Gastric antral vascular ectasia as the only presenting feature of limited cutaneous systemic sclerosis.
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Anemia, Iron-Deficiency↗
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Drug absorption in gastrointestinal disease and surgery. Clinical pharmacokinetic and therapeutic implications.
Drug absorption from the gastrointestinal (GI) tract and the impact of GI surgery and disease on drug absorption are discussed. Recommendations are made to manage problems of drug malabsorption. Absorption from the GI tract is a first-order process described by its rate and extent. GI surgery changes the anatomy of the GI tract and alters important variables in the absorption process. In the wake of procedures which diminish small bowel surface area, the extent of absorption of phenytoin, digoxin, cyclosporin, aciclovir, hydrochlorothiazide and certain oral contraceptives is reported to be reduced. The underlying cause of the reduction is unknown. When gastric emptying time or pH are altered by surgery, the rate of drug absorption appears to be reduced. However, it is not clear which variable is more important in determining therapeutic effects. The effects of coeliac and inflammatory bowel diseases on the distribution and clearance of drugs must be considered before attributing abnormal serum concentrations of drugs to malabsorption. GI disease may slow gastric emptying and delay the complete absorption of drugs when their rate of absorption depends on gastric emptying time. Other inflammatory GI diseases such as graft-versus-host disease (GVHD) of the gut, Behçet's syndrome and scleroderma involving the GI tract may directly reduce absorption of drugs such as cyclosporin, amitriptyline, benzodiazepines, anticonvulsants, paracetamol (acetaminophen) and penicillamine. GI diseases which alter gut pH affect the absorption only of drugs with limited water solubility and pH-dependent dissolution such as ketoconazole. Clinicians should be aware of the variable absorption seen after GI disease and surgery and monitor their patients accordingly.
Gastrointestinal Diseases↗
[How to recognize scleroderma].
Systemic sclerosis is a multisystem disorder characterized by the presence of connective tissue sclerosis, vascular abnormalities concerning small-sized arteries and the microcirculation, and autoimmune changes. This disease is usually preceded by Raynaud's phenomenon. Cutaneous changes are useful for diagnosis. Sclerosis is initially proeminent on hands with frequently pitted scars. Telangiectases and calcium deposits are mainly observed in a good prognosis subset of the disease (CREST) characterized by the association of limited skin involvement and anti-centromere antibodies with possible late onset of pulmonary hypertension. The bad prognosis subset is associated with diffuse cutaneous sclerosis, pulmonary fibrosis, gastrointestinal disease, myocardial involvement and anti-topo-isomerase I antibodies. Histological skin changes are similar to those observed in morphea. In morphea, there is only localized sclerosis of the skin with highly variable aesthetic disability. The condition may be subdivided clinically into the following types: circumscribed plaques, linear morphea and frontoparietal lesions. The last two forms may be associated with atrophy of the underlying anatomic structures. Many other diseases may have a scleroderma-like appearance. In these diseases, nail folds abnormalities, visceral involvement and immunological changes are usually different from those observed in systemic scleroderma.
Diagnosis, Differential↗
Current status of outcome measure development for clinical trials in systemic sclerosis. Report from OMERACT 6.
Systemic sclerosis (SSc), also known as scleroderma, is a complex, multisystem disease that results in severe morbidity, disability, and life-threatening complications. The wide range of biological systems clinically involved, and the large spectrum of disease activity and damage that occurs in this disease have limited clinical investigation of SSc, especially therapeutic trials. The OMERACT 6 Workshop on Systemic Sclerosis was conceived as a starting point for the process of assessing the current state of the science in outcome assessment in SSc and then setting a realistic research agenda and priorities for future work in this area This article reviews the current status of assessment tools for research in SSc within the main fundamental domains of illness in SSc, including problems related to skin, pulmonary, cardiac, peripheral vascular (Raynaud's phenomenon and digital ulceration), renal, and musculoskeletal systems as well as health-related quality of life and physical functioning. The current level of validation of outcome measures in SSc is assessed according to the guidelines set forth by prior OMERACT meetings.
