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Contains fulltext : 290708.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To assess the use, satisfaction, needs, and preferences regarding physical therapy (PT) in patients with systemic sclerosis (SSc). METHODS: A total of 405 SSc patients, treated in the Leiden University Medical Center multidisciplinary care program and fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 SSc criteria, received a questionnaire containing 37 questions on use and satisfaction regarding PT over a 2-year period, and their needs and preferences for future PT. RESULTS: A total of 204 SSc patients (median age 63 years, 81% female) completed the questionnaire. One hundred twenty-eight patients (63%) had used or were using PT in a primary care setting. For 39% of patients not using PT, lack of referral or lack of knowledge was the reason for not using it. The most frequently reported active treatments were muscle-strengthening (n = 92 [72%]), range of motion (n = 77 [60%]), and aerobic exercises (n = 72 [56%]). Specific SSc hand- and mouth-opening exercises were reported by 20 (15%) and 7 (6%) patients, respectively. Manual treatment (massage or passive mobilization) was reported by 83 patients (65%). The mean ± SD satisfaction score (range 0-10) was 8.2 ± 1.6. Regarding patients' needs, 96 patients (47%) of the total group wanted to receive more information concerning PT, and 128 (63%) wanted to continue, start, or restart PT in the near future, with 56 of the 128 patients (44%) favoring individual treatment on a continuous basis. CONCLUSION: We observed a significant variation in the use and content of PT for SSc patients in a primary care setting. Our results suggest potential underuse of PT care, in particular for hand and oral dysfunction, and underpin the need for initiatives to improve the quality and accessibility of PT care for SSc patients. 01 januari 2023

The aim of this study was to identify the role of nasal Staphylococcus aureus (S. aureus) colonization and the effect of systemic or local antibiotic treatment on disease activity in patients with antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis and ear nose and throat (ENT) involvement. Clinical, laboratory and histological data from all patients with ANCA-associated vasculitis and ENT involvement, who were diagnosed in two medical centres in The Netherlands between 1981 and 2020, were retrospectively collected. Nasal S. aureus colonization was defined as at least one positive nasal swab during follow-up. Data on systemic (cotrimoxazole and azithromycin) and local (mupirocin) antibiotic use were collected. Disease activity was divided into systemic and local disease activity. Univariate analyses and regression analyses (negative binomial Poisson and binary regression) were used. Two-hundred and thirteen patients were available for analysis. Median follow-up time was 8 (IQR 3–17) years. S. aureus colonization was tested in 100 (46.9%) cases of whom 44 patients (44%) tested positive. In these 100 patients, systemic and local disease activity at baseline and at last visit were comparable between patients with and without S. aureus colonization. Twenty-eight of the 44 S. aureus positive patients received antibiotics aimed at eradication of S. aureus. No statistically significant difference was found between the treated versus non-treated group with regard to systemic and local disease activity. Nasal S. aureus colonization does not influence systemic or local disease activity. Antibiotic treatment aimed at eradication did not modify disease activity.

This guideline will provide a practical roadmap for management of SSc that builds upon the previous treatment guideline to incorporate advances in evidence-based treatment and increased knowledge about assessment, classification and management. General approaches to management as well as treatment of specific complications will be covered, including lung, cardiac, renal and gastrointestinal tract disease, as well as RP, digital vasculopathy, skin manifestations, calcinosis and impact on quality of life. It will include guidance related to emerging approved therapies for interstitial lung disease and account for National Health Service England prescribing policies and national guidance relevant to SSc. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol. This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence accreditation.

Objectives: The aim of this study was to identify and prioritize aspects essential for decision making in patients with diffuse cutaneous systemic sclerosis (dcSSc) and to gain insight into information preferences of treatment options which could guide development of a leaflet for patients. Methods: A three-round Delphi study was conducted with a panel of patients with dcSSc. The questionnaire was based on a systematic literature search regarding benefits and harms of four main treatment options in dcSSc: methotrexate, mycophenolate mofetil, cyclophosphamide pulses and stem cell transplantation. Patients were asked to identify information that is essential for making a treatment decision. After the third round, a live, online discussion was held in order to reach consensus on these items and to discuss the content and design of the leaflet. Consensus was defined as ⩾75% agreement among panel members. Results: Of the 36 patients invited, 78% (n = 28) participated in one or more rounds, 67% (n = 24) completed the first, 69% (n = 25) the second and 75% (n = 27) the third round. In the last round, median age of participants was 51 years (interquartile range, 18) and median disease duration 4 years (interquartile range, 5); 52% were female. Patients had been treated with mycophenolate mofetil (67%), methotrexate (44%), cyclophosphamide (41%), autologous stem cell transplantation (26%), rituximab (4%) or were treatment-naïve (7%). Eight patients joined the live panel discussion. The panel reached consensus on seven benefits (prolonged progression-free survival, improved quality of life, improved daily functioning, improved pulmonary function, improved skin thickness, improved mobility and reduced fatigue) and four harms (treatment-related mortality, infections, cardiac damage, increased risk of cancer) as essential information for decision making. Also a design of a leaflet was made. Conclusion: This study identified information about treatment options in dcSSc that should be addressed with patients. Our results can be used to develop effective patient information.

