| 1. |
- Alexander, Tobias, et al.
(författare)
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Intestinal Microbiome in Hematopoietic Stem Cell Transplantation For Autoimmune Diseases : Considerations and Perspectives on Behalf of Autoimmune Diseases Working Party (ADWP) of the EBMT
- 2021
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Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Over the past decades, hematopoietic stem cell transplantation (HSCT) has been evolving as specific treatment for patients with severe and refractory autoimmune diseases (ADs), where mechanistic studies have provided evidence for a profound immune renewal facilitating the observed beneficial responses. The intestinal microbiome plays an important role in host physiology including shaping the immune repertoire. The relationships between intestinal microbiota composition and outcomes after HSCT for hematologic diseases have been identified, particularly for predicting the mortality from infectious and non-infectious causes. Furthermore, therapeutic manipulations of the gut microbiota, such as fecal microbiota transplant (FMT), have emerged as promising therapeutic approaches for restoring the functional and anatomical integrity of the intestinal microbiota post-transplantation. Although changes in the intestinal microbiome have been linked to various ADs, studies investigating the effect of intestinal dysbiosis on HSCT outcomes for ADs are scarce and require further attention. Herein, we describe some of the landmark microbiome studies in HSCT recipients and patients with chronic ADs, and discuss the challenges and opportunities of microbiome research for diagnostic and therapeutic purposes in the context of HSCT for ADs.
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| 2. |
- Burt, Richard K., et al.
(författare)
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New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis
- 2021
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Ingår i: Bone Marrow Transplantation. - : Springer Nature. - 0268-3369 .- 1476-5365. ; 56:7, s. 1509-1517
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Forskningsöversikt (refereegranskat)abstract
- Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of similar to 5-6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2-14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.
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| 3. |
- Carreira, Patricia E., et al.
(författare)
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Clinical determinants of elevated systolic pulmonary artery pressure measured by transthoracic Doppler echocardiography in early systemic sclerosis
- 2017
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Ingår i: Clinical and Experimental Rheumatology. - 0392-856X. ; 35, s. 114-121
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To explore the prevalence and clinical associations of elevated systolic pulmonary artery pressure (sPAP), measured by Transthoracic Dopplerechocardiography (TTE) in patients with early systemic sclerosis (SSc). Methods. A cross-sectional analysis of the prospective EULAR Scleroderma Trial and Research (EUSTAR) database was performed. SSc patients with < 3 years from the first non-Raynaud's phenomenon (RP) symptom at baseline EUSTAR visit, were selected. Elevated sPAP was defined as sPAP > 40 mmHg on baseline TTE. First visit SSc related variables, including disease subsets, antibodies and visceral involvement, were examined. Results. From 1,188 patients, 81% were women. Mean (SD) age at first non-RP symptom was 50 (14) years, 55% had limited cutaneous SSc (lcSSc) and 42% active disease. Elevated sPAP was found in 17% of patients, both lcSSc and diffuse cutaneous SSc (dc- SSc). In lcSSc, older age at first non- RP symptom, ACA positivity, joint contractures, restrictive defect and lower DLCO, were independently associated with elevated sPAP. In dcSSc, older age at first non-RP symptom, longer time between RP onset and first non-RP symptom, digital ulcers, cardiac blocks, and proteinuria were associated with elevated sPAP. Conclusion. The prevalence of elevated sPAP on TTE in early SSc patients is considerable. Association with cardiac, lung and renal involvement suggests that, although some patients might have pulmonary arterial hypertension, others may present pulmonary hypertension secondary to lung or heart involvement. Our findings emphasise the need to consider right heart catheterisation in selected early SSc patients with PH suspicion, to clearly determine the cause of PH.
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| 4. |
- Daikeler, Thomas, et al.
(författare)
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New autoimmune diseases after cord blood transplantation : a retrospective study of EUROCORD and the Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:6, s. 1059-1064
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Tidskriftsartikel (refereegranskat)abstract
- To describe the incidence, risk factors, and treatment of autoimmune diseases (ADs) occurring after cord blood transplantation (CBT), we analyzed both CBT recipients reported to EUROCORD who had developed at least 1 new AD and those who had not. Fifty-two of 726 reported patients developed at least 1 AD within 212 days (range, 27-4267) after CBT. Cumulative incidence of ADs after CBT was 5.0% +/- 1% at 1 year and 6.6% +/- 1% at 5 years. Patients developing ADs were younger and had more nonmalignant diseases (P < .001). ADs target hematopoietic (autoimmune hemolytic anemia, n = 20; Evans syndrome, n = 9; autoimmune thrombocytopenia, n = 11; and immune neutropenia, n = 1) and other tissues (thyroiditis, n = 3; psoriasis, n = 2; Graves disease, n = 1; membranous glomerulonephritis, n = 2; rheumatoid arthritis, n = 1; ulcerative colitis, n = 1; and systemic lupus erythematosus, n = 1). Four patients developed 2 ADs (3 cases of immune thrombocytopenia followed by autoimmune hemolytic anemia and 1 Evans syndrome with rheumatoid arthritis). By multivariate analysis, the main risk factor for developing an AD was nonmalignant disease as an indication for CBT (P = .0001). Hematologic ADs were most often treated with steroids, rituximab, and cyclosporine. With a median follow-up of 26 months (range, 2-91), 6 of 52 patients died as a consequence of ADs. We conclude that CBT may be followed by potentially life-threatening, mainly hematologic ADs.
