Recent studies in the metachromatic and globoid forms of diffuse sclerosis.
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Diffuse Cerebral Sclerosis of Schilder↗
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[KRABBE'S DIFFUSE SCLEROSIS].
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Diffuse Cerebral Sclerosis of Schilder↗
Effect of granulocyte macrophage-colony stimulating factor on extracellular matrix deposition by dermal fibroblasts from patients with scleroderma.
OBJECTIVE: . To investigate the in vitro effect of granulocyte macrophage-colony stimulating factor (GM-CSF) on the deposition of extracellular matrix (ECM) in fibroblasts obtained from the skin of patients with systemic sclerosis (Ssc), compared to healthy controls. METHODS: Dermal fibroblasts obtained from 14 patients with SSc (7 with the diffuse form and 7 with CREST syndrome) and from 7 controls were studied. Both SSc and normal skin fibroblast cultures were stimulated for 4 and 8 days with 100 ng/ml GM-CFS. GM-CSF receptor (GM-CSFR) expression was determined by Western blot of cell lysates. Immunofluorescence was used to determine GM-CSFR expression and to investigate the deposition of ECM (type I collagen, fibronectin, and tenascin). Quantitative analysis of ECM was performed by ELISA. Expression of type I collagen and metalloproteinase 1 (MMP-1) mRNA was determined by real-time quantitative PCR. RESULTS: Deposition of ECM by normal fibroblasts appeared not to be influenced by stimulation with GM-CSF; in contrast, after stimulation with GM-CSF SSc fibroblasts showed increased deposition of fibronectin and tenascin, while type I collagen production was decreased; these results were found with both immunofluorescence and ELISA. Quantitative PCR revealed that GM-CSF inhibited the expression of mRNA type I collagen in SSc fibroblasts but not in normal fibroblasts, whereas levels of the main collagenolytic enzyme, MMP-1, were not affected. CONCLUSION: These results suggest that in SSc fibroblasts GM-CSF exerts a blocking effect on the deposition of type I collagen, through an inhibitory action on mRNA, while the production of other components of ECM such as fibronectin and tenascin is increased by stimulation with this cytokine.
Adult↗
[Pulmonary hypertension in autoimmune rheumatic diseases].
OBJECTIVE: Pulmonary hypertension is a severe and rapidly progressive disease, particularly frequent in patients with rheumatic diseases. The aims of this study were the following: to determine the prevalence of pulmonary hypertension in Italian patients with autoimmune rheumatic diseases, and to evaluate if the presence of a rheumatic disease in general, or of a specific autoimmune rheumatic disease, is a risk factor for the development of pulmonary hypertension. PATIENTS AND METHODS: One hundred and thirteen Italian patients with connective tissue diseases (105 females, 8 males), aged 19 to 83 yrs, entered the study. Fifty-one had systemic sclerosis (SSc): 49 were females, 2 males, aged 34 to 83 yrs; 41 had limited cutaneous SSc, 8 diffuse cutaneous SSc, and 2 SSc sine scleroderma. Thirty-three patients had systemic lupus erythematosus (SLE): all but one were females, their age ranged from 19 to 82 yrs. Twenty-five had rheumatoid arthritis (RA): 21 females, 4 males, aged 26 to 45 yrs. Three females and one male, 51-77 yrs, had mixed connective tissue disease (MCTD). Systolic pulmonary arterial pressure (SPAP) was assessed by Doppler echocardiography. RESULTS: Twenty three patients had pulmonary hypertension, which was more frequent in MCTD than in SLE (75% vs 6.1%, p=0.0002) or in AR (20%, p=0.0313). Pulmonary hypertension was more frequent in SSc than in SLE (25.5% vs 6.1%, p=0.0028) and in limited than in diffuse SSc (21.6% vs 3.9%). SPAP was significantly related to age (r=0.35, p=0.0275), with patients with pulmonary hypertension older than patients with normal SPAP (66+/-13 vs 52+/-16 yrs, p=0.0003). CONCLUSIONS: These data show a significant association between pulmonary hypertension and autoimmune rheumatic diseases. Therefore, pulmonary hypertension assessment seems mandatory, at least in MCTD and SSc. However, more studies are needed to clarify the relationship between age and pulmonary hypertension and to verify whether the low prevalence of pulmonary hypertension we found in our SLE patients is related or not to their lower age.
Adult↗
[Scleroderma with anomalies of the thyroid function. 7 cases].
Thyroid function, studied in 36 scleroderma patients revealed 7 abnormal cases: 6 hypothyroid patients secondary to autoimmune thyroiditis and 1 hyperthyroidism secondary to Graves' disease. In the hypothyroid subgroup, 3 cases presented a localized systemic sclerosis and the 3 others presented a diffuse systemic sclerosis; Sjögren syndrome was found in 2 of these patients. The hyperthyroid patient presented a diffuse systemic sclerosis. Because of the association between scleroderma and thyroid diseases, we suggest to perform thyroid screening regularly for all patients with systemic sclerosis.
