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PubMed2002

Decreased MMP-9 activity in the serum of patients with diffuse cutaneous systemic sclerosis.

Matrix metalloproteinase-9 (MMP-9) and its inhibitor, tissue inhibitors of metalloproteinases-1 (TIMP-1) are involved in tissue inflammation and fibrotic processes. We previously reported an elevated serum TIMP-1 level in patients with systemic sclerosis (SSc). We measured serum TIMP-1 and active MMP-9 levels in 62 patients with SSc, 10 patients with rheumatoid arthritis (RA) and 15 normal controls using a modified enzyme-linked immunosorbent assay. The active MMP-9 level in the serum of the patients with RA or SSc was not significantly different from that of controls. Serum MMP-9 activity in patients with diffuse cutaneous SSc was significantly decreased compared with that of limited cutaneous SSc or normal controls. The MMP-9 activity and modified-Rodnan total skin thickness score in patients with SSc were negatively correlated. Serum MMP-9 activity and TIMP-1 level in patients with SSc were not correlated. Serum MMP-9 activity might be a useful indicator of disease activity, especially skin severity, in SSc patients.

Adolescent↗

PubMed1995

Genital tract abnormalities and female sexual function impairment in systemic sclerosis.

OBJECTIVE: Our purpose was to determine the involvement of the female genital tract and its functional consequences on menstrual and sexual aspects in systemic sclerosis. STUDY DESIGN: Sixty women with systemic sclerosis and 23 age- and disease duration-matched women with either rheumatoid arthritis or systemic lupus erythematosus were surveyed with a comprehensive questionnaire addressing problems before and after disease onset. Fourteen systemic sclerosis patients also had gynecologic evaluations. RESULTS: Vaginal dryness (71%), ulcerations (23%), and dyspareunia (56%) were significantly more frequent in patients with systemic sclerosis after disease onset than before and also in comparison with control subjects. Vaginal tightness and constricted introitus were present in 5 of 60 systemic sclerosis patients. More than half of systemic sclerosis patients reported a decrease in the number (p = 0.04) and intensity (p = 0.02) of orgasms, compared to < 20% of control subjects. The desire and frequency of coitus and the sexual satisfaction index were impaired equally in each group. Skin tightness, reflux-heartburn, and muscle weakness adversely affected sexual relations more in systemic sclerosis than in control subjects. On gynecologic examination 5 of 11 systemic sclerosis patients had small-sized uteri, and 3 of them had early menopause at 29, 38, and 43 years. Seven of 16 (44%) women with systemic sclerosis, compared with 6% of normal women in the United States, attained natural menopause before age 45. CONCLUSIONS: Although impairment in various indexes of sexual function occurs in a number of autoimmune diseases, decreased orgasmic function appears to be limited to systemic sclerosis. Vaginal involvement and other systemic sclerosis-related systemic symptoms adversely influence sexual relations. Menstrual abnormalities, including early menopause, affect many patients. Genital tract involvement occurs in a substantial proportion. Prospective longitudinal studies are warranted.

Adult↗

PubMed2006

En coup de sabre morphea and Parry-Romberg syndrome: a retrospective review of 54 patients.

BACKGROUND: The relationship between en coup de sabre morphea and Parry-Romberg syndrome is unclear, and not much is known regarding their demographic and clinical characteristics or the efficacy of the treatments that are used. OBJECTIVE: The purpose of this study was to describe demographic data, clinical features, and medications used in a large cohort of patients with en coup de sabre morphea and Parry-Romberg syndrome. METHODS: A retrospective review of patients diagnosed with en coup de sabre morphea or Parry-Romberg syndrome at the Mayo Clinic from 1984 to 2004 was conducted. Demographic data, examination findings, and treatments were noted. RESULTS: We identified 54 patients who met criteria for inclusion in the study. Twenty-six patients (48%) had en coup de sabre morphea, 13 (24%) had Parry-Romberg syndrome, and 15 (28%) had both. Disease was present bilaterally in 7.4% of patients. Thirteen percent of all patients in the study group had seizures. Of patients who received treatment, most were treated with antimalarial agents (57.1%) or methotrexate (28.6%). LIMITATIONS: The study design was that of a retrospective review at a tertiary care center with referral bias. There were also limitations present because of the inherent nature of the diseases studied. CONCLUSION: En coup de sabre morphea and Parry-Romberg syndrome frequently coexist and are likely both variants of morphea. Bilateral disease is more common than previously reported. The efficacy of antimalarials and methotrexate in the treatment of these diseases remains unclear.

