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1
Ananyeva, L. P., I. E. Tyurin, O. A. Koneva, L. A. Garzanova, and A. M. Lila. "Interstitial lung disease in systemic sclerosis (systemic scleroderma)." Modern Rheumatology Journal 15, no. 1S (March 17, 2021): 1–62. http://dx.doi.org/10.14412/1996-7012-2021-1s-1-62.
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In systemic sclerosis (SSc), interstitial lung disease (ILD) is common (>80%) and worsens the prognosis of the disease, but severe progressive damage develops only in 8–10% of cases. Interstitial changes in the lungs occur early (within the first 3–5 years of the disease). The histological manifestations are similar to those of idiopathic ILD.The main tool for screening and diagnosing of ILD associated with SSc is high-resolution computed tomography of the lungs, resulting data influence the choice of therapy. In most patients a relatively intact and stable forced vital capacity of the lungs is recorded for a long time, but the diffusion capacity of the lungs decreases early and steadily. Pulmonary functional tests have prognostic value.The choice of the optimal therapy for SSc with lung lesions is based on general disease activity (the severity of inflammation and fibrosis) and the its severity, rate of progression of the disease in general and the leading pathology – interstitial pneumonia (IP) – in particular. In patients with SSc and severe or progressive IP, treatment with mycophenolate mofetil (MMF), cyclophosphamide, nintedanib, or nintedanib in combination with MMF if appropriate, should be considered. If this therapy is ineffective, rituximab may be used.
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Tang, Iris Yan Ki, and So Ho. "Treatment of Systemic Sclerosis Associated Interstitial Lung Disease." Journal of Clinical Rheumatology and Immunology 20, no. 02 (November 19, 2020): 56–64. http://dx.doi.org/10.1142/s2661341720300050.
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Systemic sclerosis (SSc) is a systemic connective tissue disorder characterized by progressive skin and visceral organ fibrosis, vasculopathy, and immune dysregulation. Interstitial lung disease (ILD) is a common manifestation and major contributor to morbidity and mortality. Immunosuppression is usually indicated for extensive or progressive SSc-ILD. Recently, antifibrotic and biological therapies have been shown to be efficacious in treating SSc-ILD in various studies. In this article, we will descriptively review the latest evidence on the treatment of SSc-ILD.
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Ruaro, Barbara, Marco Confalonieri, Marco Matucci-Cerinic, Francesco Salton, Paola Confalonieri, Mario Santagiuliana, Gloria Maria Citton, Elisa Baratella, and Cosimo Bruni. "The Treatment of Lung Involvement in Systemic Sclerosis." Pharmaceuticals 14, no. 2 (February 13, 2021): 154. http://dx.doi.org/10.3390/ph14020154.
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Systemic sclerosis (SSc) patients are often affected by interstitial lung disease (ILD) and, although there have been recent treatment advances, it remains the leading cause of death among SSc, with a 10-year mortality up to 40%. African Americans and subjects with diffuse cutaneous SSc or anti-topoisomerase 1 antibodies are most commonly affected. Currently, early ILD diagnosis can be made, and it is pivotal to improve the prognosis. The diagnostic mainstay test for SSc-ILD is high-resolution computed tomography for the morphology and pulmonary function tests for the functional aspects. Treatment planning and intensity are guided by the disease severity and risk of progression. Traditionally, therapy has depended on combinations of immunosuppressants, particularly cyclophosphamide and mycophenolate mofetil, which can be supplemented by targeted biological and antifibrotic therapies. Benefits have been observed in trials on hematopoietic autologous stem cell transplantation for patients with progressive SSc, whilst lung transplantation is reserved for refractory SSc-ILD cases. Herein, recent advances in SSc-ILD treatment will be explored.
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MANETTI, MIRKO, ANNA FRANCA MILIA, SERENA GUIDUCCI, ELOISA ROMANO, MARCO MATUCCI-CERINIC, and LIDIA IBBA-MANNESCHI. "Progressive Loss of Lymphatic Vessels in Skin of Patients with Systemic Sclerosis." Journal of Rheumatology 38, no. 2 (November 15, 2010): 297–301. http://dx.doi.org/10.3899/jrheum.100767.
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Objective.Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular and fibrotic changes in the skin and internal organs. The role of blood vessel dysfunction in the pathogenesis of SSc has been extensively investigated, but few studies have addressed the involvement of the lymphatic vascular system. Our aim was to evaluate dermal lymphatic vessels in patients with SSc according to different phases of skin involvement.Methods.Skin biopsies were obtained from the forearm of 25 SSc patients (10 early/15 late-stage disease) and 13 healthy controls. Skin sections were immunostained for podoplanin (D2-40), which is selectively expressed in lymphatic endothelial cells, and examined by confocal laser scanning microscopy. Lymphatic vessels were counted in the papillary and reticular dermis. Data were analyzed using Student’s t test.Results.The number of lymphatic vessels was significantly reduced in the papillary and reticular dermis of SSc patients compared with controls. In early SSc, lymphatic vessel counts were not different from controls in the papillary dermis, and showed a trend toward a reduction in the reticular dermis. In late SSc, a significant reduction in lymphatic vessels compared with controls was found in both the papillary and reticular dermis. The number of lymphatic vessels in the papillary dermis of late SSc was significantly lower than in early SSc.Conclusion.In SSc, lymphatic microangiopathy is linked to the progression of skin involvement. The progressive disappearance of lymphatic vessels may have a critical pathogenetic role in the progression of SSc from an early edematous phase to overt fibrosis.
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Herrick, Ariane L. "Advances in the Treatment of Systemic Sclerosis." Rheumatology 1, no. 2 (2022): 61. http://dx.doi.org/10.17925/rmd.2022.1.2.61.
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Although systemic sclerosis (SSc) is currently incurable, there have been recent advances in treatment. This review article begins by providing a brief background to SSc in terms of disease subtyping and autoantibodies, because both predict disease trajectory and help clinicians to select appropriate monitoring and treatment protocols. Broad principles of management are then described: ‘disease-modifying’ therapies and therapies directed at reducing disease burden and/or progression of SSc-related digital vascular disease and of internal organ involvement. Next, advances in the management of digital vasculopathy, pulmonary arterial hypertension (PAH), interstitial lung disease (ILD) and early diffuse cutaneous SSc are discussed in turn, for example: (a) increased use of phosphodiesterase inhibitors and endothelin receptor antagonists for digital vasculopathy; (b) early recognition and treatment of PAH, including with combination therapies; (c) increased use of mycophenolate mofetil and of nintedanib in ILD; and (d) immunosuppression now as standard practice in early diffuse cutaneous SSc, and autologous haematopoietic stem cell transplantation for highly selected patients with progressive diffuse disease. Finally, future challenges are discussed, including ensuring that all patients with SSc are monitored and treated according to best practice guidelines, and whenever possible giving patients the opportunity to participate in clinical trials.
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Giovannetti, Antonello, Elisabetta Straface, Edoardo Rosato, Marco Casciaro, Giovanni Pioggia, and Sebastiano Gangemi. "Role of Alarmins in the Pathogenesis of Systemic Sclerosis." International Journal of Molecular Sciences 21, no. 14 (July 15, 2020): 4985. http://dx.doi.org/10.3390/ijms21144985.
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Systemic sclerosis (SSc) is a rare chronic autoimmune disease associated with significant morbidity and mortality. Two main subsets of SSc are recognized: (i) diffuse cutaneous SSc with rapidly progressive fibrosis of the skin, lungs, and other internal organs; and (ii) limited cutaneous SSc, which is dominated by vascular manifestations, with skin and organ fibrosis generally limited and slowly progressing. In spite of intense investigation, both etiology and pathogenesis of SSc are still unknown. Genetic and environmental factors, as well as abnormalities of immune functions, are strongly suggested for etiology, while microvascular abnormalities, immune system activation, and oxidative stress are suggested for the pathogenesis. Recently, it has been found that a multitude of mediators and cytokines are implicated in the fibrotic processes observed in SSc. Among these, a central role could be exerted by “alarmins”, endogenous and constitutively expressed proteins/peptides that function as an intercellular signal defense. This review describes, in a detailed manner, the role of alarmins in the pathogenesis of scleroderma.
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Saketkoo, Lesley Ann, Mary Beth Scholand, Matthew R. Lammi, and Anne-Marie Russell. "Patient-reported outcome measures in systemic sclerosis–related interstitial lung disease for clinical practice and clinical trials." Journal of Scleroderma and Related Disorders 5, no. 2_suppl (March 2020): 48–60. http://dx.doi.org/10.1177/2397198320904178.
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Systemic sclerosis (SSc) is a progressive vasculopathic, fibrosing autoimmune condition, portending significant mortality; wherein interstitial lung disease (ILD) is the leading cause of death. Although lacking a definitive cure, therapeutics for (SSc-ILD) that stave progression exist with further promising primary and adjuvant compounds in development, as well as interventions to reduce symptom burden and increase quality of life. To date, there has been a significant but varied history related to systemic sclerosis–related interstitial lung disease trial design and endpoint designation. This is especially true of endpoints measuring patient-reported perceptions of efficacy and tolerability. This article describes the underpinnings and complexity of the science, methodology, and current state of patient-reported outcome measures used in (SSc-ILD) systemic sclerosis–related interstitial lung disease in clinical practice and trials.
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Mackintosh, John A., Anna Stainer, Joseph L. Barnett, and Elisabetta A. Renzoni. "Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview." Seminars in Respiratory and Critical Care Medicine 40, no. 02 (April 2019): 208–26. http://dx.doi.org/10.1055/s-0039-1683431.
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AbstractInterstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). SSc-ILD adversely impacts quality of life and is currently the leading cause of death in this multisystem disease. Identifying clinically significant SSc-ILD is critically important. Accurate staging and prognostication remain difficult; however, significant advances have been made in the last decade. Evidence supports the need to treat patients with extensive and/or progressive SSc-ILD, while only a subset of patients with limited ILD may require treatment. Research is urgently required to allow improved prediction of patients at risk of ILD progression at an early point in the disease, and ideally prior to its onset, to allow prevention. The last decade has seen the publication of landmark clinical trials for SSc-ILD. More effective strategies with less toxicity are under investigation. For those with refractory or very advanced disease, studies into disease-specific palliative approaches are in their infancy. Lung transplantation as an option for SSc-ILD remains patient- and center-specific, with data to suggest equivalent outcomes to other fibrotic lung diseases, in carefully selected cases. This review aims to provide a comprehensive overview of all key aspects of SSc-ILD.
