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Mixed connective tissue disease. A newly created
pathologic concept for a combination of different collagen
diseases
Stingl G.; Holubar K.; Scherak O.; et al.
Abt. Exp. Dermatol., I. Univ. Hautklin., Wien Austria
H+G Zeitschrift fur Hautkrankheiten 1975, 50/2
(83-95)
The clinical, serologic and immunologic data of 5 patients
with the recently recognized 'mixed connective tissue disease'
are reported. Clinically, it includes symptoms of certain
collagenases such as lupus erythematosus, dermatomyositis, and
scleroderma and sometimes of rheumatoid arthritis.
Immunologically antinuclear antibodies are found which show a
'speckled pattern' by the indirect immunofluorescence method,
a high titre of hemagglutinating antibodies against extracted
nuclear antigen, inhibition of hemagglutination or extinction
of the indirect immunofluorescence if pretreated with RNAase.
The clinical and immunologic characteristics found by Sharp et
al. are confirmed. In order to determine whether there is a
renal involvement, kidney biopsies were undertaken and a
moderate immune complex precipitation together with a high
antinuclear antibody titre was found. The prognosis of this
syndrome and comparison with lupus erythematosus are
discussed.
[Observation on blood flow changes in 34 cases of
progressive systemic scleroderma treated with Chinese herbal
medicine]
Huang PP; Wang SG; Hua GX
Hospital of Hematology, Chinese Academy of Medical Sciences,
Tianjin.
Chung Kuo Chung Hsi I Chieh Ho Tsa Chih (China) Feb 1994, 14
(2) p86-8, 68
The blood flow change of 34 progressive systemic
scleroderma (PSS) patients were examined. The amplitude proved
to be lowered markedly than healthy subjects. All patients
were treated with the basic prescription of PSS as the
principal method, combined with infusion of Mailuoning
injection in 500 ml of 5% glucose. The course of treatment
lasted three months to one year. The result of treatment
showed that the abnormal blood flow of extremities of all
patients were improved remarkably. Marked improvement rate and
total effective rate were 70.5% and 100% respectively.
Significant improvements in clinical and laboratory parameters
were observed. It revealed that there was a close relationship
between the occurrence and development of PSS and blood
circulation. It is assumed that the pathogenic mechanism of
PSS is Deficiency of vitality and Excess of pathogenic factor
(Stasis of Blood), and the Qi tonifying and Blood activating,
hard lump softening and mass dissolving medicinal herbs
according to Syndrome Differentiation of TCM should be
used.
Vitamin D metabolites in generalized scleroderma.
Evidence of a normal cutaneous and intestinal supply with
vitamin D.
Serup J; Hagdrup H
Acta Derm Venereol (Sweden) 1985, 65 (4) p343-5
Vitamin D metabolites in serum were analysed in 20 patients
with generalized scleroderma. The concentration of
1,25-dihydroxyvitamin D was normal, however, significantly
lower concentrations (p less than 0.05) were found in 7
patients with cutaneous calcinosis in comparison with 13
patients with no calcinosis. Concentrations of
25-hydroxyvitamin D, 24-25-dihydroxyvitamin D, and vitamin
D-binding protein (Gc globulin) were all within the normal
range. The 24,25-dihydroxy-vitamin D level correlated with the
duration of disease (r = 0.4453, p less than 0.05), and
25-hydroxyvitamin D tended to correlate (r = 0.3016, NS). The
study strongly indicates that cutaneous synthesis, intestinal
absorption and hepatic hydroxylation of vitamin D are not
deficient in scleroderma. A relative but specific decrease in
the renal hydroxylation to 1,25-dihydroxyvitamin D, i.e. the
active hormone, as the disease progresses and calcinosis
occurs, is suspected.
Procollagen gene expression by scleroderma
fibroblasts in culture. Inhibition of collagen production and
reduction of pro alpha 1(I) and pro alpha 1(III) collagen
messenger RNA steady-state levels by retinoids.
Ohta A; Uitto J
Arthritis Rheum (United States) Apr 1987, 30 (4)
p404-11
Recent studies have demonstrated that retinoids (synthetic
vitamin A analogs) can modulate connective tissue metabolism
in human skin fibroblast cultures. In this study, we examined
the effects of 3 retinoids, all-trans-retinoic acid (RA),
13-cis-RA, and an aromatic retinoid, RO-10-9359, on collagen
gene expression in scleroderma fibroblast cultures and matched
control fibroblast cultures. The results indicated that
all-trans-RA and 13-cis-RA significantly reduced procollagen
production both in control and scleroderma fibroblast cultures
in a dose-dependent manner. The reduction in procollagen
production was paralleled by a similar decrease in
steady-state levels of type I and type III procollagen
messenger RNAs, which suggests that there is coordinate
inhibition on the transcriptional level. In contrast,
RO-10-9359 elicited only limited effects on collagen
production, and such effects were variable. The results
suggest that further development of retinoids might provide an
effective means to counteract tissue deposition of collagen in
scleroderma and other fibrotic diseases.
Essential fatty acid metabolism in diseases of
connective tissue with special reference to scleroderma and to
Sjogren's syndrome.
Horrobin DF
Med Hypotheses (England) Jul 1984, 14 (3)
p233-47
Drugs which modify the conversion of essential fatty acids
to prostaglandins and leukotrienes are the mainstays of
treatment in rheumatology. Yet these drugs have little or no
action in scleroderma or Sjogren's syndrome and under some
circumstances may have adverse effects. Patients with
scleroderma have been shown to have very high levels of
circulating prostaglandins, coupled with depletion of the
prostaglandin precursors, dihomogammalinolenic acid and
arachidonic acid. Levels of the metabolites of arachidonic
acid, 22:4n-6 and 22:5n-6, which have major roles in
maintaining normal cell membrane characteristics were
exceptionally low in both plasma and red cell membranes.
Others have observed that various functions are highly
resistant to normal actions of PGs in scleroderma. This raises
the possibility that the high rate of PG formation in
scleroderma may be beneficial, in compensation, and that
clinical symptoms develop when PG precursors begin to be
depleted. Red cell membrane fatty acids patterns in Sjogren's
syndrome are almost identical to those in scleroderma.
Placebo-controlled trials of supplementation with essential
fatty acids have been found to be beneficial in both
scleroderma and Sjogren's syndrome.