Adult↗
Gastrointestinal symptoms of patients with esophageal contraction abnormalities.
Nonesophageal, gastrointestinal symptoms were sought from consecutive patients referred for esophageal manometry in order to determine the prevalence of such symptoms in relation to manometric diagnosis. Reports by 103 patients with esophageal contraction abnormalities, a cluster of manometric findings which includes the "nutcracker esophagus" and diffuse esophageal spasm, were compared to those by patients with the achalasia pattern (21 patients) and scleroderma esophagus (19 patients). A history of persistent (greater than 3 months) bowel habit abnormality requiring medical attention was reported by 19% of those with contraction abnormalities and 26% of those with scleroderma esophagus but by no patient with achalasia (P less than 0.05 for both compared to achalasia). Patients with contraction abnormalities had complained to physicians of more gastrointestinal symptoms and had more often been diagnosed as having the irritable bowel syndrome than those with achalasia. We conclude that, with regard to gastrointestinal symptoms, patients with esophageal contraction abnormalities more closely resemble patients with a motility disorder which has the potential for diffuse symptomatic gastrointestinal involvement (scleroderma) than those with a motility disorder restricted to the esophagus (achalasia). These findings add support to the argument that functional gastrointestinal syndromes may be representative of diffuse neuromuscular derangement in the gastrointestinal tract.
Adult↗
Evaluation and management of pulmonary fibrosis in scleroderma.
Pulmonary fibrosis causes significant morbidity and mortality in patients with scleroderma. Lung inflammation identifies patients at greater risk for decline in forced vital capacity and diffusing capacity for carbon monoxide. Factors that are increased in patients with scleroderma with lung fibrosis include connective tissue growth factor, KL-6, pulmonary surfactant-D, tissue inhibitor of metalloproteinase 2, monocyte chemotactic protein-1, macrophage inhibitory protein-1 alpha, soluble interleukin-6 receptors, anti-endothelial cell antibodies, and anti-DNA topoisomerase I antibodies. Potential mechanisms of lung damage in scleroderma include increased production of profibrotic type 2 cytokines and abnormal signaling by thrombin of tenascin-C production by lung fibroblasts, with protein kinase C epsilon as an intermediate in the signaling pathway. Treatment of scleroderma lung disease with cyclophosphamide may have a beneficial effect on pulmonary function and survival. Lung transplantation provides a therapeutic option for patients with scleroderma with end-stage lung disease.
Bronchoalveolar Lavage Fluid↗
Microvascular abnormalities in Sjögren's syndrome: nailfold capillaroscopy.
OBJECTIVE: To describe microvascular abnormalities by nailfold capillaroscopy in patients with primary Sjögren's syndrome (SS) with or without Raynaud's phenomenon (RP) and those with anticentromere antibodies (ACA). METHODS: Forty patients with SS (14 without RP, 16 with RP, 10 with ACA), 20 patients with scleroderma (SSc) (10 with limited and 10 with diffuse disease) (disease control group) and 40 healthy controls (control group) were evaluated by nailfold capillaroscopy. RESULTS: Capillaroscopic abnormalities in SS ranged from non-specific findings (crossed capillaries) to more specific findings (confluent haemorrhages and pericapillary haemorrhages) or scleroderma-type findings. SS patients with RP presented capillary abnormalities in higher frequency than patients without RP. The majority of SS patients with ACA (80%) presented scleroderma-type findings. CONCLUSION: Nailfold capillaroscopy can be used as a simple non-invasive method to evaluate the microvascular abnormalities in SS patients, especially in those with RP and those with ACA.
Capillaries↗
Juvenile onset systemic sclerosis: a single center experience of 23 cases from Asia.
The aim of this paper was to study the spectrum of juvenile scleroderma (JSSc) seen at a tertiary care referral center in Asia. Retrospective analysis of case records of patients with systemic sclerosis, having age of onset less than 16 years and seen at our hospital from 1988 to 2004, was done. Patients with linear scleroderma and morphea were excluded. There were 23 patients (19 girls, 4 boys) with median age of onset of 12 years (range 5-16 years). The median age at presentation was 17 years (range 10-34 years). The median time from first symptoms to presentation was 4 years (range 0.2-26 years). Among these, 14 had diffuse systemic sclerosis (DSSc), while 9 had limited scleroderma (LSSc). The clinical features seen at presentation in patients were: Raynaud's phenomenon in 19, digital ulcers in 14, loss of finger tip pulp in 12, reflux in 8, dysphagia in 7, arthritis in 8, digital gangrene in 2, and pulmonary artery hypertension in 1. Antinuclear antibody was positive in 15 out of 18 patients tested. Interstitial lung disease was seen in 15 patients, 6 of whom had diffuse disease. The median skin score was 22 (range 7-48) . One patient died of primary pulmonary hypertension within 1 year of onset of symptoms. At a mean follow-up of 34 months, 14 patients were stable or had improvement in skin score or dyspnea on exertion. DSSc and LSSc in childhood have a clinical presentation similar to adult patients, with cardiopulmonary involvement being the major predictor of outcome. The short-term prognosis of JSSc is good.
