Ann Impens

The Scleroderma Patient-centered Intervention Network (SPIN) Cohort: protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context

Introduction Psychosocial and rehabilitation interventions are increasingly used to attenuate disability and improve health-related quality of life (HRQL) in chronic diseases, but are typically not available for patients with rare diseases. Conducting rigorous, adequately powered trials of these interventions for patients with rare diseases is difficult. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of patient organisations, clinicians and researchers. The aim of SPIN is to develop a research infrastructure to test accessible, low-cost self-guided online interventions to reduce disability and improve HRQL for people living with the rare disease systemic sclerosis (SSc or scleroderma). Once tested, effective interventions will be made accessible through patient organisations partnering with SPIN. Methods and analysis SPIN will employ the cohort multiple randomised controlled trial (cmRCT) design, in which patients consent to participate in a cohort for ongoing data collection. The aim is to recruit 1500–2000 patients from centres across the world within a period of 5 years (2013–2018). Eligible participants are persons ≥18 years of age with a diagnosis of SSc. In addition to baseline medical data, participants will complete patient-reported outcome measures every 3 months. Upon enrolment in the cohort, patients will consent to be contacted in the future to participate in intervention research and to allow their data to be used for comparison purposes for interventions tested with other cohort participants. Once interventions are developed, patients from the cohort will be randomly selected and offered interventions as part of pragmatic RCTs. Outcomes from patients offered interventions will be compared with outcomes from trial-eligible patients who are not offered the interventions. Ethics and dissemination The use of the cmRCT design, the development of self-guided online interventions and partnerships with patient organisations will allow SPIN to develop, rigourously test and effectively disseminate psychosocial and rehabilitation interventions for people with SSc.

Reliability and Validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument

OBJECTIVE To refine the previously developed scleroderma (systemic sclerosis [SSc]) gastrointestinal tract (GIT) instrument (SSC-GIT 1.0). METHODS We administered the SSC-GIT 1.0 and the Short Form 36 to 152 patients with SSc; 1 item was added to the SSC-GIT 1.0 to assess rectal incontinence. In addition, subjects completed a rating of the severity of their GIT involvement (from very mild to very severe). Evaluation of psychometric properties included internal consistency reliability, test-retest reliability (mean time interval 1.1 weeks), and multitrait scaling analysis. RESULTS Study participants were mostly women (84%) and white (81%); 55% had diffuse SSc. Self-rated severity of GIT involvement ranged from no symptoms to very mild (39%), mild (21%), moderate (31%), and severe/very severe (9%). Of an initial 53 items in the SSC-GIT 1.0, 19 items were excluded, leaving a 34-item revised instrument (the University of California, Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 [UCLA SCTC GIT 2.0]). Analyses supported 7 multi-item scales: reflux, distention/bloating, diarrhea, fecal soilage, constipation, emotional well-being, and social functioning. Test-retest reliability estimates were >/=0.68 and coefficient alphas were >/=0.67. Participants who rated their GIT disease as mild had lower scores on a 0-3 scale on all 7 scales. Symptom scales were also able to discriminate subjects with corresponding clinical GIT diagnoses. The Total GIT Score, developed by averaging 6 of 7 scales (excluding constipation), was reliable and provided greater discrimination between mild, moderate, and severe self-rated GIT involvement than individual scales. CONCLUSION This study provides support for the reliability and validity of the UCLA SCTC GIT 2.0, an improvement over the SSC-GIT 1.0, and supports a Total GIT Score in SSc patients with GIT.

Randomized Placebo-Controlled Crossover Trial of Tadalafil in Raynaud’s Phenomenon Secondary to Systemic Sclerosis

Objective. Raynaud’s phenomenon (RP) is an important clinical feature of systemic sclerosis (SSc) for which consistently effective therapies are lacking. The study was designed to assess the safety, tolerability, and efficacy of tadalafil, a selective, long acting type V cyclic GMP phosphodiesterase (PDE-5) inhibitor, in this clinical syndrome. Methods. We performed a prospective, randomized, double-blind, placebo-controlled, crossover study comparing oral tadalafil at a fixed dose of 20 mg daily for a period of 4 weeks versus placebo in women with RP secondary to SSc. Results. Thirty-nine subjects completed the study and were evaluable. There were no statistically significant differences in Raynaud Condition Score (RCS), frequency of RP episodes, or duration of RP episodes between treatment groups. Placebo response was a confounding factor. Tadalafil was well tolerated. Conclusion. Tadalafil appears to be safe and well tolerated but lacks efficacy in comparison to placebo as a treatment for RP secondary to SSc.

Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis

IntroductionSystemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monokine induced by interferon-γ (IFN-γ) (MIG/CXCL9) and IFN-inducible protein 10 (IP-10/CXCL10), inhibit angiogenesis by binding CXCR3. In addition, CXCL16 promotes angiogenesis by binding its unique receptor CXCR6. In this study, we determined the expression of these chemokines and receptors in SSc skin and serum.MethodsImmunohistology and enzyme-linked immunosorbent assays (ELISAs) were used to determine chemokine and chemokine receptor expression in the skin and serum, respectively, of SSc and normal patients. Endothelial cells (ECs) were isolated from SSc skin biopsies and chemokine and chemokine receptor expression was determined by quantitative PCR and immunofluorescence staining.ResultsAntiangiogenic IP-10/CXCL10 and MIG/CXCL9 were elevated in SSc serum and highly expressed in SSc skin. However, CXCR3, the receptor for these chemokines, was decreased on ECs in SSc vs. normal skin. CXCL16 was elevated in SSc serum and increased in SSc patients with early disease, pulmonary arterial hypertension, and those that died during the 36 months of the study. In addition, its receptor CXCR6 was overexpressed on ECs in SSc skin. At the mRNA and protein levels, CXCR3 was decreased while CXCR6 was increased on SSc ECs vs. human microvascular endothelial cells (HMVECs).ConclusionsThese results show that while the expression of MIG/CXCL9 and IP-10/CXCL10 are elevated in SSc serum, the expression of CXCR3 is downregulated on SSc dermal ECs. In contrast, CXCL16 and CXCR6 are elevated in SSc serum and on SSc dermal ECs, respectively. In all, these findings suggest angiogenic chemokine receptor expression is likely regulated in an effort to promote angiogenesis in SSc skin.

Association of gastrointestinal involvement and depressive symptoms in patients with systemic sclerosis

OBJECTIVES SSc-associated gastrointestinal tract involvement (SSc-GIT) is an important predictor of depressive symptoms. University of California at Los Angeles Scleroderma Clinical trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) is a 34-item valid instrument that captures GIT symptom severity and impact on quality of life. It has seven GI-specific scales and a total GIT score. The objectives were to assess: (i) whether there is an association between depressed mood with GI symptom scales as assessed by the UCLA SCTC GIT 2.0 instrument; and (ii) to explore which GI-specific symptom scales are associated with depressed mood in patients with SSc. METHODS One hundred and fifty-two patients with SSc completed the UCLA SCTC GIT 2.0 and the Center for Epidemiologic Studies Short Depression scale (CES-D10). Patients were divided into depressed (CES-D ≥ 10) or non-depressed group (CES-D < 10) and compared using t-test or chi-square test. Multiple linear regression was used to determine associations between GI scales and depressed mood (CES-D). RESULTS Study participants were 84% female, 78% Caucasian and 40% had depressed mood (CES-D10 ≥ 10). Patients with depressed mood had statistically worse GI scale scores (except fecal soilage) and worse total GIT score (P < 0.05). In the multivariable model reflux and constipation scales were independently associated with worse CES-D scores (P = 0.01-0.06) CONCLUSION SSc-GIT involvement is associated with depressed mood. Reflux and constipation scales of UCLA-SCTC GIT 2.0 were independently associated with CES-D. Future studies should assess if treatment of GIT symptoms will improve depressed mood in patients with SSc-GIT.

The 6-minute walk test in scleroderma—how measuring everything measures nothing

The 6-min walk test (6MWT) is a standardized measure of submaximal exercise capacity that has served as the primary measure of outcome in studies of pulmonary arterial hypertension. Never fully validated in scleroderma, a variety of data suggest that many non-pulmonary aspects of scleroderma contribute to its results thereby blunting the ability of the 6MWT to measure change in lung function. Although reproducible, the lack of correlation with measures of parenchymal lung disease demonstrates an insurmountable lack of both construct and content validity. The 6MWT should be abandoned as an outcome measure in lung disease complicating scleroderma.

Minimally important differences of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument.