In psoriatic arthritis (PsA), predisposing class I HLA alleles, the presence of synovial clonally proliferated CD8 + T cells and autoantibodies all point towards the loss of immune tolerance. However, the key mechanisms that lead to immune dysregulation are not fully understood. In other types of inflammatory arthritis, T regulatory cell (Treg) dysfunction and plasticity at sites of inflammation were suggested to negatively affect peripheral tolerance. We here addressed if Treg variances associate with psoriatic disease. We collected clinical data, sera and peripheral blood mononuclear cells from 13 healthy controls, 21 psoriasis and 21 PsA patients. In addition, we obtained synovial fluid mononuclear cells from 6 PsA patients. We studied characteristics of CD4 + CD25 + CD127loFoxp3 + Tregs by flow cytometry and used ELISA to quantify antibodies against ADAMTSL5, a recently discovered autoantigen in psoriatic disease. In comparison with their circulating counterparts, Tregs from inflamed joints express increased levels of ICOS, CTLA-4 and TIGIT. Furthermore, synovial fluid-derived Tregs have a distinct phenotype, characterized by IL-17A production and upregulation of CD161 and RORγt. We identified a subset of Tregs with intermediate Foxp3 expression as the major cytokine producer. Furthermore, ICOS + Tregs associate with PsA disease activity as measured by PASDAS. Lastly, we observed that presence of the Foxp3int Tregs associates with an increased abundance of anti-ADAMTSL5 autoantibodies. Tregs derived from the inflammatory environment of inflamed PsA joints exhibit a distinct phenotype, which associates with loss of peripheral immune tolerance in psoriatic disease.

The aim of this study was to evaluate the response of ear, nose and throat (ENT) symptoms to different immunosuppressive therapies in patients with ANCA-associated vasculitis (AAV).In this cohort study, AAV patients treated between January 2010 and April 2020 at two Dutch hospitals were included. Clinical, histological and laboratory data were collected retrospectively. ENT involvement was defined as 1) at least one ENT symptom according to the Birmingham vasculitis activity score version 3 (BVAS-3) and/or 2) presence of saddle nose deformity. Associations between therapy and ENT activity were assessed using logistic regression analysis.A total of 320 AAV patients were included, of which 209 (65.3%) had ENT involvement at some point throughout the disease course. In these 209 patients, median age at disease onset was 52.0 years (IQR 22) and 45.5% was male. Median BVAS-3 was 12 (IQR 12) at diagnosis. Despite immunosuppressive therapy 50.0% (N=77) of the patients had ENT symptoms at relapse and 29.1% (N=59) had ENT activity at last visit. No statistically significant difference in ENT activity at last visit was observed between patients treated with oral or intravenous cyclophosphamide (N=137) compared to rituximab (N=55) (adjusted OR 0.59 (95% CI 0.33-1.06), p=0.077). Lower age at disease onset and female sex were independently associated with ENT activity at last follow-up.In this cohort cyclophosphamide and rituximab therapy had similar therapeutic effects on ENT symptoms in AAV. Persistent ENT activity is a common feature despite immunosuppressive therapy.

In psoriatic arthritis (PsA), predisposing class I HLA alleles, the presence of synovial clonally proliferated CD8 + T cells and autoantibodies all point towards the loss of immune tolerance. However, the key mechanisms that lead to immune dysregulation are not fully understood. In other types of inflammatory arthritis, T regulatory cell (Treg) dysfunction and plasticity at sites of inflammation were suggested to negatively affect peripheral tolerance. We here addressed if Treg variances associate with psoriatic disease. We collected clinical data, sera and peripheral blood mononuclear cells from 13 healthy controls, 21 psoriasis and 21 PsA patients. In addition, we obtained synovial fluid mononuclear cells from 6 PsA patients. We studied characteristics of CD4 + CD25 + CD127

Background: Ear, nose and throat (ENT) manifestations are common in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), yet how to treat these manifestations remains controversial. Therefore, we systematically reviewed the literature on the efficacy of therapies on ENT manifestations in AAV. Methods: A systematic review was conducted in accordance with the PRISMA guidelines, searching Medline, Embase and Cochrane libraries, including clinical studies between January 2005 and January 2022, in adults with AAV and ENT involvement, reporting on the effects of local and systemic therapy. The critical appraisal was performed using tools provided by the Cochrane Library and the level of evidence (LoE) was scored according to the Oxford Centre for Evidence-based Medicine. Results: After screening 5609 identified studies, 136 full-text articles were assessed. Finally, 31 articles were included for critical appraisal and data-extraction. Nearly all studies (n = 29) were retrospective and scored low on LoE. The included studies evaluated local interventions (n = 11), glucocorticoids combined with conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) (n = 8), rituximab (n = 6), or mepolizumab (n = 6). Due to heterogeneity across studies meta-analysis was not performed. Four studies on mepolizumab for sinonasal symptoms (n = 92) showed response in 33–100% and relapse in 35%. Local therapy for subglottic stenosis was effective in 80–100% of patients in 11 studies (n = 157), but relapses were common (up to 83%). In five studies, hearing improvement was observed in 56–100%, with better outcomes when glucocorticoids were combined with csDMARDs compared to glucocorticoids only. Conclusion: Response rates of ENT manifestations varied widely in studies and relapses were observed frequently. Heterogeneity among studies impaired comparison.

