Jessica Meijs

Predicting cardiopulmonary involvement in patients with systemic sclerosis: complementary value of nailfold videocapillaroscopy patterns and disease-specific autoantibodies.

Objective To evaluate the prevalence of anti-extractable nuclear antigen (anti-ENA) antibodies in Dutch SSc patients and the predictive power of the combination of specific anti-ENA antibodies and nailfold videocapillaroscopy (NVC) patterns to improve identification of patients with high risk for cardiopulmonary involvement. Methods A total of 287 patients (79%) from the Leiden SSc-Cohort had data available on NVC-pattern (no SSc-specific, early, active, late) and anti-ENA antibodies. Associations between anti-ENA/NVC combinations with cardiopulmonary parameters were explored using logistic regression. Results Prevalence of ACA was 37%, anti-Scl-70 24%, anti-RNP 9%, anti-RNAPIII 5%, anti-fibrillarin 4%, anti-Pm/Scl 3%, anti-Th/To 0.3% and anti-Ku 1.4%. NVC showed a SSc-specific pattern in 88%: 10% early, 42% active and 36% late. The prevalence of different NVC patterns was equally distributed among specific anti-ENA antibodies, except for the absence of early pattern in anti-RNP positive patients. Fifty-one percent had interstitial lung disease (ILD), 59% had decreased diffusion capacity for carbon monoxide and 16% systolic pulmonary artery pressure >35 mmHg (sPAP↑). Regardless of ENA-subtype, NVC-pattern showed a stable association with presence of ILD or sPAP↑. For ILD, the odds ratios (ORs) were 1.3-1.4 ( P < 0.05 for analyses with anti-RNAPIII, anti-RNP). For diffusion capacity for carbon monoxide, the OR was 1.5 ( P < 0.05 for analyses with ACA, anti-Scl-70, anti-RNAPIII, anti-RNP). For sPAP↑, the ORs were 2.2-2.4 ( P < 0.05 for analyses with anti-RNAPIII, anti-RNP). Conclusion In Dutch SSc patients, all SSc-specific auto-antibodies were found, with ACA and anti-Scl-70 being the most prevalent. Strikingly, the association between NVC-pattern and heart/lung involvement was independent of specific anti-ENA antibodies, which might indicate microangiopathy is an important cause of organ involvement.

Therapeutic and diagnostic outcomes of a standardised, comprehensive care pathway for patients with systemic sclerosis

Objectives To determine the outcomes, including number of medical interventions and initiation of immunosuppressive treatment of a standardised, comprehensive, diagnostic care pathway for patients with systemic sclerosis (SSc). Patient characteristics associated with need for medical interventions and with need for immunosuppressive treatment were determined. Methods Data were routinely gathered in connection with a 2-day care pathway combining multidisciplinary care and complete diagnostic work-up of organ involvement in SSc. The number of patients in whom the pathway resulted in medical interventions, and/or initiation of immunosuppressives was recorded. Patient characteristics and diagnostic tests results were compared between patients with and without medical interventions, and patients with and without initiation of immunosuppressives by means of multivariable logistic regression analyses. Results During a period of 44 months, 226 patients with SSc were referred to the care pathway. They included 186 (82%) women with mean age of 54 (SD 14.5) years, and median disease duration of 4 years (range 1–11); 73 (32%) of them had diffuse cutaneous SSc. Medical interventions were initiated in 191 (85%) patients, including initiation of immunosuppressive treatment in n=49 (22%). Presence of telangiectasias and higher erythrocyte sedimentation rate were associated with any medical intervention. Of commonly available variables, lower age, higher skin score and absence of anticentromere antibody were associated with initiation of immunosuppressives. Conclusions A standardised comprehensive 2-day care pathway for patients with SSc resulted in additional diagnostic or therapeutic interventions in 85% of the patients, regardless of SSc subtype and disease duration. In 22% of the patients, immunosuppressive treatment was initiated.