Parathyroid hormone and calcium metabolism in
generalized scleroderma. Increased PTH level and secondary
hyperparathyroidism in patients with aberrant calcifications.
Prophylactic treatment of calcinosis.
Serup J; Hagdrup HK
Arch Dermatol Res (Germany, West) 1984, 276 (2)
p91-5
Parathyroid hormone (PTH) in serum and biochemical
parameters of calcium metabolism were analysed in 45 patients
with systemic sclerosis. Calcification of the skin and
subcutaneous tissue was assessed by X-ray examination of the
hands. Analyses disclosed secondary hyperparathyroidism
(increased PTH in serum, low calcium 'ion' in serum, decreased
urinary excretion of calcium and phosphate), in particular in
patients with calcinosis (P less than 0.05) as compared to
those with no calcinosis. The duration of systemic sclerosis
was longer in patients with calcinosis (P less than 0.05). The
calcinosis type of systemic sclerosis is characterized by
secondary hyperparathyroidism developed during the progression
of the disease. A hypothesis is made regarding calcium
metabolism in the early no-calcinosis (with increased
synthesis of Vitamin D) and late calcinosis types. PTH may
stimulate aberrant calcification. The hypothesis implicates
that prophylactic treatment with Vitamin D in low dose may
prevent calcinosis.
Tryptophan metabolism "via" nicotimic acid in
patients with scleroderma
De Antoni A; Muggeo M; Costa C; Allegri G; Crepaldi G
Acta Vitaminol Enzymol (Italy) 1976, 30 (4-6)
p134-9
The tryptophan metabolism "via" kynurenine was studied in
five patients with scleroderma after aminoacid loading. Four
of these patients had abnormal tryptophan metabolism,
characterized by a large urinary excretion of kynurenine and
kynurenic acid in two cases, of kynurenine,
3-hydroxykynurenine and kynurenic acid in one case and of
3-hydroxyanthranilic acid in another case and generally a
reduced excretion of xanthurenic acid and its 8-methyl ether
in comparison with a group of healthy controls. Only two of
the four patients had a normal response to tryptophan loading
after pyridoxine administration, while no one of these
responded to nicotinamide supplementation. But the
simultaneous administration of pyridoxine and nicotinamide to
three of these patients normalized the excretory picture after
tryptophan loading. This suggested the presence of a combined
vitamin deficiency in seleroderma. As four out of five
patients showed total excretory values of kynurenine,
kynurenic acid and acetylkynurenine higher than that of the
controls, the sum of these values might be considered as a
characteristic index of scleroderma.
Scleroderma-like disorders
Jablonska S.; Blaszczyk M.
Dr. S. Jablonska, Department of Dermatology, Warsaw School of
Medicine, Koszykowa 82a, 02-008 Warsaw Poland
Seminars in Cutaneous Medicine and Surgery (United States)
1998, 17/1 (65-76)
Scleroderma-like disorders are widely disparate conditions
mimicking either systemic scierosis or cutaneous localized
scleroderma, not infrequently displaying features of both.
Some are exclusively sclerotic, some scleroatrophic with
prevailing scierosis or atrophies. The recognition of
scieroderma-like disorders is of practical importance because
by establishing the cause of the disease, it is possible to
introduce an effective therapy, as in scieredema Buschke or
scieredema diabeticorum, scierodermiform porphyria, Borrelia
burgdorferiinduced scierodermiform acrodermatitis atrophicans,
scierodermitorm phenylketonuria, drug-induced conditions, and
so on. Soieroderma-like disorclers strongly suggest that the
pathogenesis of skin sclerosis and internal involvement may be
divergent, and of various causes. Some of them, such as
atrophoderma Pasini-Pierini or progressive facial
herniatrophy, frequently overlapping with scieroderma, make
the differentiation very difficult, it at all possible, and
the diagnosis is often arbitrary. Some, as scierodermiform
graft-versushost reaction, point to the autoimmune origin of
scieroderma. The amply-covered congenital scierodermiform
conditions present a large spectrum of still not widely known
and extremely heterogeneous syndromes, associated with
numerous anomalies and/or malignancies.
Management of localized scleroderma
Hunzelmann N.; Kochanek K.S.; Hager C.; Krieg T.
Dr. T. Krieg, Department of Dermatology, University of
Cologne, 50924 Cologne Germany
Seminars in Cutaneous Medicine and Surgery (United States)
1998, 17/1 (34-40)
Localized scleroclerma denotes a spectrum of conditions
characterized by circumscribed fibrotic areas involving
different levels of the dermis, subcutis, and sometimes
underlying soft tissue and bone. Although the clinical course
of the disease is often benign, widespread lesions and
disabling joint contractures may lead to significant
complications. The pathogenesis of the different types of
localized scieroderma is still unknown. Numerous therapeutic
agents have been reported to be effective in this disease
spectrum, but controlled studies are rare. The purpose of this
review is to summarize previous experience and to discuss
recent advances in the management of localized
scleroderma.
Lymphoproliferative responses to Borrelia
burgdorferi in circumscribed scleroderma
Breier F.; Klade H.; Stanek G.; Poitschek C.; Kirnbauer R.;
Dorda W.; Aberer E.
Department of Dermatology, University of Vienna Medical
School, Waehringer Guertel 18-20,A-1090 Vienna Austria
British Journal of Dermatology (United Kingdom) 1996, 134/2
(285-291)
Humoral immune responses to Borrelia burgdorferi (Bb) have
been reported to occur in certain patients with circumscribed
scleroderma (CS) (morphoea). Together with the isolation of
spirochaetes from CS skin biopsies, this finding was taken to
suggest Bb as the aetiological agent of CS. Since there is
cellular immunoreactivity to Bb in patients with chronic Lyme
borreliosis (LB), Bb-specific lymphocytic responses were
tested in patients with CS. For this purpose, peripheral blood
mononuclear cells from CS patients and, as controls, from
patients with various manifestations of LB, and from healthy
volunteers without any evidence of Bb infection, were exposed
to Bb organisms for 5 days and then assayed for DNA synthesis.
Stimulation indices (SI) > 10 were scored positive. By
performing lymphocyte proliferation tests we found:
(i) that not only patients with various manifestations of
LB but also a considerable percentage of seropositive (five of
13 = 38%) and seronegative (six of 26 = 23%) CS patients
exhibit an elevated Bb-induced lymphocyte proliferation;
(ii) that the magnitude of the cellular response seen in CS
patients is comparable to that encountered in patients with
established Bb manifestations; and
(iii) that, within a given patient, antibiotic therapy can
result in a significant reduction of this response.