Summary Systemic sclerosis (SSc) is a complex, heterogeneous autoimmune connective tissue disease. Autologous hematopoietic stem‐cell transplantation (AHSCT) has emerged as a valuable treatment option for rapidly progressive diffuse cutaneous SSc (dcSSc) patients, and thus far is the only treatment that has been shown to have a long‐term clinical benefit. AHSCT is thought to reintroduce immune homeostasis through elimination of pathogenic self‐reactive immune cells and reconstitution of a new, tolerant immune system. However, the mechanism of action underlying this reset to tolerance remains largely unknown. In this study we review the immune mechanisms underlying AHSCT for SSc, with a focus on the role of the innate immune cells, including monocytes and natural killer (NK) cells, in restoring immune balance after AHSCT., Postulated mechanistic effects of autologous hematopoietic stem‐cell transplantation on monocytes in systemic sclerosis

Objective SSc is a complex CTD affecting mental and physical health. Fatigue, hand function loss, and RP are the most prevalent disease-specific symptoms of systemic sclerosis. This study aimed to develop consensus and evidence-based recommendations for non-pharmacological treatment of these symptoms. Methods A multidisciplinary task force was installed comprising 20 Dutch experts. After agreeing on the method for formulating the recommendations, clinically relevant questions about patient education and treatments were inventoried. During a face-to-face task force meeting, draft recommendations were generated through a systematically structured discussion, following the nominal group technique. To support the recommendations, an extensive literature search was conducted in MEDLINE and six other databases until September 2020, and 20 key systematic reviews, randomized controlled trials, and published recommendations were selected. Moreover, 13 Dutch medical specialists were consulted on non-pharmacological advice regarding RP and digital ulcers. For each recommendation, the level of evidence and the level of agreement was determined. Results Forty-one evidence and consensus-based recommendations were developed, and 34, concerning treatments and patient education of fatigue, hand function loss, and RP/digital ulcers-related problems, were approved by the task force. Conclusions These 34 recommendations provide guidance on non-pharmacological treatment of three of the most frequently described symptoms in patients with systemic sclerosis. The proposed recommendations can guide referrals to health professionals, inform the content of non-pharmacological interventions, and can be used in the development of national and international postgraduate educational offerings.

Enthesitis is a common clinical feature of spondyloarthritis (SpA). For reliable assessment of enthesitis the Heel Enthesitis Magnetic Resonance Imaging Scoring System (HEMRIS) was developed. The aims of this study were to evaluate changes in HEMRIS over time and to evaluate whether these changes correlated with changes in clinical parameters. This single-center observational study followed patients with SpA and psoriasis, regardless of presence of clinical heel enthesitis, for two years. Clinical evaluation and ankle MRIs were performed annually. Changes in HEMRIS were compared at one-year intervals using the Wilcoxon signed-rank test. The association between changes in the HEMRIS with changes in clinical parameters was evaluated using Spearman’s correlation coefficient. In total, 38 patients were included. An increase in the inflammatory and structural HEMRIS was identified in, respectively, 12 (17.9%) and 4 (6.0%) patients in one-year intervals. We found non-significant changes in the HEMRIS during longitudinal follow-up. Changes in the HEMRIS did not correlate with changes in local or general disease activity. Our results show that MRI-findings of enthesitis assessed with HEMRIS changed in a small number of patients in a one-year interval in an observational setting. Changes in HEMRIS were not associated with changes in clinical disease activity.

ObjectiveThe aim of this study was to evaluate the response of ear, nose, and throat (ENT) symptoms to different immunosuppressive therapies in patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV).MethodsIn this cohort study, patients with AAV treated between January 2010 and April 2020 at 2 Dutch hospitals were included. Clinical, histological, and laboratory data were collected retrospectively. ENT involvement was defined as follows: (1) ≥ 1 ENT symptom according to the Birmingham Vasculitis Activity Score (version 3; BVAS3), and/or (2) presence of saddle nose deformity. Associations between therapy and ENT activity were assessed using logistic regression analysis.ResultsA total of 320 patients with AAV were included, of whom 209 (65.3%) had ENT involvement at some point throughout the disease course. In these 209 patients, median age at disease onset was 52.0 years (IQR 40.0-62.0) and 45.5% were male. Median BVAS3 was 12.0 (IQR 6.0-18.0) at diagnosis. Despite immunosuppressive therapy, 50% (n = 77) of the patients had ENT symptoms at relapse and 29.1% (n = 59) had ENT activity at their last visit. No statistically significant difference in ENT activity at last visit was observed between patients treated with oral or intravenous cyclophosphamide (CYC, n = 137) compared to rituximab (RTX, n = 55; adjusted odds ratio 0.59, 95% CI 0.33-1.06;P= 0.08). Lower age at disease onset and female sex were independently associated with ENT activity at last follow-up.ConclusionIn this cohort, CYC and RTX therapy had similar therapeutic effects on ENT symptoms in AAV. Persistent ENT activity is a common feature despite immunosuppressive therapy.

IntroductionPsoriatic arthritis (PsA) is a chronic, inflammatory, musculoskeletal disease that affects up to 30% of patients with psoriasis. Current challenges in clinical care and research include personalised treatment, understanding the divergence of therapy response and unravelling the multifactorial pathophysiology of this complex disease. Moreover, there is an urgent clinical need to predict, assess and understand the cellular and molecular pathways underlying the response to disease-modifying antirheumatic drugs (DMARDs). The TOFA-PREDICT clinical trial addresses this need. Our primary objective is to determine key immunological factors predicting tofacitinib efficacy and drug-free remission in PsA.Methods and analysisIn this investigator-initiated, phase III, multicentre, open-label, four-arm randomised controlled trial, we plan to integrate clinical, molecular and imaging parameters of 160 patients with PsA. DMARD-naïve patients are randomised to methotrexate or tofacitinib. Additionally, patients who are non-responsive to conventional synthetic (cs)DMARDs continue their current csDMARD and are randomised to etanercept or tofacitinib. This results in four arms each with 40 patients. Patients are followed for 1 year. Treatment response is defined as minimal disease activity at week 16. Clinical data, biosamples and images are collected at baseline, 4 weeks and 16 weeks; at treatment failure (treatment switch) and 52 weeks. For the first 80 patients, we will use a systems medicine approach to assess multiomics biomarkers and develop a prediction model for treatment response. Subsequently, data from the second 80 patients will be used for validation.Ethics and disseminationThe study was approved by the Medical Research Ethics Committee in Utrecht, Netherlands, is registered in the European Clinical Trials Database and is carried out in accordance with the Declaration of Helsinki. The study’s progress is monitored by Julius Clinical, a science-driven contract research organisation.Trial registration numberEudraCT: 2017-003900-28.