Rituximab in early systemic sclerosis

Objectives (1) Hypothesis testing of the potency of rituximab (RTX) in preventing fibrotic complications and (2) assessing acceptability and feasibility of RTX in early systemic sclerosis (SSc). Methods A small, 24-month, randomised, double-blind, placebo-controlled, single-centre trial in patients with SSc diagnosed <2 years was conducted. Patients received RTX or placebo infusions at t=0, t=15 days and t=6 months. Patients were clinically evaluated every 3 months, with lung function tests and high-resolution CT every other visit. Skin biopsies were taken at baseline and month 3. Immunophenotyping of peripheral blood mononuclear cells was performed at every visit, except at months 9 and 18. Adverse events, course of skin and pulmonary involvement and B cell populations in skin and peripheral blood were evaluated. Results In total 16, patients (rituximab n=8, placebo n=8) were included. Twelve patients had diffuse cutaneous SSc. Eighty-eight adverse events (RTX n=53, placebo n=35, p=0.22) and 11 serious adverse events (RTX n=7, placebo n=4, p=0.36) occurred. No unexpected RTX-related events were observed. Mean skin score over time did not differ between the groups. Over time, forced vital capacity and extent of lung involvement slightly improved with RTX, but this difference was insignificant. In peripheral blood B cells depletion was demonstrated. Conclusions No unexpected safety issues were observed with RTX in early SSc. Although this small trial could not confirm or reject potential efficacy of RTX in these patients, future placebo-controlled trials are warranted, specifically in the subgroup of patients with pulmonary involvement. Trial registration number EudraCT 2008-07180-16; Results.

Impact of pulmonary fibrosis and elevated pulmonary pressures on right ventricular function in patients with systemic sclerosis

OBJECTIVES Right ventricular (RV) dysfunction is of great prognostic value in patients with SSc. The aim of the present study was to assess in these patients the relationship between pulmonary fibrosis and elevated pulmonary pressure (PHT) with RV function. METHODS A total of 102 SSc patients who underwent thoracic CT and transthoracic echocardiography were included. Speckle tracking-derived RV free wall strain was used to assess RV function. RESULTS A total of 51 (50%) SSc patients did not have pulmonary fibrosis or PHT, 32 (31%) patients had pulmonary fibrosis but no PHT and the remaining 19 (19%) patients had both pulmonary fibrosis and PHT. Patients with both pulmonary fibrosis and PHT had the most impaired RV free wall strain [-16.8% (s.d. 3.1)] compared with patients with pulmonary fibrosis and no PHT [-21.5% (s.d. 3.6)] and patients with no pulmonary fibrosis and no PHT [-24.0% (s.d. 4.4)]. All three SSc groups showed impaired RV free wall strain compared with controls [-28.0% (s.d. 4.2)]. Importantly, multivariate regression analysis demonstrated that pulmonary fibrosis and left ventricular ejection fraction were independently associated with impaired RV free wall strain in SSc patients. CONCLUSION SSc patients show impaired RV function compared with controls. Both pulmonary fibrosis and PHT are independently associated with RV dysfunction.

A prediction model for progressive disease in systemic sclerosis

Objective To develop a model that assesses the risk for progressive disease in patients with systemic sclerosis (SSc) over the short term, in order to guide clinical management. Methods Baseline characteristics and 1 year follow-up results of 163 patients with SSc referred to a multidisciplinary healthcare programme were evaluated. Progressive disease was defined as: death, ≥10% decrease in forced vital capacity, ≥15% decrease in diffusing capacity for carbon monoxide, ≥10% decrease in body weight, ≥30% decrease in estimated-glomerular filtration rate, ≥30% increase in modified Rodnan Skin Score (with Δ≥5) or ≥0.25 increase in Scleroderma Health Assessment Questionnaire. The number of patients with progressive disease was determined. Univariable and multivariable logistic regression analyses were used to assess the probability of progressive disease for each individual patient. Performance of the prediction model was evaluated using a calibration plot and area under the receiver operating characteristic curve. Results 63 patients had progressive disease, including 8 patients who died ≤18 months after first evaluation. Multivariable analysis showed that friction rubs, proximal muscular weakness and decreased maximum oxygen uptake as % predicted, adjusted for age, gender and use of immunosuppressive therapy at baseline, were significantly associated with progressive disease. Using the prediction model, the predicted chance for progressive disease increased from a pretest chance of 37% to 67–89%. Conclusions Using the prediction model, the chance for progressive disease for individual patients could be doubled. Friction rubs, proximal muscular weakness and maximum oxygen uptake as % predicted were identified as relevant parameters.