Objective. To provide minimally important difference (MID) estimates for the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) in a longitudinal observational cohort. Methods. We administered the UCLA SCTC GIT 2.0 to 115 patients with systemic sclerosis (SSc) at 2 timepoints 6 months apart. The UCLA SCTC GIT 2.0 has 7 multi-item scales: Reflux, Distension/Bloating, Diarrhea, Fecal Soilage, Constipation, Emotional Well-being, and Social Functioning and a total GIT score. All scales are scored from 0 [better health-related quality of life (HRQOL)] to 3 (worse HRQOL) except the diarrhea and constipation scales (ranges 0–2 and 0–2.5, respectively). Patients also rated their overall and upper and lower GIT involvement during the second visit using a response scale with options “much better; somewhat better; almost the same; somewhat worse; or much worse.” The minimally changed group was defined by those reporting they were somewhat better or somewhat worse compared to first visit. Results. Study participants were 84% female and 81% white with a mean disease duration of 6.9 years. The MID estimates for improvement ranged from 0.07 for the Social Functioning scale to 0.36 for the Emotional Well-being scale. For worsening, the MID estimates ranged from 0.06 for the Fecal Soilage scale to 0.21 for the Social Functioning scale. Conclusion. We provide MID estimates for the UCLA SCTC GIT 2.0 scales. This information can aid in interpreting scale scores in future randomized controlled trials and observational studies.

Discordance between Patient and Physician Assessments of Disease Severity in Systemic Sclerosis

Objective. To describe the magnitude and correlates of discordance between patient and physician assessments of disease severity in patients with systemic sclerosis (SSc). Methods. Subjects were patients enrolled in the Canadian Scleroderma Research Group Registry. The outcomes of interest were patient and physician global assessments of disease severity (scales ranging from 0–10). Predictors of disease severity represented the spectrum of disease in SSc (skin involvement, severity of Raynaud’s phenomenon, shortness of breath, gastrointestinal symptoms and pain, number of fingertip ulcers, tender and swollen joints, creatinine, and fatigue). The results of the analysis were validated in an independent sample of patients with SSc from the United States. Results. Patients perceived greater disease severity than physicians (mean difference 0.78 ± 2.65). The agreement between patient and physician assessments of disease severity was, at best, modest (intraclass correlation 0.3774; weighted κ 0.3771). Although both patients and physicians were influenced by skin scores, breathlessness, and pain, the relative importance of these predictors differed. Patients were also influenced by other subjective symptoms, while physicians were also influenced by disease duration and creatinine. The predictors explained 56% of the deviance in the patient global assessments and 29% in the physician assessments. These findings were confirmed in the US dataset. Conclusion. Patients and physicians rate SSc disease severity differently in magnitude and are influenced by different factors. Patient-assessed and physician-assessed measures of severity should be considered as complementary and used together in future studies of SSc.

Digital Ischemia in Scleroderma Spectrum of Diseases

Systemic Sclerosis (Scleroderma, SSc) is a disease of unknown etiology characterized by widespread vasculopathy and extracellular matrix deposition leading to fibrosis and autoimmune processes. Digital ischemia (digital ulcers (DUs)) is the hallmark of SSc-related vasculopathy and is characterized by endothelial dysfunction leading to intimal proliferation and thrombosis. It happens frequently (30% of the patients each year) and it is associated with significant morbidity. This paper summarizes the current information regarding pathogenesis, definitions, management, and exploratory therapies in DUs associated with SSc.

A systematic review of social, economic and diplomatic aspects of short-term medical missions

BackgroundShort-term medical missions (STMMs) represent a grass-roots form of aid, transferring medical services rather than funds or equipment. The objective of this paper is to review empirical studies on social, economic and diplomatic aspects of STMMs.MethodsA systematic literature review was conducted by searching PubMed and EBSCOhost for articles published from 1947–2014 about medical missions to lower and middle income countries (LMICs). Publications focused on military, disaster and dental service trips were excluded. A data extraction process was used to identify publications relevant to our objective stated above.ResultsPubMed and EBSCOhost searches provided 4138 and 3262 articles respectively for review. Most articles that provide useful information have appeared in the current millennium and are found in focused surgical journals. Little attention is paid to aspects of volunteerism, altruism and philanthropy related to STMM activity in the literature reviewed (1 article). Evidence of professionalization remains scarce, although elements including guidelines and tactical instructions have been emerging (27 articles). Information on costs (10 articles) and commentary on the relevance of market forces (1 article) are limited. Analyses of spill-over effects, i.e., changing attitudes of physicians or their communities towards aid, and characterizations of STMMs as meaningful foreign aid or strategic diplomacy are few (4 articles).ConclusionsThe literature on key social, economic and diplomatic aspects of STMMs and their consequences is sparse. Guidelines, tactical instructions and attempts at outcome measures are emerging that may better professionalize the otherwise unregulated activity. A broader discussion of these key aspects may lead to improved accountability and intercultural professionalism to accompany medical professionalism in STMM activity.