Contains fulltext : 283379.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To assess the perspectives of physical therapists treating patients with systemic sclerosis (SSc) on their current practice and educational needs. METHOD: In July 2019, 405 SSc patients attending a multidisciplinary SSc programme received a survey on physical therapy. Patients who indicated having received physical therapy in the past 2 years were asked to invite their treating physical therapist to complete a questionnaire including sociodemographic characteristics, referral process, content of treatment, perceived knowledge and skills, and educational needs (mostly yes/no answers). RESULTS: Forty-eight of 80 possibly eligible physical therapists treating SSc patients returned the questionnaire [median age 44 years (interquartile range 35-58); 52% female; median number of SSc patients currently treated: 1 (range 1-4)]. Eighty-one per cent (n = 39) of physical therapists had received a referral, with 69% (n = 27/39) judging its content as insufficient. The most often provided types of exercises were range of motion (96%), muscle-strengthening (85%), and aerobic (71%) exercises, followed by hand (42%) and mouth (10%) exercises. Concerning manual treatment, 65% performed either massage or passive mobilization. Regarding competences, 65% indicated feeling capable of treating SSc patients. Nevertheless, 85% expressed the need for an information website on physical therapy in SSc, and 77% for postgraduate education on SSc. CONCLUSION: Primary care physical therapists treating patients with SSc used a wide range of treatment modalities. Although most stated that they treated very few patients, the majority felt capable of treating SSc patients. Nevertheless, the large majority expressed a need for additional information and educational activities concerning SSc.

Objectives The aim of this study was to explore outcomes in a cohort of dcSSc patients fulfilling eligibility criteria for stem cell transplantation (SCT) studies but receiving standard immunosuppression. Methods From a large single-centre dcSSc cohort (n = 636), patients were identified using the published SCT trials’ inclusion criteria. Patients meeting the trials’ exclusion criteria were excluded. Results Of the 227 eligible patients, 214 met the inclusion criteria for ASTIS (Autologous Stem Cell Transplantation International Scleroderma), 82 for SCOT (Scleroderma: Cyclophosphamide Or Transplantation) and 185 for the UPSIDE (UPfront autologous haematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) trial, and 66 were excluded based on age >65 years, low diffusing capacity of the lungs for carbon monoxide (DLco), pulmonary hypertension or creatinine clearance Conclusion SCT inclusion criteria identify patients with poor outcome despite current best practice treatment. Patients meeting the inclusion criteria for SCT but who would have been excluded from the trials because of age, pulmonary hypertension, poor kidney function or DLco

Background/Aims Evaluation of skin is central to both clinical practice and trials in systemic sclerosis (SSc). This is generally done with the modified Rodnan Skin Score (mRSS). Remote consultations are now widely implemented in response to the COVID-19 pandemic, which has inevitably limited evaluation of skin. To monitor skin during this pandemic and to further explore ways to assess skin, we developed the PASTUL (Patient self-Assessment of Skin Thickness in Upper Limb) questionnaire. The aim of this study was to evaluate feasibility and validity of the PASTUL in SSc. Methods The PASTUL questionnaire specifies a simple grading of skin as normal, mild, moderate, or severely thickened at eight sites of upper limb corresponding to mRSS. Assessed grades were converted to an integer scale [0, 1, 2, 3]. Detailed instructions for patients were provided. Scleroderma Skin PRO (SSPRO) and Scleroderma Health Assessment Disability Index (SHAQ-DI) were also completed. The mRSS was done in a selection of patients. Construct validity was evaluated by examining the correlation between PASTUL, mRSS, SSPRO and SHAQ-DI using Pearson’s correlation coefficient. Content validity was evaluated by scoring relevance, clarity and practical difficulty. Test-retest reliability was estimated using intraclass correlation coefficient (ICC). Results In total, 107 patients were invited of which 83 (77.6%) completed the questionnaires. The mRSS was undertaken in 61 patients. The PASTUL was completed by patients (83.1%) or by a partner/friend (16.9%). Mean PASTUL score was 11 (SD 6), mean HAQ-DI 1.47 (SD 0.76) and mean SSPRO 49.8 (SD 26.6). PASTUL and SSPRO physical limitations correlated strongly (0.62, p < 0.001). Correlations between PASTUL and total SSPRO and mRSS upper limbs were moderate to weak (0.59, 0.50 and 0.32 respectively). Correlation between PASTUL and mRSS was stronger in lcSSc compared to dcSSc patients (0.61 vs 0.29) and when assessed by a partner/friend compared to patients themselves (0.98 vs 0.45). The PASTUL demonstrated excellent test-retest reliability (ICC of 0.92) and good content validity. P151 Table 1:Correlation of PASTUL score with other outcome measuresOutcome measurePearson's correlation coefficientP-valuemRSS0.48 Conclusion Moderate and significant correlations of PASTUL scores with total SSPRO, physical limitation scores and mRSS support the usefulness of PASTUL as an outcome measure and indicates it’s potential for use in virtual clinical settings Disclosure J. Spierings: None. V.H. Ong: None. C.P. Denton: None.