Adolescent↗
Jaccoud's arthropathy in scleroderma.
Two patients with scleroderma developed a non-erosive hand deformity resembling Jaccoud's arthropathy. Neither had a history of rheumatic fever or clinical and serological features of systemic lupus erythematosus. This type of arthropathy may be more common in scleroderma than is currently appreciated.
Adult↗
[Antral vascular ectasia and scleroderma. Endoscopic, radiologic and anatomopathologic aspects of an uncommon association].
Diffuse gastric antral vascular ectasia (GAVE) is a new disease entity corresponding to peculiar acquired vascular malformations. In 1984 Jabbari et al. coined the term "Watermelon Stomach" for this lesion. We report here in a new case particular by its association with systemic sclerosis in a 66 year-old female. The diagnosis of GAVE was suggested upon endoscopic and angiographic findings. Atrophic fundic gastritis associated with achlorhydria and hypergastrinemia was also noted. Antrectomy was performed with success. Pathologic examination and morphometric analysis of the antrum specimen revealed the characteristic features of GAVE: 1) increase of the mean cross sectional area of mucosal vessel lumen and increase of the mean percentage of specimen area occupied by vessels; 2) presence of intravascular fibrin thrombi and 3) fibromuscular hyperplasia of the lamina propria.
Aged↗
[Quality of life assessment with the MOS-SF36 in patients with systemic sclerosis].
OBJECTIVE: To investigate the metric properties and the validity of the Medical Outcome Study Short Form 36 (SF-36), a questionnaire to assess the quality of life, in patients with either diffuse or limited systemic sclerosis (SS), and to examine the effect of the disease on quality of life. METHODS: Cross sectional study of 86 patients with a SS (64 diffuse SS, 22 limited SS). Disease severity was assessed by clinical examination, pulmonary functional tests and Health Assessment Questionnaire (HAQ) modified for scleroderma. RESULTS: The SF-36 scores values were lower in diffuse than in limited sclérodermie systémique. The Physical Component Score was worse in patients with than without any clinical involvement. This score increased in relation with the number of clinical involvements. The quality of life of patients with SS was correlated to its functional repercussion. CONCLUSION: The quality of life in SS patients is correlated with the clinical severity of the disease. The use of SF-36 to measure the quality of life is useful for the clinical evaluation of patients with SS.
Adolescent↗
Contribution of activin receptor-like kinase 5 (transforming growth factor beta receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts.
OBJECTIVE: To use a specific transforming growth factor beta receptor type I (TGFbetaRI; activin receptor-like kinase 5 [ALK-5]) kinase inhibitor (SD208) to determine the role of activation of the TGFbetaRI kinase (ALK-5) in maintaining the profibrotic phenotype of dermal fibroblasts in systemic sclerosis (SSc). METHODS: The effect of SD208 on the expression of key biochemical markers of the fibrotic phenotype was compared in fibroblasts cultured from clinically involved (lesional) and clinically uninvolved skin of patients with diffuse cutaneous SSc (dcSSc) and in fibroblasts from healthy controls matched for age, sex, and anatomic site. Protein expression was compared together with the ability of fibroblasts to adhere to the extracellular matrix and to remodel and contract a free-floating fibroblast-populated type I collagen lattice. RESULTS: Inhibiting TGFbetaRI kinase reduced the expression of a cohort of fibrotic markers by dermal fibroblasts from patients with dcSSc, including type I collagen and beta1 integrin. Moreover, inhibition also attenuated the elevated adhesive and contractile abilities of dcSSc fibroblasts. CONCLUSION: Our data suggest that some of the key profibrotic features of lesional SSc fibroblasts are dependent upon ALK-5 activity. Thus, TGFbetaRI kinase-mediated signaling may contribute to dermal fibrosis in dcSSc.
Activin Receptors, Type I↗
Nucleolar staining cannot be used as a screening test for the scleroderma marker anti-RNA polymerase I/III antibodies.
