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PubMed1997

The evolving role of blood and marrow transplantation for the treatment of autoimmune diseases.

With over 4 decades of seminal contributions to the development and application of BMT, Dr. Thomas stresses the importance of collaboration between rheumatologists and transplant clinicians in developing this evolving area of treatment. While the debate concerning the value of TBI in the conditioning regimen and the use of autologous or allogeneic stem cells will continue, he states there is simply no other way to answer these questions than to begin well designed clinical studies. As pointed out by Dr. Hahn, unexpected post-transplant complications may arise in patients with SSc and SLE and possibly require modifications to the transplant procedure similar to the experience in patients with other specific diseases. Other difficulties may be encountered, including restricted funding of the transplant procedure by insurance carriers. The emergence of managed care contracts and payer limitations in the United States described by Dr. Appelbaum could hinder the development of innovative, curative therapies. As initial clinical data are being collected, it is vital to actively support patient referral and participation in clinical studies that will ultimately establish the indications, risks, costs, and benefits of hematopoietic stem cell transplantation for autoimmune disease.

Autoimmune Diseases↗
PubMed2006

Use of endoluminal ultrasound to evaluate gastrointestinal motility.

The use of high-frequency ultrasound transducers in the gastrointestinal tract (GI) has already yielded remarkable findings concerning the anatomy, physiology and pathophysiology of the GI tract and of various motility disorders. These transducers have made completely invisible portions of the GI tract (the longitudinal smooth muscle, muscles of the upper esophageal sphincter, components of the gastroesophageal junction high-pressure zone, and the muscle of the anal sphincter complex) accessible to investigation. Use of simultaneous ultrasound and manometry has allowed the exploration of the normal physiology of peristaltic contraction. The components of the high-pressure zone of the distal and proximal esophagus have been isolated and the movement of these components has been studied individually and as a group. Various esophageal motility disorders have been investigated including achalasia, scleroderma, Barrett's esophagus and diffuse esophageal spasm. The possible etiology of the symptoms of esophageal chest pain and heartburn (sustained esophageal contractions of the longitudinal smooth muscle), have been studied. The possible underlying pathophysiology of GERD (the missing gastric clasp and sling fiber pressure profile) has been explored. Three-dimensional high-frequency ultrasound imaging has allowed the peristaltic contraction sequence to be viewed in a completely new and unique manner. The biomechanics of both esophageal contraction and the gastroesophageal junction high-pressure zone have been investigated and the mechanical advantage of esophageal shorting has been studied. The mechanism of action of standard surgical and newer endoscopic therapies for GERD has been defined. Future applications of this technology are limited only by our imagination.

Endosonography↗
PubMed2000

Induction of immune tolerance to human type I collagen in patients with systemic sclerosis by oral administration of bovine type I collagen.

OBJECTIVE: To determine whether oral tolerance to type I collagen (CI) could be induced in patients with systemic sclerosis (SSc). METHODS: Twenty adult patients with limited or diffuse SSc were enrolled in a study to receive 0.1 mg of solubilized native bovine CI daily for 1 month, followed by 0.5 mg daily for 11 months. Peripheral blood mononuclear cells (PBMC) were obtained from the patients and cultured with human alpha1(I) and alpha2(I) chains, before and after CI treatment. Culture supernatants were analyzed for levels of interferon-gamma (IFNgamma) and interleukin-10 (IL-10). Sera obtained before and after treatment were analyzed for levels of soluble IL-2 receptor (sIL-2R). Although this study was not intended to assess the clinical efficacy of oral CI administration in SSc, selected measures of disease severity and organ involvement were evaluated. RESULTS: Oral administration of CI to SSc patients induced significant reductions in levels of IFNgamma and IL-10 in alpha1(I)- and alpha2(I)-stimulated PBMC culture supernatants, indicating that T cell immunity to CI was decreased by this treatment. Serum levels of sIL-2R also decreased significantly after oral CI treatment, suggesting a reduction in T cell activation. Significant improvements occurred in the modified Rodnan skin thickness score and the modified Health Assessment Questionnaire after 12 months of oral CI in this open trial. The lung carbon monoxide diffusing capacity improved statistically and showed a trend toward clinically significant improvement. CONCLUSION: Oral administration of bovine CI to patients with diffuse or limited SSc induces a reduction in T cell reactivity to human CI, appears to be well tolerated, and does not worsen the disease. Further evaluation of oral tolerance to CI in patients with SSc is justified to determine whether it has therapeutic efficacy.

Administration, Oral↗
PubMed2001

Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival.

