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PubMed2004

IgG antibodies to human cytomegalovirus late protein UL94 in patients with systemic sclerosis.

Human cytomegalovirus (HCMV) has been proposed as an amplifying agent for at least some of the spectrum of systemic sclerosis (SSc; scleroderma). In support of this hypothesis, antibodies to the HCMV late protein UL94 have been detected in the majority of SSc patients in a study involving Caucasian subjects from Italy. The aim of this investigation was to determine whether elevated levels of anti-UL94 antibodies are present in African American and Caucasian SSc patients from the U.S. We further wished to determine whether there was a significant difference in the levels of anti-UL94 antibodies between the diffuse and the limited forms of the disease. IgG antibodies to a UL94 peptide were measured in 254 Caucasian and 90 African American subjects by an enzyme-linked immunosorbent assay (ELISA). In both Caucasian and African American subjects, the mean antibody level in the diffuse form of SSc was significantly higher than that in the respective control subjects (714 vs. 466 ng/ml, p = 0.005; 1226 vs. 512 ng/ml, p < 0.0001). Also, among Caucasian SSc patients, the mean antibody level in the diffuse form of SSc was significantly higher than that in the limited form of the disease (714 vs. 465 ng/ml, p = 0.02). These results show that increased levels of antibodies to the HCMV late protein UL94 are associated with SSc and they may be a marker for the severity of the disease.

Black or African American↗
PubMed2002

Ventricular late potentials in systemic sclerosis: relationship with skin involvement.

OBJECTIVE: To detect the myocardial involvement in patients with systemic sclerosis (SSc) by signal averaged electrocardiography method (SA-ECG) in relationship to the skin changes. METHODS: We selected 24 SSc outpatients according to American Rheumatism Association criteria, without clinical and instrumental evidence of cardiac disease, and compared them with 24 control subjects. All patients and controls underwent SA-ECG to detect ventricular late potentials (LP). The extent and severity of skin involvement in SSc patients was detected by modified Rodnan (m-Rodnan) skin score. RESULTS: SSc patients had higher prevalence of LP compared to controls (46 versus 8%, p < 0.003). Median skin score value in the overall SSc population was 7 [mean, SD (range): 7.8, 3.2, (4-18)]. Patients with LP had a higher median skin score value compared to SSc patients without LP [median (range): 10 (6-18) versus 6 (4-9); Mann-Whitney U test 22.5, p < 0.005]. A subset analysis was also performed to verify the correlation of antibodies positivity (anti-centromere and Scl 70) pattern and the presence of LP. Our findings showed that higher values of skin score correlated with the presence of LP independent of antibody subsets. CONCLUSIONS: Our data suggest that diffuse abnormalities of the cardiac tissue detected by SA-ECG may be present, even in patients without cardiac symptoms. The relationship between LP and skin involvement in patients without clinical evidence of cardiac involvement may help detect of a subset of patients who may develop scleroderma heart disease.

Adult↗
PubMed1995

[The assessment of left ventricular diastolic function in patients with systemic scleroderma by radionuclide ventriculography].

To assess left ventricular (LV) diastolic function in scleroderma systematica (SS) with regard to SS course and skin lesion degree, a total of 24 SS patients were examined versus control subjects. Though cardiac symptoms manifested clinically only in 8 patients, parameters of LV diastolic function underwent changes in the majority of the examinees: the time to attaining maximal filling velocity increased, contribution of the first diastolic third to LV filling diminished, hemodynamic significance of the left atrial systole grew. More pronounced dysfunction of the myocardium occurred in patients with diffuse skin lesions, acute and subacute disease who also appeared to have reduced LV ejection fraction. The conclusion is made on frequent subclinical pattern of myocardial involvement in SS patients which runs primarily as LV diastolic dysfunction. Systolic disturbance emerge later or in more active forms.

Acute Disease↗
PubMed1987

Involvement of a nucleolar component, perichromonucleolin, in the condensation and decondensation of chromosomes.