These results support a causative role of Bb in at least
some CS patients. Bb-induced lymphocyte responses were also
seen in both seropositive and seronegative erythema chronicum
migrans patients. These findings show that the pattern of
Bb-specific immune responses is more complex than previously
thought, and underscore the importance of lymphocyte function
assays in evaluating the diagnosis of potential Bb infection
in seronegative patients.
A case of localized scleroderma treated with
Sairei-to
Fushimi M.; Ogai M.; Furukawa F.
Division of Dermatology, Fujinomiya City General
Hospital,Fujinomiya Japan
Acta Dermatologica - Kyoto (Japan) 1995, 90/1
(109-112)
Sairei-to, a Chinese-Japanese herbal medicine, has been
used for the treatment of various diseases for about 3,000
years in China, and is well known to improve the symptoms of
rheumatoid arthritis and other collagen diseases. We
encountered an 18-year-old man with localized scleroderma. He
was treated with 8.1 g/day of Sairei-to (Kanebo) and topical
corticosteroids. Skin lesions were improved gradually and the
titer of anti-single stranded DNA antibody in sera reduced
from 270 U/ml to 89 U/ml after 7-month treatment. Herein, we
describe his clinical course and discuss the efficacy of
Sairei-to for the localized scleroderma.
Southwestern Internal Medicine Conference: The many
faces of scleroderma
Smiley J.D.
Arthritis Consultation Center, Presbyterian Hospital of
Dallas, 8200 Walnut Hill Lane,Dallas, TX 75231 United
States
American Journal of the Medical Sciences (United States)
1992, 304/5 (319-333)
This review integrates the clinical aspects of systemic
sclerosis (SSc; scleroderma) and scleroderma-like conditions
with new knowledge of the control of blood vessel tone and the
role of anoxia in the activation of connective tissues leading
to fibrosis. Serologic tests, high resolution computed
tomographic scanning, bronchoalveolar lavage, and physiologic
assessment of pulmonary gas diffusion are compared as
diagnostic tools and as means of quantitating internal organ
involvement. Treatment of Raynaud's disease and phenomenon,
management of scleroderma renal crisis, and new means for
improving gastrointestinal function with octreotide, the
somatostatin analogue, also are discussed. The relationship
between idiopathic forms of SSc and eosinophilic
fasciitis/eosinophilia-myalgia syndrome caused by L-
tryptophan ingestion and the scleroderma-like disease
associated with silicone breast implants also is
discussed.
Localized scleroderma - response to
1,25-dihydroxyvitamin Dinf 3
Humbert P.G.; Dupond J.L.; Rochefort A.; Vasselet R.; Lucas
A.; Laurent R.; Agache P.
Department of Dermatology, Centre Hospitalier, Universitaire
St-Jacques,25030 Besancon Cedex France
Clinical and Experimental Dermatology (United Kingdom) 1990,
15/5 (396-398)
1,25-Dihydroxyvitamin Dinf 3 (1,25(OH)inf 2 Dinf 3) may be
an immunomodulatory drug which could have a role in
controlling collagen depositioin, 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)inf
2Dinf 3 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)inf 2 Dinf 3 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.
The presence of cutaneous receptors for 1,25-dihydroxyvitamin
Dinf 3 (1,25(OHinf 2)Dinf 3) suggested that the skin was not
only the site for vitamin -D synthesis, but also a target
organ for this hormone. The observations that cultured human
dermal fibroblasts possess receptors for 1,25(OH)inf 2Dinf 3
and that this hormone is extremely potent in inhibiting their
proliferation, prompted an exploration of the possible use of
the hormone in the treatment of scleroderma.
Stimulating circulation to end statis in
scleroderma
Xie Y.; Jingde L.; Wenjie C.; et al.
Capital Hosp., Chinese Acad. Med. Sci., Beijing China
Chinese Medical Journal (China) 1981, 94/2
(85-93)
We have successfully treated 2 series of patients with the
'incurable disease' scleroderma with Chinese traditional
medicine according to the traditional medicine principle of
stimulating circulation to end stasis (SCES) (Huoxue huayu)
and have found it useful. Its value was first seen in the
first series of 104 cases treated from May 1960 to March 1966
and later confirmed in a second series of 123 cases. In the
second series, in addition to the decoction, we added
intralesional and/or acupuncture point injections of herbal
extracts. Of the 123, 43 had systemic scleroderma and 80
circumscribed scleroderma. In the systemic group, the
effective rate was 97.7%, of which 37.2% had marked
improvement, while in the 80 cases of circumscribed
scleroderma the figures were 97.5% and 46.3%. The
histopathologic changes under light and electron microscopy
confirmed the therapeutic efficacy of the combined treatment.
The main SCES therapeutic effect appears to be improvement of
circulation, especially the microcirculation, and connective
tissue metabolism.
Scleroderma
Rowell N.
Gen. Infirm., Leeds United Kingdom
Practitioner (United Kingdom) 1977, 219/1314
(820-825)
The important recent developments in diseases in which
scleroderma is a feature can be summarized as follows. The
distinction between morphoea (localized or generalized) and
systemic sclerosis is valid. The former tends to improve over
the years without treatment. Patients with systemic sclerosis
usually die from the disease but may live for over 30 years
after diagnosis. The prognosis is worse in males than in
females. The presence of histocompatibility antigen B8 and
impairment of cellular immunity in a patient with systemic
sclerosis are other adverse prognostic factors. There is still
no specific treatment for sclerodermatous disorders. Systemic
steroids may help patients with mixed connective tissue
disease and eosinophilic fasciitis. Occupational scleroderma
occurs in industry after exposure to vinyl chloride and
pesticides.
A mixture of aliphatic alcohols, tocopherol and
phytosterols ('piascledine') in treatment of scleroderma.
Preliminary report (Polish)
Szczepanski A.; Dabrowska H.; Moskalewska K.