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Zhang, Xuli Jerry, Ashley Bonner, Marie Hudson, Murray Baron, and Janet Pope. "Association of Gastroesophageal Factors and Worsening of Forced Vital Capacity in Systemic Sclerosis." Journal of Rheumatology 40, no. 6 (April 1, 2013): 850–58. http://dx.doi.org/10.3899/jrheum.120705.
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Objective.Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc) and causes death. Once lung fibrosis occurs, disease course may become stable or decline. Little is known about risks for progression. We studied SSc–gastroesophageal (GE) involvement in relation to worsening forced vital capacity (FVC) on pulmonary function tests (PFT) to investigate whether it was related to progression. Our objective was to determine whether GE reflux and dysphagia are associated with progressive moderate/severe ILD as measured by PFT over 3 years.Methods.The Canadian Scleroderma Research Group is a multicenter SSc database that collects data annually. Using indicators of GE involvement and annual PFT, comparisons were made between no/mild ILD, stable moderate/severe ILD, and progressive moderate/severe ILD groups based on changes of FVC. Multivariate analyses determined associations between GE factors and ILD development and progression.Results.There were 1043 patients with SSc (mean age 55.7 yrs, mean disease duration 10.8 yrs); one-quarter had pulmonary fibrosis on chest radiograph that was related to FVC percentage predicted (Spearman’s rho −0.39; p < 0.01). Physician indicators such as esophageal dysmotility (p = 0.009) and postesophageal dilatation (p = 0.041), and patient indicators such as difficulty swallowing (p = 0.016) and waking up choking (p = 0.026) were associated with low FVC. In comparing progressive and stable moderate/severe FVC (< 70% predicted), early satiety (p = 0.018) and a combination term of postdilatation and choking (p = 0.042) increased risk of progression of ILD. Topoisomerase I was not associated with progression over followup.Conclusion.Symptoms of esophageal dysmotility were associated with worsening FVC in SSc, especially if both need for esophageal dilatation and choking were present.
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Nagy, Tamas, Nora Melinda Toth, Erik Palmer, Lorinc Polivka, Balazs Csoma, Alexandra Nagy, Noémi Eszes, et al. "Clinical Predictors of Lung-Function Decline in Systemic-Sclerosis-Associated Interstitial Lung Disease Patients with Normal Spirometry." Biomedicines 10, no. 9 (August 31, 2022): 2129. http://dx.doi.org/10.3390/biomedicines10092129.
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Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). Progressive pulmonary fibrosis (PPF) is defined as progression in 2 domains including clinical, radiological or lung-function parameters. Our aim was to assess predictors of functional decline in SSc-ILD patients and compare disease behavior to that in idiopathic pulmonary fibrosis (IPF) patients. Patients with normal forced vital capacity (FVC > 80% predicted; SSc-ILD: n = 31; IPF: n = 53) were followed for at least 1 year. Predictors of functional decline including clinical symptoms, comorbidities, lung-function values, high-resolution CT pattern, and treatment data were analyzed. SSc-ILD patents were significantly younger (59.8 ± 13.1) and more often women (93 %) than IPF patients. The median yearly FVC decline was similar in both groups (SSc-ILD = −67.5 and IPF = −65.3 mL/year). A total of 11 SSc-ILD patients met the PPF criteria for functional deterioration, presenting an FVC decline of −153.9 mL/year. Cough and pulmonary hypertension were significant prognostic factors for SSc-ILD functional progression. SSc-ILD patients with normal initial spirometry presenting with cough and PH are at higher risk for showing progressive functional decline.
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Wielosz, Ewa, and Maria Majdan. "CLINICAL AND SEROLOGICAL PARAMETERS OF PROGRESSION AND PROGNOSIS IN PATIENTS WITH SYSTEMIC SCLEROSIS – A STATE OF THE ART REVIEW." Wiadomości Lekarskie 73, no. 7 (2020): 1528–32. http://dx.doi.org/10.36740/wlek202007140.
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Systemic sclerosis (SSc) is a multi-organ connective tissue disease that leads to the dysfunction and the impaired morphology of blood vessels due to non-specific inflammation and progressive fibrosis. Due to the diversity of SSc and even though the factors predisposing to the severe course of SSc are known, it is not always possible to predict the disease progression and to determine the prognosis. Ideally, the group of patients with faster progression of organ lesions and a worse course of the disease should be identified and the early intensive treatment should be instituted. The aim of the article, is an attempt to identify the factors that worsen the prognosis in the course of SSc. The analysis of numerous studies demonstrated that patients with short-lasting SSc, with the presence of anti-RNA polymerase III antibodies, with a generalized type of SSc with quickly progressing skin lesions and males should be most strictly monitored. Moreover, vascular complications, tendon ruptures and fast capillaries loss observed in nailfold capillaroscopy are the factors deteriorating the prognosis in SSc. In conclusion, despite the known, the factors that worsen the prognosis, it is difficult to predict the course of systemic sclerosis. Due to its incompletely elucidated etiopathology as well as the diverse and unpredictable nature of the disease, reliable markers to determine the prognosis in SSc have not been found.
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Abdulle, Amaal, Harry van Goor, and Douwe Mulder. "Hydrogen Sulfide: A Therapeutic Option in Systemic Sclerosis." International Journal of Molecular Sciences 19, no. 12 (December 19, 2018): 4121. http://dx.doi.org/10.3390/ijms19124121.
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Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide, which is known to have several effects, including a strong antioxidant and vasodilator effect, could potentially play a prominent role in the initiation and progression of vasculopathy. A better understanding of the actions of gasotransmitters, like H2S, in the development of SSc-related vasculopathy, could help to create early interventions to attenuate the disease course. This paper will review the role of H2S in vascular (patho-)physiology and potential disturbances in SSc. Moreover, current data from experimental animal studies will be reviewed. Lastly, we will evaluate potential interventional strategies.
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Chakravarty, Eliza F. "Vascular Complications of Systemic Sclerosis during Pregnancy." International Journal of Rheumatology 2010 (2010): 1–5. http://dx.doi.org/10.1155/2010/287248.
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Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by progressive fibrosis of the skin and visceral tissues as well as a noninflammatory vasculopathy. Vascular disease in systemic sclerosis is a major cause of morbidity and mortality among nonpregnant patients with SSc and is even a bigger concern in the pregnant SSc patient, as the underlying vasculopathy may prevent the required hemodynamic changes necessary to support a growing pregnancy. Vascular manifestations including scleroderma renal crisis and pulmonary arterial hypertension should be considered relative contraindications against pregnancy due to the high associations of both maternal and fetal morbidity and mortality. In contrast, Raynaud's phenomenon may actually improve somewhat during pregnancy. Women with SSc who are considering a pregnancy or discover they are pregnant require evaluation for the presence and extent of underlying vasculopathy. In the absence of significant visceral vasculopathy, most women with SSc can expect to have reasonable pregnancy outcomes.
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Nagy, Alexandra, Erik Palmer, Lorinc Polivka, Noemi Eszes, Krisztina Vincze, Eniko Barczi, Aniko Bohacs, et al. "Treatment and Systemic Sclerosis Interstitial Lung Disease Outcome: The Overweight Paradox." Biomedicines 10, no. 2 (February 13, 2022): 434. http://dx.doi.org/10.3390/biomedicines10020434.
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(1) Background: Systemic sclerosis (SSc) is frequently associated with interstitial lung diseases (ILDs). The progressive form of SSc-ILD often limits patient survival. The aim of our study is to evaluate the clinical characteristics and predictors of lung function changes in SSc-ILD patients treated in a real-world setting. (2) Methods: All SSc-ILD cases previously confirmed by rheumatologists and a multidisciplinary ILD team between January 2017 and June 2019 were included (n = 54). The detailed medical history, clinical parameters and HRCT were analyzed. The longitudinal follow-up for pulmonary symptoms, functional parameters and treatment were performed for at least 2 years in no treatment, immunosuppression and biological treatment subgroups. (3) Results: In SSc-ILD patients (age 58.7 ± 13.3 years, 87.0% women), the main symptoms included dyspnea, cough, crackles and the Raynaud’s phenomenon. The functional decline was most prominent in untreated patients, and a normal body mass index (BMI < 25 kg/m2) was associated with a significant risk of deterioration. The majority of patients improved or were stable during follow-up. The progressive fibrosing-ILD criteria were met by 15 patients, the highest proportion being in the untreated subgroup. (4) Conclusions: SSc-ILD patients who are overweight are at a lower risk of the functional decline and progressive phenotype especially affecting untreated patients. The close monitoring of lung involvement and a regular BMI measurement are advised and early treatment interventions are encouraged.
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Meier, C., K. Freiburghaus, C. Bovet, J. Schniering, O. Distler, C. Nakas, and B. Maurer. "SAT0333 SERUM METABOLITES AS BIOMARKERS IN SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1112.3–1112. http://dx.doi.org/10.1136/annrheumdis-2020-eular.702.