Objectives The level of detail included when describing nailfold videocapillaroscopy (NVC) methods varies among research studies, making interpretation and comparison of results challenging. The overarching objective of the present study was to seek consensus on the reporting standards in NVC methodology for clinical research in rheumatic diseases and to propose a pragmatic reporting checklist. Methods Based on the items derived from a systematic review focused on this topic, a three-step web-based Delphi consensus on minimum reporting standards in NVC was performed among members of the European League against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases and the Scleroderma Clinical Trials Consortium. Results A total of 319 articles were selected by the systematic review, and 46 items were proposed in the Delphi process. This Delphi exercise was completed by 80 participants from 31 countries, including Australia and countries within Asia, Europe, North America and South America. Agreement was reached on items covering three main areas: patient preparation before NVC (15 items), device description (5 items) and examination details (13 items). Conclusion Based on the available evidence, the description of NVC methods was highly heterogeneous in the identified studies and differed markedly on several items. A reporting checklist of 33 items, based on practical suggestions made (using a Delphi process) by international participants, has been developed to provide guidance to improve and standardize the NVC methodology to be applied in future clinical research studies.

Systemic sclerosis is a chronic autoimmune disease with a poor prognosis, particularly when a patient has rapidly progressive skin or pulmonary involvement. Autologous hematopoietic stem cell transplant is an emerging treatment for this condition, that has been demonstrated to be more effective than immunosuppressants. Careful selection of patients has reduced the transplant-related mortality and maximized the likelihood of benefit. In this report, we present three cases of successful autologous hematopoietic stem cell transplant in patients who would not have met inclusion criteria for entrance into the completed hematopoietic stem cell transplant. After >18 months of follow-up, three patients had clinically significant benefit in terms of skin tightening and pulmonary function tests. Future studies of hematopoietic stem cell transplant in systemic sclerosis may aim to carefully liberalize inclusion criteria to include patients who may not have otherwise been treated while still maintaining an acceptable safety profile.

IntroductionSystemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease associated with high morbidity and mortality, especially in diffuse cutaneous SSc (dcSSc). Currently, there are several treatments available in early dcSSc that aim to change the disease course, including immunosuppressive agents and autologous haematopoietic stem cell transplantation (HSCT). HSCT has been adopted in international guidelines and is offered in current clinical care. However, optimal timing and patient selection for HSCT are still unclear. In particular, it is unclear whether HSCT should be positioned as upfront therapy or rescue treatment for patients refractory to immunosuppressive therapy. We hypothesise that upfront HSCT is superior and results in lower toxicity and lower long-term medical costs. Therefore, we propose this randomised trial aiming to determine the optimal treatment strategy for early dcSSc by comparing two strategies used in standard care: (1) upfront autologous HSCT versus (2) immunosuppressive therapy (intravenous cyclophosphamide pulse therapy followed by mycophenolate mofetil) with rescue HSCT in case of treatment failure.Methods and analysisThe UPSIDE (UPfront autologous hematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) study is a multicentre, randomised, open-label, controlled trial. In total, 120 patients with early dcSSc will be randomised. The primary outcome is event-free survival at 2 years after randomisation. Secondary outcomes include serious adverse events, functional status and health-related quality of life. We will also evaluate changes in nailfold capillaroscopy pattern, pulmonary function, cardiac MR and high-resolution CT of the chest. Follow-up visits will be scheduled 3-monthly for 2 years and annually in the following 3 years.Ethics and disseminationThe study was approved by the Dutch Central Committee on Research Concerning Human Subjects (NL72607.041.20). The results will be disseminated through patient associations and conventional scientific channels.Trial registration numbersNCT04464434; NL 8720.

Treatment of early diffuse cutaneous systemic sclerosis (dcSSc) patients can be challenging especially when organ involvement is present. Comprehensive screening is therefore necessary to determine the nature and extent of heart, lung and kidney involvement. This should include ECG, cardiac MRI, thoracic HRCT, lung function testing, right heart catheterisation and laboratory tests including NT-proBNP and hs-cTnI. Such patients may be considered for autologous hematopoietic stem cell transplantation (HSCT) if they do not respond to conventional immunosuppressive medication and have other features of poor prognosis. Clinical decision making may be difficult however in those patients with cardiac involvement who are deemed at risk of serious adverse events from HSCT including treatment-related death from heart/lung failure due to cardiotoxicity of high dose cyclophosphamide, cytokine-release syndrome from ATG and/or fluid overload.

