Diffuse Cutaneous Form Of Systemic Sclerosis Research Articles

Economic burden of systemic sclerosis: systematic review

Background. Systemic sclerosis (SSc) is a severe orphan disease, one of the systemic pathologies of connective tissue. This disease has a significant negative impact on the patient’s quality of life and has a high mortality rate. Treatment of its various complications imposes a great financial burden on the healthcare system. The difficulties of daily functioning and social adaptation and the overall burden of SSc for patients, as well as their caregivers, also contribute to the economic component of the disease.Aim. To assess the social and economic burden of SSc.Materials and methods. A systematic review was conducted according to the PRISMA guidelines using predefined PICO(S) criteria. The search was carried out in December 2019 using the MeSH terms in the Embase, MEDLINE / PubMed, Cochrane library databases. The publication date range was 10 years. To identify Russian-language studies, an additional search was conducted in eLIBRARY.ru and the Internet network. The evidence levels of the included studies were determined.Results. A total of 934 studies were identified from all databases; 53 publications were selected for eligibility; 9 of which were included in the final review. There were no studies identified to assess the burden of SSc in Russia, so the evaluations were based on foreign studies. The estimates of the annual direct costs per patient with SSc for the past decade were almost similar in different countries: 5 038 Canadian dollars in Canada, 11 607 Australian dollars in Australia, 17 365-22 016 US dollars in the USA, and 1 413-17 300 Euros in Europe (an average of about 8 000 euros). The cost structure was dominated by direct medical costs for hospitalization and drug therapy and indirect costs were mostly associated with the loss of productivity and early retirement. The costs associated with the diffuse cutaneous form of SSc were statistically higher if compared to the costs for the limited form of the disease. Among the clinical manifestations of the disease, lung lesions and gastrointestinal problems made the largest contribution to the economic burden.Conclusion. SSc is associated with significant healthcare resource use compared to the general population. The economic burden of SS has grown significantly in recent years, and this trend is global. At the same time, it is difficult to evaluate the disease costs in Russia due to a lack of information on the patient population.

Pseudotumoral calcinosis in systemic sclerosis: Data from systematic literature review and case series from two referral centres

ObjectivesWe aimed to clarify the definition, distribution, clinical association and outcomes of large calcinosis in patients with systemic sclerosis (SSc). MethodsWe conducted a systematic literature review (SLR) focusing on SSc-related large calcified masses. Upon updating the terminology and definition, all cases of “pseudotumoral” calcinosis seen at the Cochin and Padova University Hospitals were reviewed. ResultsThe SLR yielded 30 SSc cases, with large calcified masses mainly defined as “tumoral” or “pseudotumoral”. Among the 629 SSc cases included in the Cochin and Padova cohorts, 19 (3%) living and 7 deceased patients were affected by pseudotumoral calcinosis; among these, the great majority had a severe vascular phenotype. The mean age in the whole population (56 cases) was 59 ± 11.4 years with a median disease duration at calcinosis onset of 7 (5–10) years. Twenty-five out of 56 patients (44.6%) had the diffuse cutaneous form of SSc. Anti-topisomerase I and anticentromere were found equally. Pseudotumoral calcinosis were commonly symmetrical and the size ranged from 2 to 15.5 cm. Most patients had multiple site involvement: 52% hand/wrist, 29% shoulders and elbows, 20% hips and 25% spinal calcinosis. Fistulization/ulceration and infections were reported in 32% and 23% of cases, respectively; nerve compression was found in 40% of spinal calcinosis and in one patient with limb calcinosis. There was no clear evidence of clinical and radiological improvement with any treatment. A partial improvement was seen in 7 patients that underwent surgery. ConclusionPseudotumoral calcinosis may occur in about 3% of SSc patients, commonly symmetrical and in multiple sites without differences regarding the cutaneous subtypes but often in those with a severe vascular phenotype. Medical treatment seems ineffective, whereas a surgical approach may be considered.

