year-old woman, who had been suffering from localized
scleroderma for 2 years, was given oral 1,25(OH)2 D3 for 6
months. The effects of the treatment were evaluated using
clinical and physical measurements (skin thickness,
extensibility properties of the skin). The evolution of the
patient's condition during the 6-month therapy suggests that
1,25(OH)2 D3 is beneficial in localized scleroderma . The
mechanisms of action are discussed in relation to the
literature, which suggests both immunoregulatory and
inhibitory effects on fibroblast growth.
Isolation and structural identification of 1, 25-
dihydroxyvitamin D3 produced by cultured alveolar macrophages
in sarcoidosis.
Adams JS; Singer FR; Gacad MA; Sharma OP; Hayes MJ; Vouros P;
Holick MF
J Clin Endocrinol Metab (United States) May 1985, 60 (5)
p960-6
Hypercalcemia and hypercalciuria in sarcoidosis are thought
to result from the endogenous overproduction of an active
vitamin D metabolite. We employed primary cultures of
pulmonary alveolar macrophages from two patients with
biopsy-proven pulmonary sarcoidosis and a recent or current
clinical abnormality in calcium metabolism to synthesize in
vitro a 1,25 - dihydroxyvitamin D3 [1,25-(OH)2D3]-like
metabolite from 25-hydroxyvitamin D3 (25OHD3). The macrophage
metabolite cochromatographed with [3H]1,25-(OH)2D3 on normal
phase and reverse phase high performance liquid chromatography
and was bound with high affinity by the chick intestinal
receptor for 1,25-(OH)2D3. On UV spectroscopy, the metabolite
possessed the carbon-5,7,10 (19) cis-triene chromophore
characteristic of a vitamin D sterol. Electron impact mass
spectrometry of trimethylsilyl ether derivatives of the
metabolite revealed a mass fragmentation pattern similar to
that of the trimethylsilyl ether derivative of authentic
1,25-(OH)2D3. The incubation of cultured macrophages from two
patients with idiopathic pulmonary fibrosis and two with
scleroderma with [3H]25OHD3 did not result in production of a
metabolite with the chromatographic identity of 1,25-(OH)2D3.
These data indicate that the metabolite of 25OHD3 synthesized
by sarcoid macrophages in vitro is 1,25-(OH)2D3 and that the
macrophage is a synthetic source of the sterol metabolite in
sarcoidosis.
Treatment of generalized systemic sclerosis.
Torres MA; Furst DE
University of Medicine and Dentistry, New Jersey, Robert Wood
Johnson Medical School, New Brunswick.
Rheum Dis Clin North Am (United States) Feb 1990, 16 (1)
p217-41
Over the years, many encouraging uncontrolled studies
extolling treatments of SSc have appeared, but initial
impressions were not corroborated when controlled trials were
done. This article points out that certain recent studies have
effectively ruled out the use of some specific therapies for
the general treatment of systemic sclerosis. Thus, sufficient
data has been generated to rule out the use of
n-acetylcysteine, colchicine, chlorambucil, cyclofenil, and
DMSO, at least in disease of longer duration. Ketanserin and
prostaglandin infusions probably also belong in this group, as
they affect only Raynaud's phenomenon. Angiotensin enzyme
inhibitors, while probably life-saving in renal crises, do not
seem to affect the underlying systemic sclerosis per se.
Another group of drugs has only limited supportive data and
await well-controlled trials to prove or disprove their
effectiveness. These include: 5-fluorouracil, D-penicillamine,
drugs affecting platelet function (dipyridamole), and
para-aminobenzoic acid. There are a few treatments which have
potential. Factor XIII has only limited data using controlled
trials, but what does exist seems positive. Apheresis is
encouraging, although the success of this treatment modality
may be dependent upon a "combination" approach. Ongoing
studies with gamma-interferon, photopheresis, and the mast
cell stabilizer ketotifen appear exciting, and we await
reports of their use in scleroderma . On another level, new
insights into genomic alterations in skin fibroblasts and
T-cell proto-oncogene expression have contributed to the
understanding of the pathogenesis of this disease at the
cellular level and new methods to measure change in disease
will help gauge response to therapy. Thus, we look forward to
more definitive treatment of SSc in the future. (129
Refs.)
[The effect of dimethyl sulfoxide on the
thromboelastographic indices and the microcirculation in
patients with rheumatic diseases]
Murav'ev IuV; Loskutova TT; Anikina NV; Shcherbakov AB;
Sokolov VB
Ter Arkh (USSR) 1989, 61 (12) p106-9
Using a blind method for assessing the results, a study was
made of the effect of dimethylsulfoxide (DMSO) on fibrin
formation and microcirculation in 42 patients with rheumatic
diseases (rheumatoid arthritis, systemic scleroderma,
Raynaud's syndrome). It has been shown that the therapeutic
effect of DMSO in rheumatic diseases is determined to a
definite degree by its normalizing action on fibrin formation
and microcirculation.
