The Enhanced Liver Fibrosis (ELF) test is a serum test including the serum concentrations of amino-terminal pro-peptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and hyaluronic acid (HA). A recent single centre study showed that ELF score and its components are markers of overall fibrosis in systemic sclerosis (SSc) mainly reflecting skin and lung involvement (1).
Objectives
To determine the value of ELF score and its single analytes in an independent multicentre cohort of SSc patients.
Methods
254 SSc patients from 6 European Rheumatology Centres were included in this study. Clinical data were collected at time of sampling. Serum samples were collected and stored according to EUSTAR biobanking recommendations (2). Sera were analysed employing a high-throughput in vitro diagnostic (Siemens Alpha-Centaur). Statistical analysis was performed with SPSS software V.24.
Results
The 254 SSc patients had a mean age 55.8±13.8 years, and included 209 females and 80 patients with diffuse cutaneous SSc (dcSSc). ELF score was overall higher in males than in females (p=0.0236) as well as in dcSSc compared to limited cutaneous SSc patients (p=0.0015). ELF score and the single markers significantly correlated with the degree of skin involvement (mRSS) and inversely correlated with FVC%, TLC% and DLCO%. Concordantly all markers significantly correlated with skin and lung severity as assessed by the Medsger9s scale (Table 1). TIMP-1 and PIIINP levels were higher in patients with lung fibrosis assessed by chest HRCT scan (p=0.0126 and p=0.0308 respectively). Significant correlation (p<0.0001) was found between ELF score, TIMP-1, PIIINP, HA and total disease severity and activity. Multivariate analysis indicated that age (p<0.0001), mRSS (p<0.0001) and DLCO% (p=0.005) were independently associated with ELF score.
Conclusions
The value of ELF score as independent marker of skin and lung involvement is confirmed in a second independent multicentre cohort of SSc patients. A longitudinal study paired with analysis of large cohort of healthy controls is currently on going to identify a SSc specific test with the highest predictive value for skin and lung progression independently of age and gender.
References
Abignano G et al. Ann Rheum Dis. 2014. Beyer C et al. Ann Rheum Dis. 2011.
Systemic sclerosis (SSc) is a disease orphan of effective disease modifying agents. The diffuse cutaneous subset (dcSSc) is targeted in most clinical trials. Nevertheless, the high variability in clinical outcome at 12 months is limiting effective RCTs design and interpretation. The Global Ranked Composite Score (GRCS) and the Composite Response Index in SSc (CRISS) are the most recent attempts to capture overall response to treatment in dcSSc [1, 2]. Activation of interferon type 1 (IFN) pathway is associated with severe clinical manifestations in SSc. Several studies have indicated that the serum concentration of CCL2, CCL8, CCL19, CXCL9, CXCL10 and CXCL11 are the most relevant to measure IFN induced activation of PBMCs [3-4].
Objectives
Here we aimed to determine whether IFN pathway activation measured by a serum test could be used to stratify patients with dcSSc for severe clinical outcome at 12 months as measured by GRCS and CRISS.
Methods
Serum concentration of CCL2, CCL8, CCL19, CXCL9, CXCL10, and CXCL11 was measured by Luminex xMAP technology (Myriad RBM) in 143 SSc patients and 35 healthy controls (HC). IFN score was calculated as the average of the natural logarithm of the above chemokines. IFN score mean + 2STDV in the HC sera was adopted as cut off for IFN LO (within this range) or HI (above) [5]. Clinical outcomes at baseline and at 12 months were recorded. GRCS and CRISS were calculated at 12 months. GRCS were compared by Mann Whitney test. Fisher exact test was used to analyse the proportion of patients with CRISS of 0% or >0%. CRISS and GRCS correlation was tested by Spearman's rank correlation.
Results
All chemokines had a higher serum concentration in SSc vs HC (p<0.0001 for all). Median IFN score was higher in SSc than HC (5.26 vs 4.70, p<0.0001). There was no difference associated with disease subset or duration. To simulate enrollment criteria in a RCT we analyzed the 12 months outcomes of the dcSSc patients with ≤6 years disease duration. Sixty six 12-month outcome data were available. 37 were IFN HI and 29 IFN LO at baseline. The IFN HI group had a higher mRSS (median 9.5 vs 5, p= 0.03), CRP (10.2 vs 5, p=0.0003) and NT-proBNP (195 vs 50.5, p=0.001). We recorded 7 deaths for SSc and 5 lung failures (3 FVC drop, 2 DLCO drop); 3 had worsening of FVC, 4 improvement and 49 no change; 11 had worsening of HAQ-DI, 5 improvement and 43 no change; 9 had worsening of mRSS, 7 improvement and 43 no change (table 1). GRCS ranged from -59 to 64 and was negative in 29 (21 IFN HI, 8 IFN LO) and positive in 37 (16 IFN HI, 21 IFN LO). IFN HI patients had a worse outcome at 12 months with GRCS median score of -12 vs 15 in IFN LO (p=0.0271)(fig. 1). Accordingly, GRCS favored IFN LO in 68.4% of 1073 (37*29) pairwise comparisons versus 31.6% of IFN HI (p=0.0001). CRISS was 0 in 46 (28 IFN HI, 18 IFN LO) and >0 in 20 (9 IFN HI, 11 IFN LO). Spearman's rank correlation of the two scores was r= 0.5113. Consistent with GRCS data, CRISS was 0 in 76% of IFN HI vs 62% of IFN LO (P=0.046).
