Progressive Systemic Sclerosis Patients Research Articles

Outcomes of conventionally-treated systemic sclerosis patients eligible for autologous haematopoietic stem cell transplantation.

Autologous haematopoietic stem cell transplantation (HSCT) has exhibited superior efficacy compared to conventional immunosuppressives in rapidly progressive diffuse systemic sclerosis (SSc) patients, albeit still of limited availability. We examined disease outcomes of conventionally-treated real-world inception patients eligible for HSCT, according to HSCT criteria used in the ASTIS and SCOT randomised trials, and compared them to the outcomes of participants in these trials. Overall and event-free survival rates in our inception cohort were analysed at 4.5 and 7 years after HSCT criteria fulfilment and compared to those reported in HSCT and control arms of ASTIS and SCOT. Forty-five of our 142 inception cohort patients fulfilled HSCT criteria within 4 years from disease onset and had comparable baseline characteristics to SCOT/ASTIS patients. Four patients underwent HSCT. The remaining 41 were treated with conventional DMARDs: cyclophosphamide (n=24), mycophenolate mofetil (n=17), rituximab (n=2), tocilizumab (n=3), methotrexate (n=6) or combinations and their 10-year survival was 56% vs. 76% in those with diffuse SSc not fulfilling HSCT criteria. Their survival rates at the time endpoints of SCOT and ASTIS (4.5 and 7 years, respectively) were comparable to the conventionally-treated SCOT/ASTIS control groups. Extrapolating from SCOT/ASTIS results, if all our patients had undergone HSCT promptly, their overall and event-free survival rates could have increased from 73/51% to 83/72% at 4.5 years, and from 63/39% to 76/72% at 7 years, respectively. Wider availability and physician's early acknowledgement and referral of eligible patients for HSCT could significantly improve disease outcomes of rapidly progressive diffuse SSc patients.

Complications and Mortality in Systemic Vasculitis – Vasculogenic Clinicopathologic Entities in Rheumatoid Arthritis and Progressive Systemic Sclerosis Autopsy Patients

Objective: The aim of this study was to determine: the complication(s) and mortality of systemic vasculitis or vascular changes of autoimmune origin (A-SV) in rheumatoid arthritis (RA) and progressive systemic sclerosis (SSc) patients, and to outline the consecutive complex pathological changes (clinicopathological entities) due to A-SV in various organs. Patients and methods: One hundred sixty one (161) non- selected autopsy patients with RA were studied. This non-selected autopsy population of RA patients was compared with 11 autopsy patients suffering of SSc. RA and SSc were confirmed clinically according to the criteria of the American College of Rheumatology (ARA). The basic disease, the complication(s), and the lethal outcome caused by vasculitis were determined and analyzed retrospectively after reviewing the clinical and pathological reports, and confirmed by a study of extensive histological material. The possible role of A-SV in RA or SSc, specifically in relation to complications and cause of death, furthermore to coexistent associated diseases was analyzed by Pearson’s chi-squared (χ2) test. Results and conclusions: A-SV complicated RA in 33 (20.49%) of 161 cases. A-SV led directly to death in 19 (57.57%) of 33 RA patients, and was present in further 14 (42.42%) of RA patients without a direct role in death. Twenty three of 33 patients died of cardiac, 6 of respiratory insufficiency, and 4 of cachexia, intestinal or renal necrosis. There was a significant and positive correlation between A-SV and multifocal myocardiocytolysis (χ2=40.7086, p<0.00001), or multifocal rheumatoid pneumonia (χ2=7.4069, p<0.006), which were outlined as new vaculogenic entities in RA. SSc was the basic disease leading to death in each of 11 patients, and all of these were complicated by A-SV (with or without fibromuscular intimal proliferation–FIP). Five of 11 SSc patients died of circulatory failure caused by complex cardiomyopathy, with or without honeycomb lung. Complex nephropathy led to uremia in 6 of 11 cases. The significant and positive correlation between FIP and myocardiocytolysis (χ2=4.4818, p<0.034), or complex nephropathy (χ2=5.3047, p<0.021) indicate that these complications were directly related to A-SV in SSc patients. The abundant interstitial fibrosis in various organs may have been generated by immunological processes independent of vascular changes.

