Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial.

BACKGROUND: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21-24 mmHg). METHODS: The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks. DISCUSSION: The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04797286.

Mental health in paediatric and adult myositis-related diseases: current state of research, interventions, and future steps from the MIHRA Psychological Impact Scientific Working Group.

Psychological and emotional well-being are critical aspects of overall health for individuals with chronic rheumatologic conditions. Mental health-related literature, however, predominantly focuses on systemic lupus erythematosus or rheumatoid arthritis, with limited emphasis on idiopathic inflammatory myopathies (IIMs). High proportions of those with juvenile myositis report psychological distress at levels warranting mental health referral. Adults with dermatomyositis diagnosed with depression or anxiety do not receive adequate mental health care. Mental health symptoms in those with IIMs are associated with worse health-related quality of life, medication adherence, and disease outcomes. Despite demonstrated high rates of mental health burden, access to mental health care remains severely lacking.Data related to mental health burden is limited by small sample size, limited generalisability, variable methods of assessment, and inconsistent diagnosis codes to define mental health conditions. Additional research is needed to validate current screening tools in myositis populations. Other relevant measurable factors include disease severity, non-health- and health-related trauma exposure, loneliness, isolation, loss of control, sleep difficulties, fatigue, pain, self-esteem, body image, sexual health, and health inequities. Studiesare needed investigating the efficacy of therapeutic and pharmacologic interventions among patients with myositis who experience depression and anxiety. Currently, knowledge and resources are limited around mental health burden and potential intervention for those living with IIMs. The Myositis International Health & Research Collaborative Alliance (MIHRA) Psychological Impact Scientific Working Group offers a preliminary road map to characterise and prioritise the work ahead to understand baseline mental health burden and compare avenues for intervention.

Developmental drugs for sarcoidosis.

Sarcoidosis is a multi-organ granulomatous inflammatory disease of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%-30% will develop a chronic progressive disease with pulmonary fibrosis leading to significant morbidity and mortality. Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited. The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity. Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.

Collaborative research in myositis-related disorders: MIHRA, a global shared community model.

Myositis International Health and Research Collaborative Alliance (MIHRA) is a newly formed purpose-built non-profit charitable research organization dedicated to accelerating international clinical trial readiness, global professional and lay education, career development and rare disease advocacy in IIM-related disorders. In its long form, the name expresses the community's scope of engagement and intent. In its abbreviation, MIHRA, conveys linguistic roots across many languages, that reflects the IIM community's spirit with meanings such as kindness, community, goodness, and peace. MIHRA unites the global multi-disciplinary community of adult and pediatric healthcare professionals, researchers, patient advisors and networks focused on conducting research in and providing care for pediatric and adult IIM-related disorders to ultimately find a cure. MIHRA serves as a resourced platform for collaborative efforts in investigator-initiated projects, consensus guidelines for IIM assessment and treatment, and IIM-specific career development through connecting research networks.MIHRA's infrastructure, mission, programming and operations are designed to address challenges unique to rare disease communities and aspires to contribute toward transformative models of rare disease research such as global expansion and inclusivity, utilization of community resources, streamlining ethics and data-sharing policies to facilitate collaborative research. Herein, summarises MIHRA operational cores, missions, vision, programming and provision of community resources to sustain, accelerate and grow global collaborative research in myositis-related disorders.

Mitochondrial transfer and implications for muscle function in idiopathic inflammatory myopathies.

