A. L. Herrick

Von Willebrand factor, thrombomodulin, thromboxane, beta-thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis.

OBJECTIVE: To determine whether measurement of different markers of endothelial damage, activation of coagulation, and platelet activation might differentiate between patients with primary Raynauds phenomenon (PRP), limited cutaneous and diffuse systemic sclerosis (lcSSc and dSSc), and healthy control subjects. METHODS: Under carefully controlled conditions, fasting blood was drawn from 19 healthy control subjects, 10 patients with PRP, 17 with lcSSc and nine with dSSc for measurement of the following: von Willebrand factor (VWF) and soluble thrombomodulin as markers of endothelial damage/activation, thromboxane (as thromboxane B2) and beta-thromboglobulin as markers of platelet activation, and tissue plasminogen activator antigen, tissue plasminogen activator activity and plasminogen activator inhibitor-1 (PAI-1) as markers of fibrinolysis. RESULTS: VWF was increased significantly in patients with SSc, and there was also a linear trend for thromboxane and tissue plasminogen activator antigen (in addition to VWF) to differentiate between different subgroups of patients with Raynauds phenomenon. Patients with dSSc had the highest values. A combined index of VWF and thromboxane showed a highly significant trend across the four groups studied. CONCLUSION: VWF, and to a lesser extent thromboxane and tissue plasminogen activator antigen, are associated with disease severity in patients with Raynauds phenomenon. Prospective studies are now required to establish if these parameters can be used as markers of disease progression.

A prospective study of systemic sclerosis-related digital ulcers: prevalence, location, and functional impact.

Objectives: Although digital ulcers (DUs) are common in patients with systemic sclerosis (SSc), prevalence estimates vary, and functional impact and pathophysiology have been relatively little studied. We investigated the point prevalence of all DUs (both digital-tip and extensor) in a cohort of patients with SSc, testing the hypothesis that both digital-tip and extensor ulcers are associated with functional impairment. Method: Over a 12-month period, patients attending an SSc clinic for annual review were assessed by specialist nurses: active DUs were documented and the Hand Mobility in Scleroderma (HAMIS) test performed. Patients also completed the Scleroderma Health Assessment Questionnaire (SHAQ), the Scleroderma Functional Index (SFI), and the Cochin Hand Function Scale (CHFS). Results: A total of 25 active DUs (nine digital-tip and 16 extensor surface) were found in 15 of the 148 patients recruited, giving a prevalence for each ulcer type of 6% and an overall point prevalence of 10%. HAMIS scores were higher (indicating greater impairment) in those with active DUs than in those without: left hand difference 8.8 points [95% confidence interval (CI) 3.2–14.5], p = 0.002; difference significant for extensor as well as digital-tip ulcers. Active DUs were associated with higher visual analogue scale (VAS) scores for pain (p = 0.04), DUs (p < 0.001), and ‘overall’ assessment (p = 0.03). Conclusions: Extensor surface ulcers have the same prevalence as digital-tip ulcers in patients with SSc, and are equally disabling. Clinical trials should therefore include both categories of DUs.

Soluble L-selectin in the connective tissue diseases

Plasma levels of the leucocyte adhesion molecule L‐selectin were measured by ELISA in 41 patients with rheumatoid arthritis, 18 with ankylosing spondylitis, 18 with systemic sclerosis and 27 with vasculitis together with 42 age‐ and sex‐matched controls. Low levels of soluble L‐selectin were found in systemic sclerosis (797 ± 302 ng/ml, P < 0.05) and vasculitis (941 ± 329 ng/ml, P < 0.05) relative to controls (1244 ± 269 ng/ml). The exact reasons for low levels of soluble L‐selectin are unclear, but may reflect reduced shedding from leucocytes and/or strong binding to its cell membrane ligand(s). An approximate inverse relationship between soluble L‐selectin and disease severity may have clinical relevance.

Pilot study of intense pulsed light for the treatment of systemic sclerosis-related telangiectases.

Background  Telangiectases represent microvascular changes inherent in the systemic sclerosis (SSc) disease process. Intense pulsed light (IPL) is an effective treatment for non‐SSc‐related cutaneous telangiectases.

Nervous system involvement in association with vasculitis and anticardiolipin antibodies in a patient with systemic sclerosis.