Klin. Dermatol., AM, Warszawa Poland
Przeglad Dermatologiczny 1974, 61/4 (525-527)
Fifteen cases of scleroderma (8 of acroscleroderma type, 2
of diffuse scleroderma, 5 of circumscribed scleroderma) were
treated with piascledine. In part of cases of acrosclerosis
treated over a period of a few months in a dose from 3 to 6
capsules an improvement was obtained. It was characterized
mainly by a decrease in the intensity of arthralgia and a
better movability of fingers and, in circumscribed
scleroderma, by a lessening of skin indurations. In all cases
but one in which transient gastrointestinal disturbances and
papular eruption occurred drug tolerance was very good.
Ascorbic acid absorption in patients with systemic
sclerosis.
Teh LS; Johns CW; Shaffer JL; Booth EJ; Aarons L; Bennett RJ;
Herrick AL; Jayson MI
Rheumatic Diseases Centre, Radioisotope Department,
University of Manchester, UK.
J Rheumatol (Canada) Dec 1997, 24 (12) p2353-7
OBJECTIVE. To investigate whether reduced circulating
levels of ascorbic acid in patients with systemic sclerosis
(SSc) are a result of malabsorption.
METHODS. Eight patients with SSc, but with no evidence of
bacterial overgrowth, and 8 healthy controls were recruited.
On the first day of study, each subject was given orally an
aliquot of [14C] ascorbic acid, which was then "flushed out"
by oral intake of unlabeled ascorbic acid for the following 7
days. Plasma samples were collected at specified intervals and
urine was collected continuously over the 8 day study period.
[14C] content of plasma and urine were measured by
scintillation counting. For each subject, a plasma [14C] decay
curve was drawn. Each subject's ascorbic acid absorption was
assessed using the area under the curve (AUC) and the apparent
renal clearance (CLr[app]). Ascorbic acid intake was assessed
using dietary history and food composition tables.
RESULTS. There were no differences in the dietary intake of
vitamin C (p = 0.16) and body mass indices (p = 0.91) between
patients and controls. The plasma [14C] AUC and CLr(app) were
similar between patients and controls [AUC patient mean
(standard deviation, SD) = 37.1 (6.8), AUC control mean (SD) =
38.6 (9.9), p = 0.74; CLr(app) patient mean (SD) = 0.57
(0.24), CLr(app) control mean (SD) = 0.47 (0.27), p =
0.45].
CONCLUSION. There was no evidence of impaired absorption of
ascorbic acid in patients with SSc without bacterial
overgrowth compared to healthy controls.
Clinical aspects of the use of gamma linolenic acid
in systemic sclerosis.
Stainforth JM; Layton AM; Goodfield MJ
Department of Dermatology, General Infirmary, Leeds, United
Kingdom.
Acta Derm Venereol (Norway) Mar 1996, 76 (2)
p144-6
Systemic sclerosis is a multi system disorder, for which
there is no satisfactory treatment. Theoretically, dietary
supplementation with essential fatty acids may lead to an
increase in their derivatives, the vasoactive prostaglandins,
which benefit the acute and chronic ischaemic lesions of this
disease. We assessed the value of concentrated essential fatty
acids in patients with systemic sclerosis, concentrating
particularly on vascular symptoms and objective tests of
vascular reactivity. Twenty-five patients with systemic
sclerosis were randomised to receive concentrated essential
fatty acids or placebo, for 6 months in a double-blind
parallel group study. There was no significant difference
between the active and placebo groups in terms of maximum
blood flow after warming, minimum blood flow after cooling or
the recovery time after cooling. There were no significant
differences between the groups in the other parameters
measured. Dietary essential fatty acids have no role in the
treatment of vascular symptoms in established systemic
sclerosis.
Dietary intake of micronutrient antioxidants in
relation to blood levels in patients with systemic
sclerosis.
Herrick AL; Worthington H; Rieley F; Clarke D; Schofield D;
Braganza JM; Jayson MI
University of Manchester Rheumatic Diseases Centre, Hope
Hospital, Salford, UK.
J Rheumatol (Canada) Apr 1996, 23 (4) p650-3
OBJECTIVE. To document habitual intakes of micronutrient
antioxidants in patients with systemic sclerosis (SSc) in
light of studies reporting subnormal levels of ascorbate and
selenium in this patient group.
METHODS. Dietary intakes of vitamin C, selenium,
alpha-tocopherol, beta-carotene, and sulfur amino acid
precursors of glutathione were assessed using the 7 day
weighed record in 12 patients with SSc and in 12 healthy
control subjects. The intakes of the first 4 substances were
examined in relation to plasma/serum levels, while intakes of
sulfur amino acids were examined in relation to urinary
inorganic sulfate.
RESULTS. Antioxidant and sulfur amino acid intakes were
similar in patients and controls, although the patients had
lower levels of selenium (median 74 compared to 87 milligrams
in controls; p = 0.014) and of vitamin C in plasma (median 6.0
compared to 11.1 milligrams/l in controls; p = 0.08).
Inorganic sulfate concentration in urine was similar in
patients and controls.
CONCLUSION. Our results suggest that reduced blood levels
of the water soluble antioxidants selenium and ascorbic acid
in patients with SSc are not due to dietary deficiency. Other
explanations must therefore be sought.
Increased susceptibility to oxidation of
low-density lipoproteins isolated from patients with systemic
sclerosis.
Bruckdorfer KR; Hillary JB; Bunce T; Vancheeswaran R; Black
CM
Department of Rheumatology, Royal Free Hospital School of
Medicine, London, England.
Arthritis Rheum (United States) Aug 1995, 38 (8)
p1060-7
OBJECTIVE. To examine the resistance to oxidation of
low-density lipoproteins (LDL) from patients with systemic
sclerosis (SSc) and primary Raynaud's phenomenon (RP) compared
with healthy controls.
METHODS. Plasma LDL were isolated from patients with
diffuse cutaneous and limited cutaneous SSc (dcSSc and lcSSc,
respectively), patients with primary RP, and healthy control
subjects. The lipoproteins were assessed for their resistance
to oxidation in the presence of cupric ions, using
spectrophotometric assays.
RESULTS. LDL from patients with dcSSc and lcSSc were more
susceptible to oxidation than were those from healthy control
subjects or patients with RP.
CONCLUSION. Our findings suggest that free radicals may
play a role in the pathology of SSc.
Micronutrient antioxidant status in patients with
primary Raynaud's phenomenon and systemic sclerosis.
Herrick AL; Rieley F; Schofield D; Hollis S; Braganza JM;
Jayson MI
University of Manchester Rheumatic Diseases Centre, Hope
Hospital, Salford, UK.