Conclusion
Serum IFN Score predicts worse clinical outcome at 12 months in dcSSc. Stratification for IFN score could aid both in clinical trial design and clinical management. Moreover, here we show that GRCS and CRISS may be sufficiently sensitive to measure difference in composite outcome at 12 months in dcSSc in an observational setting and they correlate with each other in this observational setting.
References
[1] Sullivan KM. N Engl J Med2018 [2] Khanna D. Arthritis Rheumatol2016 [3] Liu X. Arthritis Rheum2013 [4] Maija-Leena Eloranta. Ann Rheum Dis2010 [5] Bauer JW. PLoS Med2006
Disclosure of Interests
Antonio Carriero: None declared, Giuseppina Abignano: None declared, Michelle Hutchinson: None declared, Karri Ballard : None declared, Sookhoe Eng: None declared, Paul Emery Grant/research support from: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, Roche, Consultant for: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, UCB, Roche, Novartis, Gilead,Samsung, Sandoz and Lilly, Maya Buch Grant/research support from: Pfizer LTD, UCB, Consultant for: AbbVie, Eli Lilly, EMD Serono, Pfizer Ltd., Sanofi, Francesco Del Galdo: None declared
Abstract Background/Aims People with PMR report experiencing pain, stiffness and weakness, often impacting everyday tasks. Many fear exercise will exacerbate symptoms and need reassurance that exercise is helpful and not harmful. However, no PMR-specific, exercise educational resource currently exists. The aim of this funded study was to co-create an exercise educational resource for, and with, people with PMR that would be acceptable to both patients and health professionals. Methods A steering group of people with PMR and UK clinicians/academics from Keele and Leeds universities was identified. People with PMR and clinical/academic health professionals with specific interest in PMR were invited to participate in a one-hour online focus group (FG), recruited via social media, the PMRGCAuk charity and professional networks. Ethical approval was obtained. Separate FGs (four with patient participants and two with multi-disciplinary health professionals), held during the summer of 2023, were facilitated by steering group members over two rounds. Exemplars of non-PMR health education literature were shared with participants in round 1 to prompt discussion and invite participant opinions about what might be essential exercise content and the optimal format of the new PMR educational resource. Summaries of proposed content and resource format suggestions were collated after each FG and informed the next iteration of the exercise and physical activity educational resource. In the final round 3 a prototype version of the educational booklet was shared with all FG participants via email. All participants were invited to provide final feedback and comments, after which the booklet was finalised. Results Participants desired a visually appealing pocket-size (A5), multiple-page, patient education booklet suitable for either printing or reading online. Colour-themed text and images with logos of PMRGCAuk and contributing universities were requested. Positive messaging promoting movement and physical activity, as well as exercise, were considered important. Feedback following draft booklet iterations concluded “a self-help guide” title was valuable, as were starter and progression instructions to accompany exercise illustrations. Participants desired explanation of prioritised “top tips”, including keeping moving, listening to your body, balancing rest and activity, and the physical and mental health benefits of exercising. Patient quotations were included with permissions together with signposting to other resources. Conclusion An exercise-focused education booklet, acceptable to both people with PMR and UK expert health professionals, has been co-created and professionally designed. Future research plans include piloting the feasibility of using this resource to support people living with PMR to engage and continue with exercise, and to evaluate the impact of people with PMR exercising. Disclosure A.V. O’Brien: Grants/research support; This project was funded by Polymyalgia Rheumatica, Giant Cell Arteritis UK charity - PMRGCAuk. S. Eng: None. S.L. Mackie: Consultancies; Roche/Chugai, Sanofi, AbbVie, AstraZeneca, Pfizer. Grants/research support; chief investigator on STERLING-PMR trial, funded by NIHR; patron of the charity PMRGCAuk. NIHR Leeds Biomedical Research Centre. Investigator on clinical trials for Sanofi, GSK, Sparrow. N. Scrafton: None. S. Hider: None. A. Tan: None. C. McClean: None. J. Barber: None. J. Gundle: None. M. Lonsdale: None. M. Baxter: None.
People with multiple sclerosis stop working earlier than expected due to disease progression, individuals giving up work voluntarily or due to employers9 advice or requirement. Although effective symptom management, social support and psychological factors can influence job retention, the relationship between job retention and psychological factors remains unclear. Exploring this may lead to psychological interventions to aid job retention.
Methods
In phase 1 we held three focus groups with people with MS in paid employment discussing work-related experiences and concerns to elicit key psychological constructs. In phase 2 participants will complete validated questionnaires to measure the identified psychological factors, work instability and the impact of MS at four time points over 30 months.