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Background:In fibrotic diseases, metabolic processes are altered with a tendency towards an anabolic state, which is partially reflected in serum. Circulating biomarkers for interstitial lung disease (ILD), the leading cause of death in systemic sclerosis (SSc), are still sparse and not established in routine care.Objectives:To assess the potential of serum metabolites as biomarkers for the presence and progression of SSc-ILD.Methods:Age and sex matched serum samples of SSc patients from the Zurich cohort and of healthy controls (HC) were analyzed. Progressive SSc-ILD was defined as either a relative decrease in forced vital capacity (FVC) >10%, a decrease in FVC of 5-9% and a concomitant decrease of carbon dioxide diffusion capacity >15%, or an increase of the extent of lung fibrosis on computed tomography from <20% to ≥20% compared to the last visit (mean follow-up interval = 14 months (range = 9-26)). Sera of HC, non-ILD SSc and stable vs. progressive SSc-ILD patients (n = 12 per group; total n = 48) were screened for 110 metabolites by targeted liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Peak areas were analyzed with R 3.6. For univariate analysis, FDR-corrected one-way ANOVA was used. In multivariate group-wise partial least squares discriminant analysis (PLS-DA), variable importance in the projection (VIP) scores ≥2 were considered significant.Results:In total, 85 metabolites were detected. Univariate analysis of all groups were suggestive of changes for 1-methyladenosine, L-tryptophan, L-tyrosine, L-leucine and xanthosine (p = 0.077, 0.028, 0.077, 0.028 and 0.032, respectively). In PLS-DA, HCs and SSc patients differed in their levels of L-tyrosine and L-tryptophan, while levels of L-threonine, 3-aminoisobutyric acid, adenosine monophosphate and xanthosine were changed when comparing non-ILD and SSc-ILD patients. Receiver operating curve (ROC) analysis of significant metabolites from uni- and multivariate testing resulted in separation of SSc patients from HCs by L-tyrosine (area under the curve (AUC) = 0.81, 95% confidence interval (CI): 0.67-0.96), L-tryptophan (AUC = 0.86, CI: 0.75-0.97) and 1-methyladenosine (AUC = 0.82, CI: 0.71-0.94). Progressive SSc-ILD patients were separated from stable patients by their levels of L-isoleucine, L-leucine, adenosine monophosphate and xanthosine (AUC = 0.83, 0.85, 0.79 and 0.77; CI: 0.66-1.00, 0.70-1.00, 0.60-0.97 and 0.55-0.99, respectively). Validation of increased values of the branched-chain amino acids L-leucine and L-isoleucine in progressive SSc-ILD vs. stable ILD using an enzymatic assay resulted in similar results as LC-MS/MS analysis, with higher values detected in progressive vs. stable patients (mean = 286.5 and 235.5 nM, respectively; p = 0.005). In ROC analysis (AUC = 0.81, CI: 0.62-1.00), a cut-off value of 250.3 nM separated stable from progressive patients with a sensitivity of 72.7% and a specificity of 83.3%.Conclusion:This study in SSc(-ILD) patients suggested alterations in serum metabolite levels corresponding with their current state of disease, indicating the potential use of serum metabolites as discriminating biomarkers upon further confirmation in larger multicenter studies.Disclosure of Interests:Chantal Meier: None declared, Katrin Freiburghaus: None declared, Cédric Bovet: None declared, Janine Schniering: None declared, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Christos Nakas: None declared, Britta Maurer Grant/research support from: AbbVie, Protagen, Novartis, congress support from Pfizer, Roche, Actelion, and MSD, Speakers bureau: Novartis
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Aversa, Antonio, Roberto Bruzziches, Davide Francomano, Edoardo Rosato, Felice Salsano, and Giovanni Spera. "Penile involvement in Systemic Sclerosis: New Diagnostic and Therapeutic Aspects." International Journal of Rheumatology 2010 (2010): 1–5. http://dx.doi.org/10.1155/2010/708067.
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Systemic Sclerosis (SSc) is a connective tissue disorder featuring vascular alterations and an immunological activation leading to a progressive and widespread fibrosis of several organs such as the skin, lung, gastrointestinal tract, heart, and kidney. Men with SSc are at increased risk of developing erectile dysfunction (ED) because of the evolution of early microvascular tissutal damage into corporeal fibrosis. The entity of penile vascular damage in SSc patients has been demonstrated by using Duplex ultrasonography and functional infra-red imaging and it is now clear that this is a true clinical entity invariably occurring irrespective of age and disease duration and constituting the ‘‘sclerodermic penis’’. Once-daily phosphodiesterase type-5 (PDE5) inhibitors improve both sexual function and vascular measures of cavernous arteries by improving surrogate markers of endothelial dysfunction, that is, plasma endothelin-1 and adrenomedullin levels, which may play a potential role in preventing progression of penile fibrosis and ED. Also, the beneficial effect of long-term PDE5i add-on therapy to SSc therapy in the treatment of Raynaud's phenomenon is described.
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Ortiz Sanjuan, F. M., C. Pávez Perales, E. Vicens Bernabeu, C. Alcañiz Escandell, I. Cánovas Olmos, I. Chalmeta Verdejo, M. De la Rubia Navarro, et al. "AB0597 PULMONARY FUNCTION IN PATIENTS DIAGNOSED OF EARLY SYSTEMIC SCLEROSIS: A NEW TOOL FOR SYSTEMIC SCLEROSIS CLASIFFICATION?" Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1595.1–1595. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4423.
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Background:Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) and is often progressive and has a poor prognosis. A restrictive ventilatory defect could suggest ILD either alone or in combination with pulmonary arterial hypertension.Nowadays, Early-SSc is well defined as preliminary stage of SSc. Patients who meet criteria for Early-SSc could benefit from an early diagnosis of pulmonary involvement.Objectives:Our aim was to assess the pulmonary function in patients diagnosed of Early SSc.Methods:Retrospective observational study of a wide and unselected series of patients diagnosed as Early-SSc from a single university hospital from 2012 to 2019. Patients were classified as Early-SSc following Le Roy criteria. Despite this, patients already did not meet 2013 ACR/EULAR classification criteria for SSc. We reviewed pulmonary function through conventional spirometry and diffusing capacity of lung for carbon monoxide (DLCO).Results:We included 56 patients with a mean age of 52.3±12.1 years (96.4% women; 3.6% men).At the diagnosis of Early-SSc, no one of our patients evidenced a restrictive ventilatory pattern. DLCO was below normal limits in 18 patients (32.1%). Small airway obstruction expressed according decreased maximal (mid-) expiratory flow (MMEF) 25-75 was present in 24 patients (42.8%).After a mean follow-up period of 38.3±2.4 months, 29 (51.8%) patients fulfilled 2013 ACR/EULAR criteria. The average time between diagnosis of Early-SSc and achieve SSc classification was 24.4±1.8 months. The remaining 27 patients continued classified as Early-SSc.An analysis of the subgroup of patients which progressed to SSc showed that DLCO was decreased in 15 of those 29 patients (51.7%) and 18 of 29 patients (62.1%) presented decreased MMEF 25-75. Comparing with the subgroup of patients which not progressed to SSc were significant differences (Decreased DLCO: 51.7% vs 11.1%; p=0.02 and decreased MMEF 25-75: 42.8% vs 22.2%; p=0.05).The analysis of pulmonary function of the subgroup of patients continued classified as Early-SSc after follow-up period did not show significative changes after follow-up.Conclusion:In our study, a third of the patients classified as Early-SSc presented at diagnosis abnormal values of DLCO and/or signs of small airway obstruction without the presence of a restrictive ventilatory pattern. Moreover, this pulmonary disfunction was significantly more frequent in patients who progressed to definitive SSc. Patients which remains classified as Early-SSc did not experience significative changes.Our results support the concept that pulmonary function was impaired in Early-SSc and that I should probably be considered for future Early-SSc classification criteria.Disclosure of Interests:None declared
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Veltishchev, D., O. B. Kovalevskaya, O. F. Seravina, M. N. Starovoitova, and T. A. Lisitsyna. "Stress factors and mental disorders in systemic sclerosis." European Psychiatry 33, S1 (March 2016): S398. http://dx.doi.org/10.1016/j.eurpsy.2016.01.1432.
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IntroductionSystemic sclerosis (SSc) is a chronic, multisystem disease of unknown etiology characterized by autoimmune inflammation, abnormalities in small blood vessels, and progressive fibrosis of the skin and visceral organs. Mental disorders (MD), especially depression, occur quite often with SSc. The influence of childhood experience, relations’ traumatic events with SSc and MD, and MD's clinical specific have not investigated carefully still. The investigation has been realized in accordance with the interdisciplinary program “stress factors and mental disorders in auto-immune inflammatory rheumatic diseases”.MethodsSixty SSc patients (4 male and 56 female mean age 49.9 ± 13.5) were included. ICD-10 criteria were used for MD semi-structured interview. The stress factors were analyzed with the specially elaborated scale. The cognitive disorders and their severity were diagnosed by neuropsychology tests.ResultsEarly traumatic childhood experiences (parental deprivation mainly) observed in 90% cases. The significant stress factors were preceded SSc symptoms in 80% and MD in 70% cases. Most patients self-reported connection between stressful life events and exacerbation of SSc. MD preceded SSc in 76.6% cases. MD were diagnosed in 48 (80%) SSc patients: depressive episode (mild, moderate) − 26.6%, recurrent depressive disorder − 16.6%, dysthymia – 23.3%, adjustment disorder − 6.6% and schizotypal disorder – 40%. The mild or moderate cognitive impairments were diagnosed in all MD cases.ConclusionIndividual history of stressful life events is important factor for the predisposition and provocation of the rheumatic disease and MD in SSc patients. Depressive, schizotypal and cognitive disorders are the common MD in SSc patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Rutka, Katarzyna, Adam Garkowski, Katarzyna Karaszewska, and Urszula Łebkowska. "Imaging in Diagnosis of Systemic Sclerosis." Journal of Clinical Medicine 10, no. 2 (January 12, 2021): 248. http://dx.doi.org/10.3390/jcm10020248.
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Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis in skin and internal organs, progressive vascular obliteration, and the production of autoantibodies. Diagnostic imaging is irreplaceable in both diagnosing and monitoring patients suffering from systemic sclerosis. In addition to routinely used methods, such as comparative X-ray of the hands or a contrast-enhanced examination of the upper gastrointestinal tract or chest, there is an array of less widespread examinations, with an emphasis on magnetic resonance imaging (MRI) and ultrasonography, not only in the evaluation of the musculoskeletal system. This article will review the various imaging modalities available for SSc imaging and assessment, focusing on their utility as tissue-specific diagnosis and treatment monitoring.
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Khanna, Dinesh, Angelika Jahreis, and Daniel E. Furst. "Tocilizumab Treatment of Patients with Systemic Sclerosis: Clinical Data." Journal of Scleroderma and Related Disorders 2, no. 2_suppl (January 2017): S29—S35. http://dx.doi.org/10.5301/jsrd.5000267.
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Systemic sclerosis (SSc) is an immune-mediated disease characterized by progressive, and often severe, inflammation and fibrosis of the skin and internal organs, such as the lungs, heart, kidneys, and gastrointestinal tract. There is an unmet medical need to treat patients with SSc given the high SSc-related mortality rate. Furthermore, disease-modifying therapies are lacking, and current treatment options focus on the management of individual organ-specific complications associated with the disease. Immunosuppressive therapies are the mainstay of pharmacologic management of major SSc-associated complications, such as skin and lung manifestations, but their overall effectiveness is limited and toxicity issues are common. Advances in understanding of the pathological processes involved in the immunologic and fibrotic mechanisms of SSc have led to clinical research focusing on targeted immunotherapies, in an effort to develop much needed disease-modifying treatment options. The interleukin-6 receptor-alpha antagonist tocilizumab has demonstrated promising efficacy in a phase 2 trial and is being investigated in a phase 3 trial. This article provides an overview of current pharmacologic treatment options for the management of SSc-related complications and discusses tocilizumab for the treatment of SSc in clinical trials.
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Dantas, Andréa Tavares, Michelly Cristiny Pereira, Moacyr Jesus Barreto de Melo Rego, Laurindo Ferreira da Rocha, Ivan da Rocha Pitta, Cláudia Diniz Lopes Marques, Angela Luzia Branco Pinto Duarte, and Maira Galdino da Rocha Pitta. "The Role of PPAR Gamma in Systemic Sclerosis." PPAR Research 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/124624.