Impairment in cellular bioenergetics as either the cause, consequence, or major contributor of tissue damage has drawn increasing scientific curiosity across aging and chronic health conditions, with mitochondrial dysfunction emerging as a central mechanism in the pathogenesis of a variety of inflammatory and degenerative disorders. Beyond bioenergetics, mitochondria play critical regulatory roles in programmed cell death of dysfunctional/defective cells as well as in metabolite synthesis and metabolic signalling. Further, extra-cellular exposure to fragmentation of injured mitochondria is associated with incitement of systemic and organ-based inflammation. Thus, mitochondrial function has recently drawn intense, spectral scientific interest as an integral component across maladies.In muscle, mitochondrial dysfunction is clinically associated with atrophy and diminished endurance. Direct myo-histopathological evidence characterising loss of mitochondrial integrity as a hallmark of muscle compromise was first noticed in inclusion body myositis (IBM). This was followed by the discovery of multiple deletions in mitochondrial DNA in sarcopenia, IBM, and other inflammatory myopathies, like dermatomyositis. Though fraught with bioethical considerations, the transplant technology of mitochondrial transfer is swiftly gaining prominence in cellular biology and muscle physiology to remediate mitochondrial diminution and dysfunction. Assembling seminal works and recent developments, this review ventures into the rapidly evolving landscape of mitochondrial transfer, focusing on its implications on muscle function, and offers an integrated perspective on the potential roles of mitochondrial transfer and its implications for preserving and restoring muscle health. Presented here is a consolidated viewpoint on mitochondrial transfer in idiopathic inflammatory myopathies.

Sarcoidosis and frailty: recognizing factors that foster holistic resilience.

PURPOSE OF REVIEW: Sarcoidosis is a multiorgan system disease exerting significant impact on biophysical, social, psychological and emotional well-being. Mortality and disability correlate to accessible, timely, expert care for sarcoidosis and its related complications. Across health conditions, positive healthcare interactions and interventions can rehabilitate unfavourable factors tied to concepts of ' frailty' . Here, we set out to introduce concepts related to frailty and their impact in the context of sarcoidosis. RECENT FINDINGS: Studies examining frailty across other multiorgan and single organ-based diseases that mirror organ involvement in sarcoidosis demonstrate findings that bear relevance in sarcoidosis. Namely, factors predisposing a person to frailty are a multifactorial phenomenon which are also reflected in the lived experience of sarcoidosis; and that early diagnosis, intervention and prevention may alter a course towards more favourable health outcomes. SUMMARY: Factors predisposing to frailty in other health conditions may also signal a risk in sarcoidosis. In turn, proactive health preservation - regardless of age - may lead to improved biopsychosocial reserve and health-related quality of life. Fortifying holistic resilience in sarcoidosis is anticipated to reduce risk of the occurrence and prolongation of health-related complications, and facilitate swifter recovery from biophysical complications as well as from psychosocial and emotional stressors.

Construct validity and reliability of the assessment of systemic sclerosis-associated raynaud's phenomenon (ASRAP) questionnaire.

OBJECTIVES: Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). METHODS: An international multicentre study validation study of the 27-item Assessment of Systemic sclerosis-associated RAynaud's Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1-week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning. RESULTS: Four hundred and twenty SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648-0.727, p< 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258-0.504, p< 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427-0.575, p< 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (p< 0.05 for all comparisons). There was excellent repeatability at 1-week amongst patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, p< 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77 respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53-7.81, p= 0.029) was estimated. CONCLUSION: ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP.

Endothelial Biomarkers of Systemic Sclerosis-Associated Pulmonary Hypertension.

OBJECTIVE: Despite efforts at early detection, patients with systemic sclerosis (SSc) pulmonary hypertension (PH) present with advanced disease. We sought to determine whether endothelial biomarkers (asymmetric dimethylarginine [ADMA], soluble endoglin [sEng], and pentraxin-3 [PTX-3]) can determine SSc-PH risk or differentiate between SSc-PH subgroups. METHODS: ADMA, sEng, and PTX-3 were measured by enzyme-linked immunosorbent assay in four groups: 1) 18 healthy controls, 2) 74 patients with SSc-PH, 3) 44 patients at high risk for PH features, and 4) 10 patients with low risk for PH features. High-risk features included a diffusion capacity (DLco) less than 55% with a forced vital capacity (FVC) greater than 70%, an FVC/DLco ratio of >1.6, or a right ventricular systolic pressure on an echocardiogram greater than or equal to 40 mm Hg. ADMA, sEng, and PTX-3 were compared between these four groups as well as stratified based on the three SSc-PH clinical classification groups (pulmonary arterial hypertension [PAH], left-heart disease, and interstitial lung disease [ILD]). RESULTS: PTX-3 was significantly lower in subjects with SSc at low risk for PH (median 27.0 pg/ml [interquartile range (IQR) 19.0-47.3]; P < 0.003) than the other groups. The area under the receiver operating characteristic curve was 0.87 (95% confidence interval 0.76-0.98, P = 0.0002) to differentiate low risk from high risk for patients with PH. PTX-3 was significantly lower in SSc-PH from disease of the left side of the heart (57.5 pg/ml [IQR 39.8-79.0]; P < 0.01) compared to SSc-PH from either PAH (85.5 pg/ml [IQR 56.3-104.5]) or ILD (90.3 pg/ml [IQR 74.9-111.0]). Neither ADMA nor sEng differed between the four groups. CONCLUSION: PTX-3 is a promising biomarker of PH risk status in patients with SSc as well as a possible marker of precapillary PH, which should be validated in an external cohort.