J Rheumatol (Canada) Aug 1994, 21 (8) p1477-83
OBJECTIVE. To investigate the possibility that
micronutrient antioxidant status is an important factor in
determining the severity of Raynaud's phenomenon (RP) and in
differentiating between patients with primary Raynaud's
phenomenon (PRP) and those in whom Raynaud's is secondary to
systemic sclerosis (SSc).
METHODS. Four micronutrient antioxidants (selenium, vitamin
E, beta-carotene and ascorbic acid) and 2 "markers" of free
radical associated activity were assayed in peripheral blood
from 10 patients with PRP, 9 with limited cutaneous SSc
(ISSc), 9 with diffuse SSc (dSSc) and 15 healthy control
subjects.
RESULTS. Plasma ascorbic acid was reduced in all 3 groups
of patients: median level 10.6 mg/l in controls, 4.8 mg/l in
PRP (p < 0.01), 2.5 mg/l in ISSc (p < 0.01) and 6.8 mg/l
in dSSc (p < 0.05). A reduction in serum selenium was
especially found in dSSc (median 75 micrograms/l compared to
100 micrograms/l in controls, p < 0.05). In keeping with
these deficiencies, the serum concentration of 9, 11, linoleic
acid was elevated in RP patients: median values for the molar
ratio of the isomer to the parent fatty acid were 1.91% in
controls, 3.70% in ISSc (p < 0.05) and 3.85% in dSSc (p
< 0.01). Smoking patients showed lower levels of ascorbic
acid and higher levels of the linoleic isomer than
nonsmokers.
CONCLUSION. Deficiencies of ascorbic acid and selenium may
predispose towards irreversible tissue injury in RP patients
and cigarette smoke may be an independent risk factor.
Micronutrient antioxidant supplements may be of therapeutic
value.
Dietary intake and nutritional status in patients
with systemic sclerosis.
Lundberg AC; Akesson A; Akesson B
Department of Rheumatology, University of Lund, Sweden.
Ann Rheum Dis (England) Oct 1992, 51 (10)
p1143-8
Oesophageal dysmotility and abnormalities of intestinal
function are important manifestations in systemic sclerosis
and may have a significant effect on nutrient absorption and
nutritional status. In this study 30 patients with systemic
sclerosis with symptoms from the gastrointestinal tract were
compared with matched healthy control subjects with respect to
nutrient intake (four day record), anthropometric
measurements, and biochemical nutritional status. The intake
of energy (8.1 and 8.4 MJ/day) and its distribution among
nutrients did not differ between patients and control
subjects, but the lower intake of dietary fibre among patients
with systemic sclerosis suggests that they avoided food with a
coarse structure, such as coarse bread. The intake of
vegetables and fruit also tended to be lower among patients
with systemic sclerosis. Half of the patients had a subnormal
arm muscle circumference, and two patients also had a
subnormal triceps skinfold thickness, indicating severe
malnutrition. The concentration of ascorbic acid,
alpha-tocopherol, carotene, selenium, and also the proportion
of linoleic acid (18:2) in serum phosphatidylcholine was lower
in patients than in control subjects.
Essential fatty acid and prostaglandin metabolism
in Sjogren's syndrome, systemic sclerosis and rheumatoid
arthritis.
Horrobin DF
Scand J Rheumatol Suppl (Sweden) 1986, 61 p242-5
Evidence from biochemical studies and from experimental
animals indicates that abnormalities of essential fatty acid
(EFA) and eicosanoid metabolism could lead to salivary and
lacrimal gland atrophy and to immunological and
cardio-vascular defects. Measurements of EFA levels in
erythrocytes from patients with primary Sjogren's syndrome
have shown that abnormalities are indeed present. Controlled
clinical trials of supplementation with gamma-linolenic acid
(GLA) as evening primrose oil (Efamol) in both primary
Sjogren's syndrome and systemic sclerosis have given positive
results. There are strong arguments to indicate that
sophisticated manipulation of EFA metabolism may have a role
to play, not only in Sjogren's syndrome but also in other
rheumatological disorders. ( 16 Refs.)
Environmental and iatrogenic factors in systemic
sclerosis and related conditions: Review of the
literature
Halle O.; Schaeverbeke T.; Bannwarth B.; Dehais J.
O. Halle, Institut Bergonie, 180, Rue Saint-Genes, 33076
Bordeaux France
Revue de Medecine Interne (France) 1997, 18/3
(219-229)
The etiology of scleroderma remains unknown. Although a
genetic susceptibility seems to play a role, some
environmental and iatrogenic factors have been suggested to
trigger the disease. Contact for many months or years with
natural or synthetic 'toxic' products (by inhalation,
cutaneous contact, injection, swallowing or surgical implant)
could be implicated in the development of typical scleroderma
or pseudo-scleroderma. These products are either occupational
or non occupational like those used at home in daily life. We
will sum up the knowledges about this subject.
Systemic sclerosis in the elderly
Czirjak L.; Nagy Z.; Szegedi G.
3rd Department of Medicine, University Medical School,H-4004
Debrecen Hungary
Clinical Rheumatology (Belgium) 1992, 11/4
(483-485)
In our study, the characteristics of 114 patients with
systemic sclerosis (SSc) are discussed with emphasis on the
subgroup of cases whose onset of disease occurred above the
age of 60 years. Seven out of the 9 cases showed symptoms of
diffuse cutaneous systemic sclerosis with an extensive skin
involvement, and 5 of these cases died within 2 years
following the onset of SSc. Seven of the 9 cases showed a
rapid disease course with symptoms of cardiac, pulmonary
and/or renal involvement, while no secondary Sjogren's
syndrome, subcutaneous calcinosis and myositis were
demonstrated among these patients.
Progressive systemic sclerosis:
Pseudoscleroderma
Fleischmajer R.; Pollock J.L.
Hahnemann Med. Coll. Hosp., Philadelphia, Pa. United
States
Clinics in Rheumatic Diseases (United States) 1979, 5/1
(243-261)
Pseudoscleroderma is a term coined in the medical
literature to encompass a collection of diseases characterized
by skin induration or atrophy resembling that encountered in
progressive systemic sclerosis (PSS) or localized scleroderma.