FRI0471 The Value of Repeated Nailfold Videocapillaroscopy in Raynaud's Phenomenon in Daily Practice: A Follow-Up Study in the Netherlands

Background Nailfold videocapillaroscopy (NVC) visualizing microvascular damage is an important tool to differentiate Raynauds phenomenon (RP) into primary RP (PRP) and secondary RP (SRP) (1). Based on possible transition from PRP to SRP (semi)annual NVC has been advocated to detect transition to SRP as early as possible (1-3). Whether standardized (semi)annual NVC should be implemented in clinical practice is unknown. Objectives To evaluate the additive diagnostic value of repeated NVC after one year in patients with RP. Methods Patients with RP who underwent NVC at the outpatient clinic at least six months ago and did not have a definite diagnosis were invited for follow-up NVC. PRP was defined according to the definition of LeRoy (4); SRP was defined as RP associated with a connective tissue disease fulfilling applicable diagnostic criteria; the remaining patients were classified as suspected SRP (sSRP). The number of patients in which follow-up NVC resulted in change of diagnosis was determined. Results In total 107 patients with RP underwent NVC. Of these71 underwent follow-up NVC after a mean period of 12 months (range 6-25 months). At baseline, eight (11%) patients had PRP, 28 (40%) SRP and 35 (49%) sSRP. The rate of progression from PRP to SRP was 12.5% (one of eight patients). The rate of progression from sSRP to SRP was 3% (one of 35 patients). NVC pattern had changed in 21 (30%) patients: six (8%) worsened and 15 (21%) improved. In total five patients (7%) had a different diagnosis at follow-up, two of which based on clinical symptoms, three based on NVC pattern only: one changed from PRP to SRP, based on development of sclerodactyly, one changed from sSRP to SRP based on biopsy proven myositis, and three patients changed from sSRP to PRP due to normalization of NVC. Thus, NVC contributed to change in diagnosis in three out of 43 patients (7%) with PRP or sSRP, all improving from sSRP to PRP. Conclusions Although progression from PRP to SRP was observed in 12.5% and progression from sSRP to SRP in 3%, changes in NVC did not contribute to change in clinical diagnosis in these patients. Based on the findings of this study, a follow-up NVC after one year in patients with PRP or sSRP without a change in clinical symptoms cannot be advocated. Extended follow-up in a larger population is needed to confirm this observation. References Cutolo M, Smith V. State of the art on nailfold capillaroscopy: a reliable diagnostic tool and putative biomarker in rheumatology? Rheumatology 2013;52(11):1933-40. Cutolo M, Pizzorni C, Sulli A. Identification of transition from primary Raynauds phenomenon to secondary Raynauds phenomenon by nailfold videocapillaroscopy: comment on the article by Hirschl et al. Arthritis Rheum 2007;56(6):2102-3. Hirschl M, Hirschl K, Lenz M, Katzenschlager R, Hutter HP, Kundi M. Transition from primary Raynauds phenomenon to secondary Raynauds phenomenon identified by diagnosis of an associated disease: results of ten years of prospective surveillance. Arthritis Rheum 2006;54(6):1974-81. LeRoy EC, Medsger TA, Jr. Raynauds phenomenon: a proposal for classification. Clin Exp Rheumatol 1992;10(5):485-8. Disclosure of Interest B. de Boer: None declared, J. Meijs Grant/research support from: J. Meijs was supported by an unrestricted educational grant of Actelion Pharmaceuticals Nederland BV (Woerden, The Netherlands)., J. van Aken: None declared, M. Steup-Beekman: None declared, T. Huizinga: None declared, A. Schouffoer: None declared, J. de Vries-Bouwstra: None declared

SAT0459 The Influence of Immunosuppressive Treatment on Microangiopathy in Systemic Sclerosis as Measured with Nailfold Videocapillaroscopy

