A. Balbir-Gurman

Mapping and predicting mortality from systemic sclerosis

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

Objectives The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. Methods This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Results Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. Conclusions These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. Trial registration number NCT02339441.

Large leg ulcers due to autoimmune diseases

Summary Background Large leg ulcers (LLU) may complicate autoimmune diseases. They pose a therapeutic challenge and are often resistant to treatment. To report three cases of autoimmune diseases complicated with LLU. Case Report Case 1. A 55-year old woman presented with long-standing painful LLU due to mixed connective tissue disease (MCTD). Biopsy from the ulcer edge showed small vessel vasculitis. IV methylprednisolone (MethP) 1 G/day, prednisolone (PR) 1mg/kg, monthly IV cyclophosphamide (CYC), cyclosporine (CyA) 100mg/day, IVIG 125G, ciprofloxacin+IV Iloprost+enoxaparin+aspirin (AAVAA), hyperbaric oxygen therapy (HO), maggot debridement and autologous skin transplantation were performed and the LLU healed. Case 2. A 45-year old women with MCTD developed multiple LLU’s with non-specific inflammation by biopsy. MethP, PR, hydroxychloroquine (HCQ), azathioprine (AZA), CYC, IVIG, AAVAA failed. Treatment for underlying the LLU tibial osteomyelitis and addition of CyA was followed by the LLU healing. Case 3. A 20-year-old man with history of polyarteritis nodosa (PAN) developed painful LLU’s due to small vessel vasculitis (biopsy). MethP, PR 1 mg/kg, CYC, CyA 100 mg/d, AAVAA failed. MRSA sepsis and relapse of systemic PAN developed. IV vancomycin, followed by ciprofloxacin, monthly IVIG (150 g/for 5 days) and infliximab (5 mg/kg) were instituted and the LLU’s healed. Conclusions LLU are extremely resistant to therapy. Combined use of multiple medications and services are needed for healing of LLU due to autoimmune diseases.

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study

Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441.

THU0343 The effect of adalimumab on clinical manifestations and pro-inflammatory cytokines milieu in patients with behcet's disease

Background Behcets disease is a multisystemic chronic relapsing inflammatory disease, classified among the vasculitides. The aetiology of Behcets disease is unknown. Several cytokines, among them TNF-α, are involved in the pathogenesis of the disease. Objectives We aimed to assess efficacy and safety of Adalimumab (ADA) in patients with active Behcets arthritis not responding to one or more DMARDS and to assess the impact of treatment on the cytokine milieu. Methods Eligible patients (pts) with active arthritis were enrolled in a 24 weeks single center prospective open-label study. Pts who relapsed within 12 weeks following ADA discontinuation could enter a 3 year extension study. The efficacy was assessed by 68 tender and 66 swollen joint count, patient visual analogue scale (VAS) for pain, physician overall disease activity VAS, health assessment questionnaire (HAQ), Behçets Disease Current Activity Form (BDCAF), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). TNF-α,IL-1β, IL-6, INF-γ, IL-10 and IL-17a were evaluated at baseline, after 24 and 48 weeks of treatment, by ProcartaPlex Human High Sensitivity – Immunoassay kit. Trough ADA serum levels and anti-drug antibodies were measured at baseline, week 24 and 48. Results Ten pts (6 females),age (mean, standard deviation –SD) 45 (8.4) years, with a disease duration of 11.6 (10) years, were enrolled and treated with subcutaneous ADA 40mg every 2 weeks for 24 weeks. The results are described in Table1. A statistically significant improvement was observed in swollen joint count, physician VAS and BDCAF and in IL-6 levels, but not in tender joint count or HAQ. Resolution of oral and urogenital ulcers was achieved in all pts. Significant reduction of pain was reported by 40% of pts. No relapse of uveitis or other disease manifestations occurred during the study. The reduction in IL-6 levels correlated with the physician VAS and BDCAF but not with HAQ. No correlation was found between change in IL-10 level and VAS pain. The levels of INF-γ, IL-17A, TNF-α were undetectable in all pts. IL-1β was elevated in 1 patient only. ADA serum trough levels were in the therapeutic range in 7/10 pts. One patient developed high antidrug antibodies titer and ADA serum trough level of 0 with a concomitant increase in VAS pain and IL-6 concentration. Another patient with low ADA trough levels and no antibodies improved after providing ADA weekly. The disease relapsed in 9/10 pts, within 4–6 weeks following ADA interruption, 7 pts enrolled into the extension study. Baseline mean (SD) 24 weeks mean (SD) P Swollen joints 4.6 (4.2) 0.6 (0.4) 0.006 Tender joints 19 (18.7) 12.6 (10.9) Non significant (NS) Physician VAS 51.5 (18.5) 24.5 (16) 0.002 Patient pain VAS 72 (19) 56 (33) NS BDCAF 5.4 (1.6) 2.1 (1.4) 0.001 HAQ 1.76 (0.8) 1.6 (0.9) NS IL-6 pg/ml 10.06 (13.4) 2.02 (0.8) 0.042 Conclusions ADA treatment was well tolerated and achieved a significant improvement in arthritis and mucocutaneous manifestations and lowered IL-6 serum concentration in all study pts but only 40% reported significant pain reduction. A subset of pts with insufficient improvement in joint tenderness and generalized pain may require comprehensive pain management besides anti-inflammatory therapy. Acknowledgements ABBVIE donated the study medication and supported the lab work Disclosure of Interest None declared