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Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARγligands have been studiedin vitroandin vivoand some theories have emerged leading to new insights. Aberrant PPARγfunction seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-β/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARγas an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis.
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Zanatta, E., A. Martini, A. Cuberli, A. Biasiolo, P. Pontisso, and A. Doria. "AB0730 SCCA-IgM as a predictor of interstitial lung disease progression in systemic sclerosis." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1492.1–1492. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4592.
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BackgroundInterstitial Lung Disease (ILD) is the major determinant of morbidity and mortality in patients with systemic sclerosis (SSc). The course of lung involvement is extremely variable in SSc-ILD. Squamous Cell Carcinoma Antigen 1 (SCCA1) is a cysteine protease inhibitor that plays a crucial role in inflammation and fibrosis. It may be detected in serum in the form of an IgM-linked immune complex (SCCA-IgM), and we previously demonstrated that it is increased in patients with SSc-ILD (1).ObjectivesWe aimed to investigate the association between SCCA-IgM serum levels and ILD progression in a cohort of SSc patients.MethodsNinety-seven patients with SSc (2013 ACR/EULAR criteria) from the Rheumatology Unit of Padua University Hospital were consecutively enrolled in the study. Clinical, serological indices and organ involvement (pulmonary, cardiac, gastrointestinal and articular) were evaluated at the time of the SCCA-IgM assay. Pulmonary involvement was investigated by high-resolution CT (HRCT) and respiratory function tests (PFTs). Serum immune complex levels were measured by a validated ELISA assay (Hepa-IC, Xeptagen, Venice, Italy) and expressed in arbitrary units/mL (AU/mL). Follow-up period was defined as the time between baseline (i.e. SCCA-IgM blood sampling) and last PFTs and/or HRCT performed at least after 24 months. SSc-ILD progression was defined by HRCT and/or PFTs worsening. Progression on PFTs: FVC decline ≥ 10% from baseline or FVC ≥ 5-9% decline plus DLCO decline ≥ 15%; radiological progression: ILD worsening on HRCT evaluated by the same experienced thoracic radiologist.ResultsAmong the 97 SSc enrolled patients (mean age 55.4±12.5 yrs), 82 (84.5%) were female, 35 (36%) affected by diffuse cutaneous form of SSc (dcSSc) and 41 (42.3%) had ILD diagnosed by HRCT. The mean follow-up was 34.6 ± 1.8 months, with PFTs and/or HRCT data available in 86 patients, 37 (43%) of whom had ILD at baseline. Patients with ILD who progressed during follow-up were more frequently affected by dcSSc (p = 0.003), and tended to have lower values of total lung capacity (p=0,091). The median SCCA-IgM values were significantly higher in patients with progressive ILD vs. those with stable ILD: 301 (57-526) vs. 45 (34-236), respectively (p = 0.017), Figure 1. At Cox regression multivariate analysis, SCCA-IgM serum levels was the only variable independently associated with ILD progression [HR 1,003 95% CI 1,000-1,006, p=0.02].ConclusionIn conclusion, our preliminary data support SCCA-IgM as a potential candidate biomarker for progressive ILD in patients with scleroderma.References[1]Zanatta E et al, Joint Bone Spine 2020;87:331-335.Disclosure of InterestsNone declared
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Vonk, Madelon C., Ulrich A. Walker, Elizabeth R. Volkmann, Michael Kreuter, Sindhu R. Johnson, and Yannick Allanore. "Natural variability in the disease course of SSc-ILD: implications for treatment." European Respiratory Review 30, no. 159 (March 24, 2021): 200340. http://dx.doi.org/10.1183/16000617.0340-2020.
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Interstitial lung disease (ILD) affects approximately 50% of patients with systemic sclerosis (SSc) and is the leading cause of death in SSc. Our objective was to gain insight into the progression of SSc-associated ILD (SSc-ILD). Using data from longitudinal clinical trials and observational studies, we assessed definitions and patterns of progression, risk factors for progression, and implications for treatment.SSc-ILD progression was commonly defined as exceeding specific thresholds of lung function worsening and/or increasing radiographic involvement. One definition used in several studies is decline in forced vital capacity (FVC) of ≥10%, or ≥5–10% plus a decline in diffusing capacity of the lung for carbon monoxide ≥15%. Based on these criteria, 20–30% of patients in observational cohorts develop progressive ILD, starting early in the disease course and progressing at a highly variable rate.Risk factors such as age, FVC, extent of fibrosis and presence of anti-topoisomerase I antibodies can help predict progression of SSc-ILD, though composite risk scores may offer greater predictive power. Whilst the variability of the disease course in SSc-ILD makes risk stratification of patients challenging, the decision to initiate, change or stop treatment should be based on a combination of the current disease state and the speed of progression.
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Shin, Joseph Yusup, James Daniel Beckett, Rustam Bagirzadeh, Tyler J. Creamer, Ami A. Shah, Zsuzsanna McMahan, Julie J. Paik, et al. "Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis." Science Translational Medicine 11, no. 497 (June 19, 2019): eaaw0790. http://dx.doi.org/10.1126/scitranslmed.aaw0790.
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In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor–β2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFβ2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.
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Stochmal, Anna, Joanna Czuwara, Michał Zaremba, and Lidia Rudnicka. "Altered serum level of metabolic and endothelial factors in patients with systemic sclerosis." Archives of Dermatological Research 312, no. 6 (October 30, 2019): 453–58. http://dx.doi.org/10.1007/s00403-019-01993-y.
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Abstract Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by progressive fibrosis, vascular impairment and immune abnormalities. In recent years, adipokines (mediators synthetized by adipose tissue) have been indicated as a possible missing link in the pathogenesis of SSc. The aim of this study was to investigate the serum concentration of metabolic adipose tissue factors: adiponectin, resistin, leptin and endothelial proteins: endothelin-1, fractalkine and galectin-3 in patients with systemic sclerosis. The study included 100 patients with confirmed SSc diagnosis and 20 healthy individuals. The concentration of respective proteins was determined by enzyme-linked immunosorbent assay. The following markers showed statistically significant increased mean concentrations in patients with SSc in comparison to healthy control: resistin (13.41 vs 8.54 ng/mL; P = 0.0012), endothelin-1 (1.99 vs 1.31 pg/mL; P = 0.0072) and fractalkine (2.93 vs 1.68 ng/mL; P = 0.0007). Elevated serum levels of galectin-3 (4.54 vs 3.26 ng/mL; P = 0.0672) and leptin (19,542 vs 14,210 pg/mL; P = 0.1817) were observed. Decreased concentration of adiponectin was found in patients with SSc (5150 vs 8847 pg/mL; P = 0.0001). Fractalkine and galectin-3 levels were significantly higher in diffuse cutaneous SSc than limited cutaneous SSc subset (3.93 ng/mL vs 2.58 ng/mL, P = 0.0018; 6.86 ng/mL vs 3.78 ng/mL, P = 0.0008, respectively) and correlated positively with modified Rodnan Skin Score in total SSc patients (r = 0.376, P = 0.0009; r = 0.236, P = 0.018, respectively). In conclusion, an increased serum level of resistin associated with increased endothelin-1 and fractalkine level and decreased adiponectin level may indicate a significant role of the adipose tissue in the development and progression of vascular abnormalities in patients with systemic sclerosis. Fractalkine and galectin-3 may participate in promoting and exacerbating the fibrotic process in SSc.
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Lota, Harpreet K., and Elisabetta A. Renzoni. "Circulating Biomarkers of Interstitial Lung Disease in Systemic Sclerosis." International Journal of Rheumatology 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/121439.
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Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). Although a large proportion of SSc patients have only limited interstitial involvement with an indolent course, in a significant minority ILD is progressive, requiring prompt treatment and careful monitoring. One of the main challenges for the clinician treating this highly variable disease is the early identification of patients at risk of progressive ILD, while avoiding potentially toxic treatments in those whose disease is inherently stable. Easily available and repeatable biomarkers that allow estimation of the risk of ILD progression and early response to treatment are highly desirable. In this paper, we review the evidence for circulating biomarkers with potential roles in diagnosis, monitoring of disease activity, or determining prognosis. Peripheral blood biomarkers offer the advantages of being readily obtained, non-invasive, and serially monitored. Several possible candidates have emerged from studies performed so far, including SP-D, KL-6, and CCL18. Presently however, there are few prospective studies evaluating the predictive ability of prospective biomarkers after adjustment for disease severity. Future carefully designed, prospective studies of well characterised patients with ILD, with optimal definition of disease severity and outcome measures are needed.
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Benfaremo, Devis, Silvia Svegliati, Chiara Paolini, Silvia Agarbati, and Gianluca Moroncini. "Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches." Biomedicines 10, no. 1 (January 12, 2022): 163. http://dx.doi.org/10.3390/biomedicines10010163.
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Systemic sclerosis (SSc) is a systemic, immune-mediated chronic disorder characterized by small vessel alterations and progressive fibrosis of the skin and internal organs. The combination of a predisposing genetic background and triggering factors that causes a persistent activation of immune system at microvascular and tissue level is thought to be the pathogenetic driver of SSc. Endothelial alterations with subsequent myofibroblast activation, excessive extracellular matrix (ECM) deposition, and unrestrained tissue fibrosis are the pathogenetic steps responsible for the clinical manifestations of this disease, which can be highly heterogeneous according to the different entity of each pathogenic step in individual subjects. Although substantial progress has been made in the management of SSc in recent years, disease-modifying therapies are still lacking. Several molecular pathways involved in SSc pathogenesis are currently under evaluation as possible therapeutic targets in clinical trials. These include drugs targeting fibrotic and metabolic pathways (e.g., TGF-β, autotaxin/LPA, melanocortin, and mTOR), as well as molecules and cells involved in the persistent activation of the immune system (e.g., IL4/IL13, IL23, JAK/STAT, B cells, and plasma cells). In this review, we provide an overview of the most promising therapeutic targets that could improve the future clinical management of SSc.
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Kotani, Takuya, Tohru Takeuchi, Shigeki Makino, and Toshiaki Hanafusa. "Successful Treatment of Long-Term Severe Progressive Interstitial Pneumonia with Low-Dose Corticosteroid and Azathioprine in a Patient with Diffuse Systemic Sclerosis." Case Reports in Rheumatology 2012 (2012): 1–4. http://dx.doi.org/10.1155/2012/143927.
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For progressive interstitial pneumonia (progressive IP) that accompanies diffuse systemic sclerosis (diffuse SSc), no treatment guidelines have yet been established, and it is a complication with a poor prognosis. We herein report a case in which combination therapy of a low-dose corticosteroid and low-dose azathioprine was performed for progressive SSc-IP in a 64-year-old female whose respiratory function was severely damaged for a long period of time and for whom improvement was achieved. The beneficial effect has continued for 3 years with no side effects being observed during the course.