Despite improved health care standards and better understanding of pathophysiology, systemic sclerosis (SSc) has an increased mortality and high morbidity. Management of SSc can be challenging due to its heterogeneous nature, multi-organ involvement and limited therapeutic options. This thesis zooms in on organisation of health care and autologous stem cell transplantation (SCT) as potential targets to improve outcomes. The organization of Dutch SSc care was investigated and evaluated from different perspectives. Ways to improve quality of care were explored. Our large cross-sectional study including 650 Dutch SSc patients from thirteen hospitals, showed that patients are generally satisfied with their care. Most important points for improvement from the patient' perspective were education, clear and transparant definitions of SSc expert centers accesible for patients, and collaboration between doctors. Also, patients prioritized good patient-doctor interaction and structural multidisciplinary collaboration as the most relevant quality indicators for SSc care. In addition to the perspective of patients on health care organization, recommendations were formulated in a multidisciplinary study among doctors, nurses and paramedics. Five domains in need for improvement (shared care and multidisciplinary collaboration, exchange of medical data, education, patient empowerment and non-pharmacological care) were identified and discussed in this meeting. Furthermore, in order to support collaboration and referral structures on a regional and national level, a Delphi consensus study was done, resulting in requirements for two types of SSc centres with different levels of expertise. Another neglected area in SSc care is the perspective of caregivers. In an exploratory study the impact of SSc on caregivers and their unmet needs are described. Caregivers reported that their relationship, social lives and emotional wellbeing were affected by the disease of their loved-one. Moreover, supporting their partner or friend was sometimes hindered by a lack of knowledge about the disease, insight in the overall treatment strategy and skills to optimise communication. The importance of support and information for patients, also provided by health care professionals and peers was emphasized in this thesis. This is particularly true in the context of a complex treatment modality such as SCT. SCT is increasingly used in severe form of SSc. This treatment has demonstrated to greatly improve long-term outcomes in the diffuse subset of SSc. However, treatment-related mortality is relatively high. In the absence of strong evidence on the exact place of SCT in the course of the disease, treatment decision-making rests on the shoulders of patients and their doctors. Patient reported that this process can be very difficult and strongly guided by the physician. Also, a study on the experiences of patients during and after SCT showed that this therapy has a major physical and psychosocial impact, and that post-treatment counseling should be offered pro-actively. Lastly, in order to optimise outcomes, more research is needed to determine the optimal treatment strategy. The international UPSIDE study aims to provide more insight in optimal timing and patient selection with regard to SCT and immunosuppressive therapy. The study design is described in this thesis.

Contains fulltext : 238555.pdf (Publisher’s version ) (Open Access) The objective is to describe the spectrum of the health professional (HP) treatment approach for systemic sclerosis (SSc) from the perspective of Dutch HPs, including alignment of treatment goals set by HPs with self-reported referral reasons, coverage of patient-reported unmet care needs, and quality of communication between HPs and rheumatologists. Dutch HPs were invited through their patients with SSc to complete an anonymous online survey. The survey covered referral reasons, treatment goals, and interventions of the last patient treated, as well as the perceived quality of communication between HPs and rheumatologists. Referral reasons and treatment targets were linked to the International Classification of Functioning, Disability and Health following the refined ICF Linking Rules. Seventy-nine HPs from 8 professions (including 58 physiotherapists, 73%) completed the survey. One hundred and thirty-three different referral reasons were reported, yielding 58 different ICF codes, with 41 (70.7%) being linked to the ICF domain "body structures and functions." The reported interventions focused on body functions/structures (27.9%), training of daily activities (25.6%), education and advice (26.3%), and psychosocial interventions (20.2%). The quality of communication between HPs and rheumatologists was perceived as low. Our findings revealed numerous treatment options offered by Dutch HPs addressing the unmet care needs of patients with SSc. There is an overlap in the content of the various HP disciplines, and HP treatment goals are not sufficiently aligned with referrals of rheumatologists. HP treatment offer seemed inefficiently organized, possibly precluding rheumatologists from making targeted referrals. Communication between rheumatologists and HPs should be improved.

Objectives: To gain insight into the experiences of patients with diffuse cutaneous systemic sclerosis during and after autologous hematopoietic stem cell transplantation. Methods: Semi-structured interviews were conducted with patients who underwent hematopoietic stem cell transplantation in four university hospitals in the Netherlands. Interviews were transcribed verbatim and thematically analyzed. Results: Nine male and seven female patients were interviewed, median age 47 years (range: 27–68). Patients mentioned their life was severely disrupted before hematopoietic stem cell transplantation and remained unsettled a long time after treatment. Uncertainty because of disease progression, loss of control over health and the sense of time and fear of treatment-related adverse events were common during hospitalization. After hematopoietic stem cell transplantation, patients experienced more physical limitations than they had expected, and recovery took longer and was mentally taxing. Going back to work and finding a new balance in personal relations and social life was complicated. Patients described various strategies to deal with challenges. Family and friends provided essential support, although many experienced a dwindling social circle. Most patients also appreciated peer support. All patients were satisfied with the low threshold for contact with physicians and nurses during hospitalization. However, aftercare focused on medical aspects rather than on psychological well-being and social issues. Moreover, patients would have preferred to be better prepared on what to expect after discharge, and lacked information about self-management, prognosis, optimal recovery, work, sexuality, and family planning. Conclusion: Hematopoietic stem cell transplantation has a major physical and psychological impact on patients with diffuse cutaneous systemic sclerosis. The course of recovery after this intensive therapy was unexpectedly long for some patients and offer of support was far less pro-active post-HSCT compared to pre-HSCT and during HSCT.

Purpose This study aims to gain insight into the care provided to patients with antiphospholipid syndrome (APS) in The Netherlands and to identify areas for improvement from the perspective of both patients and clinicians. Methods APS care was evaluated using qualitative and quantitative methods. Perspectives on APS care were identified using semi-structured interviews with medical specialists, patient focus groups and a cross-sectional, online patient survey. In order to examine differences in medical practice, medical records were reviewed retrospectively regarding clinical and laboratory manifestations, pharmacological treatment and management of disease in six hospitals throughout The Netherlands. Results Fourteen interviewed medical specialists, fourteen focus group participants and 79 survey respondents participated in the study. 237 patients were included in medical record review. Only one-third of patients were diagnosed with APS within three months after entering specialist care. Diagnosis and management varied between centres and specialists. Almost 10% of triple positive patients did not receive any treatment at the time of medical record review. Major challenges according to specialists and patients were poor recognition of APS by health care professionals, fragmentation of care and lack of accessible, reliable patient education and psychosocial support. Conclusion This study describes delayed diagnosis, variability in management strategies and a burden placed on patients to orchestrate their own care in APS care in The Netherlands. Of note, almost 10% of triple positive patients did not receive any treatment, despite this group of patients being at the highest risk of recurrent thrombosis. Acknowledgements This work was supported by the Arthritis Research and Collaboration Hub (ARCH) Foundation.