Clinical Trials as Topic↗
Taste dysfunction and changes in zinc and copper metabolism during penicillamine therapy for generalized scleroderma.
The taste function and the zinc and copper levels in serum and urine were followed for up tp 16 weeks in ten patients who were started on penicillamine therapy for generalized scleroderma (9 patients) and rheumatoid arthritis (one patient). During therapy the serum zinc concentration remained unchanged, whereas the serum copper concentration increased significantly during the first 4--5 weeks and then tended to decrease. Urinary copper rose significantly and remained considerably above the upper normal limit throughout the study. Six of the patients complained after about 4--5 weeks of a decreased taste function, which was gradually restored whether the medication was stopped or continued. The alterations in the taste acuity for sweet, salt, sour, and bitter significantly paralleled the variations in urinary copper before as well as during therapy. Thus, the patients who showed the most pronounced loss of taste, had a lower urinary copper output than those whose taste acuity was less disturbed.
Adult↗
Systemic sclerosis with renal crisis and pulmonary hypertension: a report of eleven cases.
OBJECTIVE: To describe a series of systemic sclerosis (SSc) patients with the unusual combination of scleroderma renal crisis (SRC) and pulmonary hypertension (PHT) without interstitial lung disease. METHODS: The medical records of 2,459 SSc patients in the University of Pittsburgh Scleroderma Databank first evaluated between 1972 and 1999 were reviewed. RESULTS: Eleven patients (0.45%) had both SRC and PHT. All had been evaluated since 1979, when angiotensin-converting enzyme (ACE) inhibitor therapy for SRC became available. Seven had SSc with limited cutaneous involvement, and 4 had SSc with diffuse cutaneous involvement. SRC occurred first in all patients except 1, in whom the onsets of SRC and PHT were simultaneous. SRC preceded PHT by a mean of 4.3 years. Four patients had anti-Th/To antibody, 5 had anti-RNA polymerase III antibody, 2 had anti-U3 RNP antibody, and none had anticentromere or antitopoisomerase I antibody. Ten of the 11 patients died, 8 from PHT. Ten patients were being treated with ACE inhibitor drugs when PHT developed. CONCLUSION: In SSc, SRC and PHT are not mutually exclusive complications. SSc patients surviving SRC who have serum antibodies to Th/To, RNA polymerase III, or U3 RNP are at increased risk to develop PHT. ACE inhibitor therapy did not prevent the development of PHT.
Acute Kidney Injury↗
[Pulmonary involvement in scleroderma assessed with high-resolution computerized tomography and functional tests].
This study was aimed at investigating and analyzing lung involvement in scleroderma patients with different imaging methods, toward a rational diagnostic approach. Twenty-four patients with systemic sclerosis were examined with pulmonary function tests (PFT), spirometry and diffusing capacity for carbon monoxide (DLCO), chest radiography and high-resolution Computed Tomography (HRCT). Abnormal findings were present in 42% of cases on X-ray films and in 71% of cases on HRCT images. PFT was abnormal in the spirometries of 42% of cases and in DLCO tests in 50% of cases. The most common findings at HRCT were the small reticular and the ground-glass patterns. HRCT emerged as the most effective method to evaluate lung involvement in systemic sclerosis. In our series, HRCT allowed possibly curable lung lesions to be differentiated from incurable ones. However, HRCT is suggested in the patients with impaired pulmonary function to allow treatment choice; on the contrary, in the patients with no functional impairment, HRCT adds little information to clinical findings, showing only limited focal lesions.
Adult↗
Circulating type I collagen degradation products: a new serum marker for clinical severity in patients with scleroderma?