High reactive oxygen species in fibrotic and nonfibrotic skin of patients with diffuse cutaneous systemic sclerosis

Systemic sclerosis (SSc) is a chronic multisystemic connective tissue disease characterized by progressive fibrosis affecting skin and internal organs. Despite serious efforts to unveil the pathogenic mechanisms of SSc, they are still unclear. High levels of reactive oxygen species (ROS) in affected patients have been shown, and ROS are suggested to play a role in fibrosis pathogenesis. In this study we evaluate ROS levels in nonfibrotic and fibrotic skin of patients with SSc and we compare them with those obtained from healthy controls. We enrolled nine SSc patients fulfilling the EULAR/ACR classification criteria and seven healthy controls. Patients included four men and five women with mean age of 46±10 years. Controls were matched by sex and age. All patients were affected by the diffuse cutaneous form of SSc and the ANA pattern anti-Scl70. Mean disease duration was 7.5±5 years. Skin involvement was evaluated by modified Rodnan skin score. Skin samples (4-mm punch biopsy) were taken from fibrotic skin and nonfibrotic skin of patients and from healthy controls as well. To detect ROS, specimens were analyzed immediately after sampling by electron paramagnetic resonance spectroscopy. Blood samples were drawn from all patients and controls to assess oxidative stress biomarkers. ROS levels (expressed as median and range, in nmol/L/min/mg of dry weight) were 24.7 (10.9–47.0) in fibrotic skin, 18.7 (7.3–34.0) in nonfibrotic skin, and 7.7 (3.5–13.6) in healthy control skin. ROS levels in fibrotic and nonfibrotic skin of SSc patients were significantly higher than in healthy controls (p=0.002 and p=0.009, respectively). ROS levels in fibrotic skin were raised in comparison to nonfibrotic skin, when samples related to each patient were compared (p=0.01). ROS levels in fibrotic skin were correlated with forced vital capacity (r=−0.75, p=0.02) and erythrocyte sedimentation rate (r=0.70, p=0.04). All other clinical and lab parameters showed no significant correlation. Compared to controls, blood from SSc patients showed lower ascorbate (vitamin C) levels (8 (3.8–9.8) vs 10.5 (9–19.1) mg/L, p=0.004) and higher lipid peroxides (873.5 (342–1973) vs 422 (105–576) μmol/L, p=0.004). Our results indicate the presence of high oxidative stress in both nonfibrotic skin and fibrotic skin of SSc patients, but with higher tendency in the latter. Raised ROS levels in nonfibrotic skin of SSc patients might be a hint of early involvement in skin fibrogenesis. However, a longitudinal prospective study is necessary for such proof.

FRI0400 Right ventricular function by 3d-echocardiography and 2d- speckle tracking in scleroderma patients without pulmonary hypertension

BackgroundRight ventricular (RV) involvement in Systemic Sclerosis (SSc) is usually related to the appearance of pulmonary hypertension (PH). It’s unknown if SSc can directly affect RV function in absence of...

Tumoral Calcinosis of Thoracic Spine Associated with Systemic Sclerosis: Figure 1.

Soft-tissue calcinosis is a common manifestation in patients with systemic sclerosis (SSc), most typically seen as subcutaneous and intracutaneous calcium deposition in the extremities. By contrast, spinal calcinosis has been the subject of only limited reports1–8. We describe a woman with the diffuse cutaneous form of SSc who presented with serious neurological symptoms, including a rapidly progressive course of motor and sensory disturbance. Computed tomography (CT) of her thoracic spine showed massive intraspinal calcinosis and paraspinal calcinosis causing spinal cord compression. A 53-year-old woman, diagnosed 10 years previously as having the diffuse cutaneous form of SSc, was admitted to our hospital with a 2-week history of rapidly increasing weakness and numbness of her bilateral lower extremities. She had daily episodes of Raynaud’s phenomenon, esophageal hypomotility, and interstitial lung disease. On admission, physical examination revealed skin thickening over the trunk, face and limbs, multiple ulcerations of her fingertips, peripheral calcinosis cutis, and telangiectasia. Neurologic examination revealed severe weakness in her bilateral lower extremities …

Incidence of lymphoma in systemic sclerosis: a retrospective analysis of 218 Hungarian patients with systemic sclerosis