Adolescent↗

PubMedDate not supplied

Dehydroepiandrosterone sulphate serum levels in systemic sclerosis.

OBJECTIVE: To evaluate in a cohort of women with systemic sclerosis (SSc) the dehydroepiandrosterone sulphate (DHEAS) serum levels and their relationship with disease severity. METHODS: DHEAS serum concentrations were measured by radioimmunoassay in 40 SSc patients and compared with those in 40 controls matched for sex and reproductive status. IL-2 sR alpha was evaluated as a disease activity index. A preliminary organ/system severity scale proposed by Medsger et al. in 1999 was used to evaluate disease severity. RESULTS: Mean serum levels of DHEAS in SSc women of childbearing age were significantly lower than in controls (0.87 +/- 0.85 microgram/ml versus 2.75 +/- 0.42 micrograms/ml; p < 0.001). On the contrary, no difference was found between postmenopausal women and controls. A reduction below the 95% confidence limits was found in 10 out of 11 patients of childbearing age and in 8 out of 29 postmenopausal women, respectively. In 5 out of 11 patients of childbearing age taking steroids for their SSc (< 10 mg/daily) DHEAS levels were significantly lower than in patients not taking steroids (p = 0.01). On the contrary, 16 out of 29 postmenopausal women using steroids had lower DHEAS concentrations than in patients not taking steroids, although the difference was not statistically significant. There was no statistically significant difference in DHEAS levels between patients with diffuse or limited SSc, or between those with or without organ system involvement. No correlations were found either in pre- and post-menopausal steroid nonusers, or in limited and diffuse subsets, between DHEAS levels and age, postmenopausal years, disease duration, IL-2 sR alpha, disease organ/system severity scale. CONCLUSION: Our data show that, as in other autoimmune diseases, low serum DHEAS is a feature of premenopausal SSc patients. More extensive prospective studies are needed to define the exact role of DHEAS dysregulation in SSc.

Adolescent↗

PubMed1994

Immunocytochemical localization and serologic detection of transforming growth factor beta 1. Association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon.

OBJECTIVE: To determine the presence of transforming growth factor beta 1 (TGF beta 1) and inflammatory cell markers (HLA-DR and Factor XIIIa) and to compare these with the presence of type I procollagen, in clinically uninvolved and involved skin from patients with different subsets of systemic sclerosis (SSc), and to analyze circulating levels of TGF beta 1 in SSc patients. METHODS: TGF beta 1, HLA-DR, Factor XIIIa, and type I procollagen were detected in skin biopsy sections using a biotin-streptavidin-peroxidase system. Levels of circulating TGF beta 1 were measured using a capture enzyme-linked immunosorbent assay technique. RESULTS: Patients with active diffuse cutaneous SSc (dcSSc) showed minimal TGF beta 1 but significant type I procollagen staining in involved skin, while the clinically uninvolved skin of these patients showed moderate extracellular and intra-epidermal TGF beta 1 immunoreactivity. Patients with limited cutaneous SSc (lcSSc) showed elevated TGF beta 1 staining in both involved and uninvolved skin, as well as procollagen staining. Significant TGF beta 1 reactivity, HLA-DR and Factor XIIIa immunoreactivity, numerous inflammatory cells, and procollagen staining were seen in specimens from patients with morphea. Sequential biopsies suggested the presence of cytokine activity at the earliest stages of disease, which was not maintained with progression of sclerosis. Among the disease groups studied, elevated levels of circulating TGF beta 1 were seen only in patients with morphea. CONCLUSION: The pattern of TGF beta 1 staining in dermal sections from patients with dcSSc, lcSSc, and morphea suggests that this cytokine is important in the pathogenesis of scleroderma. Furthermore, the presence of TGF beta 1 prior to the onset of fibrosis indicates an early involvement of this growth factor, possibly in the inflammatory stage of the disease.

Biomarkers↗

PubMed1989

Activation of the complement system in systemic sclerosis. Relationship to clinical severity.