A component of the nucleolar material, perichromonucleolin (PCN), was identified by a specific antiserum against nucleoli obtained from a scleroderma patient. The distribution and changes of PCN during the mitotic cycle were followed using this antiserum and indirect immunofluorescence microscopy. Based upon the behavior of PCN during mitosis, it could be differentiated into chromosomal and nonchromosomal portions. During prophase the former gradually associates with the surface of the condensing chromosomes and forms the coat or pellicle around the metaphase and anaphase chromosomes. This pellicle PCN is carried by the anaphase chromosomes to the daughter nuclei. During the time from telophase to interphase, the pellicle PCN dissociates from the decondensing chromosomes and is incorporated into the new nucleoli. The nonchromosomal PCN, after the breakdown of the nuclear membrane, distributes in the cytoplasmic region around the condensed chromosomes and diffuses into the cytoplasm during anaphase. Preliminary biochemical analysis by immunoblotting showed that the PCN consists of two main proteins with molecular masses of 36 kDa and 30 kDa.

Animals↗
PubMed1982

The immunopathology of progressive systemic sclerosis (PSS).

Progressive systemic (sclerosis) is one of the most enigmatic of the rheumatic diseases. It is a connective tissue disorder of unknown etiology characterized by fibrosis in skin and internal organs. Although similar lesions are found with increased prevalence in workers exposed to coal, gold, silica, and polyvinyl chloride, most patients have had no known predisposing factors. Select reports of a familial occurrence of PSS have been observed but a definitive genetic basis is lacking and no clear associations with the major histocompatability complex have been demonstrated. Moreover, although a variety of immunologic abnormalities in patients with PSS have been reported, they are generally diffuse and non-diagnostic. Such abnormalities include defects in cell mediated immunity, increases in sera immunoglobulins, antinuclear antibodies, and cryoglobulins. In contrast to these non-specific findings, there appears to be significant evidence of a relationship between cell mediated immunity to collagen and appearance of scleroderma. For example, peripheral blood lymphocytes in patients with scleroderma undergo lymphocyte transformation when cultured with specific collagen preparations. The pathology of skin and internal organs in PSS generally reflects both collagen deposition and small vessel occlusion. All organ systems may be involved but mortality significantly increases with involvement of heart, kidney, or lung. Unfortunately, at present a reliable experimental model of PSS has not been found although similar immunopathology can be induced in homologous disease of rats and in chronic graft vs host disease of humans.

Animals↗
PubMedDate not supplied

An unusual case of generalized oedema.

We present the case of a 66-year-old woman with generalized oedema and pain in the four limbs. Physical examination revealed a diffuse, painful, partly pitting, oedema of forearms, hands, lower legs and feet. There were no signs of synovitis. Laboratory investigation was non relevant, except for mild eosinophilia, which normalized subsequently. Cardiac, nephrological and venous disturbances were excluded. More uncommon disorders, such as eosinophilic fasciitis, early stage of scleroderma and polymyositis were considered. MRI scanning of the right forearm revealed an increased signal intensity in the superficial muscle fibers and thickening of the fascia (figure 1). Subsequently a full thickness biopsy of the musculus flexor digitorum superficialis was performed, revealing an inflammatory infiltration of lymphocytes and eosinophils, localized in the fascia. There was no necrosis of muscle fibers. No signs of scleroderma were found. The biopsy confirmed the diagnosis of eosinophilic fasciitis. Clinical and MRI findings suggested an early stage of disease and the patient was treated with low-dose corticosteroids.

Adrenal Cortex Hormones↗
PubMed2002

[Pathogenesis of systemic scleroderma: immunological aspects].

Systemic sclerosis (SSc) is a connective tissue disorder that is characterized by excessive collagen synthesis by fibroblasts and by vascular hyperreactivity and obliteration phenomena. Excessive collagen production is the consequence of abnormal interactions between endothelial cells, fibroblasts and mononuclear cells. Immunological abnormalities are present very early in the development of SSc. Mononuclear cells, particularily macrophages and T lymphocytes play a prominent role in fibroblast activation and collagen synthesis through the cytokines they produce. Thus, lymphocytic infiltrates in the skin and in the lung are preferentially composed of CD8+ T lymphocytes, that produce important amounts of interleukin 4 (IL-4). The effects of IL-4 are added to these of transforming growth factor B (TGF-B) and connective tissue growth factor (CTGF) that stimulate collagen synthesis by fibroblasts. T lymphocytes produce important amounts of gamma interferon (INF-gamma) that is the best inhibitor of collagen synthesis by fibroblasts. However, the inhibitory effect of INF-gamma on collagen synthesis is diminished in SSc patients. Numerous autoantibodies can be evidenced in the serum of SSc patients. Three of them are specific for SSc and mutually exclusive: anti-centromere antibodies (Ab) in limited SSc, anti-Scl70 Ab in diffuse SSc and anti-RNA polymerase III Ab in diffuse SSc with renal involvement. These autoantibodies are good prognosis markers but their pathogenic role remains uncertain.