Double-blind, multicenter controlled trial
comparing topical dimethyl sulfoxide and normal saline for
treatment of hand ulcers in patients with systemic
sclerosis.
Williams HJ; Furst DE; Dahl SL; Steen VD; Marks C; Alpert EJ;
Henderson AM; Samuelson CO Jr; Dreyfus JN; Weinstein A; et
al
Arthritis Rheum (United States) Mar 1985, 28 (3)
p308-14
A prospective, randomized, double-blind trial compared
topical therapy with 0.85% normal saline, 2% dimethyl
sulfoxide (DMSO), and 70% DMSO for treatment of digital ulcers
in 84 patients with systemic sclerosis. There were no
statistically significant differences among the 3 treatment
groups in the improvement in the total number of open ulcers,
total surface area of open ulcers, average surface area per
open ulcer, number of infected ulcers, number of inflamed
ulcers, or patient pain assessment. While some patients
improved during the study, improvement could not be attributed
to a specific treatment. Over one-quarter of the patients
treated with 70% DMSO were withdrawn for significant skin
toxicity.
The effect of percutaneous dimethyl sulfoxide on
cutaneous manifestations of systemic sclerosis.
Scherbel AL
Ann N Y Acad Sci (United States) 1983, 411
p120-30
DMSO exerts a palliative, therapeutic effect on healing of
cutaneous ulcers in systemic sclerosis. The therapeutic
response was variable and, therefore, the concentration of
DMSO, as well as frequency and duration of treatments, should
be individualized to obtain maximum healing effect with a
minimum of adverse reactions. There was no evidence of ocular
toxicity or other serious toxicity manifestations in this
group of patients treated with topical DMSO for one year or
longer. Delayed improvement was observed in the untreated
extremity in the majority of patients studied. In no instance
did improvement in the untreated extremities exceed
improvement in the treated, bilateral counterpart. It is
believed this resulted from a systemic, carry-over effect of
DMSO rather than spontaneous improvement in the disease
course. DMSO is a worthwhile, supplemental, therapeutic agent
providing the limitations of therapy are understood.
DMSO revisited
Namaka M.; Briggs C.
Health Sciences Centre,Winnipeg, Man. Canada
Canadian Pharmaceutical Journal (Canada) 1994, 127/5
(248-249+255)
Dimethylsulfoxide, more commonly referred to as DMSO, was
discovered in 1866. A clear, colorless, odorless industrial
solvent, it is hygroscopic in nature and miscible with water
and organic solvents. In the mid 1960s, DMSO became popular
for its potential as a therapeutic agent and a pharmaceutical
solvent. Known as a wonder drug, it was alleged useful in a
variety of indications ranging from arthritis to mental
retardation. In 1965, the legal use of DMSO was restricted
because of ocular toxicity produced in animals during various
investigational studies. This side effect was not confirmed in
humans and DMSO is currently approved in Canada for two
indications: scleroderma and interstitial cystitis. Various
experiments have looked at the external and systemic adverse
effects of topical application of DMSO . Hemolysis, CNS
toxicity, nephrotoxicity and hepatotixicity have occurred
after IV administration of DMSO in humans. Similar toxicities
have appeared when DMSO was given orally. The route of
administration influenced the nature and degree of toxicity
observed. Ocular toxicity was more prone to develop in animals
when DMSO was given orally. Teratogenic effects of DMSO have
been demonstrated in rabbits and chickens, but not observed in
other species.
Control trials of dimethyl sulfoxide in rheumatoid
and collagen diseases
Alyabyeva A.P.; Muravyev Y.V.
Inst. Rheum., USSR Acad. Med. Sci., AMN Moscow Russia
Annals of the New York Academy of Sciences (United States)
1983, Vol. 411/- (309-315)
This is a report of control trials using DMSO in 199
patients. Seventy patients were diagnosed as suffering from
rheumatoid arthritis (RA), and ranged in age from 17 to 75
years. Thirty-five children ages 5-13 were diagnosed with
juvenile chronic arthritis (JCA). The diagnosis was made
according to American Rheumatology Association (ARA) criteria.
Sixty-five patients ranging in age from 18-65, had Sjogren's
syndrome. The diagnosis was based on clinical and laboratory
findings. Twenty-nine patients suffered from systemic
scleroderma with pronounced and extensive skin involvement. In
6 patients, ulcerations of fingers were seen. All 199 patients
continued basic anti-inflammatory therapy: 60 received
corticosteroids (20-30 mg by mouth), 40 received
intra-articular hydrocortisone injections (due to resistant
synovitis) which were, however, ineffective. The key selective
principle was the absence or a slight effect in response to
the basic therapy. Before DMSO application, all patients had
undergone a tolerance test: 50% DMSO (always diluted with
distilled water) was applied on the back of the hand and 30%
solution over the parotid glands. The follow-up lasted for 24
hours. Dermatitis on the tested areas was seen in only two
cases. These patients were excluded from the trial. Patients
and physicians knew that they were receiving DMSO application
but not the concentration or drug combinations. These details
were known only to the chief of the experimental trial, Dr.