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| 5. |
- Daikeler, Thomas, et al.
(författare)
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Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; Aug 11:118(6), s. 1693-8
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Tidskriftsartikel (refereegranskat)abstract
- To specify incidence and risk factors for secondary autoimmune diseases (AD) after HSCT for a primary AD, we retrospectively analysed AD patients treated by HSCT reported to EBMT from 1995 to 2009 with at least one secondary AD (cases) and those without (controls). After autologous HSCT, 29 amongst 347 patients developed at least one secondary AD within 21.9 (0.6-49) months and after allogeneic HSCT, 3 amongst 16 patients. The observed secondary AD included: autoimmune hemolytic anemia (n=3), acquired haemophilia (n=3), autoimmune thrombocytopenia (n=3), antiphospholipid syndrome (n=2), thyroiditis (n=12), blocking TSHR-ab (n=1), Graves' disease (n=2), myasthenia gravis (n=1), rheumatoid arthritis (n=2), sarcoidosis (n=2), vasculitis (n=1), psoriasis (n=1) and psoriatic arthritis (n=1). After autologous HSCT for primary AD, the cumulative incidence of secondary AD was 9.8+/-2 % at 5 years, lupus erythematosus as primary AD and antithymocyte-globulin use plus CD34+ graft selection were important risk factors for secondary AD by multivariate analysis. With a median follow-up of 6.2 (0.54-11) years after autologous HSCT, 26/29 patients with secondary AD were alive, 2 died during their secondary AD (antiphospholipid syndrome, haemophilia) and 1 death was HSCT related. This European multicenter study underlines the need for careful management and follow-up for secondary AD after HSCT.
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| 6. |
- Greco, Raffaella, et al.
(författare)
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Autologous hematopoietic stem cell transplantation in neuromyelitis optica : A registry study of the EBMT Autoimmune Diseases Working Party
- 2015
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Ingår i: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 21:2, s. 189-197
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the central nervous system, hallmarked by pathogenic anti-aquaporin 4 antibodies. NMO prognosis is worse compared with multiple sclerosis.OBJECTIVE:The European Group for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) conducted a retrospective survey to analyze disease outcome following autologous stem cell transplantation (ASCT).METHODS:This retrospective multicenter study assessed the efficacy and safety of ASCT in 16 patients suffering from refractory NMO reported to the EBMT registry between 2001 and 2011.RESULTS:Fifteen patients were successfully mobilized with cyclophosphamide (Cy) and G-CSF, one with G-CSF alone. All patients received an unmanipulated autologous peripheral blood stem cell graft, after conditioning with BEAM plus anti-thymocyte globulin (ATG, n = 9 patients), thiotepa-Cy (n = 3) or Cy (200 mg/kg) plus ATG (n = 4). After a median follow-up of 47 months, three of 16 cases were progression and treatment free, while in the remaining 13 patients further treatments were administered for disability progression or relapse after ASCT. Altogether, relapse-free survival at three and five years was 31% and 10%, respectively, while progression-free survival remained 48% at three and five years.CONCLUSIONS:In these NMO patients, highly resistant to conventional treatment, ASCT allows for temporary control of the disease, despite a tendency to progress or relapse in the long term.
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| 7. |
- Greco, Raffaella, et al.
(författare)
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Innovative cellular therapies for autoimmune diseases : expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee
- 2024
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Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 69
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert -based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 8. |
- Herrick, Ariane L, et al.
(författare)
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Treatment outcome in early diffuse cutaneous systemic sclerosis : The European Scleroderma Observational Study (ESOS)
- 2017
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76:7, s. 1207-1218
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. Methods: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Results Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. Conclusions: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.
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| 9. |
- Ingegnoli, Francesca, et al.
(författare)
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A comparison between nailfold capillaroscopy patterns in adulthood in juvenile and adult-onset systemic sclerosis: A EUSTAR exploratory study
- 2015
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Ingår i: Microvascular Research. - : Elsevier BV. - 1095-9319 .- 0026-2862. ; 102, s. 19-24
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Qualitative capillaroscopy patterns in juvenile- and adult-onset systemic sclerosis (SSc) were studied in adulthood using data from the EULAR Scleroderma Trials and Research (EUSTAR) database. Methods: Data collected between June 2004 and April 2013 were examined with focus on capillaroscopy. In this retrospective exploratory study, series of patients with juvenile-onset SSc were matched with series of adult-onset SSc having the same gender and autoantibody profile. Results: 30 of 123 patients with juvenile-onset and 2108 of 7133 with adult-onset SSc had data on capillaroscopy. Juvenile-onset SSc showed scleroderma pattern more frequently than adult-onset SSc (93.3% and 88%). The OR was 2.44 and 95% Cl 0.57-10.41. An active scleroderma pattern was present in 58% of juvenile- and 61% of adult-onset SSc. The OR was 0.91 and 95% Cl 0.28-2.93. The late scleroderma pattern was present in 61% of juvenile- and 55.5% of adult-onset SSc. The OR was 1.06 and 95% Cl 0.34-3.56. Conclusion: This is the first exploratory study on the comparison of capillaroscopy between juvenile- and adult-onset SSc in adulthood. Juvenile-onset SSc had an increase prevalence of sderoderma pattern, but a similar distribution of the three patterns was suggested. Further studies are needed to define this issue. (C) 2015 Elsevier Inc. All rights reserved.