OBJECTIVE: To assess the rate of progression of pulmonary hypertension (PHT) in systemic sclerosis (SSc) and its bearing on mortality. METHODS: A retrospective record review of 930 patients with SSc attending a specialist centre was carried out. Those at risk for both idiopathic and secondary PHT were assessed by serial Doppler echocardiography. Mortality data were reviewed. RESULTS: The cumulative prevalence of PHT was 13%. Pressures remained static in most cases. The mortality among those with a single pressure reading of 30 mmHg or higher was 20% at 20 months. An increased mortality risk was associated with high initial pressures and rising pressures. Rapid pressure rises occurred more frequently in limited than in diffuse SSC. CONCLUSIONS: The prevalence of PHT in SSc is high and the detection of PHT at any time in the disease course is associated with substantial mortality. These results demonstrate the value of echocardiographic screening for PHT in all patients with SSC.

Adult↗
PubMed1999

Clinical and immunological characterization of patients with systemic sclerosis overlapping primary biliary cirrhosis: a comparison with patients with systemic sclerosis alone.

Limited cutaneous systemic sclerosis (lSSc) or CREST syndrome is sometimes complicated by primary biliary cirrhosis (PBC). To characterize the clinical and immunological features of patients with SSc overlapping PBC (SSc-PBC), the clinical and laboratory data of 11 SSc-PBC were studied. Since all of the SSc-PBC were lSSc, the features of SSc-PBC were compared with those of 266 patients with lSSc alone. The sera from SSc-PBC showed a significantly higher positivity for anti-centromere antibody (ACA) (p < 0.0005) and higher reactivity to centromere protein-C. Although SSc-PBC more frequently exhibited calcinosis and telangiectasia (p < 0.05), there was no statistical difference in other features of CREST syndrome. There was no statistical difference in other scleroderma-related features either. SSc-PBC were more frequently complicated with Sjögren syndrome (p < 0.05). The most prominent feature of SSc-PBC was a higher incidence of ACA than in lSSc alone.

Adult↗
PubMed1997

Nailfold capillary abnormality and pulmonary hypertension in systemic sclerosis.

BACKGROUND: Patients with systemic sclerosis (SSC) show a capillary abnormality of nailfolds with controversial correlation with organ involvement. Our purpose was to study the correlation between this nailfold capillary abnormality and pulmonary hypertension in patients with SSC. METHODS: We studied the nailfold capillaries, using capillary microscopy, and the pulmonary arterial pressure, using right-heart catheterization, in 44 patients with SSC. Canonical discriminant analysis was used to define the capillary abnormality in patients with SSC, which was then compared with that of 40 normal controls. The correlations between the patterns of nailfold capillaries and the cardiopulmonary findings, including the pulmonary arterial pressure, were examined using Fisher's test. RESULTS: Thirty-two of 44 patients with SSC could be differentiated from normal controls by our definition of the SSC pattern. The SSC pattern correlated significantly with elevated pulmonary vascular resistance, as well as with pulmonary fibrosis, electrocardiographic abnormalities, decreased vital capacity, and decreased diffusing capacity for carbon monoxide. All SSC patients with pulmonary hypertension showed this SSC pattern. In patients with elevated pulmonary arterial pressure, capillary microscopy and diffusion capacity for carbon monoxide (DCCM) showed the highest rate of abnormalities. A limited-type SSC significantly correlated with DCCM and with anticentromere antibody, and the diffuse-type SSC with pulmonary fibrosis and anti-sci-70 antibody. CONCLUSION: Our data suggest that in patients with SSC, nailfold capillary abnormalities correlate with pulmonary arterial hypertension as well as with clinical and laboratory findings indicating pulmonary hypertension.

Adolescent↗
PubMedDate not supplied

Systemic sclerosis complicated by diffuse alveolar hemorrhage.

A 38-year-old woman with limited cutaneous systemic sclerosis and pulmonary fibrosis developed diffuse alveolar hemorrhage during the course of her disease that responded well to steroids. We present the clinical history of the patient and discuss the different theories behind the association. The importance of steroid therapy for treatment of alveolar hemorrhage in this particular condition is emphasized.

Adult↗
PubMed1988

Differential isotype recognition of two centromere associated polypeptides by immunoblotting in connective tissue disease.