Background/ objective To gain insight in the use of current systemic sclerosis (SSc) care provided by health professionals from the patient perspective. We focused on referral reasons, treatment goals, the alignment with unmet care needs, and outcome satisfaction. Methods Dutch SSc patients from 13 participating rheumatology departments were invited to complete an online survey. Descriptive statistics were used to describe current use of non-pharmacological care and outcome satisfaction. Reasons for referral and treatment goals were encoded in International Classification of Function and Disability (ICF) terms. Results We included 650 patients (mean (standard deviation [SD]) age, 59.4 (11.4) years. 50% had contact with a health professional in the past year; 76.3% since disease onset. Physiotherapists were the most frequently visited in the past year (40.0%), followed by dental hygienists (11.4%) and podiatrists (9.2%). The three most common referral reasons were pain, joint mobility and cardiovascular functions. Fatigue, Raynaud’s phenomenon, physical limitations, reduced hand function and joint problems were mentioned by more than 25% of all respondents as unmet needs. The proportion of patients treated in the past year by a health professional who were satisfied with knowledge and expertise of their health professionals was 74.4%; 73% reported improved daily activities and better coping with complaints. However, 48.9% perceived that the collaboration between rheumatologist and health professional was never or only sometimes sufficient. Conclusion Despite the high outcome satisfaction and good accessibility of health professionals, there are obstacles in the access to non-pharmacological care and communication barriers between health professionals and rheumatologists.

To provide an overview of recently published work on autologous hematopoietic stem-cell transplantation (HSCT) in patients with systemic sclerosis (SSc).Superiority of HSCT vs. intravenous cyclophosphamide pulses was demonstrated in the randomized controlled American Scleroderma: Cyclophosphamide or Transplantation (SCOT) Trial (n = 75), supporting the results from earlier studies. In the SCOT Trial, total body irradiation was used instead of the nonmyeloablative regimens used in other trials, and considered well tolerated during a follow-up time of 4.5 years. Three small uncontrolled prospective cohorts (n = 4, 14 and 18) and one retrospective analyses (n = 18), using various nonmyeloablative regimens, also showed improvement in skin involvement and lung volumes post-HSCT. Transplant-related toxicity and mortality remain an essential issue in HSCT. High treatment-related mortality was reported in one prospective cohort (n = 18), using alemtuzumab as a conditioning agent. Furthermore, cardiac complications, either treatment or disease related, require special attention. In translational studies, trends are reported in number of regulatory T cells and diversity of T-cell receptor repertoire at baseline and post-HSCT correlating with treatment response.There is increasing evidence that patients with rapidly progressive SSc may benefit from HSCT. However, optimal patient selection, pretransplantation workup and posttransplant management, still have to be established.

Immune mediated inflammatory diseases (IMIDs) have similarities in pathophysiology and treatment. Not much is known, however, about health-related quality of life (HR-QoL) in IMIDs. We assessed and compared HR-QoL, using the validated EuroQoL 5-dimensions 5-levels questionnaire, in an observational cohort comprising 530 patients (67.5% female, mean age 49 years (95% CI 35.9-50.9), mean disease duration 31.0 months (95% CI 27.2-34.8)), with the following IMIDs: connective tissue diseases (32.6%), uveitis (20.8%), inflammatory arthritis (17.7%), psoriasis (15.5%), vasculitis (6.2%), primary antiphospholipid syndrome (4.2%), and autoinflammatory diseases (2.8%). Patients used either no anti-inflammatory therapy (31.5%), monotherapy (28.7%), or a combination of anti-inflammatory drugs (39.8%). The mean HR-QoL utility score was 0.75 (95% CI 0.72-0.78). Multinominal logistic regression analysis showed a statistically significant association between a very low HR-QoL (utility score (0.70)) and female sex, rheumatological IMID or psoriasis, smoking or having smoked in the past, and current biological disease modifying anti-rheumatic drugs use.

Background Connective tissue disease associated interstitial lung disease (CTD-ILD) is associated with decreased quality of life and high mortality risk. Outcome and treatment response is unpredictable. This study aimed to identify clinical predictors for CTD-ILD with poor outcome. Methods We performed a retrospective single centre cohort study in outpatients with CTD-ILD seen between 2004 and 2018. Clinical and biochemical data, pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) results were analysed. Overall survival and progressive fibrosing ILD (PF-ILD, defined as a significant deterioration of PFT or HRCT) after two years of follow-up were assessed. Results In total, 150 patients with CTD-ILD were included. Thirty (20%) deaths occurred during a median follow-up of 40 months (IQR 27.3–60.8), which were attributed to pulmonary infection in six (4%), respiratory failure due to PF-ILD in ten (7%) and due to other causes in fourteen patients. PF-ILD occurred in 76 (50.7%) patients and was associated with poor overall survival (adjusted HR 5.73, 95%CI 1.17–28.11). Age, smoking, C-reactive protein, and steroid-use were independently associated with increased mortality risk as well. Furthermore, patients with diabetes mellitus (adjusted OR 4.52, 95%CI 1.10–18.51), steroid-use (adjusted OR 2.26, 95%CI 1.04–4.93), and a fibrotic HRCT pattern at baseline (adjusted OR 3.11, 95%CI 1.15–8.38) had a higher risk of PF-ILD. Conclusion PF-ILD is associated with increased mortality in patients with CTD-ILD. Patients with a fibrotic HRCT pattern at baseline, diabetes mellitus and steroid-use have a higher risk of developing PF-ILD.