Recent results suggest that B cells may have multiple pathogenic roles in systemic sclerosis (SSc) and there may be increased incidence of B cell lymphomas in SSc. Here, we assessed the prevalence of lymphomas in a large SSc cohort. We analyzed data of 218 Hungarian patients undergoing follow-ups in our institutions between 1995 and 2007. During this follow-up period, there were three SSc patients, who eventually developed B cell lymphoma. The first case is a woman with diffuse cutaneous form of SSc (dcSSc) including pulmonary, cardiac, gastrointestinal, and renal manifestations and anti-topoisomerase I antibody positivity. B cell chronic lymphocytic leukemia (B-CLL) with Zap70 expression (Rai I stage) developed 2 years after the onset of SSc. The second case is a woman with dcSSc presenting with pulmonary, cardiac, and gastroesophageal manifestations. Twenty-one months after disease onset, a chronic small lymphocytic B cell non-Hodgkin's lymphoma was diagnosed from retroperitoneal lymph nodes. Our third case is a woman with dcSSc and no internal organ manifestations. She also developed Zap70-positive B-CLL, stage Rai I 9 months after the onset of SSc. Thus, there were three cases of B cell lymphoma among our 218 SSc patients (1.38%). The association of scleroderma and non-Hodgkin's lymphoma may be a rather uncommon feature; however, the incidence of lymphoma among Hungarian SSc patients may be 1.9-2.5 times higher than that in the general population. In our three patients, B cell lymphoma developed within 2 years after the onset of SSc. Altered B cell function implicated in the pathogenesis of SSc may lead to the development of lymphoid malignancies.

Effect of a single IV administration of l-propionylcarnitine on myocardial microcirculation assessed by coronary flow velocity reserve measurement in patients with systemic sclerosis: A pilot study

Background: Scleroderma-related cardiac involvement primarily affects coronary microvascular structures and function. The microvasculature disorder is responsible for impairment of coronary flow velocity reserve (CFVR), which has been reported in studies of patients with systemic sclerosis (SSc). l-Propionylcarnitine (L-PC) is a metabolic substance that is associated with a beneficial effect on both microcirculation and myocyte function. Objective: The objective of this study was to determine whether or not CFVR was acutely improved or restored in patients with SSc after a single administration of IV L-PC. Methods: In this pilot study, we screened volunteers with SSc who had no clinical evidence of ischemic heart disease. CFVR was determined by a blinded investigator by evaluating the left anterior descending coronary artery (LADCA) by transthoracic echocardiography during adenosine infusion (140 μg/kg · min −1 for 5 minutes), 30 minutes before and 15 minutes after administration of L-PC (300 mg IV in 5-minute bolus). Results: Thirty-three patients were screened for this study. Fourteen patients (mean [SD] age, 54.3 [11.2] years; mean [SD] weight, 63.8 [14.5] kg; mean [SD] height, 156.3 [8.7] cm) with SSc and no evidence of coronary heart disease were included in the study; 13 women and 1 man (4 with the diffuse cutaneous form of SSc and 10 with the limited cutaneous form). After administration of L-PC to patients with SSc, median CFVR was significantly increased from 2.60 to 3.23 ( P < 0.001), whereas peak diastolic velocity in the LADCA decreased significantly at the basal evaluation (30.0 vs 26.0, P = 0.009) and significantly increased (80.0 vs 87.5, P = 0.005) during adenosine infusion. No adverse events occurred before, during, or after L-PC infusion. Conclusions: Acute administration of L-PC was associated with a short-term beneficial effect on CFVR in this pilot study of patients with SSc. These results suggest that further, randomized, controlled, double-blind evaluation of longer-term administration to patients with SSc should be considered.

Treatment of pulmonary fibrosis in systemic sclerosis: Light at the end of the tunnel?