AB0653 Gastric Antral Vascular Ectasia in Systemic Sclerosis Patients: Long-Term Prognosis and Treatment

Background Gastric antral vascular ectasia (GAVE) is characterized by a pathognomonic endoscopic pattern, mainly represented by red spots either organized in stripes radially departing from pylorus, defined as “watermelon stomach”, or arranged in a diffused-way, the so called “honeycomb stomach”. In our previous work we found a prevalence of GAVE in 35% of systemic sclerosis (SSc) patients that had an upper gastrointestinal (GI) endoscopy for evaluation of symptoms. The main complication of GAVE is symptomatic anemia due to GI bleeding requiring blood transfusion. As the pathogenesis is unknown, the aim of the therapy is to decrease GI bleeding. Endoscopic therapy (endotherapy) is the mainstay of treatment with surgery reserved for severe refractory cases. The data on the efficacy of endotherapy and treatment requirements of SSc patients with GAVE is very limited. Objectives The aim of our study is to assess the treatment requirements of SSc patients with GAVE and the efficacy of endotherapy in particular. Methods Retrospective analysis of a prospectively maintained database of SSc patients followed in a tertiary referral center for SSc. Our cohort is part of the EUSTAR cohort. Statistical analysis: descriptive, students T test, Mann-Whitney test. Results Fifty SSc patients were diagnosed with GAVE. Seventeen patients (34%) suffered of symptomatic anemia and were treated with argon plasma coagulation (APC) for a mean (SD) of 4.5 (4.3) sessions per patient. The mean (SD) hemoglobin was 9.4 (1.7) gr% in the group who required endotherapy compared to 11.5 (1.3) in the group which did not need any intervention. Four patients needed more than 6 sessions of treatment. Mean (SD) follow up was 4.1 (2.4) years. Nine patients required a total of 73 packed blood cells units and another 4 had intravenous iron replacement. Four patients died during the first 2 years after diagnosis, none of them due to bleeding complications. None of the patients that survived more than 2 years required further endotherapy or blood transfusions. No significant complications of APC occurred. Interestingly, all those who survived,had received immunotherapy with cyclophosphamide or mycophenolate mofetil due to multisystem involvement and disease activity. Conclusions Long term survivors among SSc patients with GAVE had an excellent response to APC and did not require blood transfusions or endotherapy after 2 years follow up. All the long term survivors received immunotherapy. This observation might hint to the pathogenesis of GAVE in SSc. Disclosure of Interest None declared