Systemic sclerosis (SSc; scleroderma) results in the excessive deposition of extracellular matrix components in affected organs. This is partly due to enhanced synthesis; however, the role of degradative processes in this disease is still poorly understood. Sera of 32 patients with SSc (22 with the diffuse, 10 with the limited form) and of six patients with morphoea were assessed using radioimmunoassays for the cross-linked carboxy terminal telopeptide of type I collagen (ICTP) and for the amino terminal propeptide of type I procollagen (PINP) reflecting type I collagen degradation and synthesis, respectively. In 27 of the 32 patients with SSc, the concentration of ICTP was above the upper limit of the normal value (4.6 micrograms/L) and the mean level was clearly elevated at 7.92 micrograms/L. The ICTP concentration correlated with the skin score measuring the extent of the lesions, whereas no such correlation was found for PINP. The ICTP antigen in serum, studied by immunoblotting, had a molecular weight of about twice that of the trypsin-generated fragment isolated from human bone collagen. The mean concentration of serum PINP was 43.9 micrograms/L and no patient exceeded the upper limit of the normal range (80 micrograms/L). We report here for the first time that the concentration of the type I collagen degradation product ICTP in serum shows a close correlation with the extent of skin fibrosis in patients with SSc. We conclude that the increased deposition of type I collagen in this disease is accompanied by an increased turnover of this molecule, indicating a more complex derangement of synthetic and degradative processes than previously acknowledged.
Adult↗
Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway.
OBJECTIVE: To explore the role of reactive oxygen species (ROS) in the in vitro activation of skin fibroblasts from patients with systemic sclerosis (SSc). METHODS: Fibroblasts were obtained from involved skin of patients with limited or diffuse SSc. Oxidative activity imaging in living cells was carried out using confocal microscopy. Levels of O2- and H2O2 released from fibroblasts were estimated by the superoxide dismutase (SOD)-inhibitable cytochrome c reduction and homovanilic acid assays, respectively. To verify NADPH oxidase activation, the light membrane of fibroblasts was immunoblotted with an anti-p47phox-specific antibody. Fibroblasts were stimulated with various cytokines and growth factors to determine whether any of these factors modulate ROS generation. Cell proliferation was estimated by 3H-thymidine incorporation. Northern blot analysis was used to study alpha1 and alpha2 type I collagen gene expression. RESULTS: Unstimulated skin fibroblasts from SSc patients released more O2- and H2O2 in vitro through the NADPH oxidase complex pathway than did normal fibroblasts, since incubation of SSc fibroblasts with diphenylene iodonium, a flavoprotein inhibitor, suppressed the generation of ROS. This suppression was not seen with rotenone, a mitochondrial oxidase inhibitor, or allopurinol, a xanthine oxidase inhibitor. Furthermore, the cytosolic component of NADPH oxidase, p47phox, was translocated to the plasma membrane of resting SSc fibroblasts. A transient increase in ROS production was induced in normal but not in SSc fibroblasts by interleukin-1beta (IL-1beta), platelet-derived growth factor type BB (PDGF-BB), transforming growth factor beta1 (TGFbeta1), and H2O2. Treatment of normal and SSc fibroblasts with tumor necrosis factor a (TNFalpha), IL-2, IL-4, IL-6, IL-10, interferon-alpha (IFNalpha), IFNgamma, granulocyte-macrophage colony-stimulating factor (GM-CSP), G-CSF, or connective tissue growth factor (CTGF) had no effect on ROS generation. Constitutive ROS production by SSc fibroblasts was not inhibited when these cells were treated with catalase, SOD, IL-1 receptor antagonist, or antibodies blocking the effect of TGFbeta1, PDGF-BB, and other agonists (IL-4, IL-6, TNFalpha, CTGF). In contrast, treatment of SSc fibroblasts with the membrane-permeant antioxidant N-acetyl-L-cysteine inhibited ROS production, and this was accompanied by decreased proliferation of these cells and down-regulation of alpha1(I) and alpha2(I) collagen messenger RNA. CONCLUSION: The constitutive intracellular production of ROS by SSc fibroblasts derives from the activation of an NADPH oxidase-like system and is essential to fibroblast proliferation and expression of type I collagen genes in SSc cells. Our results also exclude O2-, H2O2, IL-1beta, TGFbeta1, PDGF-BB, IL-4, IL-6, TNFalpha, or CTGF as mediators of a positive, autocrine feedback mechanism of ROS generation.