Multi-Organ System Screening, Care, and Patient Support in Systemic Sclerosis.

Systemic sclerosis (SSc) is a heterogenous systemic autoimmune disease of complex multi-organ manifestations with a disease-specific mortality of >50%. The patient journey is fraught with severe, diverse, and diffuse physical impairment, psychological burden, and diminishing health-related quality of life. SSc remains unfamiliar to many clinicians. Delayed/misdiagnosis, inadequate screening, and attention for common complications with potentially preventable disability/death contribute to patients feeling isolated and unsupported. We present actionable standards including screening, anticipatory guidance, and counseling in patient-centered SSc-care emphasizing psycho-social health as the central goal, whereas robust vigilance and efforts to improve biophysical health and survival are imperatives that support this goal.

Patient Experience of Systemic Sclerosis-Related Calcinosis: An International Study Informing Clinical Trials, Practice, and the Development of the Mawdsley Calcinosis Questionnaire.

Systemic sclerosis (SSc) -related calcinosis can be a debilitating, constantly painful, poorly understood vascular complication of calcium hydroxyapatite deposition in soft tissue structures that affects approximately 40% of both limited and diffuse cutaneous SSc subtypes. This publication describes the iterative and multitiered international qualitative investigations that yielded remarkable insights into natural history, daily experience, and complications of SSc-calcinosis providing pivotal information for health management. Patient-driven question development and field testing, according to Food and Drug Administration guidance, propelled the development of a patient-reported outcome measure for SSc-calcinosis, the Mawdsley Calcinosis Questionnaire.

Assessment of the Systemic Sclerosis-Associated Raynaud's Phenomenon Questionnaire: Item Bank and Short-Form Development.

OBJECTIVE: To develop, refine, and score a novel patient-reported outcome instrument to assess the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). METHODS: The Assessment of Systemic Sclerosis-Associated Raynaud's Phenomenon (ASRAP) questionnaire items were developed with patient insight partner support and grounded in the lived patient experience of SSc-RP. ASRAP items underwent formal qualitative assessment and linguistic testing. An international multicenter study was undertaken to field test the preliminary ASRAP questionnaire. RESULTS: A preliminary 37-item ASRAP questionnaire was supplemented with 2 additional items following expert review to enhance content coverage before undergoing formal linguistic testing to optimize readability. Patient cognitive debriefing interviews were undertaken to enhance comprehension, ambiguity, cognitive difficulty, relevance, and content coverage of both the ASRAP items and instructions. We enrolled 420 SSc patients from scleroderma centers in the UK and US over 2 consecutive winters. Factor analysis with item response theory was undertaken to remove redundant and poorly fitting items. The retained 27-item long-form ASRAP questionnaire was calibrated and scored using the graded response model. A fixed 10-item short-form ASRAP questionnaire was developed using computerized adaptive testing simulations. CONCLUSION: The ASRAP questionnaire has been developed with extensive SSc patient input, with items grounded in the lived experience of SSc-RP to ensure strong content validity, with a focus on how patients feel and function. An advanced psychometric approach with expert input has removed redundant and/or poorly fitting items without eroding content validity. Long- and short-form ASRAP questionnaires have been calibrated and scored to permit formal validation.