Although systemic sclerosis (SSc) is a multisystem disease, signs and symptoms of neurological involvement are unusual, and in contrast to the situation in other connective tissue disorders, vasculitis is thought to be rare. We report a 51 year old man with diffuse SSc who developed vasculitis affecting peripheral nerve and muscle, and subsequently generalised seizures. He first became unwell in 1985, aged 45 years, when he developed fibrosing alveolitis. Subsequently he developed arthralgias, Raynauds phenomenon, vasculitic lesions of his finger-tips and mild proximal muscle weakness with elevated creatine phosphokinase (CPK). In 1987 sclerodactyly and skin tethering of the anterior abdominal wall were noted, and skin biopsy of both involved and clinically uninvolved skin showed features of SSc with intimal thickening, oedema and a mild inflammatory cell infiltrate. As well as diffuse skin thickening he

HLA-DRB1 associations with rheumatoid arthritis-related pulmonary fibrosis

The aetiology of rheumatoid arthritis (RA)-related pulmonary fibrosis (PF), one of the major extraarticular manifestations of RA (1), remains unknown and is likely to be multifactorial (2). However, to date only a few studies have examined its genetic basis (3). The association between RA and a number of human leucocyte antigen (HLA)-DRB1 alleles that share a common sequence (4), known as the shared epitope (SE), is well known. Our objective was to perform a pilot study to determine whether there is a difference between HLA-DRB1 alleles associated with susceptibility to RA-related PF compared with RA alone. Fifty-two Caucasian patients (33 males, median age at onset of RA 54 years, median disease duration 11 years) with RA-related PF were recruited from hospitals across North West England. The study was approved by the North West Research Ethics Committee and all patients signed an informed consent form. PF was confirmed by high-resolution computed tomography in 48 (92%) cases: in the other four, diagnosis was on the basis of bilateral basal shadowing on chest X-ray with a restrictive defect on pulmonary function testing. DNA samples from 537 healthy Caucasian controls and 3397 Caucasian RA patients recruited by the UK Rheumatoid Arthritis Genetics (UKRAG) Consortium were available for comparison. HLA-DRB1 genotyping was performed using Dynal RELI sequence-specific oligonucleotide (SSO) HLA-DRB1 kits. HLA-DRB1 allele frequencies in patients with RA-related PF were compared with those in healthy controls, and with RA patients from the UKRAG Consortium (Table 1). A two-stage statistical analysis was used to account for the multi-allelic nature of HLA-DRB1 and the small sample size. An overall Pearson χ test of broad-type HLA-DRB1 allele frequencies was performed, and allele frequencies were compared with a reference allele using multinomial logistic regression. Allele and phenotype frequencies for the broad-type HLA-DRB1 alleles in RA-related PF cases, RA cases, and healthy controls are shown in Table 1. HLA-DRB1 SE analysis: The frequency of SE carriage was 70, 75, and 46% in RA-related PF, RA, and healthy controls, respectively. Carriage of SE was significantly higher in RA-related PF cases compared with healthy controls [odds ratio (OR) 2.80, 95%

AB0727 There is a Need for New Systemic Sclerosis Subset Criteria. A Content Analytic Approach

Background Systemic sclerosis (SSc) is a family of diseases unified by the presence of immune activation, vasculopathy and fibrosis. The concept of SSc subsets cannot be easily defined but is clinically indisputable. Objectives To evaluate the purpose, strengths and limitations of the limited/diffuse subset criteria, and identify areas requiring improvement. Methods We conducted a cross-sectional study with 30 SSc experts using a semi-structured interview. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. This was followed by serial cross-referential analyses establishing a set of pervasive complex thought clusters. Results Of the 30 experts, 26 (87%) were male, 19 (63%) were from Europe and 11 (37%) were from North America. The experts had seen SSc patients for a mean 23 (SD 10.7) years, and saw a mean of 122 (SD 185) new SSc patients annually. Three thematic clusters were noted regarding the utility of subsetting: to facilitate research and communication, to inform management, and to inform prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system has “little or no value”. Limitations of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold is arbitrary. 87% use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody determined subsets, subsetting based on speed of progression, and age of onset (juvenile, elderly). Considerations for the next phase of criteria development include incorporation of rate of change and hierarchal clustering (limited/diffuse, then by antibodies). Conclusions We interviewed international SSc experts and synthesized their views on subset criteria. These results can inform future efforts to develop revised criteria to guide research, prognostication and management. Acknowledgements This work was supported by the World Scleroderma Foundation. Disclosure of Interest S. Johnson Grant/research support from: Canadian Institutes of Health Research, J. Fransen: None declared, D. Khanna Grant/research support from: NIH/NIAMS K24, F. van den Hoogen: None declared, M. Baron: None declared, M. Matucci-Cerinic: None declared, C. Denton: None declared, T. Medsger: None declared, P. Carreira: None declared, G. Riemekasten: None declared, J. Distler: None declared, A. Gabrielli: None declared, V. Steen: None declared, L. Chung: None declared, R. Silver: None declared, J. Varga: None declared, U. Muller-Ladner Grant/research support from: EULAR/EUSTAR and FP7 Desscipher, M. Vonk: None declared, U. Walker: None declared, F. Wollheim: None declared, A. Herrick: None declared, D. Furst: None declared, L. Czirjak: None declared, O. Kowal-Bielecka: None declared, F. DelGaldo: None declared, M. Cutolo: None declared, N. Hunzelmann: None declared, C. Murray: None declared, I. Foeldvari: None declared, L. Mouthon: None declared, N. Damjanov: None declared, B. Kahaleh: None declared, T. Frech: None declared, S. Assassi: None declared, L. A. Saketkoo: None declared, J. Pope: None declared