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Tomcik, Michal. "Frontiers of Targeted Therapy and Predictors of Treatment Response in Systemic Sclerosis." Biomedicines 10, no. 12 (November 28, 2022): 3053. http://dx.doi.org/10.3390/biomedicines10123053.
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Systemic sclerosis (scleroderma, SSc) is one of the most challenging rheumatic diseases, characterized by vasculopathy, dysregulation of the immune response, and progressive tissue fibrosis affecting the skin, lungs, heart, digestive tract, and kidneys [...]
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Ciurea, Andreea, Nicolae Voicu Rednic, Andrada Soancă, Iulia Cristina Micu, Alina Stanomir, Diana Oneț, Petra Șurlin, et al. "Current Perspectives on Periodontitis in Systemic Sclerosis: Associative Relationships, Pathogenic Links, and Best Practices." Diagnostics 13, no. 5 (February 22, 2023): 841. http://dx.doi.org/10.3390/diagnostics13050841.
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Systemic sclerosis is a chronic, autoimmune, multisystemic disease characterized by aberrant extracellular matrix protein deposition and extreme progressive microvasculopathy. These processes lead to damage within the skin, lungs, or gastrointestinal tract, but also to facial changes with physiognomic and functional alterations, and dental and periodontal lesions. Orofacial manifestations are common in SSc but are frequently overshadowed by systemic complications. In clinical practice, oral manifestations of SSc are suboptimally addressed, while their management is not included in the general treatment recommendations. Periodontitis is associated with autoimmune-mediated systemic diseases, including systemic sclerosis. In periodontitis, the microbial subgingival biofilm induces host-mediated inflammation with subsequent tissue damage, periodontal attachment, and bone loss. When these diseases coexist, patients experience additive damage, increasing malnutrition, and morbidity. The present review discusses the links between SSc and periodontitis, and provides a clinical guide for preventive and therapeutical approaches in the management of these patients.
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Kowal-Bielecka, Otylia, Jaap Fransen, Jerome Avouac, Mike Becker, Agnieszka Kulak, Yannick Allanore, Oliver Distler, et al. "Update of EULAR recommendations for the treatment of systemic sclerosis." Annals of the Rheumatic Diseases 76, no. 8 (November 9, 2016): 1327–39. http://dx.doi.org/10.1136/annrheumdis-2016-209909.
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The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
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INGRAHAM, KRISTIN M., MARIE S. O’BRIEN, MAX SHENIN, CHRIS T. DERK, and VIRGINIA D. STEEN. "Gastric Antral Vascular Ectasia in Systemic Sclerosis: Demographics and Disease Predictors." Journal of Rheumatology 37, no. 3 (January 15, 2010): 603–7. http://dx.doi.org/10.3899/jrheum.090600.
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Objectives.To evaluate patients with systemic sclerosis (SSc) who have gastric antral vascular ectasia (GAVE), to further characterize this disease association, and to identify factors that may predict which patients with SSc are at greatest risk for the development of GAVE.Methods.Patients with a diagnosis of both SSc and GAVE were identified from the Division of Rheumatology at Georgetown University and Thomas Jefferson University. A chart review was conducted to obtain the demographic data.Results.Twenty-eight patients were included in this analysis, including 17 with diffuse cutaneous (dcSSc) and 11 with limited cutaneous SSc (lcSSc). The mean disease duration at diagnosis with GAVE was 21.5 months for dcSSc and 84.3 months for lcSSc (p = 0.025). Seventy-six percent of patients with dcSSc developed GAVE within 18 months of first scleroderma symptom onset. Over half of patients with early GAVE also had rapidly progressive cutaneous disease. Only 4% had antitopoisomerase I antibody. Although only 1 patient was tested and had positive RNA polymerase (RNAP) III, RNAP III may be overrepresented in this GAVE population. Mean hematocrit levels were 23.8% in dcSSc and 29% in lcSSc.Conclusion.dcSSc is associated with earlier development of GAVE, as well as more severe anemia requiring more therapeutic interventions. Rapid progression of cutaneous disease may suggest earlier development of GAVE. Absence of antitopoisomerase I antibodies and presence of antibodies to RNAP III/speckled antinuclear antibody pattern may be useful to identify the subset of patients with SSc with increased risk for GAVE.
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Tyler, Anna, J. Matthew Mahoney, and Gregory W. Carter. "Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis." G3: Genes|Genomes|Genetics 10, no. 1 (November 6, 2019): 151–63. http://dx.doi.org/10.1534/g3.119.400775.
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Scleroderma, or systemic sclerosis (SSc), is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. The most common cause of death in people with SSc is lung disease, but the pathogenesis of lung disease in SSc is insufficiently understood to devise specific treatment strategies. Developing targeted treatments requires not only the identification of molecular processes involved in SSc-associated lung disease, but also understanding of how these processes interact to drive pathology. One potentially powerful approach is to identify alleles that interact genetically to influence lung outcomes in patients with SSc. Analysis of interactions, rather than individual allele effects, has the potential to delineate molecular interactions that are important in SSc-related lung pathology. However, detecting genetic interactions, or epistasis, in human cohorts is challenging. Large numbers of variants with low minor allele frequencies, paired with heterogeneous disease presentation, reduce power to detect epistasis. Here we present an analysis that increases power to detect epistasis in human genome-wide association studies (GWAS). We tested for genetic interactions influencing lung function and autoantibody status in a cohort of 416 SSc patients. Using Matrix Epistasis to filter SNPs followed by the Combined Analysis of Pleiotropy and Epistasis (CAPE), we identified a network of interacting alleles influencing lung function in patients with SSc. In particular, we identified a three-gene network comprising WNT5A, RBMS3, and MSI2, which in combination influenced multiple pulmonary pathology measures. The associations of these genes with lung outcomes in SSc are novel and high-confidence. Furthermore, gene coexpression analysis suggested that the interactions we identified are tissue-specific, thus differentiating SSc-related pathogenic processes in lung from those in skin.
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Feng, Daniel, and Casimiro Gerarduzzi. "Emerging Roles of Matricellular Proteins in Systemic Sclerosis." International Journal of Molecular Sciences 21, no. 13 (July 6, 2020): 4776. http://dx.doi.org/10.3390/ijms21134776.
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Systemic sclerosis is a rare chronic heterogenous disease that involves inflammation and vasculopathy, and converges in end-stage development of multisystem tissue fibrosis. The loss of tight spatial distribution and temporal expression of proteins in the extracellular matrix (ECM) leads to progressive organ stiffening, which is a hallmark of fibrotic disease. A group of nonstructural matrix proteins, known as matricellular proteins (MCPs) are implicated in dysregulated processes that drive fibrosis such as ECM remodeling and various cellular behaviors. Accordingly, MCPs have been described in the context of fibrosis in sclerosis (SSc) as predictive disease biomarkers and regulators of ECM synthesis, with promising therapeutic potential. In this present review, an informative summary of major MCPs is presented highlighting their clear correlations to SSc- fibrosis.
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Cutolo, Maurizio, Barbara Ruaro, Carmen Pizzorni, Francesca Ravera, Vanessa Smith, Giuseppe Zampogna, Sabrina Paolino, Bruno Seriolo, Marco Cimmino, and Alberto Sulli. "Longterm Treatment with Endothelin Receptor Antagonist Bosentan and Iloprost Improves Fingertip Blood Perfusion in Systemic Sclerosis." Journal of Rheumatology 41, no. 5 (April 1, 2014): 881–86. http://dx.doi.org/10.3899/jrheum.131284.
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Objective.To evaluate the longterm effects of endothelin-1 (ET-1) antagonism on peripheral blood perfusion (PBP) in patients with systemic sclerosis (SSc).Methods.Twenty-six patients with SSc already receiving cyclic intravenous iloprost (ILO) for severe Raynaud phenomenon were enrolled. Thirteen patients continued the treatment for a further 3 years (ILO group) and 13 patients, because of the appearance of digital ulcers, received in addition bosentan (BOS; 125 mg twice/day) for 3 years (ILO + BOS group). Both PBP at fingertips and nailfold microangiopathy were evaluated yearly by laser Doppler flowmetry and nailfold videocapillaroscopy, respectively.Results.A progressive significant increase of PBP was observed in the ILO + BOS group during the 3 followup years (p = 0.0007, p = 0.0002, p = 0.01, respectively). In contrast, an insignificant progressive decrease of PBP was observed in the ILO group. Difference of perfusion between the PBP evaluations at basal temperature and at 36°C (to test capillary dilation capacity), was found progressively decreased during the 3-year followup only in the ILO group (p = 0.05, p = 0.26, p = 0.09, respectively). A progressive increase of nailfold capillary number was observed only in the ILO + BOS group after 2 and 3 years of followup (p = 0.05).Conclusion.Longterm treatment of SSc patients with ET-1 antagonism, in combination with ILO, seems to increase fingertip blood perfusion, as well as both capillary dilation capacity and number.
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Smith, Vanessa, Amber Vanhaecke, Els Vandecasteele, Miguel Guerra, Sabrina Paolino, Karin Melsens, and Maurizio Cutolo. "Nailfold Videocapillaroscopy in Systemic Sclerosis–related Pulmonary Arterial Hypertension: A Systematic Literature Review." Journal of Rheumatology 47, no. 6 (August 15, 2019): 888–95. http://dx.doi.org/10.3899/jrheum.190296.
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Objective.Pulmonary arterial hypertension (PAH) is one of the leading causes of death in systemic sclerosis (SSc). Current screening algorithms are hampered by low positive predictive values. Outcome measures that could add to performance characteristics would be welcome. We aim to evaluate the role of nailfold videocapillaroscopy (NVC) using standardized definitions, in SSc-related PAH (SSc-PAH).Methods.A systematic review to identify original research papers documenting an association between NVC and right heart catheterization-defined SSc-PAH was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Subsequently, NVC characteristics were subdivided into quantitative (capillary density, dimension, morphology, and hemorrhages), semiquantitative, and qualitative assessment (NVC pattern), according to the definitions of the European League Against Rheumatism Study Group on Microcirculation in Rheumatic Diseases.Results.The systematic search identified 316 unique search results, of which 5 were included in the final qualitative analysis. The occurrence of incident SSc-PAH unequivocally associated in 2 longitudinal studies with progressive capillary loss (p = 0.04 and p = 0.033) and the progression to a severe (active/late) NVC pattern (p = 0.05/0.01 and HR = 5.12, 95% CI 1.23–21.27). In 3 cross-sectional studies, SSc-PAH was found to be unequivocally inversely associated with capillary density (p = 0.001 and p < 0.05) and associated with the presence of a severe NVC pattern (p = 0.03 and p < 0.05).Conclusion.This is the first systematic literature review investigating the role of NVC in SSc-PAH using standardized description, to our knowledge. Unequivocal associations were found between (incident) SSc-PAH and capillary density and NVC pattern. Integration of NVC into current screening algorithms to boost their performance may be a future step.