Autoantibodies↗
PubMed1991

Serum aminoterminal propeptide of type III procollagen in systemic sclerosis. A follow-up--investigations in subclasses and during therapy.

Fifty-seven patients with systemic sclerosis were investigated for connective tissue turn-over related to type III collagen. Sera from 13 patients with diffuse cutaneous systemic sclerosis and 44 patients with limited cutaneous systemic sclerosis were analysed for aminoterminal propeptide of type III procollagen (PIIINP) by a radioimmunoassay based on human propeptide. Increased levels of PIIINP in serum correlated with skin involvement and the clinical course. All patients with diffuse cutaneous systemic sclerosis had levels above the normal range, and in limited cutaneous systemic sclerosis elevated PIIINP levels seemed to be correlated with rapid progression and with extension of lesions. Immunosuppressive drugs, cyclosporin A, and prednisone with or without cyclophosphamide, which were given to patients with rapid disease progression, significantly reduced PIIINP. This was also the case with penicillamine, but to a lesser degree. Our data support the suggestion that immunosuppressive agents are justified in rapidly progressive, life-threatening or disabling disease, when used with the necessary precautions. Serum PIIINP may be utilized as a marker of type III collagen fibrogenesis in systemic sclerosis and be of prognostic value. PIIINP may also be of use in the differential diagnosis between diffuse cutaneous systemic sclerosis and scleredema.

Drug Therapy, Combination↗
PubMed2006

Esophageal involvement in scleroderma: gastroesophageal reflux, the common problem.

OBJECTIVES: Systemic sclerosis (SSc) is a multisystem disease characterized by abnormalities of small blood vessels, and fibrosis of the skin and internal organs including gastrointestinal tract. This article reviews the esophageal involvement in SSc, emphasizing the gastroesophageal reflux, which is a common problem in SSc patients. METHODS: We conducted a Medline search from 1966 to 2005. The keywords "systemic sclerosis," "esophageal involvement," "gastroesophageal reflux," "esophagitis," and "treatment" were used. RESULTS: The gastrointestinal tract is frequently affected in diffuse and limited disease. Although any part of the gastrointestinal tract can be involved, esophageal disease occurs in nearly all patients with SSc. Common esophageal manifestations in SSc include motility abnormalities and gastroesophageal reflux (GER), Barrett's esophagus, adenocarcinoma, infectious esophagitis, and drug-induced esophagitis. Common complications of GER include esophagitis with erosions and bleeding and stricture formation. Extraesophageal manifestations of GER include mouth ulcers, chronic cough, hoarse voice, sore throat, pharyngitis, laryngospasm, asthma, and recurrent pneumonia. Diagnostic procedures used in the investigation of esophageal involvement include barium esophagram, esophageal manometry, 24-hour ambulatory pH, and endoscopy. Treatment of GER in SSc includes behavioral modification and medical therapy, mainly with proton pump inhibitors. Surgical intervention has a limited role in the management of GER in selected SSc patients. CONCLUSIONS: Esophageal involvement is frequent in SSc patients. Gastroesophageal reflux may cause high morbidity. Careful examination of the patients reveals gastrointestinal abnormalities even in patients without symptoms. Appropriate treatment of esophageal involvement ameliorates symptoms and prevents complications.

Esophagitis↗
PubMed2006

Allogeneic marrow transplantation in patients with severe systemic sclerosis: resolution of dermal fibrosis.