On investigating the immunoblotting profile of 65 systemic sclerosis patients, a 140 kD polypeptide was recognised by sera from 16, when immunoblotted against a nuclear-enriched K562 cell sonicate. All 16 sera contained anticentromere antibodies (ACA) detected by immunofluorescence (IF) and 15 of 16 also recognized a 19 kD polypeptide on immunoblotting. Two ACA positive sera failed to recognize the 140 kD polypeptide but one of these recognized the 19 kD polypeptide. The 140 kD polypeptide identified a group with more limited skin involvement (P less than 0.05) and all 16 had Raynaud's phenomenon. The sera from three of 100 systemic lupus erythematosus (SLE) patients also recognized both polypeptides. On investigating the isotype specificity, the 140 kD polypeptide was strongly detected by an IgM autoantibody and the 19 kD polypeptide by an IgG autoantibody.

Antibodies, Antinuclear↗
PubMed1996

Malignant vascular disease of the kidney: nature of the lesions, mediators of disease progression, and the case for bilateral nephrectomy.

A case of thrombotic microangiopathy presenting as a hemolytic uremic syndrome complicated by untreatable hypertension and ultimately requiring bilateral nephrectomy is discussed. Severe hypertension and renal failure may complicate the course of vascular diseases of the kidney, including thrombotic microangiopathy, chronic hypertension, and scleroderma. Toxins, pressure stress, and immune material may trigger the initial injury to vascular endothelium. The malignant course of these renal vascular diseases seems linked to the severity of vascular injury. Endothelial injury manifests with swelling and detachment of endothelial cells from the basement membrane, expansion of the subendothelial space, and newly formed basement membrane-like material. In arterioles, endothelial injury precedes myointimal swelling and proliferation, leading to vascular lumina narrowing or obliteration and secondary glomerular ischemia, with glomerular tuft collapse and garland-like wrinkling and thickening of the capillary wall. Endothelial cell injury is very likely the common determinant of a cascade of events that lead to irreversible renal failure. When the initial insult (toxins, mechanical stress, antibodies) is promptly removed, lesions are self-limiting and the patient usually recovers. However, a severe insult persisting for some time can lead to chronic and irreversible vascular lesions that, through renal ischemia, trigger maximal activation of the renin angiotensin system with a brisk elevation in arterial blood pressure that may combine to further vascular injury and renal ischemia. Moreover, enhanced shear stress in the severely narrowed microcirculation, through abnormal von Willebrand factor processing, can also favor endothelial injury and platelet aggregation, which may further worsen the vascular lesions and sustain the microangiopathic process. Plasma manipulation, arteriolar vasodilators, and angiotensin-converting enzyme inhibitors normally control the vicious circle, but in few severe cases bilateral nephrectomy remains the last chance to save the patient's life.

Adult↗
PubMed1994

Chondrodermatitis nodularis helicis occurring with systemic sclerosis--an under-reported association?

Three cases of chondrodermatitis nodularis helicis (CDNH) in patients with the limited form of systemic sclerosis are described. Two of the three cases were noted during regular follow-up visits and the third case was found as part of a survey of the 21 other patients with systemic sclerosis routinely seen in the department. While CDNH is known to have several predisposing causes there are no reports in the literature of this condition occurring in association with systemic sclerosis.

Adult↗
PubMed2002

The polymorphism of transforming growth factor-beta1 gene in Japanese patients with systemic sclerosis.

BACKGROUND: Transforming growth factor (TGF)-beta has been shown to be a potent stimulator of collagen production by fibroblasts, and could play a role in the pathogenesis of systemic sclerosis (SSc). OBJECTIVE: To study the possible involvement of TGF-beta1 gene polymorphism in Japanese patients with SSc. METHODS: Fifty-nine patients with SSc and 110 normal subjects were studied. Genomic DNA was extracted from skin tissues, and was amplified in a thermal cycler, generating a TGF-beta1 gene fragment with a size of 294 bp. The T to C transition at T869C (Leu10Pro) and the G to C transition at G915C (Arg25Pro) were identified by digestion with MspA1I and BglI, respectively. RESULTS: At T869C (Leu10Pro), the frequency of the C allele in SSc (65.3%) was significantly higher than in normal controls (50.5%) (P < 0.01). SSc showed C/C allele 42.4%, C/T 45.8% and T/T 11.2%. Normal controls showed C/C allele 26.4%, C/T 48.2% and T/T 25.5%. The frequency of the C/C allele in SSc was significantly higher than in normal controls, in comparison with the T/T allele (P < 0.02), but no significant difference was found between the frequency of the C/C allele vs. the C/T allele. The frequency of the C/C allele showed no significant difference between diffuse and limited SSc. At G915C (Arg25Pro), all the normal controls and SSc patients showed only the G/G allele. These results are different from a previous study in which the frequency of the T/T allele was high in SSc at T869C (Leu10Pro). CONCLUSIONS: This discrepancy may indicate that Japanese patients with SSc show a different genetic predisposition to TGF-beta1.