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Frade, Stephanie, Melainie Cameron, Sean O'Neill, and David Greene. "Rheumatology Practitioners' View of Exercise in Adults With Systemic Sclerosis or Systemic Lupus Erythematosus." Journal of Clinical Exercise Physiology 10, no. 4 (December 1, 2021): 134–41. http://dx.doi.org/10.31189/2165-6193-10.4.134.
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ABSTRACT Background Exercise is part of the general recommendations for care of people with most arthropathies or connective tissue diseases, but it does not feature specifically in the clinical guidelines for management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) by rheumatology practitioners. In this study, we sought to explore rheumatologists' (RHs') and rheumatology nurses' (RNs') perspectives and use of exercise interventions for adults with SLE or SSc. Methods Semistructured interviews were conducted with Australian RHs and RNs online using Zoom (video conferencing software). Interviews were transcribed verbatim, then coded and analyzed using NVivo for content analysis of themes. Results Seventeen participants completed the interviews (RHs n = 12, RNs n = 5). Five themes were identified: rheumatology practitioners perceive that (1) exercise is beneficial for adults with SLE or SSc, especially in managing fatigue, pain, and wellbeing; (2) exercise presents some general, structural, and disease-related barriers for adults with SLE or SSc; (3) rheumatology practitioners are confident in providing general exercise advice but lack time and confidence in prescribing exercise; (4) rheumatology practitioners' concerns about exercise are limited to those with heart and lung disease, inflamed joints, ulcerated fingertips, and severe contractures; and (5) to facilitate safe and attainable exercise, rheumatology practitioners recommend long-term, supervised, gradual, and affordable exercise options. There were no clear differences identified between the views of RNs and RHs. Conclusion Rheumatology practitioners require information and options for long-term and affordable exercise for adults with SLE or SSc that are supervised, individualized, and focus on a gradual progressive approach.
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Artene, D. M., and C. Ancuta. "AB0740 INTERSTITIAL LUNG DISEASE SYSTEMIC SCLEROSIS: AN EAST-EUROPEAN EUSTAR CENTER EXPERIENCE." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1496.1–1496. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4923.
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BackgroundSystemic sclerosis (SSc) is a complex autoimmune connective tissue disorder defined by multifaceted visceral involvement. Still considered the leading cause of morbidity and mortality, interstitial lung disease (ILD) remains one the most common complication of SSc that involves vascular, immunological, and fibrotic processes.ObjectivesWe aimed to assess the relationship between demographic, clinical features and risk factors for the development of lung fibrosis in patients with SSc as well as the specific management.MethodsWe performed a retrospective observational study in a series of 45 patients with SSc and ILD followed-up in East-European EUSTAR center (Department of Rheumatology 2, Clinical Rehabilitation Hospital, Iasi, Romania). We analyzed the frequency of known risk factors associated with progressive interstitial lung disease such as diffuse cutaneous SSc, male sex, presence of anti-topoisomerase I and absence of anti-centromere antibodies as well as risk factors for mortality in SSc-ILD including older age, male sex, extent of disease on high-resolution computed tomography (HRCT), lower pulmonary function tests (PFTs), lower diffusing capacity of the lung for carbon monoxide (DLCO).ResultsThe study included 35 females, 10 males, with the mean age of 55.5 years. The diagnosis of interstitial lung disease was based on HRCT findings (bibasilar ground glass opacities, crazy-paving pattern, nodules, honeycombing and traction bronchiectasis, mosaic pattern, air trapping, pulmonary artery and lymph node enlargement). Symptoms of the ILD (dry cough, different stages of dyspnea, VELCRO crackles) were reported in 14 cases (25.45%). Furthermore, 25 patients had a significant decline in PFTs and DLCO, being associated with extensive pulmonary fibrosis on HRCT (p<0.05%). Almost all patients with SSc-ILD had diffuse cutaneous involvement and anti-Scl-70 antibodies positivity. Despite identifying a higher percentage of women with ILD (35/45, 63.63%), the extent and progression of pulmonary fibrosis was more significant in males. The treatment for SSc-ILD with ongoing evidence of disease progression based on PFT decline or radiographic deterioration has focused on immunosuppressive therapies, particularly cyclophosphamide and only in selected cases on antifibrotic agents.ConclusionIt is important to identify the risk factors for developing ILD, in order to complete the diagnostic and staging parameters early so that the treatment can be initiated as soon as possible in progressive pattern. Our data showed that the extent of pulmonary fibrosis in HRCT was associated with low values of PFTs and DLCO, and men had a more severe prognostic than women. ILD-SSc was more frequent in patients with diffuse cutaneous involvement than limited cutaneous subtype, and in those with anti-Scl-70 positivity.References[1]Perelas A, Silver RM, Arrossi A et al, Systemic-sclerosis associated interstitial lung disease, Lancet Respir Med 2020, https://doi.org/10.1016/S2213-2600(19)30480-1[2]N Tanaka, Y Kunihiro M Kubo et al, HRCT findings of collagen vascular disease-related interstitial pneumonia (CVD-IP): a comparative study among individual underlying diseases, Clinical Radiology 73 (2018) 833.e1-833.e10, https://doi.org/10.1016/j.crad.2018.04.017[3]Dinesh Khanna, Donald P. Tashkin, Etiology, Risk Factors, and Biomarkers in Systemic Sclerosis with Interstitial Lung Disease, Am J Respir Crit Care Med. 2020 Mar 15; 201(6): 650–660. DOI: https://dx.doi.org/10.1164%2Frccm.201903-0563CI[4]Vincent Cottin, Kevin K. Brown, Interstitial lung disease associated with systemic sclerosis (SSc-ILD), Cottin and Brown Respiratory Research (2019) 20:13 https://doi.org/10.1186/s12931-019-0980-7[5]Padmini Khedoe, Emiel Marges, Pieter Hiemstra, Interstitial Lung Disease in Patients With Systemic Sclerosis: Toward Personalized-Medicine-Based Prediction and Drug Screening Models of Systemic Sclerosis-Related Interstitial Lung Disease (SSc-ILD).Front Immunol. 2020 Sep 4;11:1990, doi: 10.3389/fimmu.2020.01990.Disclosure of InterestsNone declared
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Su, Li, Na Zhang, Hui Wang, Zhenwen Yang, and Wei Wei. "Relapsing polychondritis presenting 2 years after systemic sclerosis with pulmonary arterial hypertension." Rheumatology and Immunology Research 2, no. 2 (June 1, 2021): 121–23. http://dx.doi.org/10.2478/rir-2021-0016.
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Abstract Relapsing polychondritis (RPC) is a systemic immune-mediated disease characterized by recurrent and progressive inflammation of cartilaginous tissues. 64% of RPC patients concurrent with other autoimmune disorders, there are very few reports about the concomitant RPC patients with systemic sclerosis (SSc). Herein we report a case of RPC in a 50-year-old female following SSc with pulmonary arterial hypertension (PAH) 2 years ago. She was treated with corticosteroids, immunosuppressive drugs, oral endothelin-A receptor antagonist and phosphodiesterase type 5 inhibitors. Her ocular and auricular symptoms disappeared quickly. The hemodynamic parameters were also significantly improved after treatment. To our knowledge, this is the first RPC complicated with SSc-PAH reported.
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Usategui, Alicia, Gabriel Criado, Elena Izquierdo, Manuel J. Del Rey, Patricia E. Carreira, Pablo Ortiz, Warren J. Leonard, and José L. Pablos. "A profibrotic role for thymic stromal lymphopoietin in systemic sclerosis." Annals of the Rheumatic Diseases 72, no. 12 (February 14, 2013): 2018–23. http://dx.doi.org/10.1136/annrheumdis-2012-202279.
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ObjetiveSystemic sclerosis (SSc) is an autoimmune disease characterised by progressive fibrosis. Although SSc shares pathogenetic features with other autoimmune diseases, the participation of profibrotic Th2 cytokines is unique to SSc, but the mechanisms of Th2 skewing are unknown. We have analysed the expression and function of thymic stromal lymphopoietin (TSLP), a central regulator of Th2-mediated allergic inflammation, in human SSc, primary lung fibrosis and in a mouse model of scleroderma.MethodsTSLP expression was analysed by immunohistochemistry in human SSc skin, primary lung fibrosis and mouse bleomycin-induced skin fibrosis, and by quantitative RT-PCR in mouse skin and cultured fibroblasts. The regulation of TSLP expression by specific toll-like receptors (TLR)-2, -3 and -4 agonists was analysed in human dermal fibroblast cultures. The role of TSLP in skin fibrosis and local cytokine expression was analysed in TSLP receptor (TSLPR)-deficient mice.ResultsTSLP was overexpressed by epithelial cells, mast cells and fibroblasts in human SSc skin and lung fibrosis, and in the bleomycin model of scleroderma. In cultured human and mouse skin fibroblasts, TSLP expression was inducible by activation of TLR, particularly TLR3. In TSLPR-deficient mice, bleomycin-induced fibrosis was significantly reduced in parallel with significantly reduced local expression of IL-13.ConclusionsThese data provide the first evidence of TSLP overexpression in SSc and other non-allergic fibrotic conditions, and demonstrate a profibrotic role that is potentially meditated by specific changes in the local cytokine milieu. Thus, modulating TSLP may have antifibrotic therapeutic implications.
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Sulli, A., S. Paolino, C. Pizzorni, G. Ferrari, G. Pacini, G. Pesce, L. Carmisciano, V. Smith, and M. Cutolo. "Progression of nailfold capillaroscopic patterns and correlation with organ involvement in systemic sclerosis: a 12 year study." Rheumatology 59, no. 5 (September 17, 2019): 1051–58. http://dx.doi.org/10.1093/rheumatology/kez374.