A.P. Alyabyeva. The course of treatment lasted for two weeks.
Each patient received 200 ml of 50% DMSO .
Experimental and clinical evaluation of topical
dimethyl sulfoxide in venous disorders of the
extremities
Kappert A.
Dept. Clin. Angiol., Univ. Med. Sch., Bern Switzerland
Annals of the New York Academy of Sciences 1975, Vol. 243/-
(403-407)
The topical use of dimethyl sulfoxide (DMSO) as a trigger
substance for the accumulation of antiinflammatory, analgesic,
and venotropic compounds in regions of the extremities that
have acute or chronic venous disorders offers a new approach
to this still neglected therapeutic field. The clinical
results are in accordance with the experimental findings and
with the known properties of DMSO itself.
Medical management of diseases of the small
intestine
Levin M.S.
Department of Medicine, Washington University, School of
Medicine, Box 8124, 660 South Euclid Ave,St Louis, MO 63110
United States
Current Opinion in Gastroenterology (United Kingdom) 1992,
8/2 (224-231)
Issues in the medical management of small intestinal
disease that were addressed in the recent scientific
literature include the following: 1) bile acid malabsorption,
including the etiologic role of an ileal brush-border bile
salt carrier and the diagnostic value of the sup 7sup 5Se
homocholic acid taurine test; 2) small bowel bacterial
overgrowth, including the role of bacteria in vitamin B12
malabsorption in atrophic gastritis and in pathogenesis of
hepatobiliary complications; 3) short bowel syndrome,
including the effects of somatostatin analogue therapy; 4)
small intestinal tumors, including the diagnostic value of
small bowel enteroscopy and plasma postheparin diamine oxidase
measurements and therapy for carcinoid syndrome and primary
intestinal lymphoma; 5) prevention and treatment of radiation
enteropathy; and 6) pathogenesis and diagnosis of nonsteroidal
anti-inflammatory drug enteropathy.
Slides of lumbogluteal sclerodermas induced by
intramuscular injections of vitamin K1
Calas M.E.; Sayag J.; Castelain P.Y.; et al.
France
Marseille Med. 1975, 112/7-8 (419)
There was a presentation of several slides corresponding to
5 cases aged from 60 to 70 years, similar to 9 cases collected
by the Dermatological School of Bordeaux and published in No 4
of 1972 of Annales de Dermatologie. It is the mixing of other
products (adrenoxyl, reptilase, vitamin B12) with vitamin K1
that seems to produce a pharmacodynamic incompatibility in
subjects, mostly cirrhotics, with a haemorrhagic syndrome. The
lumbo gluteal infiltrations appear in the months following the
injections. They spread out in plaques of scleroderma, like a
belt of armour, right up to the trochanteric regions. They
develop for several years and no treatment is really
efficacious.
Glucose intolerance in patients with chronic
inflammatory diseases is normalized by glucocorticoids.
Hallgren R; Berne C
Acta Med Scand (Sweden) 1983, 213 (5) p351-5
Nine of 16 patients with inflammatory connective tissue
diseases (rheumatoid arthritis, polymyalgia rheumatica,
scleroderma and mixed connective tissue disease) had glucose
intolerance defined a a K-rate less than one but a normal
early insulin response to intravenous glucose loading. The
degree of the impaired glucose handling was related to the
degree of inflammatory activity as defined by acute phase
reactants. Glucocorticoid therapy induced within three days an
improved and normalized glucose tolerance and an augmented
early insulin response (p less than 0.001). The glucocorticoid
effect was still present up to six months of ongoing therapy.
It is suggested that glucose intolerance in chronic
inflammation is a consequence of a peripheral insulin
antagonism and an inhibition of insulin secretion. This
inhibition may be mediated directly or indirectly by
inflammatory cell products and may be sensitive to
glucocorticoids.
Vitamin K1-induced localized scleroderma (morphea)
with linear deposition of IgA in the basement membrane
zone.
Alonso-Llamazares J; Ahmed I
Department of Dermatology, Mayo Clinic and Mayo Foundation,
Rochester, Minnesota, USA.
J Am Acad Dermatol (United States) Feb 1998, 38 (2 Pt 2)
p322-4
We describe a 45-year-old white man in whom distinctive
clinical and histologic features of localized scleroderma
developed at sites of injection of vitamin K1 (phytonadione).
A direct immunofluorescence test demonstrated prominent linear
deposition of IgA along the basement membrane zone. No
circulating antibasement membrane zone IgA antibodies were
identified on indirect immunofluorescence testing. We believe
that the unusual immunofluorescence finding in our patient is
nonspecific and represents an epiphenomenon caused by
cutaneous injury. (18 Refs.)