Adolescent↗
PubMed1995

Molecular structure and function of autoantigens in systemic sclerosis.

Autoantibodies in systemic sclerosis target a limited set of nuclear proteins, principally those of the nucleolus and RNA transcription complexes. These antibodies have proved helpful in diagnosis of this disease, and have been used extensively as probes of nuclear structure and function. Despite these advances, the events that initially trigger autoantibody production in systemic sclerosis are not yet known. While these ANA are not known to disrupt cellular processes by entering living cells, or to cause tissue injury (in contrast to SLE, where autoantibodies may mediate tissue damage), it seems likely that they do not merely represent epiphenomena of the disease. Rather, it is logical to assume that their origin is in some manner tied to etiology of systemic sclerosis, since they segregate by syndrome within the spectrum of this disease (for example, anti-kinetochore antibodies occur in limited cutaneous disease, and anti-topoisomerase I and anti-RNA polymerase antibodies occur in diffuse disease), and since they are distinct from the ANA found in other connective tissue diseases in their selectivity for the nucleolus and RNA polymerases.

Antigens, Nuclear↗
PubMed1999

Discrepant expression of neprilysin on fibroblasts in diffuse systemic sclerosis.

OBJECTIVE: Neprilysin (NEP; EC3.4.24.11) is an ectopeptidase mainly produced by fibroblasts and cleaving a large number of neuropeptides. We previously found increased plasma circulating levels of NEP in patients with systemic sclerosis (SSc), but in SSc fibroblasts derived from the diffuse subset NEP was present in lower concentration. We evaluate in vitro fibroblasts of both subsets of the disease, diffuse and limited, the intracellular levels of NEP, and its expression as CD10 on the cellular surface. METHODS: Fibroblasts, derived from biopsies taken from affected skin of 8 patients with the limited subset and 5 with the diffuse subset, were grown in vitro and intracellular levels of NEP activity were measured with a fluorometric method, while CD10 surface expression was evaluated by FACS analysis. Cell proliferation was assessed by 3HThymidine incorporation. RESULTS: Intracellular NEP activity was significantly increased in diffuse (7.02+/-4.8 pg/ml/min 10(6) cells) compared to limited SSc (1.11+/-2.0) and control fibroblasts (1.41+/-0.9). CD10 expression was significantly impaired on diffuse SSc fibroblasts (47.3+/-15%) compared to controls (74.6+/-11%) and the limited subset (82.7+/-11%). Cell proliferation of diffuse SSc fibroblasts was strikingly higher than controls and limited SSc fibroblasts. CONCLUSION: These results confirm that NEP is produced by fibroblasts and indicate that in diffuse SSc fibroblasts NEP is produced in higher quantities, while the expression of the enzyme on the cell surface is significantly reduced. This condition may affect the proliferation rate of fibroblasts as well as the metabolism of various peptides.

Cell Division↗
PubMed2003

Scleromyxoedema-like changes in four renal dialysis patients.

We describe four renal dialysis patients from our hospital who, over a 6-month period, developed erythematous, thickened, indurated dermal plaques. The plaques were limited to the limbs and in three patients there were associated flexion contractures. The clinical features most resembled scleromyxoedema. All patients had previously received at least one renal transplant. Histopathology of the plaques showed features of scleromyxoedema in two patients, whereas the other two showed a different picture, more suggestive of a morphoea-like process. There are important differences between our patients and classical scleromyxoedema. All four patients had normal immunoglobulins and no paraprotein was detected. Almost all cases of classical scleromyxoedema are associated with an IgGlambda paraproteinaemia. We have not yet identified an underlying cause for this cluster of cases in our hospital. It is possible that the skin changes seen may have been precipitated by an environmental agent, such as in 'toxic oil syndrome' and vinyl chloride-induced scleroderma. We discuss the differences between our patients and those with scleromyxoedema, localized or generalized morphoea and environmentally induced scleroderma. We feel that our patients show a constellation of features similar, but not identical, to scleromyxoedema. There has been only one previous report of similar patients. We believe this to be a new and distinct phenomenon.

Adult↗
PubMed1994

Frequency and clinical associations of anti-chromo antibodies in connective tissue disease.