Acetylcysteine↗
[Effects of long-term iloprost therapy on Raynaud's phenomenon in progressive systemic sclerosis].
One of the most appealing current pathogenetic concepts is that progressive systemic sclerosis (PSS) is a reaction to repeated episodes of endothelial cell injury. Injury of small arteries and capillary endothelium initiates reactions which involve increased permeability of the vessels, platelet adherence, myointimal cell proliferation, luminal narrowing and heightened sensitivity of the vessel wall. Clinical evidence of the vessel damage is Raynaud's phenomenon, involving both skin and viscera. The Authors evaluated the effects of iloprost on Raynaud's phenomenon in patients with PSS. This drug provides prolonged vasodilation, reduces platelet aggregation and promotes endothelial lining function repair. This last pattern is of primary importance because it may stop the vicious circle: endothelial injury-platelet hyperaggregation-microangiospasm. Five females were recruited, aged 41-66 years, suffering from well-documented (ARA criteria) PSS, associated with typical Raynaud's phenomenon. The trial provided for intravenous infusion of iloprost at a rate of 1-2 ng/kg/min. First treatment consisted of six-hour infusions on six successive days. After this first treatment, weekly infusions during the winter months were carried on. Drug effectiveness was considered through subjective and objective parameters. All patients showed prominent reduction of number, duration and severity of attacks of Raynaud's phenomenon, improvement of prehensile strength, healing of finger ulcerations and improvement or normalization of digital photoplethysmography. So far, the treatment has been prolonged for years in our patients and still goes on. The side effects of iloprost (headache, flushing, nausea) have been very poor. Therefore, iloprost proved to be a valid drug in the management of Raynaud's phenomenon in patients with PSS, but the inconvenience of intravenous administration may limit its routine use.
Adult↗
[The coronary hyperemic reaction in scleroderma].
Functional, organic and vascular anomalies could play an important role in systemic scleroderma. We have studied the coronary hyperemic reaction in subjects with primitive sclerodermatous cardiomyopathy, in order to specify the vascular anomalies. The coronary hyperemic reaction consists of a transient rise in coronary flow after selective injection of a contrast agent into the left coronary artery. In sclerodermatous subjects this coronary hyperemic reaction is significantly smaller than in control subjects. This limitation of the hyperemic reaction reflects a decrease in the ability of small arteries or coronary arterioles to dilate in sclerodermatous subjects. This anomaly could play an important role in primitive sclerodermatous cardiomyopathy.
Cardiac Catheterization↗
Autoantibodies to myeloperoxidase in systemic sclerosis.
OBJECTIVE: Although antimyeloperoxidase (MPO) antibodies provide a sensitive serological test for vasculitis, their significance in sera from a small proportion (about 10%) of patients with autoimmune rheumatic disease is controversial. Our aim was to determine the incidence of anti-MPO antibodies in sera from patients with systemic sclerosis (SSc) and their relation to renal disease. METHODS: Thirty-eight patients had limited cutaneous SSc (lSSc) and 43 diffuse cutaneous SSc, and within each group, 24 and 27 patients, respectively, had renal impairment (defined as stable creatinine clearance less than 60 ml/min). Six patients previously had had a scleroderma renal crisis. After screening for antineutrophil cytoplasmic antibodies (ANCA) by indirect immunofluorescence, the levels of IgM and IgG anti-MPO antibodies in 8 patients with SSc was determined by ELISA, with human MPO as antigen. RESULTS: Sera from 2 patients, both with lSSc and renal impairment, were perinuclear p-ANCA positive and had significant levels of circulating IgM and IgG anti-MPO antibodies. In one patient, anti-MPO antibodies appeared in the serum only after D-penicillamine was introduced, continued to rise after withdrawal of the drug, and fell only after immunosuppressive therapy. Renal biopsy confirmed vasculitis. The 2nd patient died of unrelated disease before further investigations could be performed. CONCLUSION: We suggest that circulating anti-MPO antibodies are not a feature of SSc per se and, if found, may indicate the presence of an unrelated pathology, such as idiopathic or drug induced vasculitis.