A broad spectrum of aetiologically unrelated disorders has
been included in the pseudosclerodermas. The skin induration
in this heterogeneous group is due to a variety of factors,
including an increase in collagen and glycosaminoglycans,
deposition of amyloid, and changes in the fatty acid
composition of the subcutaneous tissue (Jablonska, 1975). In
this chapter, the term pseudoscleroderma will be restricted to
a group of disorders characterized by skin induration due to
fibrosis of the dermis and/or the subcutaneous tissue. We
include among the pseudosclerodermas: scleredema, diffuse
fasciitis with blood eosinophilia, progeria, Werner's disease,
carcinoid syndrome, chronic graft-versus-host disease,
porphyria cutanea tarda, phenylketonuria, scleromyxoedema,
scleroderma-like lesions due to bleomycin therapy,
occupational sclerodermas and melorheostosis with linear
scleroderma. The clinical picture and pathogenesis of each
disease are reviewed, and the cutaneous manifestations
resembling scleroderma are described in detail.
Clastogenic activity in the plasma of scleroderma
patients: a biomarker of oxidative stress.
Emerit I; Filipe P; Meunier P; Auclair C; Freitas J;
Deroussent A; Gouyette A; Fernandes A
Institut Biomedical des Cordeliers, Universite Paris VI, et
CNRS, France.
Dermatology (Switzerland) 1997, 194 (2) p140-6
BACKGROUND: Scleroderma patients exhibit increased
chromosomal instability due to circulating clastogenic plasma
factors (CF). Formation and action mechanisms of CF are
mediated by superoxide. In addition, previous work detected
inosine triphosphate (ITP) in the plasma of 2 patients, and
the enzyme adenosine deaminase (ADA) was found to be
increased.
OBJECTIVE: To study correlations between CF, ITP and ADA
levels, CF and disease activity, as well as other biomarkers
of oxidative stress.
METHODS: Clastogenic activity was evaluated by means of
cytogenetic methods in 48 patients and 55 healthy subjects.
ITP was detected by mass spectrometry and electrospray
ionisation. ADA was measured with a colorimetric assay and
malondialdehyde using the Yagi method.
RESULTS: Clastogenic activity was significantly increased
in patients' plasma compared to controls. In 10 patients CF,
ITP and ADA were studied simultaneously. All three parameters
were increased in the 7 patients of subgroups 2 (skin and
esophagus involvement) and 3 (skin plus multiple organ
involvement). ITP was not detected in 2 patients of subgroup 1
(skin involvement only) with low ADA and CF values.
CONCLUSION: ITP, the deamination product of ATP, is one of
the clastogenic and superoxide generating components of CF.
The formation of this deamination product of ATP is probably
related to the increase in ADA. CF are biomarkers of oxidative
stress and can be used for evaluation of antioxidant
treatments in scleroderma.
Evidence of free radical-mediated injury
(isoprostane overproduction) in scleroderma.
Stein CM; Tanner SB; Awad JA; Roberts LJ 2nd; Morrow JD
Vanderbilt University, Nashville, Tennessee 37232, USA.
Arthritis Rheum (United States) Jul 1996, 39 (7)
p1146-50
OBJECTIVE. Free radical-induced oxidative stress with
consequent lipid peroxidation and resultant tissue damage has
been suggested as a potential mechanism of the pathogenesis of
scleroderma. However, because reliable measurement of lipid
peroxidation in vivo is difficult, it has not been possible to
adequately examine this hypothesis. We have previously
described a series of bioactive prostaglandin F2-like
compounds, termed F2-isoprostanes, produced in vivo in humans
by the non-cyclooxygenase, free radical-catalyzed,
peroxidation of arachidonic acid and have shown them to be a
reliable measure of lipid peroxidation in vivo. In the present
study, we determined whether scleroderma is associated with
enhanced oxidative stress.
METHODS. As a measure of oxidative stress, we determined
urinary concentrations of a tetranor-dicarboxylic acid
metabolite of F2-isoprostanes (F2IP-M) by mass spectrometry in
8 patients with scleroderma (representing a wide spectrum of
disease, including limited disease with refractory digital
ulceration or pulmonary hypertension, and diffuse disease) and
in 10 healthy control subjects.
RESULTS. F2IP-M concentrations were significantly higher in
patients with scleroderma (mean +/- SEM 3.41 +/- 0.64 ng/mg of
creatinine) than in healthy controls (1.22 +/- 0.14 ng/mg of
creatinine) (P = 0.002). These elevations occurred in patients
with limited disease and in those with diffuse disease.
CONCLUSION. The increased level of urinary F2IP-M supports
the hypothesis that free radical-induced oxidative injury
occurs in scleroderma and provides a biologic marker whose
relationship to disease activity and disease therapy may be
important. These findings may also provide a rationale for
exploring whether antioxidant therapy may influence the
natural course of the disease.
Antimyenteric neuronal antibodies in
scleroderma.
Howe S; Eaker EY; Sallustio JE; Peebles C; Tan EM; Williams
RC Jr
Department of Medicine, University of Florida, Gainesville
32610.
J Clin Invest (United States) Aug 1994, 94 (2)
p761-70
The pathogenesis of gastrointestinal (GI) dysmotility in
scleroderma is incompletely understood, although previous
studies have proposed a neuropathic mechanism. We studied
patients with scleroderma as compared with other connective
tissue disease patients and normal controls for the presence
of circulating antibodies to myenteric neurons. Serial
dilutions of sera were overlaid on rat intestine,
double-labeled with antineurofilament antibody as a myenteric
plexus marker, and imaged using indirect immunofluorescence
techniques. High titer sera (> or = 1:50) from 19 out of 41
scleroderma patients stained myenteric neurons, whereas none
of 22 normals or 5 patients with idiopathic GI dysmotility
were positive. Although 6 out of 20 SLE and 6 out of 10 mixed
connective tissue disease patients' sera stained myenteric
plexus neurons, when positive sera were absorbed with calf
thymus extract to remove antinuclear antibody, 15 scleroderma
sera, 0 SLE, and 2 mixed connective tissue disease patients
retained positive staining of myenteric neurons. Western
blotting using actin and neuronal intermediate filament
preparations failed to show immunoreactivity with scleroderma
sera containing antimyenteric neuronal antibodies.
Paraneoplastic sera associated with GI dysmotility stained
myenteric neurons in a different pattern than seen with
scleroderma sera. A positive correlation between the presence
of Raynaud's phenomenon and antimyenteric neuronal antibodies
was observed in scleroderma patients. Our results indicate
that IgG antibodies reacting with myenteric neurons are
present in many patients with scleroderma. Although the
neuronal antigen has not yet been identified, the presence of
myenteric neuronal antibodies in patients with GI dysmotility
and scleroderma suggests a neuropathic process.