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Abstract Objective The aim of this observational study was to investigate the evolution of scleroderma microangiopathy throughout different nailfold videocapillaroscopy (NVC) patterns (‘early’, ‘active’, ‘late’) as well as the prevalence of organ involvement in SSc patients during a 12-year follow-up. Methods Thirty-four SSc patients showing at baseline (first capillaroscopic analysis) the ‘early’ NVC pattern of microangiopathy were enrolled and followed for 12 years (s.d. 2). Complete NVC analysis and clinical and serological findings were collected. Patients were in a standard therapeutic care setting. Statistical analysis was carried out by non-parametric tests. Results After a 12-year follow-up, the ‘early’ NVC pattern changed from baseline in 76% of the patients. The NVC pattern was found to be ‘active’ in 9 patients (26%), ‘late’ in 13 (38%) and characterized by non-specific capillary abnormalities in 4 (12%). In the subgroup whose microangiopathy progressed from the ‘early’ to the ‘late’ NVC pattern, the median time of progression from the ‘early’ to the ‘active’ pattern was significantly shorter (11 months) when compared with patients who progressed from the ‘early’ to the ‘active’ NVC pattern (55 months) (P = 0.002). The median time of progression between NVC patterns was significantly shorter in SSc patients showing either a nucleolar ANA pattern or Scl70 autoantibodies (P = 0.048). Organ involvement was progressively greater in SSc patients with ‘early’, ‘active’ and ‘late’ NVC patterns, respectively. Conclusions This longitudinal study confirms over a 12-year follow-up the evolution of specific NVC patterns associated with the progressive severity of organ involvement in SSc patients in a standard clinical care setting.
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Gressenberger, Paul, Philipp Jud, Gabor Kovacs, Sonja Kreuzer, Hans-Peter Brezinsek, Katharina Guetl, Viktoria Muster, et al. "Rituximab as a Treatment Option after Autologous Hematopoietic Stem Cell Transplantation in a Patient with Systemic Sclerosis." Journal of Personalized Medicine 11, no. 7 (June 25, 2021): 600. http://dx.doi.org/10.3390/jpm11070600.
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Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy and organ fibrosis. Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for the treatment of selected patients with rapid progressive SSc at high risk of organ failure. It, however, remains elusive whether immunosuppressive therapies such as rituximab (RTX) are still necessary for such patients after AHSCT, especially in those with bad outcomes. In the present report, a 43-year-old man with diffuse cutaneous SSc received AHSCT. Despite AHSCT, SSc further progressed with progressive symptomatic heart failure with newly developed concomitant mitral and tricuspid valve insufficiency, thus the patient started on RTX 8 months after AHSCT. Shortly after initiation of RTX, clinical symptoms and organ functions ameliorated subsequently. Heart valve regurgitations were reversible after initiation of RTX treatment. Currently, the patient remains in a stable condition with significant improvement of clinical symptoms and organ functions. Reporting about therapies after AHSCT in SSc is a very important issue, as randomized controlled trials are lacking, and therefore this report adds to evidence that RTX can be considered as a treatment option in patients with SSc that do not respond to AHSCT.
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Anggraini, Wilujeng, and Perdana Aditya Rahman. "Single Case Experience of Immunosuppressant Administration to Systemic Sclerosis-ILD Patients with Aspergilloma." Indonesian Journal of Rheumatology 14, no. 1 (July 12, 2022): 616–23. http://dx.doi.org/10.37275/ijr.v14i1.197.
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Background: Systemic sclerosis (SSc) is a chronic autoimmune disease that still poses a great challenge to clinicians. SSc is characterized by immune dysregulation and progressive fibrosis that typically affects variable internal organ involvement such as lungs. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death. The immunosuppressive drug is the main treatment to suppress the inflammation process in SSc.
Case presentation: In this case we report a 40-year-old female to suffer ILD-SSc. According to High-Resolution Computed Tomography (HRCT) thorax, we found that it was interstitial lung disease with aspergilloma. She got methylprednisolone 3x8 mg and azathioprine 2x50 mg. At the end of the treatment, the patient showed improvement in her clinical condition and showed no worsening condition in the HRCT evaluation for her fungal aspergilloma.
Conclusion: Systemic sclerosis (SSc) is a rare autoimmune disease involving the skin and internal organs. The immunosuppressive agent is still the drug of choice for most autoimmune diseases. Immunosuppressive may promote fungal growth and have been associated with increased risk in most serious fungal diseases including aspergilloma.
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Vasil'ev, V. I., B. D. Chal'tsev, V. R. Gorodetskii, S. G. Pal'shina, N. S. Shornikova, L. P. Anan'eva, I. V. Gaiduk, et al. "The relationship between Sjogren’s syndrome, systemic sclerosis and lymphoproliferative diseases." Terapevticheskii arkhiv 92, no. 12 (December 15, 2020): 126–36. http://dx.doi.org/10.26442/00403660.2020.12.200443.
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Despite the large number of studies devoted to the study of systemic sclerosis (SSc), the high risk of developing lymphomas in this disease, the relationship of their development with certain subtypes of SSc and specific SSc-associated autoantibodies is still debated in the literature.
Aim.To study demographic, clinical, laboratory and immunological characteristics of patients with a combination of primary Sjogrens syndrome (pSS) and SSc and diagnosed lymphoproliferative diseases (LPDs); to characterize morphological/immunomorphological variants and course of non-Hodgkins lymphomas (NHL), developing in patients with these rheumatic diseases (RDs).
Materials and methods.In 19982018 at the Nasonova Research Institute of Rheumatology, 13 patients with clinical and laboratory manifestations of pSS (12) and SSc (13) were diagnosed with various lymphoproliferative diseases (LPDs). In 3 cases, an induced RD was observed: 1 case of a diffuse, rapidly progressive form of SSc, 2 cases of pSS in combination with a limited form of SSc after chemotherapy and radiation therapy of Hodgkins lymphoma (1), B-cell NHL (1) and CR of the breast (1) respectively. The first 2 cases were excluded from the analysis, since the development of lymphomas is not pathogenetically associated with RD.
Results.Of 11 patients with LPDs, 10 after a long course of RDs were diagnosed with NHL [MALT lymphoma of the parotid salivary glands 7, disseminated MALT lymphoma 2, disseminated MALT lymphoma with transformation into diffuse large B-cell lymphoma (DLBCL) 1]. RDs debuted with Raynauds phenomenon (RP) in 64.5% and pSS manifestations in 45.5% of patients. Stomatological manifestations of pSS were characterized by recurrent parotitis in 36%, significant parotid gland enlargement with massive infiltration of labial salivary glands (focus score 4) in 100%, severe xerostomia in 70%, extraglandular manifestations and lymphadenopathy in 50% of patients. The course of the SSc was characterized by mild RP with various types of capillaroscopic changes and mild lung changes and non-significant progression during long-term follow-up (median 22 years). The entire spectrum of SSс specific antibodies (anticentromere antibodies 60%, antibodies to ribonucleoprotease III 30%, Pm/Scl 10%), excepting antibodies to topoisomerase I, as well as pSS specific autoantibodies (antiRo/La 70%, RF (rheumatoid factor) 90%), were detected in patients with a combination of these RDs.
Conclusion.pSS is often combined with a limited form of SSc regardless of the type of autoantibodies detected. The presence of pSS, rather than SSc, is a high-risk factor for the development of NHL in this group of patients. The patients with pSS and SSc are characterized by a steady progression of pSS with a slow and mild course of SSc throughout the observation period. The development of severe stomatological manifestations and high immunological activity of pSS contribute to the development of localized MALT lymphomas (70%) and disseminated MALT lymphomas (30%) with primary lesions of the salivary glands and transformation into DLBCL in case of their late diagnosis. The optimal method for preventing the development of NHL in this group of patients is the early diagnosis of pSS, the appointment of alkylating cytotoxic agents and/or anti-B-cell therapy in the early stages of pSS. Given the possibility of transformation of localized NHL into DLBCL, for early diagnosis, minimally invasive surgical biopsies of significantly enlarged parotid salivary glands should be performed before glucocorticoids are prescribed. Detection of positive B-cell clonality and lymphoepithelial lesions in the parotid salivary gland is considered a predictor of MALT lymphoma development during follow-up. Localized and disseminated MALT lymphomas in patients with pSS and SSc respond well to therapy, in contrast to MALT lymphomas transformed into DLBCL.
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Ramahi, A., A. Lescoat, D. Roofeh, S. Jaafar, V. Nagaraja, S. Huang, D. O’dwyer, K. Flaherty, E. Kazerooni, and D. Khanna. "POS0902 RISK FACTORS FOR LUNG FUNCTION DECLINE IN SYSTEMIC SCLEROSIS INTERSTITIAL LUNG DISEASE IN A LARGE SINGLE-CENTER COHORT." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 750.1–750. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3648.
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BackgroundSystemic sclerosis associated interstitial lung disease (SSc-ILD) is the leading cause of scleroderma-related mortality.ObjectivesThis work identifies factors associated with SSc-ILD decline on pulmonary function testing (PFT).MethodsThis single center cohort identified 312 patients with ILD as determined by high resolution chest. 184 patients (59% of 312) completed baseline and serial PFTs (with at least two follow-up PFTs) and were included in this analysis. Mixed linear models were fit to assess the decline in the percent predicted forced vital capacity (ppFVC) over time. Demographics, disease factors, autoantibodies, and ILD features were included in the univariate mixed linear model; those achieving a p-value <0.20 were included in the multivariable mixed linear model. Patients were followed longitudinally, with survival as an endpoint identified using the National Death Registry Index, reviewing death certificates, and hospital records.ResultsThe 184 patients were an average of 53.2 [12.1] years old; the median [IQR] disease duration from the first non-Raynaud’s phenomenon symptom was 1.8 [0.7, 4.8] years. SSc subtype was diffuse in 55.4% (n=102), limited in 32.6% (n=60), overlap syndrome in 8.2% (n=15), and SSc sine scleroderma in 3.87% (n=7). Serologies were positive for anti-topoisomerase I (ATA), anti-centromere and anti-RNA polymerase III in 31.4% (n=53/169), 10.4% (16/154) and 22.9% (25/109) respectively. Mean ppFVC was 70.8 (18.9) and ppDLco 57.2 (20.8). Whole lung involvement (WLI%) of ≥20% on visual read was found in 49.3% of subjects (74/150 (49.3%)) where quantification was available. Over a median of 4.9 (2.4, 6.8) years, 21 patients (11.4%) died. The ppFVC declined a mean of 0.28/year in the overall group. There were differences in terms of ppFVC decline/year between patients who died in the first 2 years (n=10, -8.28%), 2-8 years (n=5, -3.89%), after 8 years (n=6, -1.00%), or who were still alive (n=163, -0.13%). The primary cause of death was ILD (6/21, 28.6%); those who died in the first 2 years most often died from progressive ILD (4/6, 67%). Factors significantly associated with decline in ppFVC on univariate analyses, included longer disease duration (ref. < median, P=0.0048), ATA positivity (ref. negative, P=0.0081), and WLI ≥20% (ref. 0-20%, P=0.0484). In multivariate analysis the only statistically significant variable associated with decline in ppFVC/ year was ATA positivity.ConclusionIn a large single center cohort of SSc-ILD, ATA positivity is a risk factor for developing progressive SSc-ILD, consistent with other SSc-ILD cohorts. Stratifying patients by survival demonstrates that lung function declines dramatically in those who died within 2 years, whose main cause of death was progressive ILD. These data support the growing need to identify risk factors for disease severity and risk for progression, and to target intervention in patients most likely to develop progressive SSc-ILD1,2.References[1]Roofeh D, Lin CJF, Goldin JG, et al. Tocilizumab Prevents Progression of Early Systemic Sclerosis Associated Interstitial Lung Disease. Arthritis Rheum. 2021[2]Roofeh D, Lescoat A, Khanna D. Treatment for systemic sclerosis-associated interstitial lung disease. Curr Opin Rheumatol. 2021Disclosure of InterestsNone declared
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Nowaczyk, Joanna, Leszek Blicharz, Michał Zawistowski, Mariusz Sikora, Michał Zaremba, Joanna Czuwara, and Lidia Rudnicka. "The Clinical Significance of Salusins in Systemic Sclerosis—A Cross-Sectional Study." Diagnostics 13, no. 5 (February 23, 2023): 848. http://dx.doi.org/10.3390/diagnostics13050848.