Impact of lung function and baseline clinical characteristics on patient-reported outcome measures in systemic sclerosis-associated interstitial lung disease.

OBJECTIVE: The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with SSc-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken. METHODS: Patient-reported outcome (PRO) measures [St. George's Respiratory Questionnaire (SGRQ), Functional Assessment of Chronic Illness Therapy (FACIT)-Dyspnoea, and HAQ-Disability Index (HAQ-DI), incorporating the Scleroderma HAQ visual analogue scale (SHAQ VAS)] at baseline and week 52 were assessed for associations to SSc-ILD severity. RESULTS: At baseline and at week 52, forced vital capacity (FVC) <70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted [week 52: SGRQ 45.1 vs 34.0 (P < 0.0001); FACIT-Dyspnoea 48.9 vs 44.5 (P < 0.0001); HAQ-DI 0.7 vs 0.6 (P < 0.0228); SHAQ VAS breathing problems 3.6 vs 2.6 (P < 0.0001)]. Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with >30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (P < 0.001). CONCLUSION: Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL. TRIAL REGISTRATION: clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933.

'I turned in my man card': a qualitative study of the experiences, coping styles and support needs of men with systemic sclerosis.

OBJECTIVES: Men with SSc have a more severe clinical phenotype and reduced survival compared with women. No previous psychosocial studies have focused solely on men with SSc. This study aimed to explore experiences, coping strategies and support preferences of men with SSc. MATERIAL AND METHODS: An international qualitative research study comprising seven focus groups (three USA, four UK) of 25 men with SSc. Transcripts were analysed using reflexive thematic analysis. RESULTS: Three overarching themes and one underpinning theme were identified. In 'impact of SSc on masculinity', the men described an 'impact on roles and activities', reported 'sex, intimacy, and erectile dysfunction' as a salient issue that may be overlooked by clinicians, and experienced challenges to 'masculine self-image'. 'Dealing with SSc' meant 'always being prepared', 'becoming an expert' and 'balancing priorities' in responsibilities, activities and symptom management. In 'support for living with SSc' men were selective in '(Not) talking about SSc', would '(reluctantly) accept help' and described 'preferences for support'. Underpinning these experiences was 'facing an uncertain future' with some participants preferring not to focus on an unpredictable future, and others worrying about disease progression. CONCLUSION: These novel data suggest SSc impacts male patients' masculine identity and roles, and although they will accept practical help, they may mask the full emotional impact. Sex and intimacy are important overlooked issues with erectile dysfunction often not discussed at diagnosis. Further research should develop a self-management intervention for men with rheumatic diseases with a combination of disease-specific and common core components.

Nephrogenic systemic fibrosis-related pulmonary restriction: An under-appreciated manifestation potentially reversible with imatinib therapy.

Nephrogenic systemic fibrosis typically occurs in patients with renal failure and is strongly associated with gadolinium exposure through stimulation of macrophage-activated fibrosis. Patients present with prominent fibrosis of the skin and internal organs. Quality of life is significantly diminished due to impairment from restrictive mobility of large and small joint contractures, pain, and ensuing psychological stress. Nephrogenic systemic fibrosis can be severe and life-threatening. Nephrogenic systemic fibrosis patients reliant on hemodialysis with cutaneous symptoms, defined as hyperpigmentation, hardening, and tethering of skin on the extremities, experience rates of mortality as high as 48%. Physician awareness and preventive strategies coincided with a reduction in the incidence of nephrogenic systemic fibrosis. Several treatments, of which physical therapy may be a key adjuvant, have been used to treat nephrogenic systemic fibrosis, with variable and inconsistent results, lacking wide consensus. Improvement of renal function may improve nephrogenic systemic fibrosis, with some patients demonstrating stabilization or improvement after renal transplantation or resolution of acute renal failure. Imatinib, a tyrosine kinase inhibitor, demonstrates antifibrotic effects in the skin and recently was used to successfully treat nephrogenic systemic fibrosis. We report a case of severe nephrogenic systemic fibrosis with extensive skin fibrosis causing extrapulmonary restriction who demonstrated improved lung function following treatment with imatinib.