THU0361 Increased Body Mass Index and Biologics Drug Survival in Patients with Inflammatory Rheumatic Diseases

Background Recent studies have suggested that obesity may reduce the response rate to TNFα blockers (1,2). Objectives The objective of this study was to determine whether body mass index (BMI) affects drug survival of Tumor Necrotic Factor (TNF)-α blockers in patients suffering from rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Methods The data were extracted from the prospective Israeli registry for use of biological agents in patients treated with TNF-α blockers for RA, PsA and AS. Patients were divided according to the baseline BMI as normal BMI (BMI <25), overweight (BMI 25-30, 30-35) and obese (BMI>35). The drug survival was analyzed using the Kaplan-Meier curves. The influence of different covariates on drug survival was analyzed by Cox regression. Results 574 patients (344 patients with RA, 131 with PSA and 99 with AS) from four Israeli Academic center for rheumatic diseases received 1218 treatment series (etanercept-305, adalimumab-244, infliximab -257); 635 of them were discontinued (391 (62%) because of loss of efficacy. The distribution of BMI was higher but not statistically significant in PsA (median 27.4, IQR 24,3-30.8) in comparison with RA (26.2,23.4-30.5) and AS (26.8,24.1-30.1). Significant overall correlation was found between BMI and biologic treatment effectiveness survival (log-rank p=0.022) for all biologics (non-anti TNF α agents) and (log-rank p=0.011) for anti TNF-α agent particularly. Looking at each of the 3 anti-TNF- α agent separately the association was significant for etanercept drug survival (log-rank p=0.028) but not for Infliximab or adalimumab. Etanercept median survival was 1343, 961, 700, and 580 days for BMI <25,25-30,30-35, and >35 respectively. Conclusions Increased BMI significantly decreases the drug survival of etanercept in patients with AS, RA, and PsA. Our study results provide basis to suggest that in patients with increased BMI, etanercept should not be recommended as the 1st TNF α blocker References Iannone F, Fanizzi R, Notarnicola A, Scioscia C, Anelli M, Lapadula G. Obesity reduces the drug survival of second line biological drugs following a first TNF-α inhibitor in rheumatoid arthritis patients. Joint Bone Spine. 2015 Jan 22 Gremese E, Bernardi S, Bonazza S, Nowik M, Peluso G, Massara A et al. Body weight, gender and response to TNF-α blockers in axial spondyloarthritis. Rheumatology (Oxford). 2014 May;53(5):875-81 Disclosure of Interest None declared

FRI0509 Upper Gastrointestinal Bleeding is Associated with Significantly Higher Mortality in Systemic Sclerosis Patients

Background The gastrointestinal tract is involved in nearly all patients with systemic sclerosis (SSc) and is a source of significant morbidity and even mortality. Objectives To assess whether there is correlation between upper gastrointestinal (UGI) endoscopy findings and mortality in SSc patients. Methods The records of 256 SSc patients seen in our rheumathologic clinic between 2003-2013 were reviewed. 140 patients who had at least one detailed upper endoscopy report and at least 6 months follow-up were included in the study. Patient data included demographics, type of SSc, disease duration, modified Rodnan skin score (mRSS), lung, cardiac, renal or musculoskeletal involvement, hemoglobin at endoscopy and type of antibodies. Endoscopic findings that were included in the analysis were esophagitis, ulcerations, tumors, gastric antral vascular ectasia (GAVE), gastric erosions, submucosal hemorrhages and lumenal blood. The statistical methods used included descriptive statistics, T test, bivariable analysis, cox regression analysis Results Forty seven patients (16 diffuse SSc) had evidence of GAVE or antral erosions and hemorrhage. The mortality rate in this group, during the follow up was 37% vs. 25% in the group of 93 (39 diffuse) SSc patients without GAVE or UGI bleeding (p=0.001). There were no statistical differences between the groups regarding mean ages (55) or Hb (10.87 in the group with the UGI bleeding vs 11.77). The mean mRSS score was higher in the group with UGI bleeding 8 vs.5.6 (p=0.019). Mean (median) disease duration was 6.9 (4.5) years in the group with UGI bleeding vs 10.4 (10) (p<0.001). Esophagitis was found in 90% of patients, despite use of PPI. Co-morbidity of myositis had a negative impact on survival. The mortality hazard ratio (95% CI) for UGI bleeding, myositis and interstitial lung disease were 5.9 (2.7-13.2), 4.9 (2-12.4) and 2.7 (1.3-5.8) respectively. Conclusions A diagnosis of GAVE or UGI bleeding on upper endoscopy was associated with significantly higher mortality. In our cohort of SSc patients, myositis was associated also with increased mortality. The long-term survival of patients with GAVE/UGI bleeding was similar to the patients with myositis that were free of such GI complications. The patients with both myositis and GI bleeding had a very poor prognosis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3613