Retrospective analysis of infections prevalence in patients with progressive systemic sclerosis treated with cyclophosphamide

Aim. Assessment of infections prevalence rate, type and severity in patients diagnosed with progressive systemic sclerosis (PSS), treated with cyclophosphamide (CTX), during 12 months of observations. Material and methods. A retrospective analysis of mild, moderate and severe infections in 17 women with a mean age of 58.8 ± 10.0, based on an interview, physical examination, additional tests, and available medical records. Results. 46 various infections were diagnosed in the analysed group of patients. 32 (69.6%) infections involved the respiratory system, and 14 (30.4%) infections concerned the urinary tract. The average frequency per one patient was 2.7 ± 3.5 (median: 2) events during 12 months of observations. The majority of infections, 60.9 % (n = 28), were mild ones of slight intensity, and 37.0% (n = 17) were moderate ones. Only one person (2.2% of all infections) had a severe infection requiring hospitalisation.Conclusions. In the studied group the infection prevalence rate was comparable to that in a healthy population. The majority of infections were mild and involved the respiratory system. Basis of conducted analysis 12 months intravenous administration of CTX is not a factor significantly increasing a risk of severe infections in the studied group of patients. In PSS patients CTX pulse therapy is relatively safe, as it does not cause severe infections requiring hospitalisation

Treatment Options Are Limited for Patients with Progressive Systemic Sclerosis

Unfortunately, no definitive treatment or disease-modifying therapies exist for progressive systemic sclerosis (PSS). The most important pharmacologic advance in treating patients with this disease is use of angiotensin-converting–enzyme (ACE) inhibitors, which profoundly affect renal survival: Before ACE inhibitors were introduced, PSS patients with renal crisis often underwent bilateral nephrectomy. …

Systemic Vasculitis in Various Organs of 33 Rheumatoid Arthritis and 11 Progressive Systemic Sclerosis Patients – A Comparative Postmortem Study

Objective: The aim of this study was (1) to compare the prevalence and severity of Systemic Vasculitis (SV) in various organs of Rheumatoid Arthritis (RA) and of progressive Systemic Sclerosis (SSc) patients, (2) To determine the complications and lethal outcome caused by vasculitis in RA and SSc. Patients and Methods: Twelve organs (heart, lung, liver, spleen, kidneys, pancreas, gastrointestinal tract, adrenal glands, skeletal muscle, peripheral nerve, skin and brain) of 33 RA and of 11 SSc with SV were studied microscopically. RA and SSc were confirmed clinically according to the criteria of the American College of Rheumatology. The basic disease, the complications, and the lethal outcome caused by vasculitis were determined and analyzed retrospectively, reviewing the clinical and pathological reports, tissue samples, and the histological slides. The existence (prevalence) of vasculitis in various organs was determined based on the presence of vasculitis in blood vessels of different calibers. The severity of vasculitis in various organs was evaluated by semi-quantitative, visual estimation on a 0 to 3 plus scale (based on the number of involved vessels/light microscopic field x40). Results and Conclusions: SV was observed in all of 33 RA and 11 SSc patients with variable prevalence and severity. The average value of prevalence and severity/organ in SSc was appreciably higher than that of RA. In RA patients, not all investigated organs were involved with SV and the existence of blood vessels with vasculitis in each organ was different. In SSc patients SV was present in each of the investigated organs, but with different severity. In RA the heart, skeletal muscle, pancreas, lung, kidneys and gastrointestinal tract were most markedly involved, while in SSc the kidneys, spleen, lung, pancreas, heart and gastrointestinal tract were. The high prevalence of SV and the consecutive fibrosis in these organs identify the main targets of autoimmune processes in RA and SSc prior to the more visible skin involvement. The most markedly involved organs denote a favorable site for histological diagnosis of SV, for example skeletal muscle with peripheral nerve (sural nerve) or gastrointestinal tract in RA and the gastrointestinal tract in SSc. The course of the disease, more precisely mortality due to SV,

Pro- and antiangiogenic markers in patients with pulmonary complications of systemic scleroderma