Adult↗
[The clinical significance of detecting the inhibition of topoisomerase I by the sera of patients with systemic scleroderma].
Topoisomerase I activity was studied by electrophoresis in agarose gel according to plasmid DNA relaxation. Sera from 62 patients with systemic scleroderma, 35 with Raynaud's syndrome, 8 with focal scleroderma, 15 with systemic lupus erythematosus, 20 with rheumatoid arthritis and 20 healthy subjects were examined. Out of 62 sera from SSD patients, anti-topoisomerase activity was found in 67.8% of cases. The test appeared positive in 79% of patients with diffuse and 63% with limited disease patterns. The mean age and disease standing were similar in the positive and negative groups. An increase of the skin count and more frequent occurrence of trophic disorders in patients with inhibition of the enzyme were recorded. 40% of the patients demonstrated the coincidence of the results with the use of the topoisomerase test and ELISA. In patients with other rheumatic diseases and in the healthy subjects, no inhibition of the enzyme was found.
Animals↗
Surgery of the hand in patients with systemic sclerosis: outcomes and considerations.
OBJECTIVE: To assess the current status of hand surgery in patients who have systemic sclerosis (SSc) and to elucidate special issues of surgery in this patient group. METHODS: A systematic review of English language original studies of surgical procedures of the hand in patients with SSc was performed using Medline, PreMedline, Embase, and Web of Science, from 1975 to March 15, 2004. RESULTS: Thirty-four studies were reviewed: 5 describing surgical procedures on joints, 13 on calcinosis removal, and 20 on digital sympathectomy. When the hand is affected by advanced contracture and deformity due to scleroderma, a nominal measured improvement in position and function may lead to a substantial improvement in the patient's adaptive ability to perform certain activities of daily living. A major concern is the potential for postoperative digital ischemia secondary to vascular involvement, as most of these patients exhibit blood vessel wall changes and Raynaud's phenomenon. Surgical wounds generally heal well following fusion of the proximal interphalangeal (PIP) or distal interphalangeal joint. Correction of severe flexion contractures of the PIP joint improves function and may reduce the frequency of dorsal skin ulceration. Recurrent digital tip ulceration occurs in 31.8-71.4% (median 45.2%) of scleroderma patients, reported to progress to gangrene and autoamputation in 14-29% of cases. Microsurgical revascularization of the hand, digital arterial reconstruction, and peripheral sympathectomy may improve digital vascular perfusion, heal digital ulcers, and relieve pain. Subcutaneous calcifications occur in 8.9-73.1% (median 44.1%) of SSc patients, most commonly at the fingertip, causing pain, functional impairment, and ulceration. Calcinosis can be partially removed with a high-speed burr or carbon dioxide laser. CONCLUSION: The goals of surgery for advanced SSc affecting the hand are limited and include pain relief through sympathectomy and increased perfusion, repositioning the digit, providing a functional position of fusion, and modest mobilization through resection arthroplasty.
Calcinosis↗
Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases.
This paper reports the experiences of our group with 68 patients with progressive systemic sclerosis (PSS) admitted to hospitals of the University of Pittsburgh Health Center between 1955 and 1981 with scleroderma renal crisis (SRC). The onset of SRC was characterized by four features, namely, onset or aggravation, usually abrupt, of arterial hypertension; appearance of Grade III or IV retinopathy; elevations of peripheral renin activity to at least twice the upper limit of normal; and rapid deterioration of renal function within a period of less than one month. Over 90% of our patients in whom these criteria could be determined had at least three of them present with the onset of SRC. Management of these patients during the first 15 years of this period was uniformly ineffective. Before 1971, no patients lived longer than a year; usual survival ranged from 1 to 3 months. With the advent of renal dialysis and the more effective treatment of severe hypertension, along with the utilization of bilateral nephrectomy in selected anuric patients, some improvement in longevity was achieved. However, only in the past few years have we accumulated a group of 11 patients who have survived for longer than one year. The clinical characteristics of the onset and progression of SRC suggest the sudden imposition of severe stress such as cold or an autoimmune insult affecting vulnerable arteries and arterioles. The renal damage becomes self-perpetuating with extremely high renin activity causing further rise in blood pressure and additional renal and systemic vascular damage. Progress in the last few years seems to have been achieved primarily by the advent of pharmacologic agents that specifically block the effect of angiotensin II by inhibiting the angiotensin I converting enzyme. When diagnosis is prompt and the condition is treated as an emergency with these compounds, we and others have found that normal renal function can be restored in a number of patients. The result is a considerably brighter outlook for patients with this previously rapidly fatal complication of progressive systemic sclerosis.