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| 10. |
- Lanza, Francesco, et al.
(författare)
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Individual Quality Assessment of Autografting by Probability Estimation for Clinical Endpoints : A Prospective Validation Study from the European Group for Blood and Marrow Transplantation
- 2013
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier. - 1083-8791 .- 1523-6536. ; 19:12, s. 1670-1676
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Forskningsöversikt (refereegranskat)abstract
- The aim of supportive autografting is to reduce the side effects from stem cell transplantation and avoid procedure-related health disadvantages for patients at the lowest possible cost and resource expenditure. Economic evaluation of health care is becoming increasingly important. We report clinical and laboratory data collected from 397 consecutive adult patients (173 non-Hodgkin lymphoma, 30 Hodgkin lymphoma, 160 multiple myeloma, 7 autoimmune diseases, and 28 acute leukemia) who underwent their first autologous peripheral blood stem cell transplantation (PBSCT). We considered primary endpoints evaluating health economic efficacy (eg, antibiotic administration, transfusion of blood components, and time in hospital), secondary endpoints evaluating toxicity (in accordance with Common Toxicity Criteria), and tertiary endpoints evaluating safety (le, the risk of regimen-related death or disease progression within the first year after PBSCT). A time-dependent grading of efficacy is proposed with day 21 for multiple myeloma and day 25 for the other disease categories (depending on the length of the conditioning regimen) as the acceptable maximum time in hospital, which together with antibiotics, antifungal, or transfusion therapy delineates four groups: favorable (<= 7 days on antibiotics and no transfusions; <= 21 [25] days in hospital), intermediate (from 7 to 10 days on antibiotics and <3 transfusions, <= 21 to 25 days in hospital or >= 7 days on antibiotics and no transfusions; from 21 to 30 days [25 to 34] in hospital), unfavorable (>7 days on antibiotics, >3 but <6 transfusions; >30/34 days in hospital after transplantation), and very unfavorable (>10 days on antibiotics, >6 transfusions; >30 to 34 days in hospital). The multivariate analysis showed that (1) PBSC harvests of >= 4 x 10(6)/kg CD34 + cells in 1 apheresis procedure were associated with a favorable outcome in all patient categories except acute myelogenous leukemia and acute lymphoblastic leukemia (P = .001), (2) >= 5 x 10(6)/kg CD34 + cells infused predicted better transplantation outcome in all patient categories (P < .0001) except acute myelogenous leukemia and acute lymphoblastic leukemia, (3) 1 or 2 aphereses (P = .001) predicted good outcome, (4) toxicity increased with higher graft volume reinfused (>500 mL) (P = .002), and (5) patients with a central venous catheter during both collection and infusion of PBSC had a more favorable outcome post-PBSCT than peripheral access (P = .007). The type of mobilization regimen did not affect the outcome of auto-PBSCT. The present study identified predictive variables, which may be useful in future individual pretransplantation probability evaluations with the goal to improve supportive care. (C) 2013 American Society for Blood and Marrow Transplantation.
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| 11. |
- Peytrignet, Sébastien, et al.
(författare)
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Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study.
- 2018
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 57:2, s. 370-381
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Tidskriftsartikel (refereegranskat)abstract
- Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features.Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined.The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001).The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.
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| 12. |
- Sharrack, Basil, et al.
(författare)
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Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases : updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)
- 2020
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Ingår i: Bone Marrow Transplantation. - : Springer Nature. - 0268-3369 .- 1476-5365. ; 55:2, s. 283-306
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Tidskriftsartikel (refereegranskat)abstract
- These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
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| 13. |
- Snowden, John A., et al.
(författare)
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Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases
- 2017
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Ingår i: Blood Advances. - : AMER SOC HEMATOLOGY. - 2473-9529 .- 2473-9537. ; 1:27, s. 2742-2755
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Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [<1-62]) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index (P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10(-5)), relapse/ progression (P < 10(-5)), and nonrelapse mortality (P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFSwas associated with experience (>= 23 transplants for AD, P = .001), learning (time from first HSCT for AD >= 6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status (P = .02). Despite improved survival over time (P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD.
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| 14. |
- Tyndall, Anthony J., et al.
(författare)
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Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database
- 2010
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 69:10, s. 1809-1815
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To determine the causes and predictors of mortality in systemic sclerosis (SSc). Methods Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. Results Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). Conclusion Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.
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