Systemic sclerosis (SSc) is an autoimmune disorder characterized by skin and internal organs fibrosis and concomitant vascular abnormalities. Although SSc is considered mainly fibrosing disease, underlying vascular pathology plays a fundamental role in its pathogenesis.We have focused on positive and negative serum markers of angiogenesis and fibrosis (pigment epithelium-derived factor [PEDF], vascular endothelial growth factor [VEGF], and soluble VEGF receptor [sVEGFR]), in progressive SSc patients at baseline and after follow-up in relation to cardiopulmonary complications (systemic hypertension [HT], pulmonary arterial hypertension [PAH] and pulmonary fibrosis [PF]).VEGF and PEDF but not sVEGFR were reciprocally regulated in SSc progression. Moreover, VEGF/PEDF ratio significantly increased during follow up suggesting that it might be used as a biomarker of disease progression. No correlation between the studied markers and cardiopulmonary complications was observed.In conclusion, VEGF and PEDF level, and the VEGF/PEDF ratio are significantly changed in the course of SSc progression and these markers can be used to assess SSc activity.

AB0630 Severity of Systemic Vasculitis in Rheumatoid Arthritis and Progressive Systemic Sclerosis – A Comparative Postmortem Study

BackgroundThe vascular system is the most important target of immunological processes, manifesting as vasculitis or characteristic structural changes of blood vessels. Vasculitis and/or structural changes of blood vessels are the...

RETRACTED ARTICLE: Ten-year survival rates of methylprednisolone plus cyclophosphamide followed by mycophenolate mophetyl of azathiopurine for progressive systemic sclerosis patients

RETRACTED ARTICLE: Ten-year survival rates of methylprednisolone plus cyclophosphamide followed by mycophenolate mophetyl of azathiopurine for progressive systemic sclerosis patients

Autoantibodies against eukaryotic protein L7 in patients suffering from systemic lupus erythematosus and progressive systemic sclerosis: frequency and correlation with clinical, serological and genetic parameters. The SLE Study Group.

Recent studies have shown that sera of patients suffering from systemic autoimmune diseases contain autoantibodies directed against the eukaryotic ribosomal protein L7 [1]. In the present study we screened a large panel of sera from patients with systemic lupus erythematosus (SLE) for the presence of anti-L7 autoantibodies and their relationship to clinical, serological and genetic parameters of SLE. By means of an ELISA employing recombinant protein L7 as antigen we detected anti-L7 autoantobodies in 172 of 506 SLE sera (34%). Negative correlations were observed between the presence of anti-L7 autoantibodies, serum IgG levels and proteinuria; a potentially positive relationship existed with lung fibrosis. In order to analyse further this possibility we screened sera of 129 patients suffering from progressive systemic sclerosis (PSS) for anti-L7 reactivity; 45 of these patients had lung fibrosis. Of the PSS patients, 41% exhibited anti-L7 autoantibodies, but positive reactions were evenly distributed among patients with and without lung fibrosis. Protein L7 thus represents a major autoantigen of systemic autoimmune diseases, but does not so far define a distinct subpopulation of patients.

Detection of circulating FcɛR2/CD23+ monocytes in patients with rheumatic diseases

Recently, in vitro studies have demonstrated that expression of Fc epsilon R2/CD23 on normal monocytes can be specifically induced by IL-4. In order to investigate the interaction of IL-4 and monocytes in rheumatic diseases, flow cytometry studies were performed. Elevated numbers of circulating Fc epsilon R2/CD23+ monocytes were detected in patients with progressive systemic sclerosis (PSS) as compared with controls. In addition, supernatants derived from phytohaemagglutinin-stimulated peripheral blood mononuclear cells of PSS patients contained high activity to induce Fc epsilon R2/CD23 on CD14+ monocytes. An increased frequency of Fc epsilon R2/CD23+ monocytes was also observed in rheumatoid arthritis, and sequential studies in patients with systemic lupus erythematosus showed a close relationship between Fc epsilon R2/CD23+ monocytes and disease activity. It is suggested that IL-4 has an important role in the pathogenesis of PSS by activating monocytes, and might also contribute to monocyte activation in other rheumatic diseases.

Elevated soluble Fas/APO-1 (CD95) levels in silicosis patients without clinical symptoms of autoimmune diseases or malignant tumours.