[A clinico-immunological assessment of the efficacy
of combined methods of treating patients with different
immunopathological forms of focal scleroderma]
Suchkova TN; Sharova NM; Suchkov SV
Vestn Dermatol Venerol (USSR) 1990, (2) p47-50
To help the physicians choose a rational scheme of combined
therapy of patients with various immunopathologic forms of
focal scleroderma, the authors present a clinical and
immunologic assessment of the efficacies of 2 combined
therapeutic courses, enzyme immunotherapy and penicillin
immunotherapy, as well as of the individual course of tactivin
immunotherapy. Inclusion of tactivin in any complex
therapeutic scheme appears to be necessary. In patients
suffering from the condition for a long time, with multiple
foci of involvement, tactivin should be combined with enzymic
drugs, like hyaluronidase (lydase). Enzyme immunotherapy
promoted a more active resolution of the skin process.
Penicillin immunotherapy alone is disputable, and further
studies of such treatment are necessary. Enzyme immunotherapy
should be considered as the optimal scheme of rational
combined treatment for focal scleroderma.
Avian scleroderma : evidence for qualitative and
quantitative T cell defects.
Wilson TJ; Van de Water J; Mohr FC; Boyd RL; Ansari A; Wick
G; Gershwin ME
Department of Internal Medicine, University of California,
Davis 95616.
J Autoimmun (England) Jun 1992, 5 (3) p261-76
T cell activation is dependent upon calcium influx and
protein kinase C activation, with subsequent lymphocyte
proliferation dependent upon IL-2. Abnormalities in T cell
proliferation, including abnormal calcium influx and defective
protein kinase C activation, have been identified in aged mice
and humans and many autoimmune diseases including diabetes,
lupus and scleroderma. Since UCD line 200 chickens, which
spontaneously develop a scleroderma-like disease, have both
thymic defects and a diminished peripheral blood lymphocyte
response to IL-2, we have further investigated T cell function
in these birds. Interestingly, line 200 T cells respond poorly
in vitro to a variety of diversely acting T cell mitogens
including concanavalin A, phytohemagglutinin and anti-chicken
CD3 monoclonal antibody. Moreover, they do not respond well
even to phorbol myristate acetate in conjunction with
ionomycin. Addition of exogenous IL-2-containing supernatant
concurrently with mitogenic stimulation also had no
significant effect. Analysis of intracellular free calcium
demonstrated that the lymphocytes from diseased birds had a
reduced influx of calcium (or release for intracellular
stores) following stimulation. These data clearly reflect a
unique defect in T cell activation associated with avian
scleroderma. Analysis of chicken CD3, CD4 and CD8 expression
revealed a 39% decrease in peripheral blood CD4+ cells in
scleroderma birds, although this decrease was not sufficient
to explain the 80-90% decrease observed in proliferation
assays and calcium influx. Our data support the hypothesis
that avian scleroderma is mediated via abnormal function of
lymphocyte co-stimulatory molecules or intracellular calcium
regulators.
[The cyclic nucleotide system of patients with
focal scleroderma]
Suchkova TN; Sharova NM; Cheknev SB; Suchkov SV
Vestn Dermatol Venerol (USSR) 1990, (3) p35-8
Studies of the function of cyclic nucleotide system in the
lymphocytes of patients with focal scleroderma have revealed
that this condition is characterized by growth of the
intracellular cAMP/cGMP ratio, correlating with the process
duration, severity, and dissemination. A correlation between
lymphocyte regulatory function defect and the presence of
immunodeficiency syndrome was demonstrated. Sensitivity of
lymphocytic cyclic nucleotides in focal scleroderma patients
to thymoptin, a thymic agent, was examined. Manifest clinical
effect of this drug is based on stabilization of the function
of lymphocytic cyclic nucleotides system and, consequently, on
normalization of the immunologic parameters. Potentialities
and prospects of thymic factors immunotherapy of focal
scleroderma patients are discussed.
D-penicillamine therapy and interstitial lung
disease in scleroderma. A long-term followup study.
de Clerck LS; Dequeker J; Francx L; Demedts M
Arthritis Rheum (United States) Jun 1987, 30 (6)
p643-50
Sequential lung function tests were performed on 17
scleroderma patients who were treated with D-penicillamine
(DP) (total of 66 treatment years) and on 10 control
scleroderma patients who were not treated or were treated with
low-dose prednisone (total of 25 treatment years). Cusum plots
showed significant differences between the 2 groups in their
cumulative changes in carbon monoxide diffusing capacity
(DLCO) (P less than 0.005) and in DLCO/lung volume (P less
than 0.02). The end value of the DLCO was greater than 10%
lower than the initial value in 3 of the 17 DP-treated
patients versus 5 of the 10 control patients (P less than
0.01, Fisher's exact probability test); in 3 DP-treated
patients and 8 control patients (P less than 0.003, Fisher's
exact probability test), the end value of the DLCO/lung volume
was greater than 10% lower than the initial value. We conclude
that DP has a beneficial effect on interstitial lung disease
in patients with scleroderma.
Failure of dimethyl sulfoxide in the treatment of
scleroderma.
Binnick SA; Shore SS; Corman A; Fleischmajer R
Arch Dermatol (United States) Oct 1977, 113 (10)
p1398-402
Nineteen patients with systemic scleroderma and five with
localized scleroderma were treated with topical dimethyl
sulfoxide by painting and immersion techniques. Partial
control was obtained by using a very low concentration (5%) on
one side when involvement was symmetrical. Duration of
treatment ranged from 3 to 15 months. Topical dimethyl
sulfoxide did not improve the skin induration, range of
motion, or Raynaud's phenomenon in the scleroderma patients.
No substantial beneficial effect was noted on the healing of
ischemic ulcers, and the continuous application of dimethyl
sulfoxide did not prevent new ulceratins from developing.
Relief of pain was noted in ten of 16 patients, probably due
to the local analgesic effect of dimethyl sulfoxide.
D penicillamine in the treatment of rheumatoid
arthritis and progressive systemic sclerosis
Davis P.; Bleehen S.S.