Results
20 employed people with MS participated in 3 focus groups. The key themes identified were disclosure, self-management/coping, work environment and illness-related. A questionnaire pack was developed to include the identified themes. 221 employed people with MS have been recruited to phase 2 of the study and 213/221 (96.4%) completed the baseline questionnaire. 91% have relapsing-remitting MS.
Discussion
We have identified the main themes which impact on employment for people with MS. We will explore the impact of these on job retention in the longitudinal study.
To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort.Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software.Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score.Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.
In systemic sclerosis, outcome measures of skin microvasculopathy are needed for both clinical trials and practice. The aim of this study was to determine whether dynamic-optical coherence tomography (D-OCT) is able to provide information on microvasculopathy compared with the current gold standard, nailfold videocapillaroscopy (NVC), in patients with systemic sclerosis. This case-controlled study included (i) 40 patients with systemic sclerosis, classified by NVC pattern in four age- and sex-matched groups (normal/nonspecific, early, active, late); (ii) a fifth group of 10 age- and sex-matched healthy controls. All participants underwent NVC and D-OCT. D-OCT images were compared with the corresponding NVC images. Reliability was assessed. D-OCT images visualized the corresponding NVC patterns. D-OCT microvascular flow density was different across the five NVC pattern groups (P = 0.0114) with a significant trend test (P = 0.0006). Microvascular flow density correlated with the NVC semiquantitative score (r = -0.7, P < 0.0001), number of abnormal shapes/mm (r = ‒0.3, P = 0.0264), and number of capillaries/mm (r = 0.6, P < 0.0001). Reliability was excellent (intraclass correlation coefficient > 0.9). In conclusion, in patients with systemic sclerosis, D-OCT provided qualitative and quantitative information on nailfold microvasculopathy, showing a correlation between microvascular flow density and NVC scores. The development of D-OCT as a standardized imaging technique could provide a quantitative outcome measure in clinical trials and practice.
Reduction in capillaries number is the defining feature of microvascular disease in Systemic Sclerosis (SSc) and it concurs to the ischemic manifestations of the disease. Digital Ulcers (DUs) are the major complication of ischemic peripheral vasculopathy. Dynamic optical coherence tomography (D-OCT) is a recently developed imaging technique that allows non-invasive in vivo study of the microvasculature of the skin. In addition to the skin architecture and vessels morphology, it offers information about flow status, allowing the functional and quantitative evaluation of the microcirculation.1
Objectives
To determine the face and content validity of D-OCT as outcome measure of the skin microvascular disease, assuming the presence of current DUs, distal to the DIP joints, as gold standard for ischemic peripheral vasculopathy in SSc.
Methods
A total of 54 patients were enrolled in this cross-sectional study, including 18 SSc patients with current DUs (DU group); 18 SSc patients without current DUs (no DU group) and 18 patients with Raynaud9s phenomenon and SSc specific ANA, who did not fulfilled ACR/EULAR 2013 classification criteria (SRP group). For each patient, we performed a D-OCT scan on both index and middle fingers, on the dorsal aspect of the second phalanx, employing Vivosight Scanner(Michelson Diagnostics). The speckle variance signal of D-OCT images within the first mm of skin depth was extracted, quantified as area under the curve (AUC) and defined as Micro Vascular Flow (MVF). MVF comparison between the groups was done using parametric or non-parametric tests as appropriate. Statistical Analysis was performed with SPSS V.22.
Results
All three groups were comparable in terms of age and gender distribution (p>0.80 for both) as well as disease duration and clinical subset between the two SSc groups (p=0.839 and p=0.646, resp.). With a scan time <1 minute, D-OCT allowed the visualization and quantification of capillaries within the first millimeter of skin depth (Figure 1). The distribution of MVF was not significantly different among the four fingers within each group (DU group: p=0.459, no DU group: p=0.953 and SRP group: p=0.616). On the contrary, the distribution and median MVF for all fingers was significantly different among the 3 groups: DU group=0.134 (IQR 0.121–0.134), no DU group=0.153 (IQR 0.132–0.153) and SRP group=0.167 (IQR 0.148–0.167) (p<0.0001), as well as in the DU group vs. no DU group (p<0.001) or DU vs SRP group (p<0.001). Further, sub analysis of the DU group showed that 10 of the total 20 DUs were on the left index finger. Within this subgroup the MVF of patients on Sildenafil (n=6) was significantly higher than the rest of the group (0.148±0.021 vs. 0.113±0.019, p=0.03).
Conclusions
MVF assessed by D-OCT is a quantitative, non-invasive surrogate outcome measure of severe peripheral ischemic vasculopathy in SSc. Longitudinal studies assessing its sensitivity to change will inform whether MVF can be used as end point of skin microvascular involvement in SSc.
References
C. Tolosa-Vilella et al. Semin Arthritis Rheum 46(2016):200–208.
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