World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) Core Set Development for Interstitial Lung Disease.

Background: The World Health Organization (WHO) introduced the International Classification of Functioning, Disability, and Health (ICF) as a scientific method of disability data collection comprised of >1,200 categories describing the spectrum of impairment types (functional, symptoms-based and anatomical) under the bio-psycho-social model with consideration of environmental and personal factors (pf). ICF Core Sets and ICF Checklists are streamlined disease-specific resources for clinical use, service provision, and for use in health economics and health policy. ICF can disclose strengths and weaknesses across multiple patient-reported outcome measures (PROMs) and help consolidate best-fitting question-items from multiple PROMs. Interstitial lung diseases (ILDs), are generally progressive, with restrictive physiology sometimes occurring in the context of multi-organ autoimmunity/inflammatory conditions such as connective tissue diseases (CTDs). In spite of significant associated morbidity and potential disability, ILD has yet to be linked to the ICF. Methods: Each instrument and their question-items within the consensus-recommended core sets for clinical trials in ILD were deconstructed to single concept units, and then linked per updated ICF linkage rules. Inter-linker agreement was established. Three additional subsequently validated measures were also included. Results: One-hundred-eleven ICF categories were identified for ten PROMs and three traditional objective measures that were amenable to ICF linkage. The proportion of agreement ranged from 0.79 (95% CI: 0.62, 0.91) to 0.93 (0.76, 0.99) with the overall proportion of inter-linker agreement being very high 0.86 (0.82, 0.89) for the initial instruments, with 94-100% for the three additional PROMs. Thirty-four new 'Personal Factors' emerged to capture disease-specific qualities not elsewhere described in ICF, e.g. 'pf_embarrassed by cough' or 'pf_panic/afraid when can't get a breath'. Conclusion: This first known effort in ICF linkage of ILD has provided important revelations on the current utility of the ICF in lung disease. Results have indicated areas for meaningful assessment of ICF descriptors for lung impairment. The mapping across PROMs provides insight into possibilities of developing more streamline and precise instrumentation. Finally, familiarity with the ICF in ILD may enable clinicians to experience a smoother transition with the imminent harmonization of ICD and ICF, ICD-11.

Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches.

Sarcoidosis is a systemic granulomatous inflammatory disease of unknown etiology. It affects the lungs in over 90% of patients yet extra-pulmonary and multi-organ involvement is common. Spontaneous remission of disease occurs commonly, nonetheless, over 50% of patients will require treatment and up to 30% of patients will develop a chronic progressive non-remitting disease with marked pulmonary fibrosis leading to significant morbidity and death. Guidelines outlining an immunosuppressive treatment approach to sarcoidosis were recently published, however, the strength of evidence behind many of the guideline recommended drugs is weak. None of the drugs currently used for the treatment of sarcoidosis have been rigorously studied and prescription of these drugs is often based on off-label" indications informed by experience with other diseases. Indeed, only two medications [prednisone and repository corticotropin (RCI) injection] currently used in the treatment of sarcoidosis are approved by the United States Food and Drug Administration. This situation results in significant reimbursement challenges especially for the more advanced (and often more effective) drugs that are favored for severe and refractory forms of disease causing an over-reliance on corticosteroids known to be associated with significant dose and duration dependent toxicities. This past decade has seen a renewed interest in developing new drugs and exploring novel therapeutic pathways for the treatment of sarcoidosis. Several of these trials are active randomized controlled trials (RCTs) designed to recruit relatively large numbers of patients with a goal to determine the safety, efficacy, and tolerability of these new molecules and therapeutic approaches. While it is an exciting time, it is also necessary to exercise caution. Resources including research dollars and most importantly, patient populations available for trials are limited and thus necessitate that several of the challenges facing drug trials and drug development in sarcoidosis are addressed. This will ensure that currently available resources are judiciously utilized. Our paper reviews the ongoing and anticipated drug trials in sarcoidosis and addresses the challenges facing these and future trials. We also review several recently completed trials and draw lessons that should be applied in future.