For decades, 3 components—vascular, immunologic, and fibrotic—have characterized systemic sclerosis (SSc). The interrelationship among these components is still not well elucidated, but each has been a target of therapy. The immunologic abnormalities involve T and B lymphocytes. Early skin lesions show lymphocyte infiltration with enrichment of Th2 cells. In contrast to normal skin, early lesions in patients with the diffuse cutaneous form of SSc (dcSSc) contain T cells expressing CD4 ,CD8 / cell surface markers that produce large amounts of interleukin-4 (1). Polarization of lymphocytes is also observed in the lungs of patients with dcSSc. Presumably, such cells contribute to shaping the fibroblast phenotype of SSc, although direct evidence of their in vivo role is lacking. Autoantibodies recognizing nuclear components are found in a majority of, if not all, patients with SSc and define clinical subgroups. Autoantibodies are present early in the course of the disease, sometimes before the full-blown form develops, but they have not been shown to be directly pathogenic. They are instrumental in distinguishing between dcSSc and limited cutaneous SSc (lcSSc). The latter is more insidious by nature, is associated with anticentromere antibodies, and is more “vascular” than is the more “fibrotic” diffuse form. A recent report regarding a stimulating autoantibody to platelet-derived growth factor (PDGF) receptor (2) is of potential interest in view of the central role of PDGF and transforming growth factor (TGF ) signaling in fibrosis in SSc, but the observation needs confirmation. The antibody was present in all (!) of 46 patients and in none of the controls, but the authors did not provide details regarding clinical features. These findings, if confirmed, leave open some questions, e.g., whether the antibodies really reach target cells and whether they can stimulate lesional fibroblasts in vivo. The distinction between lcSSc and dcSSc is evident early, without clinical overlap. Features of the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) occur in both forms, but they differ in the extent of skin involvement. By nailfold capillaroscopy it has been shown that capillaries are both abnormal and reduced in number in both forms; neointima formation and media thickening also occur in both forms. A fundamental question remains regarding the origin of the stimulated fibroblasts. Is their abnormal function induced in situ by cytokines or other mediators, or do they constitute a new population of cells related to circulating fibrocytes, myofibroblasts, or pericytes derived from blood vessel walls? It is reasonable to assume that epithelial mesenchymal transition is involved in the process. Vascular dysfunction can now be treated with some success with angiotensin-converting enzyme inhibitors, prostacyclin derivatives, and inhibitors targeting endothelin receptors (the nonselective oral A and B receptor inhibitor bosentan and, more recently, the oral selective endothelin receptor A inhibitor sitaxsentan [3], which was approved in Europe in August 2006 for the treatment of pulmonary arterial hypertension [PAH]). These agents represent a breakthrough in the treatment of PAH in that they are associated with improved physical function; however, reduced mortality remains to be demonstrated. They are also very expensive, even compared with biologic agents such as tumor necrosis factor inhibitors. Bosentan has not been proven effective in the treatment of interstitial lung disease. The search for effective antifibrotic agents in SSc has been a source of continuing disappointment. For many years D-penicillamine was the recommended antifibrotic therapy, but the first controlled trial, published only as recently as 2004, showed no effect (4). This trial compared low-dose and high-dose treatment (150 mg Frank A. Wollheim, MD, PhD, FRCP: Lund University Hospital, Lund, Sweden. Address correspondence and reprint requests to Frank A. Wollheim, MD, PhD, FRCP, Department of Rheumatology, Lund University Hospital, Kioskgatan 3, S-221 85 Lund, Sweden. E-mail frank.wollheim@med.lu.se. Submitted for publication August 20, 2006; accepted in revised form September 29, 2006.

Fibrosing alveolitis in systemic sclerosis: the need for early screening and treatment

Abnormalities in lung function occur in 70% of patients with systemic sclerosis (SSc). Fibrosing alveolitis in SSc (FASSc) is more commonly seen in the diffuse cutaneous form of SSc, particularly in the presence of antitopoisomerase antibodies (Scl70), and with the decreasing incidence of scleroderma renal crisis it is now the major cause of mortality in this patient population. Screening of patients recently diagnosed with SSc by pulmonary function tests and the performance of high resolution computed tomography when physiological abnormalities are identified has resulted in the identification of significant numbers of patients with early, asymptomatic FASSc. Whether these patients should be further investigated with a surgical lung biopsy or receive immunosuppression is unclear, because it cannot yet be reliably predicted who will develop progressive disease and the evidence to support the efficacy of treatment is not strong. The objective of the present article was to review the evidence to support the use of immunosuppressive therapy in FASSc and, based on these data, to propose an algorithm for the investigation and management of this difficult clinical problem.