Soluble Fas (sFas) is produced as translation products of alternative mRNA splicing, and antagonizes the membranous Fas molecule in Fas/Fas ligand interactions. We investigated the serum sFas levels in 64 Japanese silicosis patients with no clinical symptoms of autoimmune diseases or malignant tumours, using ELISA for sFas. The serum sFas levels in the silicosis patients were significantly higher than those in healthy volunteers. Elevated serum sFas levels were also detected in patients with systemic lupus erythematosus but, unexpectedly, no difference was observed in sFas levels between progressive systemic sclerosis patients and healthy volunteers. On the other hand, there was no significant difference in the expression of Fas on peripheral blood lymphocytes between the patients with silicosis and age-matched healthy volunteers. These observations provided the first evidence that serum sFas levels are elevated in silicosis patients without clinical symptoms of autoimmune diseases or malignant tumours. It remains to be clarified whether patients with elevated sFas levels have a tendency to develop autoimmune diseases later, or whether some other distinct factor(s) is necessary to initiate the progression of autoimmune diseases.

KIRs and autoimmune disease: studies in systemic lupus erythematosus and scleroderma

We investigated killer immunoglobulin-like receptors (KIRs) and the human leukocyte antigen (HLA)-C ligands for the corresponding inhibitory KIRs in Caucasian patients, 304 with systemic lupus erythematosus (SLE) and 90 with scleroderma [or progressive systemic sclerosis (PSS)] compared with 416 Caucasian controls. Compared with controls, KIR2DS1 in the absence of KIR2DS2 was increased in both SLE (P= 0.04) and PSS (P= 0.02). Only 42% of KIR2DS1-positive PSS patients had the appropriate HLA-C ligand for the corresponding inhibitory KIR compared with 61% of KIR2DS1 positive controls (P= 0.02). In the PSS group the presence of at least either activating KIR2DS1 and/or 2DS2 was significantly increased in patients when compared with controls (P= 0.001). This suggests that KIR receptors play a role in susceptibility to both PSS and SLE.

MRNA expression of procollagen and SMADs in lesional skin of progressive systemic sclerosis

To investigate the mRNA expression of type I and type III procollagen and SMADs in the lesional skin of progressive systemic sclerosis (PSS) and analyze the role in pathogenesis of scleroderma thereof. Real time PCR was used to detect the mRNA expression of type I and type III procollagen, and SMADs (SMAD 2, SMAD 3, SMAD 4, and SMAD 7) in the lesional skin specimens of 11 patients with PSS and 11 specimens of normal skin. Type I procollagen alpha1, type III procollagen alpha1, SMAD 4, and SMAD 7 were expressed at the mRNA level significantly higher in the lesional skin tissues of the PSS patients than in the normal skin tissues (all P < 0.05). SMAD 4 mRNA expression was positively correlated with type I procollagen alpha1 mRNA expression (r = 0.728, P < 0.05) and the type III procollagen alpha1 mRNA expression (r = 0.678, P < 0.05). SMAD3 mRNA expression was positively correlated with the type I procollagen alpha1 mRNA expression (r = 0.859, P < 0.01). Increased SMAD4 mRNA in the lesional skin of systemic sclerosis is positively correlation with increased type I and type III procollagen alpha1 mRNA expression and may be one of the main pathogenesis in resulting in excessive type I and type III collagen accumulation in PSS lesional skin.

ACE Inhibitor-induced Acute Renal Failure in a Patient with Progressive Systemic Sclerosis: Ischemic Nephropathy Mimicking PSS Renal Crisis

A 79-year-old woman with progressive systemic sclerosis (PSS) presented with acute pulmonary edema, hypertension and renal failure. Administration of angiotensin-converting enzyme (ACE) inhibitor under suspicion of PSS renal crisis resulted in worsening of the renal function, which necessitated hemodialysis. Magnetic resonance arteriogram (MRA) demonstrated stenosis of the right renal artery, and ischemic nephropathy was diagnosed. Renal function improved after the discontinuation of ACE inhibitor. ACE inhibitor/angiotensin II receptor blocker (ARB), which is recommended for PSS renal crisis, should be avoided in ischemic nephropathy. In elderly PSS patients, careful exclusion of ischemic nephropathy is warranted before the administration of ACE inhibitor/ARB.