OBJECTIVES: To assess the frequency and clinical associations of anti-chromo antibodies in connective tissue disease and to study their relationship to anti-centromere autoreactivity. METHODS: Anti-chromo and anti-centromere antibodies (ACA) were measured by immunoblotting in 50 patients with systemic sclerosis (SSc) and 58 connective tissue disease controls. Common epitopes on centromere and chromo antigens were sought using affinity-purified antibodies from immunoblots. RESULTS: Anti-chromo antibodies were detected in three of 32 sera with ACA and no controls. The three patients with anti-chromo antibodies had limited cutaneous SSc, and two had erosive arthritis. No cross-reactivity between chromo or centromere-related proteins was demonstrated. CONCLUSIONS: Anti-chromo antibodies form a rare autoantibody specificity that may identify an overlap group of patients with SSc and arthritis. Chromo and centromere antigens are associated but immunologically distinct autoimmune targets. Whether they localise to the same chromosomal site remains unknown.

Antibodies, Antinuclear↗
PubMed1993

[The clinical spectrum of patients with anticentromere antibodies].

In order to define the clinical associations and diagnostic meaning of anticentromere antibodies in a random population of patients, clinical and serological findings were studied with the evolution of 16 patients selected only because of their positiveness to anticentromere antibodies, detected by indirect immunofluorescence on HEp-2 cells and confirmed in chromosome spreads of HMcB cells. The most frequent diagnosis was systemic sclerosis in 9 patients (56%) especially in its variety Limited Cutaneous Systemic Sclerosis/CREST (7 patients). The rest of the cases (44%) showed different diseases (3 isolated Raynaud's phenomena, 1 Sjögren's syndrome, 1 seronegative polyarthritis, 1 undifferentiated connective tissue disease and a probable sarcoidosis). Therefore, even tough the more frequent clinical entity associated to anticentromere antibodies was systemic sclerosis and especially its variety Limited Cutaneous Systemic Sclerosis/CREST its diagnostic specificity is relatively low. The most frequent clinical association in our group of patients with positive anticentromere antibodies has been Raynaud's phenomena, alone or associated to other processes, being found in all but one of the studied patients (94%).

Antibodies, Antinuclear↗
PubMed2002

[Cardiovascular involvement in systemic sclerosis].

Heart involvement is frequent in systemic sclerosis. Cardiomyopathy is the main localization but its diagnosis is often late. Cardiac echography or radionuclide imaging show early involvement of the myocardium while showing alterations of diastolic function of the left ventricle or perfusion defects. The pathogenesis of this cardiomyopathy is supposed to be related to myocardial ischemia in relation with vasospasm, or with organic lesions of small arteries or coronary microcirculation. Pericarditis rarely is of clinical significance. Pulmonary hypertension concerns patients with proximal and advanced systemic sclerosis or limited forms such as CREST. It can be efficiently diagnosed by doppler echography but its therapy is difficult and its prognosis is poor. Epoprostenol in continuous venous infusion seems to be efficient but the accessibility to this therapy is difficult. While the involvement of middle-sized arteries of the hands is common, systemic sclerosis seems to be associated to an increased frequency of large-sized arteries disease.

CREST Syndrome↗
PubMed2006

Submaximal exercise testing in the assessment of interstitial lung disease secondary to systemic sclerosis: reproducibility and correlations of the 6-min walk test.

BACKGROUND: The 6-min walk test (6MWT) is increasingly used as an outcome measure in interstitial lung disease (ILD). AIM: To evaluate the usefulness of the 6MWT in a cohort of patients with ILD secondary to systemic sclerosis (SSc) and to correlate with established physiological parameters. METHODS: 163 patients with SSc-ILD were recruited for a multicentre, randomised, double-blind clinical trial. Available data at protocol screening included repeated 6MWTs, pulmonary function testing with diffusing capacity, Doppler echocardiography and high-resolution computed tomography of the thorax. Borg Dyspnoea Index was evaluated before and after 6MWT. RESULTS: Mean (standard deviation (SD)) distance walked during walk test 1 was 396.6 (84.55) m compared with 399.5 (86.28) m at walk test 2. The within-subject, intertest correlation as determined by Pearson's correlation coefficient testing was 0.95 (p<0.001). However, only weak correlations of 6MWT with percentage forced vital capacity and the Borg Dyspnoea Index were observed, and no correlation was observed with percentage diffusing capacity. CONCLUSION: These data confirm the high reproducibility of the 6MWT in patients with SSc-ILD and therefore the validity of the test in this cohort. The lack of correlation of 6MWT with standard physiological parameters of ILD suggests a multifactorial basis for limited exercise capacity in patients with SSc and calls into question the utility of the 6MWT as a measure of outcome in future studies on SSc-ILD.

Adult↗