Background Microangiopathy in systemic sclerosis (SSc), as visualized by nailfold videocapillaroscopy (NVC), is a dynamic and sequential process (1). In time, NVC patterns progress from early, to active and finally late SSc pattern. A relation between reverse transition of NVC patterns and treatment with immunosuppressive drugs has been suggested in small studies (2;3). Objectives To evaluate prevalence of transition of NVC patterns in 138 patients with SSc over time, and to evaluate the influence of immunosuppressive treatment on rate and direction of NVC transition. Methods NVC was performed annually in SSc patients participating in a multidisciplinary health care program. Patients were included if at least two NVCs were performed. NVC was analyzed by qualitative assessment (pattern recognition). The frequency of stable, progressive and reverse transition of the NVC patterns was assessed. In order to asses the association between immunosuppressive treatment and relative rates of transition of NVC patterns a maximum likelihood estimation in a multistate model was used (Figure 1). For the current analysis, influence of autologous hemopoetic stem cell transplantation (HSCT) and cyclophosphamide was evaluated, adjusted for age, gender and disease duration.The hypothesis is that treatment can either decrease the rate of progressive NVC patterns or lead to rapid reverse transition. Results In 98 patients, NVC was performed twice, in 35 patients NVC was performed 3 times and in 5 patients NVC was performed 4 times. Included patients were mostly females (82%), had a mean age of 51 years and median disease duration of 3 years. At baseline, 6 patients had a normal/aspecific pattern, 4 borderline changes, 13 early pattern, 54 active pattern, and 61 late SSc pattern. Over time, NVC pattern was stable in 53%, progressive in 21% and 26% showed reverse transition. Treatment with HSCT was significantly associated with higher rate of reverse transition (relative transition rates [95% CI] 5.382 [1.0047-28.83]), but not with a decreased rate of progression (4.393, [0.7232-26.68]). No association between cyclophosphamide and rate and direction of transition of NVC pattern was found. Conclusions Transition of NVC pattern was observed in 47% of SSc patients; 26% showed reverse transition. Rapid reverse transition was associated with treatment with HSCT. This observation could indicate that aggressive immunosuppressive treatment like HSCT can ameliorate microangiopathy in SSc, and advocates further research to unravel the link between microangiopathy and autoimmunity in SSc. References Sulli A, Pizzorni C, Smith V, Zampogna G, Ravera F, Cutolo M. Timing of transition between capillaroscopic patterns in systemic sclerosis. Arthritis Rheum 2012 March;64(3):821-5. Aschwanden M, Daikeler T, Jaeger KA, Thalhammer C, Gratwohl A, Matucci-Cerinic M, et al. Rapid improvement of nailfold capillaroscopy after intense immunosuppression for systemic sclerosis and mixed connective tissue disease. Ann Rheum Dis 2008;67(7):1057-9. Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One 2008;3(1):e1452. Disclosure of Interest None declared

AB0705 Psychopathologic Involvement in Systemic Sclerosis: A Pilot Study

Background Involvement of the brain in systemic sclerosis (SSc) could be suspected given the presence of disturbances on cerebrovascular imaging or mental dysfunction, including disorders of cognition or mood. It is important to confirm this since the intervention of first choice for cognitive disorders is highly depending on the pathophysiology. Objectives To investigate whether mental complaints in patients with SSc are related to organic brain dysfunction. Methods Twenty SSc patients with self-reported mental complaints, including concentration problems, fatigue, memory loss, or depression, were cross-sectionally assessed by neuropsychological testing, psychiatric evaluation and magnetic resonance imaging (MRI) of the brain. All patients completed the Hospital Anxiety and Depression Scale, Dissociation Experience Scale, a screenings tool for fatigue (MFI-20), Short Form-36 and Neuropsychiatric Inventory. Patients were compared with 20 age and sex matched healthy controls. Results Patients and healthy controls did not differ with respect to sociodemographic characteristics. In 5 SSc patients cognitive dysfunction was considered questionable by the neuropsychologist. Patients performed slightly worse on cognition tasks as compared to healthy controls, but all test results were within the normal range. The MRI showed small white matter hyperintensities (WMH) in 18 patients and in 15 healthy controls. The neuropsychological tests were completely normal within those 15 healthy controls. Thirteen SSc patients with WMH on MRI, had normal neuropsychological tests and no mood disorder. Four patients with WMH had a mood disorder. Conclusions Based on this pilot study, SSc patients show slight disturbances of mental functioning as compared to healthy controls, but their performance is within the normal range. No clear association between mental dysfunction and organic brain abnormalities could be detected. In case of mental dysfunctioning in SSc patients, we propose psychological intervention, starting with psychoeducation and in some cases cognitive-behavioural therapy, is the best treatment. Disclosure of Interest J. Meijs Grant/research support from: Jessica Meijs was supported by an unrestricted educational grant of Actelion Pharmaceuticals Nederland BV (Woerden, The Netherlands)., E. Ercan: None declared, E. Baptist: None declared, N. van der Wee: None declared, O. Tritanon: None declared, M. van Buchem: None declared, T. Huizinga: None declared, A. Schouffoer: None declared, H. Middelkoop: None declared, J. de Vries-Bouwstra: None declared