The natural course of progressive systemic sclerosis patients with interstitial lung involvement

The aim of the study is to assess the natural course of systemic sclerosis (SSc) in patients with interstitial lung involvement and to evaluate the effects of treatment. Sixty SSc patients with interstitial lung involvement were included in the study and history and retrospective data records of the patients were reviewed. It was observed that 47 patients (78.3%) had Raynaud's phenomenon, 7 patients (11.7%) had skin involvement, 5 patients (8.3%) had joint involvement, and 1 patient (1.7%) had gastrointestinal system involvement as the first manifestation of the disease. Lung involvement had developed on an average of 113 +/- 106 months after the first manifestation of the disease and was apparent within the first year in 10 patients (16.7%), between 1 and 2 years in 3 patients (5%), between 2 and 3 years in 2 patients (3.3%), between 3 and 4 years in 5 patients (8.3%), between 4 and 10 years in 21 patients (35%), and after 10 years in 19 patients (31.7%). When the symptoms of lung involvement appeared, 37 patients (61.7%) were not receiving treatment while 23 (38.3%) were using an immunosuppressive agent. The time interval of lung involvement for the treated patients was 131 +/- 95 months while it was 101 +/- 112 months in untreated patients (p>0.05). In SSc patients with interstitial pulmonary involvement, the disease frequently starts with Raynaud's phenomenon and pulmonary symptoms tend to appear at a mean of 7 years after the onset of disease. The first sign of the disease, the probability of interstitial pulmonary involvement, is highest during the first 15 years after. Although this probability decreases after 15 years, in up to 10% of the patients, interstitial pulmonary involvement can still occur even up to 40 years. Immunosuppressive treatment is not effective in preventing the development of pulmonary involvement. However, it delays the manifestation of pulmonary symptoms for nearly 4 years.

Prokinetic therapy: What can be measured by gastric scintigraphy?

To evaluate whether gastric scintigraphy with quantitative analysis of gastric peristalsis may be a useful tool for documenting the effects of prokinetic therapy. Gastric emptying was determined in eight patients with insulin dependent diabetes mellitus (IDDM) and nine patients with progressive systemic sclerosis (PSS) after ingestion of a semi-solid test meal. Fourier analysis of condensed images was used to evaluate contraction amplitudes of the entire stomach, as well as frequency and velocity of gastric contractions. Patients were studied twice, first under baseline conditions and then after 4 weeks of continuous oral prokinetic therapy with cisapride (10 mg t.i.d.). Findings were compared with data derived from 15 healthy controls. At baseline conditions IDDM and PSS patients exhibited reduced gastric peristalsis and delayed emptying compared to controls. After 4 weeks of prokinetic treatment, gastric contraction amplitudes increased significantly, especially in the gastric corpus and the proximal stomach, associated with a slight improvement of gastric emptying. Changes in frequency and velocity of gastric contractions during prokinetic treatment correlated with the improvement of gastric motility and emptying. Prokinetic therapy with cisapride stimulates gastric motility, and could be non-invasively monitored by scintigraphy. This radionuclide technique provides a number of relevant parameters of gastric function, such as gastric emptying, contraction amplitudes, frequency and velocity of gastric contractions, which give crucial insights into the mechanisms of action of prokinetic drugs.

Histopathology of the gastric oxyntic mucosa in two different patient groups during long-term treatment with omeprazole.

Hypochlorhydria, hypergastrinaemia, inflammation and Helicobacter pylori infection, dose and duration of omeprazole treatment may separately, or in combination, influence the proliferation of enterochromaffin-like (ECL) cells and parietal cell changes in gastric mucosa. To assess the effects of these variables comparisons were carried out in patients with the acid related Zollinger-Ellison syndrome (ZES) versus patients with progressive systemic sclerosis (PSS) and gastro-oesophageal reflux disease. Twenty-five patients with PSS and 16 patients with ZES were included and received continuous omeprazole treatment for a mean of 7.5 and 9 years. The patients were investigated every 6-12 months with endoscopy, biopsies and histology, and plasma gastrin measurements. PSS patients were titrated by 24 h pH-metry to oesophageal pH>4, and all ZES patients were titrated to a basal acid output of zero H+. Changes towards diffuse and linear ECL cell hyperplasia were observed in 41% of the PSS patients. Micronodular hyperplasia and neoplasia were not seen. In the ZES patients changes towards linear and micronodular hyperplasia were observed in all patients. Two patients developed ECL cell carcinoids; one of these had MEN-1 syndrome. Also parietal cell changes were more pronounced in the ZES group than in the PSS group. In patients without intrinsic acid hypersecretion and hypergastrinaemia significant proliferation of ECL cells is not an issue irrespective of gastric mucosal inflammation, omeprazole dose, duration of treatment and acid inhibition. The level of gastrin secretion and high plasma gastrin appear to accelerate ECL cell proliferation and parietal cell changes possibly influenced by chronic gastritis and H. pylori infection.