FRI0157 Rheumatologic Manifestations in Inflammatory Bowel Disease Patients Referred to the Rheumatology Service in A Tertiary Referral Center

Background Musculoskeletal manifestations occur in 20-50% of patients (pts) with inflammatory bowel disease (IBD) and they have an impact on the clinical course and therapeutic approach. Objectives To summarize the rheumatologic manifestations of IBD pts referred to the rheumatology service in a tertiary referral center and to assess the impact of gastro-rheumatologic inter-disciplinary clinic on patient management. Methods Medical records of 100 consecutive IBD pts referred to rheumatology unit and the inter-disciplinary clinic were retrospectively reviewed. Data regarding age, gender, diagnosis, disease duration, clinical and laboratory features, previous and current therapy were entered into a database and analyzed. The statistical methods used included descriptive statistics, T test, Spearmans correlation and multiple logistic regression analysis. Results Seventy pts suffered of Crohns disease, 29 of ulcerative colitis, and 1 patient of celiac disease. The mean (median) age was 43 (41.5) years, 68 pts were females, the mean (median) disease duration 7.7 (5) years, range 0-40 years. The referrals were for joint pain (73%), back pain (15%), myalgia (3%), fever (2%), and miscellaneous (7%). Spondyloarthropathy was diagnosed in 56 out of 88 pts referred for joint or back pain (35 pts with peripheral arthritis, 13 pts with axial involvement - symptomatic sacroiliitis or spondylitis, confirmed by imaging and 8 pts with enthesopathies). Hypermobility was found in 18 pts referred for joint pain. The other “musculoskeletal” entities included avascular necrosis of hips (2pts), Takayasu arteritis (1patient), IBD related myositis (1patient), steroid-induced myopathy (2pts), systemic lupus erythematosus (1patient), pseudogout (1patient), insufficiency fractures (1patient) osteoarthritis (2pts).Seventeen pts developed chronic peripheral arthritis which did not correlate to IBD activity and did not consistently respond to IBD-targeted immunomodulatory treatment, including anti-TNF agents, but responded to non anti-TNF biologicals. Nine pts had psoriasis or familial history of psoriasis; all of them developed chronic arthropathy (peripheral or axial). The assessment of the patients at the inter-disciplinary clinic had an important impact on the management in almost 70% of cases referred. Conclusions An accurate assessment of joint inflammation in the context of IBD activity may lead to changes in the use of disease modifying drugs or biological agents. Not every joint or back pain in IBD pts is arthritis or spondyloarthropathy. The treatment of IBD pts with chronic arthritis in whom the IBD is silent should be focused on articular inflammation. We suggest that multidisciplinary clinic might have an important role in correctly diagnosing and treating rheumatologic manifestations in IBD pts. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3629

Association of Hodgkin lymphoma and polymyositis

Abstract Background: Coexistence of inflammatory myopathies and malignant conditions is a well-known phenomenon. The contemporary association of polymyositis (PM) and Hodgkin lymphoma (HL) is a very rare