Using newly developed techniques, we investigated the complement pathways and the extent of their activation in patients with systemic sclerosis (SSc) of both the diffuse cutaneous and limited cutaneous types. Plasma levels of the fragments C3d, C4d, and Ba were measured in patients with SSc and in matched control subjects. All fragments and ratios were higher in SSc patients than in controls (P less than 0.05), demonstrating that complement activation occurs in SSc. Levels of C3d, C3d:C3, Ba, and Ba:factor B were higher in patients with diffuse cutaneous SSc patients than in controls (P less than 0.01). C3d, C3d:C3, C4d, and C4d:C4 levels were also higher in patients with limited cutaneous SSc than in controls (P less than 0.05). These results show that complement activation occurs in SSc patients and that it reflects clinical severity. Complement activation may therefore have a pathogenetic role in SSc, and its measurement may prove useful in monitoring the disease.

Adult↗

PubMed1998

Association of esophageal dysfunction and pulmonary function impairment in systemic sclerosis.

OBJECTIVE: The aim of this study was to investigate the relationship between esophageal dysfunction and pulmonary involvement in patients with systemic sclerosis (SSc). METHODS: Pulmonary function parameters were compared between groups of patients with and without manometric evidence for SSc-induced esophageal dysmotility. RESULTS: Twenty-six of 43 patients (60.5%) exhibited a marked hypo- or aperistalsis of the smooth muscle portion of the esophagus. Total lung capacity, inspiratory vital capacity, and forced vital capacity were significantly lower in patients with esophageal dysfunction compared with those with normal esophageal peristalsis (p < 0.001). Patients with the diffuse form of SSc (n = 20) had significantly lower values for total lung capacity and inspiratory vital capacity compared with patients with the limited type of SSc (n = 23; p < 0.05). CONCLUSION: There is a significant association of esophageal dysmotility with reduced lung volumes in SSc. Possible explanations for these findings are pulmonary damage due to increased gastroesophageal reflux and, more likely, simultaneous involvement of the lungs and the esophagus in the disease process.

Esophageal Motility Disorders↗

PubMed2003

Low-dose intravenous cyclophosphamide in systemic sclerosis: a preliminary safety study.

Both oral and intravenous high-dose cyclophosphamide (CYC) regimens are associated with serious side effects when used for the treatment of systemic sclerosis (SSc). The aim of the present trial was to test the safety of low-dose intravenous CYC in patients with SSc. Eight SSc patients, in whom CYC treatment was warranted, were studied at baseline and after 6 months' intravenous CYC treatment (500 mg pulses at weeks 0, 1, 2, 6, 10, 14, 18 and 22). Side effects probably related to CYC treatment were carefully investigated. The development of amenorrhea was assessed during the period of treatment and over the following 12 months. The therapy was well tolerated overall. No patient discontinued treatment because of side effects. Leukopenia, premature ovarian failure, hemorrhagic cystitis, microscopic hematuria and liver toxicity were never detected. The most common adverse events were mild and self-limiting nausea and weakness. Our data suggest that low-dose intravenous CYC is relatively safe, at least in the short term. Further studies are needed to assess both the efficacy and the long-term safety.

Adolescent↗

PubMed2004

IgG reactivity with a 100-kDa tissue and endothelial cell antigen identified as topoisomerase 1 distinguishes between limited and diffuse systemic sclerosis patients.

We have analyzed antibody (Ab) reactivities of patients with limited systemic sclerosis (SSc) and anti-centromere Ab, patients with diffuse SSc and anti-topoisomerase 1 (anti-topo 1) Ab, patients with diffuse SSc without anti-topo 1 or anti-centromere Ab and age- and gender-matched healthy controls with normal human tissue and endothelial cell (EC) antigens. IgG reactivities with tissue antigens differed significantly between patients with anti-topo 1 Ab and patients with anti-centromere Ab. One 100-kDa band identified as topoisomerase 1 in macrovascular and microvascular EC extracts was recognized by IgG from patients with anti-topo 1 Ab and 50% of patients without specific Ab. IgG from patients with limited SSc and anti-centromere Ab, but not those of other patients or controls specifically recognized a 80-kDa band only in microvascular EC. Our results indicate that Ab from patients with limited or diffuse SSc with or without anti-topo 1 Ab exhibit specific and mutually exclusive reactivity patterns.

Autoantibodies↗

PubMed2006

Systemic sclerosis in childhood.

Juvenile systemic sclerosis (jSSc) is a rare disease of childhood, and the amount of published data is limited. It appears that its clinical presentation differs from adult disease and the limited form affects only very few children. The organ involvement pattern differs also from the adult form. Prognosis seems to be better with a 5-yr survival of 95% of the jSSc patients. The validation of the outcome measures for children with jSSc is currently in progress. Regarding effective treatment, there are no paediatric data and the paediatric rheumatologist needs to rely on the experiences in adult disease.