OBJECTIVE: Anti-RNA polymerase I/III (anti-RNAP I/III) antibodies are clinically useful markers of scleroderma, and their presence is associated with diffuse skin disease and an increased risk of cardiac and kidney involvement. Although RNAP I antibodies localize to the nucleolus, nucleolar staining by many anti-RNAP antibody-positive sera is not always observed. Nucleolar staining by anti-RNAP antibody-positive sera was examined by double staining with antifibrillarin antibodies to evaluate whether nucleolar staining can be used as a screening test for anti-RNAP I/III antibodies. In addition, the relationships between nucleolar staining and levels of anti-RNAP III antibodies were examined by enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation (IP) assay. METHODS: Sera were tested using immunofluorescent antinuclear antibodies on HEp-2 cell slides, by anti-RNAP III ELISA, and by IP assay using (35)S-labeled K562 cell extract. Nucleolar staining by anti-RNAP antibody IP-positive sera was confirmed by double staining using antifibrillarin monoclonal antibodies. The levels of anti-RNAP III antibodies were quantitated by ELISA and by IP assay using a serially diluted reference serum as a standard, and their relationship was analyzed. RESULTS: All 18 anti-RNAP I/III antibody-positive sera showed nuclear speckled patterns, but nucleolar staining was readily noticeable in only 44% of the sera. A positive correlation was found between ELISA and IP units for anti-RNAP III antibodies. The levels of anti-RNAP III antibodies and anti-RNAP I antibodies correlated well, with the exception of a few sera. Levels of anti-RNAP III antibodies were low in sera with nucleolar staining, whereas several sera with high levels of anti-RNAP I antibodies clearly showed nucleolar staining. CONCLUSION: Although some sera positive for anti-RNAP I/III antibodies clearly stain nucleoli, nucleolar staining is inconsistent and cannot be used to screen for anti-RNAP I/III antibodies.
Autoantibodies↗
The effects of pregnancy on autoimmune diseases.
Internal gestation of a genetically foreign conceptus challenges the maternal host to circumvent immunological processes that recognize and eliminate nonself molecules. Accordingly, human viviparity involves a wide range of immunological modifications. This review examines the relationship between pregnancy and several autoimmune diseases prevalent in women. Pregnancy is associated with improvement in the clinical signs and symptoms of rheumatoid arthritis in more than 70% of patients. Maternal-fetal disparity in alleles of HLA-DRbeta1, DQalpha, and DQbeta has been reported to be associated with pregnancies characterized by remission or improvement. These observations suggest that presentation of fetal DQalpha peptides might correct autoimmunity in patients with RA either by induction of maternal-regulatory T cells, or by affecting the maternal T cell receptor repertoire. In contrast, the course of systemic lupus erythematosus is more variable. Whether flare rates increase during or after pregnancy is unsettled, since individual patient series vary in the characteristics of patients accepted for study and in definitions of flare. Despite a high overall flare rate in some series approaching 60%, recorded flares were usually not severe. Only limited data are available regarding the incidence or outcome for either the mother with scleroderma or her fetus. The extent of diffuse skin disease and systemic involvement, particularly pulmonary, cardiac and renal, may be more important than the duration of the disease; limited disease carries a better prognosis for the mother and fetus. Highly specific autoantibody profiles in the mother (independent of whether she has a clinical disease) are associated with fetal demise and neonatal lupus syndromes, the most serious manifestation of which is isolated congenital heart block. The former is associated with antiphospholipid antibodies and the latter with antibodies directed against SSA/Ro and SSB/La polypeptides.
Antiphospholipid Syndrome↗
Eosinophilic fasciitis: report of a case with features of connective tissue diseases.
A patient suffering from eosinophilic facsiitis is described and the literature reviewed. The original description of eosinophilic fasciitis was that of a benign scleroderma-like disease with eosinophilia, hypergammaglobulinemia and diffuse thickening and inflammation of the fascia and subcutaneous tissue. Our patient like a few others, presented additional findings, namely, Raynaud's phenomenon and mild myhositis. She is the first patient described with Sjögren's syndrome. It is important that eosinophilic faciitis be recognized clinically because it seems to be a benign and treatable entity.
Connective Tissue Diseases↗
Scleroderma renal crisis in pregnancy associated with massive proteinuria.
Scleroderma renal crisis is a well-recognized complication of systemic sclerosis (SSc) usually occurring early in the course of the disease in patients with diffuse skin involvement. We report the diagnostic challenge of a case of scleroderma renal crisis associated with massive proteinuria at approximately 20 weeks gestation in a pregnant patient with diffuse cutaneous systemic sclerosis.
Adult↗
Lack of clinical benefit after treatment of systemic sclerosis with total lymphoid irradiation.
Six patients with systemic sclerosis and internal organ involvement were randomized to receive total lymphoid irradiation (TLI) or to serve as untreated controls. Despite evidence of profound immunosuppression, we were unable to detect any longlasting clinical benefit in the treated patients, with follow-ups ranging from 1-4 years after TLI. Moreover, the results suggest that this therapy may accelerate pulmonary and gastrointestinal deterioration in scleroderma.
Adult↗