Dept. Med., Univ. Alberta, Edmonton Canada
British Journal of Dermatology 1976, 94/6
(705-711)
D Penicillamine (B'B'' dimethylcysteine) is a drug widely
known for its clinical therapeutic benefit in the treatment of
Wilson's disease and cystinuria. A number of recent studies
have demonstrated that penicillamine may be therapeutically
active in other diseases including rheumatoid arthritis (RA),
progressive systemic sclerosis (PSS), morphea and active
chronic hepatitis, as well as acting as a chelator of a number
of heavy metals. The increasing number of therapeutic
indications for D penicillamine therapy need to be clearly
defined and its ill effects plainly identified. This review
concentrates on the present value of this drug in the
treatment of rheumatoid arthritis and progressive systemic
sclerosis.
Elevated plasma superoxide dismutase activity in
patients with systemic sclerosis.
Morita A; Minami H; Sakakibara N; Sato K; Tsuji T
Department of Dermatology, Nagoya City University, Medical
School Nagoya, Japan.
J Dermatol Sci (Ireland) Mar 1996, 11 (3)
p196-201
Injury to vessel walls, especially microvascular damage due
to free radicals, has been a focus of interest concerning the
pathogenesis of systemic sclerosis. Excess reactive oxygen
species may induce antioxidant defenses. We therefore measured
plasma superoxide dismutase (SOD) activity in patients with
systemic sclerosis and found average SOD activity of plasma in
16 patients with systemic sclerosis (5.00 +/- 3.10 U/ml) to be
significantly (P < 0.001) higher than those in 89 healthy
volunteers (1.56 +/- 0.234 U/ml). Patients with Raynaud's
phenomenon and/or skin sclerosis had particularly high SOD
activity. These findings suggest that plasma SOD activity may
serve as a useful parameter for assessment of sclerotic
progression and the presence of Raynaud's phenomenon.
[Myasthenia gravis induced by D-penicillamine in a
patient with progressive systemic sclerosis]
Marchiori PE; Scaff M; Cossermelli W; De Assis JL
Arq Neuropsiquiatr (Brazil) Dec 1984, 42 (4)
p380-3
The development of autoimmune diseases in some patients
treated with D-penicillamine (DPA) suggests that the reported
occurrence of a conduction disorder at the neuromuscular
junction and the development of a reversible myasthenia gravis
in rheumatoid disease, progressive systemic sclerosis or
Wilson's disease after the use of DPA are part of a general
predisposition for autoimmune disease related to DPA therapy.
The case reported is an example. The DPA- induced myasthenia
gravis (MG) is similar to the spontaneous MG clinically and
electrophysiologically, though ocular signs prevail in the
former. Antibodies to acetylcholine receptor have been
demonstrated and thymic hyperplasia also has been formed.
Regarding the onset of myasthenic manifestations the duration
of the treatment with DPA varies from 6 to 10 months. The
action of DPA on the neuromuscular junction is different from
that occurring in spontaneous MG. The pathogenesis of the DPA
induced MG is still obscure. The chemical properties of DPA
permit it to react with many proteins and some alteration of
proteins may appear, with structural changes in the
composition and antigenicity of the collagen fibers. In vitro
DPA causes disorder of acetylcholine receptor bridges to
alpha, beta, gamma sub-units with reduction of the S-S bridges
in the gamma-subunit. This decreases the linkage of high
affinity and abolishes its positive cooperative system,
reducing the S-S connection in the alpha-unit near the
acetylcholine linkage. The interaction between DPA and
receptor may induce antigenic alteration in this latter,
starting the autoimmune phenomena. The other possibility is
the stimulation of prostaglandin E-1 synthesis by DPA may fill
the allosteric place of ACh receptor, interfering on the
neuromuscular junction.
The thymus in systemic sclerosis.
Carter J; Ewen SW; Gray E; Beck JS
J Pathol (England) May 1973, 110 (1) p97-100
No abstract.
Treatment of systemic sclerosis.
Pope J
University of Western Ontario, London, Canada.
Curr Opin Rheumatol (United States) Nov 1993, 5 (6)
p792-801
Although there have been no major breakthroughs in
scleroderma therapy, new treatments have been tested in
patients with systemic sclerosis, including both interferon
alfa and interferon gamma. These biologic agents can reduce
collagen synthesis, which is a rational target for scleroderma
therapy. Debate about the use of photopheresis continues, and
it was suggested in a recent editorial that photopheresis is
no better than D-penicillamine in the treatment of scleroderma
and is more expensive. Cyclosporine appears to have frequent
renal toxicity when used to treat scleroderma. Outcome
measurements have been concentrated on in scleroderma trials.
Several types of scleroderma classifications were compared,
and the classification of diffuse and limited scleroderma was
strongly related to disease severity. Skin score was
systematically compared with mapping the surface area of
involved skin, and the skin score was found to be more
reliable. A possible prognostic indicator in scleroderma is
high-resolution pulmonary computed tomography, which is
sensitive in early detection of scleroderma-associated
interstitial lung disease. Classification of Raynaud's
phenomenon into primary and secondary forms has been proposed,
and further testing of the criteria and long-term follow-up is
necessary to validate this classification. Over the past year,
treatment of vasospasm with prostacyclin analogues has been
efficacious with iloprost but not with low-dose oral
cicaprost. Tissue plasminogen activator is not beneficial in
the treatment of Raynaud's phenomenon. A report of radical
microarteriolysis for the treatment of refractory Raynaud's
phenomenon seems promising, warranting further investigation.
(70 Refs.)
Penicillamine in systemic sclerosis: a
reappraisal.
Sattar MA; Guindi RT; Sugathan TN
Department of Medicine, Faculty of Medicine, Kuwait
University.
Clin Rheumatol (Belgium) Dec 1990, 9 (4) p517-22
In a 36-month prospective trial 21 patients with systemic
sclerosis (diffuse systemic sclerosis 16 patients and 5
subjects with limited cutaneous subtype) were treated with
D-penicillamine. In all patients with diffuse systemic
sclerosis there was objective improvement. The degree and
extent of skin involvement decreased significantly (p less
than 0.001), whereas no objective improvement was noted in
patients with limited cutaneous subtype. Further, no systemic
progression of the disease was observed during the study
period. Our results suggest that a prolonged treatment with
D-penicillamine in small doses is not only beneficial and
effective but also free of side-effects, if used at an earlier
stage.
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