Acute Kidney Injury↗
Elevated plasma histamine levels in systemic sclerosis (scleroderma).
Systemic sclerosis is characterized by excessive deposition of collagen and other matrix proteins in the skin and internal organs. One hypothesis supports fibroblast stimulation for production of excess amounts of collagen by factors present in the blood or released by cells composing inflammatory tissue infiltrates. Increased numbers of mast cells are present in the involved skin of patients with systemic sclerosis, and histamine has been thought to be a possible mediator of fibrosis in this and other fibrotic conditions. We therefore measured plasma histamine levels in 32 patients with systemic sclerosis and found elevated levels in 18 patients (56%). Elevated plasma histamine levels were more common in patients with diffuse disease (74%), in contrast to limited disease (31%). The degree of clinical activity and the duration of disease could not be correlated with histamine levels.
Adult↗
Antibodies to human cytomegalovirus protein UL83 in systemic sclerosis.
OBJECTIVE: To determine whether elevated levels of antibodies to HCMV protein UL83 were present in patients with SSc and if their prevalence was associated with major SSc-associated autoantibodies. METHODS: The study population consisted of 253 Caucasian subjects (110 SSc patients and 143 controls). IgG antibodies to UL83 were measured by an enzyme-linked immunosorbent assay (ELISA). Antibodies to centromere and RNA polymerase (RNAP) were determined by indirect immunofluorescence and immnoprecipitation methods, respectively. RESULTS: The mean level of anti-UL83 antibodies in the sera of SSc patients as a whole was significantly higher than that in control subjects (14.75 vs 10.6 units/microl, p = 0.002). Both subgroups of patients contributed to this variation: compared to controls, anti-UL83 antibody levels were higher in diffuse (16.32 vs 10.6 units/microl, p = 0.012) as well as in those with the limited form of the disease (13.95 vs 10.6 units/microl, p = 0.015). Anti-UL83 antibodies were not associated with major SSc associated autoantibodies. CONCLUSION: Humoral immunity to HCMV protein UL83 may be relevant to the etiopathogenesis of scleroderma.
Autoantibodies↗
Chronic graft-versus-host disease after granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation: the role of donor T-cell dose and differentiation.
The use of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood as a source of stem cells has resulted in a high incidence of severe chronic graft-versus-host disease (cGVHD), which compromises the outcome of clinical allogeneic stem cell transplantation. We have studied the effect of G-CSF on both immune complex and fibrotic cGVHD directed to major (DBA/2 --> B6D2F1) or minor (B10.D2 --> BALB/c) histocompatibility antigens. In both models, donor pretreatment with G-CSF reduced cGVHD mortality in association with type 2 differentiation. However, after escalation of the donor T-cell dose, scleroderma occurred in 90% of the recipients of grafts from G-CSF-treated donors. In contrast, only 11% of the recipients of control grafts developed scleroderma, and the severity of hepatic cGVHD was also reduced. Mixing studies confirmed that in the presence of high donor T-cell doses, the severity of scleroderma was determined by the non-T-cell fraction of grafts from G-CSF-treated donors. These data confirm that the induction of cGVHD after donor treatment with G-CSF is dependent on the transfer of large numbers of donor T cells in conjunction with a putatively expanded myeloid lineage, providing a further rationale for the limitation of cell dose in allogeneic stem cell transplantation.
Animals↗