OBJECTIVE: To evaluate the safety and efficacy of allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning in patients with severe systemic sclerosis (SSc). METHODS: Eligibility criteria for the study included SSc patients with features indicative of a poor prognosis. The myeloablative conditioning regimen included busulfan, cyclophosphamide, and antithymocyte globulin. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and methotrexate. Bone marrow was transplanted from HLA-identical siblings. RESULTS: Two patients with diffuse cutaneous SSc and lung involvement who were refractory to conventional immunosuppressive treatment were enrolled in the study. In patient 1, there were no complications related to the conditioning regimen, and GVHD did not develop after transplantation. At 5 years after HCT, there was nearly complete resolution of the scleroderma and marked improvement in physical functioning. Internal organ function improved (lung) or remained stable. On examination of serial skin biopsy samples, there was resolution of the dermal fibrosis. Patient 2 experienced skin toxicity from the conditioning regimen and hypertensive crisis that was likely related to high-dose corticosteroids given for treatment of GVHD. Although this patient experienced an improvement in scleroderma and overall functioning, a fatal opportunistic infection developed 17 months after HCT. CONCLUSION: Allogeneic HCT may result in sustained remission of SSc. GVHD and opportunistic infections are the major risks associated with allogeneic HCT for SSc, as for allogeneic HCT in general.

Adult↗
PubMed1995

Characterisation of anticytoplasmic antibodies and their clinical associations.

OBJECTIVES: To characterise the cytoplasmic staining patterns identified by indirect immunofluorescence (IF) of human epithelial (HEp-2) cells and the antigens recognised using additional serological techniques. To define the disease associations of anticytoplasmic antibodies. METHODS: Sera from 1173 patients were screened for cytoplasmic IF staining on HEp-2 cells and the patterns characterised. The presence of antimitochondrial antibodies (AMA) was evaluated by a sensitive anti-pyruvate dehydrogenase complex enzyme linked immunosorbent assay (ELISA) (IgG) and by immunoblotting. Detection of antibodies to extractable nuclear antigens (ENA) was performed by double immunodiffusion and the presence of anti-ribosomal P antibodies was determined by immunoblotting. RESULTS: Cytoplasmic IF staining was demonstrated in 75 sera (6.4%). Six different patterns were recognised: coarse granular filamentous speckles (AMA, n = 9); condensed large speckles (anti-golgi apparatus antibodies, n = 3); cytoskeletal (n = 9); centriolar (n = 4); diffuse coarse speckles (n = 33); and fine speckles (n = 17). Of the nine sera with an AMA pattern, the presence of these antibodies was confirmed in seven by the ELISA (n = 6) and on immunoblotting (n = 7). One of the seven patients had primary biliary cirrhosis, and two had scleroderma. Two patients with anti-golgi antibodies had rheumatoid arthritis and two with anticentriolar antibodies had scleroderma. Of 33 sera that had cytoplasmic staining and were ANA negative, three were positive for anti-Ro and two were positive for anti-Jo-1 antibodies. CONCLUSIONS: In general, defined cytoplasmic IF patterns have no specific disease associations. However, the finding of cytoplasmic fluorescence should not be ignored, as it may indicate the presence of antibodies to ENA in the absence of nuclear staining.

Antibodies, Antinuclear↗
PubMed1995

Electrophysiological evidence of "nerve entrapment syndromes" and subclinical peripheral neuropathy in progressive systemic sclerosis (scleroderma).

We report the electrophysiological findings and the management of 5 subjects with progressive systemic sclerosis (PSS) and clinical evidence of nerve entrapment. Three had carpal tunnel syndrome (CTS), 1 bilateral CTS and right tarsal tunnel syndrome (TTS) and 1 Guyon's canal syndrome. Only 1 patient (with CTS) showed significant clinical improvement after surgical decompression; the other 4 demonstrated a slight recovery of conduction without lasting clinical relief after conventional treatment. To explain these failures we hypothesized that these entrapment syndromes were the clinical expression of underlying diffuse damage to the peripheral nervous system (PNS). The conduction values of nerves unaffected by entrapment syndromes were within normal limits, but almost all distal velocities were below the mean of controls. Such subclinical distal peripheral neuropathy was also verified in a selected sample of 17 patients with PSS, without clinical symptoms or signs of PNS involvement. In these 17 cases the mean distal sensory and motor conduction findings of the median, ulnar, sural and tibial nerves were significantly lower than those of a control group, while no significant differences were found in the more proximal tracts of the same nerves. Furthermore, 3 of the 17 patients showed classical electrophysiological evidence of TCS and TTS without any clinical symptoms. We conclude that the subjects with PSS had subclinical polyneuropathy which may become plain polyneuropathy or nerve entrapment syndromes perhaps induced by other risk factors.

Adult↗