Histopathology of the gastric oxyntic mucosa in two different patient groups during long-term treatment with omeprazole

Objectives Hypochlorhydria, hypergastrinaemia, inflammation and Helicobacter pylori infection, dose and duration of omeprazole treatment may separately, or in combination, influence the proliferation of enterochromaffin-like (ECL) cells and parietal cell changes in gastric mucosa. To assess the effects of these variables comparisons were carried out in patients with the acid related Zollinger-Ellison syndrome (ZES) versus patients with progressive systemic sclerosis (PSS) and gastrooesophageal reflux disease. Methods Twenty-five patients with PSS and 16 patients with ZES were included and received continuous omeprazole treatment for a mean of 7.5 and 9 years. The patients were investigated every 6-12 months with endoscopy, biopsies and histology, and plasma gastrin measurements. PSS patients were titrated by 24 h pH-metry to oesophageal pH > 4, and all ZES patients were titrated to a basal acid output of zero H+. Results Changes towards diffuse and linear ECL cell hyperplasia were observed in 41% of the PSS patients. Micronodular hyperplasia and neoplasia were not seen. In the ZES patients changes towards linear and micronodular hyperplasia were observed in all patients. Two patients developed ECL cell carcinoids; one of these had MEN-1 syndrome. Also parietal cell changes were more pronounced in the ZES group than in the PSS group. Conclusions In patients without intrinsic acid hypersecretion and hypergastrinaemia significant proliferation of ECL cells is not an issue irrespective of gastric mucosal inflammation, omeprazole dose, duration of treatment and acid inhibition. The level of gastrin secretion and high plasma gastrin appear to accelerate ECL cell proliferation and parietal cell changes possibly influenced by chronic gastritis and H. pylori infection.

Renal Vascular Resistance in Progressive Systemic Sclerosis: Evaluation with Duplex Doppler Ultrasound

The study was planned to evaluate renal vascular resistance by means of duplex Doppler ultrasonography in patients with progressive systemic sclerosis (PSS) with or without signs of renal involvement. Twenty-two female patients with PSS (mean age 38.5 +/- 17.3 years) and 20 age-matched (mean age 36.7 +/- 7.2 years) female healthy controls participated to the study. Doppler indices of renal vascular resistance--resistive index (RI), pulsative index (PI), and systolic-to-diastolic flow velocities ratio (S/D ratio)--were determined on main renal artery and interlobar artery. RI, PI and S/D ratio were found to be increased in PSS patients with signs of renal involvement as compared to those without renal manifestations and healthy controls (p<0.0001 for all groups). Doppler indices of renal vascular resistance were closely related to the duration of the disease, age, and plasma renin activity. Doppler ultrasound is a useful and informative technique in the monitoring of PSS patients with renal involvement.

Hearing loss in progressive systemic sclerosis patients: A comparative study

Objective: To investigate the middle and inner ear involvement in patients with progressive systemic sclerosis (PSS). Study Design and Settings: We prospectively evaluated 34 PSS patients. All patients underwent a complete ear-nose-throat physical examination and audiological evaluation with pure tone, impedance, and speech audiometry. In addition, systemic manifestations of the disease and drug therapy were recorded. Finally, all patients were tested for the presence of autoantibodies. The results were compared with those of 45 age-matched healthy subjects. Results: We found a sensorineural hearing loss in 20% and mixed type hearing loss in 3.3% of the patients. There was no correlation of hearing loss with age, systemic manifestations of the disease, presence of autoantibodies, and drug therapy. Ten percent of the patients had patulous eustachian tubes. Conclusion: One fourth of PSS patients had a hearing loss affecting the middle and mainly the high frequencies. This is a lower percentage than that reported by other investigators. A significant prevalence of bilateral patulous eustachian tubes was noticed as well. Further investigation is needed for a better understanding of the mechanism of ear damage in PSS patients. (Otolaryngol Head Neck Surg 2001;124:522-5.)