Inhibition of collagen production by traditional
Chinese herbal medicine in scleroderma fibroblast
cultures.
Sheng FY; Ohta A; Yamaguchi M
Department of Internal Medicine, Saga Medical School.
Intern Med (Japan) Aug 1994, 33 (8) p466-71
The in vitro effect of one traditional Chinese herbal
medicine (Japanese name: "Keishi-bukuryo-gan"), which has been
empirically used in scleroderma patients in China and Japan,
on collagen production in fibroblast cultures was studied.
Fibroblasts from 3 scleroderma patients and 2 normal controls
were incubated with various concentrations of
"Keishi-bukuryo-gan" and collagen production was then
determined by a radiochemical method. "Keishi-bukuryo-gan"
significantly and selectively inhibited collagen synthesis in
a dose-dependent manner, with a tendency of a stronger effect
on scleroderma fibroblasts than control cells. The results may
explain the clinical usefulness of this medicine, and it may
become a promising new agent for the treatment of
scleroderma.
Chloracne, palmoplantar keratoderma and localized
scleroderma in a weed sprayer.
Poskitt LB; Duffill MB; Rademaker M
Department of Dermatology, Waikato Public Hospital, Hamilton,
New Zealand.
Clin Exp Dermatol (England) May 1994, 19 (3)
p264-7
The case of a 53-year-old man who developed chloracne,
palmoplantar keratoderma and scleroderma after many years of
exposure to a variety of chloracnegens is reported. Chloracne
is a rare but important acneiform eruption associated with
exposure to halogenated aromatic compounds used primarily in
agriculture. However, to our knowledge, the association of
palmoplantar keratoderma and scleroderma with exposure to
chloracnegens has not been previously reported.
[Studies on stimulating circulation to end stasis
in scleroderma]
Yuan X; Li JD
Chung Hsi I Chieh Ho Tsa Chih (China) Jan 1989, 9 (1) p19-21,
5
Of 725 cases of scleroderma, 265 were of systemic type (the
sex ratio being 1M:6F) and 460 of circumscribed type (the sex
ratio being 1M:9F). The patients were divided into three
groups and treated with three different stimulating
circulation to end stasis (SCES) prescriptions. Satisfactory
therapeutic effects were obtained in all. According to the
clinical practice and laboratory findings, although SCES
therapy exerted manifold actions on the disease, it not only
softened the indurated connective tissues, tonified the body
and improved the symptoms, but also improved laboratory
indexes as follows: nailfold bed capillary, parameter of the
peripheral blood stream in patients, content of urinary
2-ketol, 17-KS, free corten, serum joint-hexose, amino-hexose
and histopathology including ultrastructure of the skin. The
main effect was the improvement of circulation, especially the
microcirculation and regulation of the metabolism of the
connective tissues. Great attention should be paid to the
drug's function of softening the indurated connected tissues.
For further investigation, the authors have stressed three
important points: screening of clinical symptoms and signs,
examination of blood circulatory disturbances, and examination
of pathological changes of the connective tissue. The
necessity of developing new criteria for judging the
therapeutic effects was emphasized.
Lymphocyte subpopulations and reactivity to
mitogens in patients with scleroderma.
Baron M; Keystone EC; Gladman DD; Lee P; Poplonski L
Clin Exp Immunol (England) Oct 1981, 46 (1)
p70-6
T lymphocyte subpopulations were studied in 40 patients
with scleroderma (PSS), 26 of whom were studied simultaneously
for lymphoproliferative responses to phytohaemagglutinin
(PHA), concanavalin A (Con A) and pokeweed mitogen (PWM). PSS
patients exhibited a reduction relative to 42 age- and
sex-matched controls in the absolute number and percentage of
early E rosettes, late E rosettes and E rosettes formed with
aminoethylisothiouronium bromide (AET) treated sheep red blood
cells. There was no difference between patients and controls
in the proportions of B lymphocytes. PSS patients exhibited
normal lymphocyte transformation responses to PHA and ConA and
an augmented response to PWM. The mitogen responses did not
correlate with the absolute number or percentage of
lymphocytes or T and B lymphocyte subpopulations. No
correlation was observed between any immunological variable
studied and the extent of skin or organ involvement, disease
duration or therapy.
Lymphocyte reactivity to mitogens in subjects with
systemic lupus erythematosus, rheumatoid arthritis and
scleroderma.
Horwitz DA; Garrett MA
Clin Exp Immunol (England) Jan 1977, 27 (1)
p92-9
The mitogenic reactivity of lymphocytes from subjects with
systemic lupus erythematosus, rheumatoid arthritis and
scleroderma was studied. Cultures containing either
unseparated or separated lymphocytes were stimulated with
phytohaemagglutinin, Con A and pokeweed mitogen after
inhibitory serum factors were eluted from the cell surface.