Age of Onset↗

PubMed1994

Skin scoring in systemic sclerosis: a modification--relations to subtypes and the aminoterminal propeptide of type III procollagen (PIIINP).

Forty-one patients with systemic sclerosis were investigated with a new and simple skin score method measuring the degree of thickening and pliability in seven regions together with area involvement in each region. The highest values were, as expected, found in diffuse cutaneous systemic sclerosis (type III SS) and the lowest in limited cutaneous systemic sclerosis (type I SS) with no lesions extending above wrists and ancles. A positive correlation was found to the aminoterminal propeptide of type III procollagen, a serological marker for synthesis of type III collagen. The skin score is considered simpler than previous methods and is recommended for more general use.

Arm↗

PubMed1993

[Pulmonary hypertension and systemic sclerosis].

BACKGROUND: Pulmonary involvement in systemic sclerosis (SS) is a frequent complication and is associated with a poor prognosis. Pulmonary hypertension may or may not develop, however, its recognition is usually possible only in advanced stages. METHODS: In this study we noninvasively evaluated the pulmonary artery systolic pressure in 31 patients with SS using Doppler echocardiography. Pulmonary hypertension was detected in 48.4% of the patients. RESULTS: The prevalence of pulmonary hypertension was similar in patients with limited SS and diffuse SS (42.9% and 52.9%, respectively; p = NS). No differences were observed in pulmonary artery systolic pressure between patients with limited or diffuse SS and pulmonary hypertension. Pulmonary hypertension was usually mild, and only in two cases was pulmonary systolic pressure higher than 50 mmHg (63 and 107 mmHg, respectively). CONCLUSIONS: Pulmonary hypertension is frequently observed in patients with SS. The patients with diffuse or limited SS are equally affected by this complication. Doppler echocardiography has proved to be the technique of choice for the evaluation of pulmonary involvement in patients with SS because it is noninvasive, inexpensive and allows serial examinations. Early recognition of pulmonary hypertension may favor the use of therapeutical strategies to prevent the progression to advanced forms.

Adult↗

PubMed2006

Hutchinson-Gilford progeria syndrome: review of the phenotype.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide-spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non-classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non-classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant-negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A.

Abnormalities, Multiple↗

PubMed1987

Rational approach to long-term use of H2-antagonists.

Although the approved indications for long-term histamine (H2) receptor-antagonists are limited to the management of hypersecretory states and prophylaxis against recurrent duodenal ulcer, these agents are often prescribed indiscriminately. Definitive guidelines concerning proper patient selection for prophylaxis against duodenal ulcer recurrence are lacking. Persons likely to benefit from maintenance therapy include those who smoke and those with a long duration of symptoms or prior history of an ulcer complication. Although not an approved indication, maintenance therapy to prevent recurrent gastric ulcer is appropriate for elderly persons receiving nonsteroidal anti-inflammatory drugs or in patients with poor cardiopulmonary status who may not tolerate surgery for an ulcer-related complication. The role of long-term H2-antagonist therapy in reflux esophagitis is not defined but may be appropriate in scleroderma and Barrett's esophagus. Finally, several miscellaneous conditions, including cystic fibrosis, Menetrier's disease, and pancreatic exocrine insufficiency, may benefit from long-term H2-antagonist therapy. Currently, clinical trials document the efficacy of maintenance therapy in duodenal ulcer for up to a three-year period; however, for gastric ulcer and chronic reflux esophagitis, the duration and benefit of long-term therapy is not established, and treatment regimens need to be individualized. Therapy may be required indefinitely in the miscellaneous states mentioned previously.

Esophagitis, Peptic↗

PubMed2004

Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis.