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Background: Systemic sclerosis (SSc) is a connective tissue disease manifesting with progressive fibrosis of the skin and internal organs. Its pathogenesis is strictly associated with vascular disfunction and damage. Salusin-α and salusin-β, endogenous peptides regulating secretion of pro-inflammatory cytokines and vascular smooth muscle proliferation, may potentially play a role in SSc pathogenesis. Objectives: The aim of this study was to assess the concentration of salusins in sera of patients with SSc and healthy controls and to evaluate correlations between the salusins levels and selected clinical parameters within the study group. Materials and methods: 48 patients with SSc (44 women; mean age, 56.4, standard deviation, 11.4) and 25 adult healthy volunteers (25 women; mean age, 55.2, standard deviation, 11.2) were enrolled. All patients with SSc were treated with vasodilators and twenty-seven of them (56%) also received immunosuppressive therapy. Results: Circulating salusin-α was significantly elevated in patients with SSc in comparison to healthy controls (U = 350.5, p = 0.004). Patients with SSc receiving immunosuppression had higher serum salusin-α concentrations compared with those without immunosuppressive therapy (U = 176.0, p = 0.026). No correlation was observed between salusins concentrations and skin or internal organ involvement parameters. Conclusions: Salusin-α, a bioactive peptide mitigating the endothelial disfunction, was elevated in patients with systemic sclerosis receiving vasodilators and immunosuppressants. Increased salusin-α concertation may be associated with the initiation of atheroprotective processes in patients with SSc managed pharmacologically, which requires verification in future studies.
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Benfaremo, D., G. Stronati, L. Manfredi, L. Zuliani, A. Ferrarini, C. Fischetti, C. Dichiara, F. Guerra, A. Dello Russo, and A. Gabrielli. "SAT0307 PROGRESSION OF SUBCLINICAL MYOCARDIAL INVOLVEMENT IN PATIENTS WITH SYSTEMIC SCLEROSIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1098.1–1099. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2824.
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Background:Systemic sclerosis (SSc) is a progressive autoimmune disease affecting the skin as well as internal organs, including the heart. A few studies have identified a subclinical heart involvement in patients with no pulmonary hypertension. Changes in myocardial deformation are consistent with the idea of SSc-related cardiomyopathy as a primary condition affecting the heart globally through microvascular dysfunction and subsequent myocardial fibrosis.Objectives:The aim of the present study is to describe the progression of myocardial deformation in patients with SSc and no overt cardiac disease.Methods:Prospective longitudinal study enrolling consecutive SSc patients referred to the Clinica Medica, University Hospital ‘Ospedali Riuniti’, Ancona, Italy, from February 2016 to December 2018. All patients fulfilled the 2013 ACR/EULAR classification criteria for SSc. Patients with structural heart disease, heart failure, atrial fibrillation or pulmonary hypertension were excluded. Disease subset, antibodies pattern, cardiovascular risk factors and involvement of other organ systems were recorded for each patient. An echocardiographic exam was performed for all patients at baseline and during their follow-up evaluation. Standard and speckle-tracking derived variables for the systolic and diastolic function of the left ventricle (LV) and right ventricle (RV) were acquired. Speckle tracking analysis software (EchoPAC 13.0; GE Medical Systems, Milwaukee, USA) was used to assess the GLS of the left and right ventricle, excluding the ventricular septum from right ventricular GLS calculations.Results:Seventy-two patients (68 females, age 56.6±15.4 years) were enrolled. Common echocardiographic parameters of left and right systolic function were within normal range at baseline and did not change during follow-up. Mean GLS, however, worsened for both left (from -19.8±3.5% to -18.7±3.5%, p=.034) and right ventricle (from -20.9±6.1% to -18.7±5.4%, p=.013) during a median follow-up of 20 months (1st-3rd quartile 12-24 months). The increased impairment registered in SSc patients was homogenous across endocardial layers (LV from -22.5±-3.9 to -21.4±3.9, p=.041; RV from -24.2±6.2 to -20.6±5.9, p=.001), mesocardial layers (LV -19.7±3.6 to -18.7±3.5, p=.043; RV from -21.3±5.9 to -18.8±5.7, p=.012) and epicardial layers (LV from -17.1±3.0 to -16.4±3.1, p=.112, RV -18.8±6.3 to -16.0±8.4, p=.035), as well as myocardial segments. No difference in progression rate was observed stratifying patients according to disease subset or other clinical parameters.Conclusion:GLS impairment progressed over a 20-month follow-up period in a cohort of SSc patients without clinically overt cardiac involvement. Further studies are needed to assess the significance of subclinical heart involvement and its progression in patients with SSc.Disclosure of Interests:None declared
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Ovsyannikova, O. B., L. P. Ananyeva, O. A. Koneva, L. A. Garzanova, R. U. Shayakhmetova, O. V. Desinova, M. N. Starovoitova, and A. M. Lila. "Autologous hematopoietic stem cell transplantation in the treatment of systemic sclerosis. Part 1. Clinical aspects." Modern Rheumatology Journal 14, no. 4 (November 25, 2020): 91–97. http://dx.doi.org/10.14412/1996-7012-2020-4-91-97.
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Diffuse cutaneous systemic sclerosis (SSc) characterized by an acute, rapidly progressive course and severe damage to the internal organs has an unfavorable prognosis, while the treatment of this often fatal type of the disease has not been sufficiently developed. This paper reviews an update on an autologous hematopoietic stem cell transplantation (auto-HSCT) procedure, transplantation stages, and conditioning modes in patients with SSc. It presents the characteristics of auto-HSCT studies conducted in 2005 to 2016. The inclusion and exclusion criteria used in these studies are described and their outcomes compared. The results of three randomized controlled trials concerning auto-HSCT are analyzed separately. These findings confirm that auto-HSCT is currently more effective than standard immunosuppressive therapy. Auto-HSCT produces better results that can provide a more favorable long-term prognosis of SSc; it can prevent worsening of organ damages and improve skin scores and lung function. Patients with early diffuse SSc, a rapidly progressive course, and poor prognostic factors in the first 4–5 years of the disease before the development of functional insufficiency of the vital organs can be considered most promising for auto-HSCT.
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McSweeney, Peter A., Richard A. Nash, Keith M. Sullivan, Jan Storek, Leslie J. Crofford, Roger Dansey, Maureen D. Mayes, et al. "High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes." Blood 100, no. 5 (September 1, 2002): 1602–10. http://dx.doi.org/10.1182/blood.v100.5.1602.h81702001602_1602_1610.
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Systemic sclerosis (SSc) is a multisystem disease of presumed autoimmune pathogenesis for which no proven effective treatment exists. High-dose immunosuppressive therapy (HDIT) has been proposed as an investigational treatment for severe autoimmune diseases. Nineteen patients with poor-prognosis SSc underwent HDIT. The median age was 40 years (range, 23-61 years), the median modified Rodnan skin score (a measure of dermal sclerosis) was 31, and the median DLCO was 57%. Conditioning therapy involved 800 cGy total body irradiation (TBI) (± lung shielding to approximately 200 cGy), 120 mg/kg cyclophosphamide, and 90 mg/kg equine antithymocyte globulin. CD34-selected granulocyte–colony-stimulating factor–mobilized autologous blood stem cells provided hematopoietic rescue. With median follow-up at 14.7 months, the Kaplan-Meier estimated 2-year survival rate was 79%. Three patients died of treatment complications and one of disease progression. Two of the first 8 patients had fatal regimen-related pulmonary injury, a complication not found among 11 subsequent patients who received lung shielding for TBI. Overall, internal organ functions were stable to slightly worse after HDIT, and 4 patients had progressive or nonresponsive disease. As measured by modified Rodnan skin scores and modified health assessment questionnaire disability index (mHAQ-DI) scores, significant disease responses occurred in 12 of 12 patients evaluated at 1 year after HDIT. In conclusion, though important treatment-related toxicities occurred after HDIT for SSc, modifications of initial approaches appear to reduce treatment risks. Responses in skin and mHAQ-DI scores exceed those reported with other therapies, suggesting that HDIT is a promising new therapy for SSc that should be evaluated in prospective randomized studies.
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Bagnato, Gianluca, Antonio Giovanni Versace, Daniela La Rosa, Alberta De Gaetano, Egidio Imbalzano, Marianna Chiappalone, Carmelo Ioppolo, et al. "Autologous Haematopoietic Stem Cell Transplantation and Systemic Sclerosis: Focus on Interstitial Lung Disease." Cells 11, no. 5 (March 1, 2022): 843. http://dx.doi.org/10.3390/cells11050843.
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Autologous hematopoietic stem cells transplantation (AHSCT) has been employed as treatment for severe systemic sclerosis (SSc) with high risk of organ failure. In the last 25 years overall survival and treatment-related mortality have improved, in accordance with a better patient selection and mobilization and conditioning protocols. This review analyzes the evidence from the last 5 years for AHSCT-treated SSc patients, considering in particular the outcomes related to interstitial lung disease. There are increasing data supporting the use of AHSCT in selected patients with rapidly progressive SSc. However, some unmet needs remain, such as an accurate patient selection, pre-transplantation analysis to identify subclinical conditions precluding the transplantation, and the alternatives for post-transplant ILD recurrence.