Incorporation of [3H]thymidine in patient cultures was
compared to that of normal controls. Greatly decreased
reactivity was found in SLE to all three mitogens.
Significantly decreased values to some mitogens was also
observed in rheumatoid arthritis and scleroderma, but the
defect was less severe. Cultures of study subjects contained
significantly fewer small lymphocytes than normal controls and
this finding explained at least in part the decreased
mitogenic reactivity.
Pattern of gastric emptying in patients with
systemic sclerosis.
Mittal BR; Wanchu A; Das BK; Ghosh PP; Sewatkar AB; Misra
RN
Department of Nuclear Medicine, Sanjay Gandhi Postgraduate
Institute of Medical Sciences, Lucknow, India.
Clin Nucl Med (United States) May 1996, 21 (5)
p379-82
Gastric emptying studies, using an indigenously prepared
radiolabeled solid food marker in the form of Indian bread
called Chapati, were performed on 13 patients with systemic
sclerosis. Six patients had limited cutaneous disease and
seven had diffuse cutaneous disease. Earlier, the procedure
was standardized in 30 healthy volunteers. Seven of the 13
(54%) patients (five with diffuse and two with limited
cutaneous disease) had delayed gastric emptying. Most of these
patients had gastric symptoms. This pattern of gastric
emptying may be clinically significant, particularly in
patients with diffuse cutaneous disease.
Overlap syndrome of progressive systemic sclerosis
and polymyositis: report of 40 cases.
Yuan X; Chen M
PUMC Hospital, CAMS, Beijing.
Chin Med Sci J (England) Jun 1991, 6 (2) p107-9
Forty cases of overlap syndrome of progressive systemic
sclerosis and polymyositis (OS PSS-PM) are reported in this
paper. All of these cases had manifestations of both PSS and
PM as well as Raynaud's phenomenon. The sclerodermatous skin
changes were diffused over the whole body in most cases. All
cases had muscular weakness, elevated skeletal muscle enzyme
levels and muscle damage as seen on the electromyogram.
Histopathologic changes showed characteristics of myositis.
There was noticeable systemic involvement, especially with the
digestive and circulatory systems. Serologic examination
frequently revealed autoantibodies. The patients responded
well to traditional Chinese medicines and corticosteroids.
Antiphospholipid syndrome associated with
progressive systemic sclerosis.
Chun WH; Bang D; Lee SK
Department of Dermatology, Yonsei University College of
Medicine, Seoul, Korea.
J Dermatol (Japan) May 1996, 23 (5) p347-51
We report a case of secondary antiphospholipid syndrome
(APS) occurring in a progressive systemic sclerosis (PSS)
patient who took herbal medication. Clinical findings
compatible with APS included positive IgM anticardiolipin
antibody (ACL), thrombocytopenia, and obstruction of the left
radial artery on digital subtraction angiography (DSA).
Clinical findings compatible with PSS included sclerodactyly
and digital ulcers, Raynaud's phenomenon, pulmonary fibrosis
and pulmonary hypertension, proteinuria and renal mesangial
reaction, and myocarditis.
Progressive systemic sclerosis (PSS): Review of the
pathophysiological, clinical and pharmacological aspects of
the syndrome
Bostrom H.; Herbai G.
Med. Klin., Akad. Sjukh., Uppsala Sweden
Lakartidningen (Sweden) 1979, 76/4 (207-210)
Scleroderma is an uncommon but complex disease. The onset
is slow and the progress chronic. The main pathophysiological
changes vary, affecting blood vessels, connective tissue,
collagen fibres, fibrin deposition and inflammatory reactions.
There may be early oedema and a wide spectrum of organic
involvement. Clinically, all the fibril-containing and
connective tissue organs are subject to various degrees of
attack. The most common organic manifestations are: the
Raynaud phenomenon in the arms and hands, vascular fibrosis,
stiff and hard facial skin, restriction of joint movement by
pericapsular hardening, calcium deposition and capsular
rigidity. In the gastro-intestinal tract, muscular atrophy,
collagen and connective tissue damage are common, especially
at the cardia of the stomach. Malabsorption may occur.
Progressive pulmonary fibrosis leads to formation of cor
pulmonale and respiratory insufficiency. The liver, kidneys
and endocrine glands are seldom involved, however. Therapeutic
trials have been performed using many different groups of
drugs: experiment to influence connective tissue, thyroxine,
and a variety of anti-rheumatic agents. In the last decade the
best short-term clinical results have been achieved with
penicillamine, some vasodilators, chlorambucil (Leukeran),
and, recently a potent anti-oestrogen: cyclofenil, which has
marked connective tissue and collagen metabolism influencing
properties. Good therapeutic effects without serious
sideeffects have been achieved.
Topical lithium succinate ointment (Efalith) in the
treatment of AIDS-related seborrhoeic dermatitis.
Langtry JA; Rowland Payne CM; Staughton RC; Stewart JC;
Horrobin DF
Department of Dermatology, Westminster Hospital, London,
UK.