OP0148 A validation of the 2017 eular/acr idiopathic inflammatory myopathies classification criteria in an expert-defined single-centre ten year incident cohort

Background The recently published 2017 European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups reflect a long-appreciated need for more accurate case definition in ongoing research in these complex and heterogenous diseases.1 However a number of issues remain unresolved. There was a high frequency of missing data in both the derivation and validation samples, only one of the now numerous myositis specific autoantibodies is included, and certain well recognised IIM subtypes are not specifically classified despite their well phenotyped and differing natural histories, clinical features and treatment modalities.2 3 Objectives To perform an external validation of the EULAR/ACR classification criteria in an incident IIM cohort and examine how classification criteria-assigned IIM subtype correlates with expert opinion. Methods Adults with newly diagnosed IIM attending Salford Royal NHS Foundation Trust Neuromuscular services were identified. A retrospective review of all putative cases was performed, and cases fulfilling a consensus expert-opinion diagnosis of definite IIM included. A broad range of clinical, serological and histological data were collected and each case assigned a single IIM subtype by expert opinion. The EULAR/ACR classification criteria were applied and sensitivity, specificity, positive and negative predictive value calculated, presented with 95% confidence intervals (CI). Results A total of 922 cases were screened with 255 expert opinion definite IIM identified. The sensitivity to diagnose an IIM was 99.6% (97.2–100) and 80.9% (76.0–85.8) for the classification criteria cut-points of ‘probable’ and ‘definite’ respectively. The sensitivity for ‘definite’ IIM improved to 90.2% (86.5–93.8) when biopsy data for 24/34 initially missed cases were excluded. In 94/255 cases the IIM subtype differed between expert opinion and classification criteria, most strikingly in the group subtyped ‘polymyositis’ using the EULAR/ACR criteria, where there was discrepancy in the majority (87/161).Abstract OP0148 – Table 1 PM, polymyositis; DM, dermatomyositis; IBM, inclusion body myositis; ADM, amyopathic dermatomyositis; IMNM, immune-mediated necrotizing myopathy; ASS, anti-synthetase syndrome; OM, overlap myositis. Conclusions The criteria performed with high sensitivity in identifying IIM in an external cohort of IIM patients. However, substantial disagreement exists in subtype assignment, especially resulting in a larger proportion of cases of ‘polymyositis’ with heterogeneous features, important to consider in the application of these criteria to subsequent research. References [1] Lundberg IE, Tjärnlund A, Bottai M, Werth VP, Pilkington C, Visser M De, et al. EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis2017;76:1955–64. [2] Betteridge Z, McHugh N. Myositis-specific autoantibodies: An important tool to support diagnosis of myositis. J Intern Med2016;280:8–23. [3] Longo DL, Dalakas MC. Inflammatory muscle diseases. N Engl J Med2015;372:1734–47. Disclosure of Interest None declared

AB0003 A mif promoter polymorphism is associated with the susceptibility to pulmonary arterial hypertension in diffuse cutaneous systemic sclerosis patients

Background Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in SSc patients. However, the genetic factors involved in lung complication are not well-defined. Objectives We aimed to revisit the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, besides testing the association of this polymorphism with SScrelated pulmonary involvement. Methods A total of 4,393SSc patients and 16,591 unaffected controls from six cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to meta-analyze the data. Results A statistically significant increase of the MIF rs755622*C allele frequency compared to controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: P=3.20E-2, OR=1.13; PAH: P=2.19E-02, OR=1.32). However, our data revealed a stronger effect size with the subset of SSc patients showing both clinical manifestations (dcSSc with PAH: P=6.91E-3, OR=2.05). Conclusions We revisited the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in dSSc patients. Disclosure of Interest None declared

SP0030 Capillaroscopic versus Laser Doppler Analysis of The Microcirculation

Nailfold capillaroscopy is used primarily to study microvascular structure, and in patients with Raynauds phenomenon (RP) helps to differentiate between primary (idiopathic) RP and RP secondary to an underlying systemic sclerosis-spectrum disorder. In contrast, laser Doppler techniques measure microcirculatory blood flow, and therefore assess microvascular function. Capillaroscopy and laser Doppler are therefore complementary. There are different laser Doppler techniques: flowmetry (using a single probe), laser Doppler imaging (LDI), and laser speckle contrast imaging (LSCI). LDI and LCSI both measure blood flow over an area rather than at a single site. Laser Doppler techniques have been applied in research studies in patients with RP and systemic sclerosis, including as outcome measures in clinical trials: protocols often involve dynamic imaging, measuring blood flow response to (for example) a standard temperature stimulus. This lecture will describe the main applications of capillaroscopy and laser Doppler techniques in clinical practice and research, relevant to the rheumatologist, and the rationale underpinning these. Upon completion of the session, participants should be able to: 1. Discuss applications of capillaroscopy and different laser Doppler methods in patients with RP and systemic sclerosis 2. Discuss similarities and differences between the techniques. Disclosure of Interest None declared