COVID-19 pandemic heralds the biggest challenge faced by health services worldwide and remote consultations are now widely implemented. Evaluation of skin involvement with modified Rodnan Skin Score (mRSS) is central in systemic sclerosis (SSc) as it is associated with internal organ manifestations and mortality, and an increase in mRSS requires attention in all SSc subsets.1 To monitor skin activity remotely during this pandemic we developed the PASTUL (Patient self-Assessment of Skin Thickness in Upper Limb) questionnaire. The questionnaire specifies a grading of skin (normal (0), mild (1), moderate (2), severely (3) thickened) at eight sites corresponding to mRSS with maximum score assigned to each site.2 We evaluated the PASTUL questionnaire on feasibility and validity in patients with SSc who had either a remote or face-to-face appointment at the Royal Free Hospital London, UK. Informed consent was obtained and patient instructions were provided. Scleroderma Skin Patient Reported Outcome (SSPRO),3 Scleroderma Health Assessment (SHAQ),4 the Scleroderma Functional Score (SFS)5 and the mRSS were collected to evaluate construct validity. The …

We read with great interest the article of Milette and colleagues, which provides valuable insights in the interaction between patients with systemic sclerosis (SSc) and close relatives, from a pat...

Objectives To examine the treatment decision-making process of patients with dcSSc in the context of haematopoietic stem cell transplantation (HSCT). Methods A qualitative semi-structured interview study was done in patients before or after HSCT, or patients who chose another treatment than HSCT. Thematic analysis was used. Shared decision-making (SDM) was assessed with the 9-item Shared Decision Making Questionnaire (SDM-Q-9). Results Twenty-five patients [16 male/nine female, median age 47 (range 27–68) years] were interviewed: five pre-HSCT, 16 post-HSCT and four following other treatment. Whereas the SDM-Q-9 showed the decision-making process was perceived as shared [median score 81/100 (range 49–100)], we learned from the interviews that the decision was predominantly made by the rheumatologist, and patients were often steered towards a treatment option. Strong guidance of the rheumatologist was appreciated because of a lack of accessible, reliable and SSc-specific information, due to the approach of the decision-making process of the rheumatologist, the large consequence of the decision and the trust in their doctor. Expectations of outcomes and risks also differed between patients. Furthermore, more than half of patients felt they had no choice but to go for HSCT, due to rapid deterioration of health and the perception of HSCT as ‘the holy grail’. Conclusion This is the first study that provides insight into the decision-making process in dcSSc. This process is negatively impacted by a lack of disease-specific education about treatment options. Additionally, we recommend exploring patients’ preferences and understanding of the illness to optimally guide decision-making and to provide tailor-made information.

Background: Systemic sclerosis (SSc) is a rare, chronic and heterogenous disease with many possible outcomes and an uncertain horizon which presents difficulties not only for patients, but also for caregivers. Objectives: To gain more insight in the experiences and unmet needs of caregivers for people with SSc in the Netherlands. Methods: The study had a qualitative design. Participants were recruited by the Dutch patient organization (NVLE) using social media. One focus group and two individual interviews with a semi structured approach were held. Participants were asked to note down their associations with the disease, which lead on to a group conversation moderated by two researchers (MRS, CHE). The focus group was audiotaped and transcribed. Individual telephone interviews were summarized. All participants verified and approved the reports afterwards. Results: Eight caregivers (4 males, 4 females: 4 partners, 2 widowers, 1 parent and 1 friend) of patients with SSc participated. Six attended the focus group session, two were interviewed over the phone. Several challenges were reported by the participants. The first challenge is coping with the chronic disease course, unawareness of treatment options and lack of information about limitations in treatment modalities. Furthermore, the witness of patients’ ailing, changing bodies, decreasing mobility and poor energy levels without being able to provide a cure, was experienced as a huge burden by caregivers. Alongside this distress, caregivers personal lives are also affected; future opportunities are cut off, such as starting a family or continuing an active life style. Caregivers addressed invalidation and the decrease in support from others due to misjudgment and misconceptions about severity, duration and impact of the illness. Over time, this resulted in a dwindling network of social and emotional support, affecting family-life, relationships and mental health of both patient and caregiver. Another strain was the complex mutual process of coping and the lack of frank communication about the condition between the partners, towards their social network and the medical staff. This is partly due to the indolent course of the disease, but also due to fear of what the future would hold and lack of insight in prognosis. Caregivers reported that care provided at the hospital did not actively involve caregivers, nor provided them with the much-needed information with regard to prognosis, long-term treatment plans or daily care. Conclusion: SSc has a major impact on the lives of caregivers, however, current care does not actively inform, include or support them to relieve some of this burden. Further research should focus on the modalities in which caregivers can be involved in the care and which information and support is required. Disclosure of Interests: Rita Schriemer: None declared, Julia Spierings Grant/research support from: Boehringer Ingelheim, Jeska de Vries-Bouwstra: None declared, Lian De Pundert: None declared, C.H.M. van den Ende: None declared, Madelon Vonk Grant/research support from: Madelon Vonk has received unrestricted research funds from Actelion and Therabel, Consultant for: Madelon Vonk was a consultant for Actelion, Boehringer-Ingelheim, Speakers bureau: Actelion, Boehringer-Ingelheim, Roche