Clin Exp Dermatol (England) Sep 1997, 22 (5)
p216-9
A randomised, double-blind, placebo-controlled trial with
lithium succinate ointment was conducted in patients with
AIDS-associated facial seborrhoeic dermatitis. Twice daily
applications of the ointment brought about a rapid (2.5 days)
and highly significant (P = 0.007) improvement in the severity
of the condition. Lithium succinate ointment is well tolerated
and can be a useful treatment for seborrhoeic dermatitis in
this group of patients.
Topical calcipotriene for morphea/linear
scleroderma.
Cunningham BB; Landells ID; Langman C; Sailer DE; Paller
AS
Department of Pediatrics, Northwestern University Medical
School, Chicago, Illinois, USA.
J Am Acad Dermatol (United States) Aug 1998, 39 (2 Pt 1)
p211-5
BACKGROUND: Morphea and linear scleroderma are
characterized by erythema, induration, telangiectasia, and
dyspigmentation. There is no universally effective treatment.
Oral calcitriol has been beneficial in the treatment of
localized and extensive morphea/scleroderma, but the use of
topical calcipotriene has not been reported.
OBJECTIVE: The purpose of this study was to evaluate the
efficacy and safety of topical calcipotriene 0.005% ointment
in the treatment of localized scleroderma.
METHODS: In a 3-month open-label study, 12 patients aged 12
to 38 years with biopsy-documented active morphea or linear
scleroderma applied calcipotriene ointment under occlusion
twice daily to plaques for 3 months. The condition of each
patient had previously failed to respond to potent topical
corticosteroids and, for some patients, systemic medications.
Efficacy was assessed at baseline, 1 month, and 3 months.
Levels of serum ionized calcium, intact parathyroid hormone,
and 1,25-dihydroxyvitamin D and of random urinary calcium
excretion were measured.
RESULTS: During the 3-month trial, the condition of all 12
patients showed statistically significant improvement in all
studied features. No adverse effects were reported or detected
through laboratory monitoring of mineral metabolism.
CONCLUSION: Topical calcipotriene 0.005% ointment may be an
effective treatment for localized scleroderma, but
double-blind placebo controlled studies are needed for
confirmation.
Management of severe scleroderma with long-term
extracorporeal photopheresis.
Krasagakis K; Dippel E; Ramaker J; Owsianowski M; Orfanos
CE
Department of Dermatology, University Medical Center Benjamin
Franklin, Free University of Berlin, Germany.
Dermatology (Switzerland) 1998, 196 (3) p309-15
BACKGROUND: The management of systemic sclerosis remains
unsatisfactory. Thus far, the action of extracorporeal
photopheresis (ECP) in severe systemic scleroderma has been
evaluated in short-term studies, and only limited experience
has been obtained with long-term application.
OBJECTIVE: The aim of the present study was to evaluate
prospectively the long-term effect of ECP in a group of 16
patients suffering from severe scleroderma, showing visceral
involvement and progressive clinical course.
METHODS: Fourteen patients with systemic scleroderma
involving several organs, 1 with CREST syndrome and another
with scleroderma-myositis overlap syndrome were treated with
ECP over a period of 6-45 months. In 3 cases, gamma-IFN was
additionally administered. Skin and visceral involvement were
assessed by evaluating a series of clinical criteria and
results from laboratory, imaging and functional tests.
RESULTS: Overall, clear improvement was encountered in 6
patients, mixed response in 2, stable disease in 3 and
continuing progressive course in 5 patients. Four out of 6
patients with improvement were treated with ECP early after
onset of scleroderma (< or = 2 years), whereas all patients
with a progressive course under ECP had had scleroderma for
longer than 2 years. Immunosuppressive drugs previously
administered could be reduced or fully withdrawn under ECP
treatment in 5 patients, but additional oral medication was
introduced in 4 patients due to disease progression. Addition
of gamma-IFN to ECP did not reveal further benefit . No
side-effects were recorded under ECP treatment.
CONCLUSIONS: Based on this observation, we believe that
long-term ECP represents an effective treatment modality in
severe scleroderma particularly when started early, with
stabilization of the disease course and partial remission of
the cutaneous findings, whereas visceral involvement, if
present, may rarely improve.
Successful treatment of scleroderma with PUVA
therapy.
Kanekura T; Fukumaru S; Matsushita S; Terasaki K; Mizoguchi
S; Kanzaki T
Department of Dermatology, Kagoshima University Faculty of
Medicine, Japan.
J Dermatol (Japan) Jul 1996, 23 (7) p455-9
PUVA therapy was carried out on four patients with
scleroderma; three of them had cutaneous manifestations of
progressive systemic sclerosis and one other exhibited
generalized morphea. PUVA therapy was given with daily doses
of 0.25J/cm2 or 0.4J/cm2 for 3-8 weeks, resulting in total
doses between 3.5J/cm2 and 9.6J/cm2. All four patients
responded well to this treatment; improvements of hand
closure, skin sclerosis index, and flexion of fingers or knee
joints were obtained. Thus, PUVA appeared to be beneficial for
treating scleroderma.