OBJECTIVE: Circulating endothelial cells (CECs) have been described in different conditions involving vascular injury. Vascular abnormalities play a key role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to search for the presence of CECs in patients with SSc and to evaluate their clinical associations and possible pathogenic role. METHODS: The study cohort included 46 patients with SSc and 40 healthy controls. Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD34 positive, and P1H12 positive, and activated CECs were defined as CD45 negative and P1H12 positive, CD62 positive, or CD106 positive. Progenitors were identified as CD34 positive and CD133 positive. RESULTS: Total and activated CEC counts were significantly higher in SSc patients compared with healthy controls and were positively correlated with the disease activity score. With respect to visceral involvement, significant correlation was observed between the CEC number and the severity of pulmonary hypertension. High levels of endothelial progenitors were observed in patients with SSc, and the counts were higher in the early stages of disease. CONCLUSION: The presence of CECs in patients with SSc may represent direct evidence of endothelial disease and may be a promising new clinical marker for active SSc. Notably, the association between CECs and pulmonary hypertension and impaired carbon monoxide diffusing capacity was evident in patients with limited cutaneous SSc only, suggesting an important role for CECs in this disease subset with prominent vascular changes. Detection of circulating endothelial progenitors may represent a response to vascular ischemia in early SSc, as an attempt at revascularization.

Adult↗

PubMed1999

Local cold exposure test with a new arterial photoplethysmographic sensor in healthy controls and patients with secondary Raynaud's phenomenon.

Local cold exposure tests are used to diagnose cold-induced vasospastic disorders and to evaluate therapeutic success. We investigated the pulsatile signal detected with a newly developed arterial photoplethysmography (APPG) method and the signal change induced by local cold exposure using a temperature-controlled finger holder, comparing it with laser Doppler flux (red and green laser, rLDF and gLDF) and red blood cell velocity measured in nailfold capillaries (CBV). Ten healthy volunteers and 10 age- and sex-matched patients suffering from Raynaud's phenomenon due to systemic sclerosis were investigated using a moderate cooling temperature of 16 degrees C for 5 min. All signals were recorded simultaneously. The results show a significant reduction of CBV (P < 0.0001), rLDF (P < 0.0003), and gLDF (P = 0.0214) during cooling and characteristic changes in the APPG signal (for instance a decrease in pulse wave amplitude; P < 0.0001). Significant differences in the APPG amplitude could be detected under resting conditions; at cooling temperatures there were also significant differences in CBV and APPG. The temperature-controlled finger holder with its built-in APPG probe appears to be a useful tool for evaluating the effect of local cooling on finger skin perfusion and differentiating between healthy controls and patients with secondary Raynaud's phenomenon due to systemic sclerosis. The gLDF signal was rather weak, limiting its value in cold stress tests. The differences between controls and patients in CBV were somewhat smaller than in previous studies, suggesting the advantage of lower local cooling temperatures, e.g., 12 degrees C.

Adult↗

PubMed2004

[Treatment of pulmonary arterial hypertension associated to systemic sclerosis].

PURPOSE: Pulmonary arterial hypertension (PAH) is one of the main causes of death in patients with systemic sclerosis (SSc), particularly in its limited forms. CURRENT KNOWLEDGE AND KEY POINTS: Survival with conventional treatment associated with Epoprostenol is two times less in SSc patients than in idiopathic PAH. WHO recommendations (annually heart echoscreening) must be applied in all patients with SSc. Conventional therapy associates anticoagulation, to avoid excessive exertion, pregnancy, warm baths, no pressurised flights. Calcium-channel blockers give long term survival in patients with positive acute vasodilatator test with nitric oxide (NO) but these patients are very rare in SSc. Diuretics are very useful in treating right heart insufficiency. Randomized control trials in PAH have demonstrated the short term efficacy of i.v. epoprostenol, nebulized iloprost, oral beraprost and oral bosentan, a dual endothelin-1 receptor antagonist. Results in SSc are very limited except for i.v. epoprostenol. Long-term efficacy in terms of survival has been demonstrated in non randomized studies for i.v. epoprostenol and oral bosentan in patients with idiopathic and familial PAH. Atrial septostomy and lung transplantation could be an alternative to treatment, even in SSc patients, in case of refractory evolution. FUTURE PROSPECTS AND PROJECTS: Randomized control trials with sildenafil and selective endothelin-1 receptor antagonists are ongoing.

Antihypertensive Agents↗

PubMed2003

Systemic sclerosis: current views of its pathogenesis.

Systemic sclerosis (SSc) is an autoimmune disorder of unknown etiology characterized by severe and often progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immune abnormalities. Clinically, SSc is very heterogeneous, encompassing a spectrum ranging from mild limited forms of skin sclerosis with minimal internal organ involvement to severe skin and multiple internal organ fibrosis. Mortality and morbidity in SSc are very high and are directly related to the extent of the fibrotic and microvascular alterations. A better understanding of the pathogenesis of this incurable disorder will help to better target and design effective therapy in the future.

Autoimmune Diseases↗