Effects of calcitriol on fibroblasts derived from
skin of scleroderma patients.
Boelsma E; Pavel S; Ponec M
Department of Dermatology, University Hospital Leiden, The
Netherlands.
Dermatology (Switzerland) 1995, 191 (3) p226-33
BACKGROUND: Scleroderma is a fibrotic disorder of unknown
etiology that is characterized by excessive collagen synthesis
and its deposition in the skin and various internal
organs.
OBJECTIVE: To examine whether an overproduction of
extracellular matrix molecules is a result of either increased
fibroblast proliferation or increased collagen synthesis. As
results of clinical trials with 1,25-dihydroxyvitamin D3
(calcitriol) have suggested beneficial effect in the treatment
of scleroderma patients, the effects of calcitriol on
fibroblasts derived from scleroderma and normal skin has been
examined as well.
METHODS: Cultures of fibroblasts were established from
biopsies from involved and uninvolved skin of scleroderma
patients and from skin of healthy subjects, and compared with
respect to proliferation, collagen synthesis and collagen
lattice contraction.
RESULTS: No significant differences in cell proliferation
and in the extent of fibroblast-induced collagen lattice
contraction have been found between scleroderma patients
exhibited a disorganized growth pattern in a monolayer culture
in contrast to normal fibroblasts. Collagen synthesis tends to
be higher in scleroderma fibroblasts as compared with
controls. Calcitriol exerted an antiproliferative and
antisynthetic effect on fibroblasts, which, however, did not
discriminate healthy fibroblasts from fibroblasts derived from
involved or uninvolved scleroderma plaques.
CONCLUSIONS: Our findings suggest that collagen
accumulation may not result from increased proliferation or
altered dynamic properties of fibroblasts in a scleroderma
lesion but from increased collagen biosynthesis. We
additionally found that calcitriol does not selectively affect
scleroderma fibroblasts.
Effects of tumor necrosis factor-alpha on
connective tissue metabolism in normal and scleroderma
fibroblast cultures.
Takeda K; Hatamochi A; Arakawa M; Ueki H
Department of Dermatology, Kawasaki Medical School,
Kurashiki, Japan.
Arch Dermatol Res (Germany) 1993, 284 (8) p440-4
Recent studies have demonstrated that tumor necrosis
factor-alpha (TNF-alpha) selectively decreases production of
collagens I and III, the major types of collagen in the
dermis, and increases production of collagenase in cultured
dermal fibroblasts. The effects of TNF-alpha on collagens I,
III and VI, fibronectin and collagenase gene expression by
fibroblasts derived from normal individuals and patients with
systemic sclerosis (SSc) were studied. SSc is characterized by
excessive accumulation of collagen in the skin and in certain
organs. TNF-alpha inhibited collagen production and mRNA
levels of collagens I and III and of fibronectin, and
stimulated collagenase activity and collagenase mRNA levels in
SSs fibroblasts. Levels of mRNA for alpha 1 (VI) and alpha 3
(VI) collagen and for beta-actin were unaltered in SSc
fibroblasts incubated with TNF-alpha. Similar results were
observed for mRNA levels in normal fibroblasts incubated with
TNF-alpha. These results suggest that TNF-alpha could be
expected to be beneficial in the treatment of SSc. In
addition, our results indicated that collagen-VI expression is
regulated independently from expression of collagens I and
III, and expression of fibronectin and collagens I and III are
regulated in parallel in fibroblasts treated with
TNF-alpha.
[Treatment of severe Raynaud syndrome in
scleroderma or thromboangiitis obliterans with prostacyclin
(prostaglandin I2)]
Ruthlein HJ; Riegger G; Auer IO
Medizinische Universitatsklinik Wurzburg.
Z Rheumatol (Germany) Jan-Feb 1991, 50 (1)
p16-20
Eleven patients with severe Raynaud's syndrome were treated
with intravenous infusion of prostacyclin (Prostaglandin I2).
Raynaud's syndrome was caused by inflammatory diseases such as
progressive systemic sclerosis (N = 9) or thromboangiitis
obliterans (N = 2). Five patients had acral ulcerations.
Treatment with prostacyclin lead to immediate cessation of
acral pain in all patients if doses of 5-6 ng/kg/min were
tolerated. In 7 out of 11 patients there was a long-term
analgesic effect with clinical improvement of Raynaud's
syndrome. In three of five patients we achieved healing of the
ulcerations within a few weeks. Plasmaconcentrations of
prostaglandin F1-alpha, the main metabolite of prostacyclin,
were about 10 times above normal during infusion and returned
to normal levels within 30 min after the end of the infusion,
in spite of the prolonged clinical effect. Therefore,
prostacyclin alone cannot be responsible for the long-term
clinical benefit . (Parts of this publication were published
as an abstract and presented at the 23rd Congress of the
Deutsche Gesellschaft fur Rheumatologie (15).
A double-blind randomized controlled trial of
ketotifen versus placebo in early diffuse scleroderma.
Gruber BL; Kaufman LD
Department of Medicine, State University of New York, Stony
Brook 11794-8161.
Arthritis Rheum (United States) Mar 1991, 34 (3)
p362-6
To determine the efficacy of the mast cell-stabilizing drug
ketotifen in scleroderma, we conducted a 6-month, randomized,
prospective, double-blind, placebo-controlled trial in 24
patients. No significant improvement in the clinical
parameters, pulmonary function, global assessments, and mast
cell releasability was noted. Pruritus tended to improve in
the group taking the active drug. Six months of treatment with
ketotifen (6 mg/day), therefore, produced no apparent benefit
in patients with early scleroderma. We were unable to address
the role of mast cells in scleroderma since mast cell
suppression was not achieved.
Factor XIII in scleroderma: in vitro studies.
Paye M; Read D; Nusgens B; Lapiere CM
Laboratory of Experimental Dermatology, Tour de Pathologie,
CHU du Sart Tilman, University of Liege, Belgium.
Br J Dermatol (England) Mar 1990, 122 (3)
p371-82
The administration of Factor XIII (FXIII) produces a
beneficial effect on the skin lesions in about 50% of the
treated patients with progressive systemic sclerosis (PSS).
The effect of FXIII on various skin fibroblast functions
(proliferation, attachment, biosynthetic activity and
mechanical properties) was investigated in vitro using normal
and PSS strains. In cell culture, most of the PSS fibroblast
strains synthesized excessive amounts of collagen. Other cell
functions such as adhesion to collagen I or III, to
fibronectin, retraction of collagen lattices, proliferation in
low serum concentration and degradation of newly synthesized
collagen were not significantly different. The addition of
FXIII (I U/ml) inhibited the synthesis of collagen by normal
fibroblasts and reduced it in PSS fibroblasts to a level
similar to that of normal fibroblasts. This effect was
observed for cells cultured on plastic or in a collagen
lattice. In the latter, an increased amount of collagen
degradation was observed. No significant effect of FXIII on
the other cell functions was noted. Excessive collagen
production by PSS fibroblasts can be repressed by FXIII in
vitro by at least two distinct mechanisms: a reduction of
collagen synthesis and an increased degradation of the newly
synthesized collagen.
5-fluorouracil in the treatment of scleroderma: a
randomised, double blind, placebo controlled international
collaborative study.
Casas JA; Saway PA; Villarreal I; Nolte C; Menajovsky BL;
Escudero EE; Blackburn WD; Alarcon GS; Subauste CP
Department of Medicine, Universidad Peruana Cayetano Heredia,
Lima, Peru.
Ann Rheum Dis (England) Nov 1990, 49 (11) p926-8
A six month controlled study of 5-fluorouracil in the
treatment of scleroderma showed a modest benefit in skin
scores, Raynaud's phenomenon, and patients' global assessment.
Visceral organ and hand function were unaffected. Mild to
moderate toxicity was common in the 5-fluorouracil treated
patients but usually responded to dose reduction. Two patients
receiving 5-fluorouracil died from causes seemingly unrelated
to treatment. Significant clinical improvement in scleroderma
was not noted in the first six months of treatment with
5-fluorouracil.
Systemic scleroderma. Clinical and pathophysiologic
aspects.
Krieg T; Meurer M
Dermatology Clinic and Polyclinic, Ludwig-Maximilian
University of Munchen, FRG.
J Am Acad Dermatol (United States) Mar 1988, 18 (3)
p457-81
Systemic scleroderma is a generalized disease of connective
tissue involving mainly the skin, the gastrointestinal tract,
the lungs, the heart, and the kidneys. It can be present in
different forms, of which acroscleroderma, with limited
cutaneous and extracutaneous involvement, and diffuse
scleroderma within a more rapid progression are most
characteristic. Circulating antibodies against antinucleolar
antigens are present in most patients with systemic
scleroderma. They are helpful for establishing a
classification and for determining the prognosis of the
disease; their involvement in the pathogenesis, however, is
still unclear. Alterations of the blood vessels and induction
of fibroblasts by potent mediators are thought to play an
important role in the early phase of scleroderma. Therefore
early diagnosis is required, which then can initiate
vasoactive therapy. In patients with systemic scleroderma, who
also suffer from additional myositis, interstitial lung
diseases, or arthritis, anti-inflammatory treatment with
prednisolone and azathioprine is suggested. Development and
progression of fibrosis cannot yet be influenced sufficiently.
Only D-penicillamine affecting cross-linking of collagen has
been widely used in scleroderma and has some beneficial
effect. (160 Refs.)
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