Anne A. Schouffoer

Increased incidence of pregnancy complications in women who later develop scleroderma: a case control study

IntroductionStudies have shown that fetal progenitor cells persist in maternal blood or bone marrow for more than 30 years after delivery. Increased trafficking of fetal cells occurs during pregnancy complications, such as hypertension, preeclampsia, miscarriage and intra-uterine growth restriction (IUGR). Women with these pregnancy complications are significantly more often HLA-class II compatible with their spouses. Women who later develop scleroderma also give birth to an HLA-class II child more often. From these prior studies we hypothesized that preeclampsia and other pregnancy complications could be associated with increased levels of fetal cell trafficking, and later be involved in the development of scleroderma.MethodsThis study was a retrospective multi-centre matched case-control study. One-hundred-and-three women with systemic sclerosis (SSc) and 103 women with no history of SSc or other autoimmune disease were given a questionnaire regarding complications during pregnancy, such as hypertension, intra-uterine growth restriction (IUGR) and miscarriage. Conditional logistic regression analysis was used to assess associations.ResultsWe found a statistically significantly increased incidence of having had a pregnancy history of hypertension or a fetus with IUGR in women who subsequently developed SSc compared to healthy controls. We found an odds ratio of 2.6 (95% confidence interval (CI): 1.1 to 4.6) for hypertensive complications during pregnancy and an odds ratio of 3.9 (95% CI: 1.2 to 12.3) for intra-uterine growth restriction for women with SSc compared to healthy controls.ConclusionsThis is the first study to show an association between hypertensive complications during pregnancy or IUGR and the development of SSc at a later age. We speculate that the pregnancy abnormalities may have resulted in increased fetomaternal trafficking, which may have played a role in the increased incidence of SSc. Further studies are indicated to examine this putative relationship.

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

ObjectivenTo 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.nnnMethodsnA 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.nnnResultsnPrevalence 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).nnnConclusionnIn 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.

Using Optimal Test Assembly Methods for Shortening Patient-Reported Outcome Measures: Development and Validation of the Cochin Hand Function Scale-6: A Scleroderma Patient-Centered Intervention Network Cohort Study.

To develop and validate a short form of the Cochin Hand Function Scale (CHFS), which measures hand disability, for use in systemic sclerosis, using objective criteria and reproducible techniques.

Determinants of reaching drug-free remission in patients with early rheumatoid or undifferentiated arthritis after one year of remission-steered treatment

OBJECTIVEnThe aim of this study was to assess whether baseline characteristics in patients with undifferentiated arthritis or early RA affect the possibility of achieving drug-free remission after 1 year (DFR1 year) of early remission induction therapy.nnnMETHODSnWe included 375 patients participating in the IMPROVED study who achieved remission (DAS < 1.6) after 4 months (early remission) and were by protocol able to achieve DFR1 year. Having started with MTX plus prednisone, patients tapered prednisone to zero; after 8 months, those still in remission tapered MTX to zero, while those not in remission restarted prednisone. Characteristics of patients achieving and not achieving DFR1 year were compared. Logistic regression was performed to identify predictors of DFR1 year.nnnRESULTSnAfter 1 year, 119 patients (32%) were in DFR. Presence of RF, fulfilling the 2010 criteria for RA, and a low tender joint count were associated with achieving DFR1 year, whereas presence of ACPA was not. None of the baseline characteristics was independently associated with DFR1 year. DFR1 year was sustained for 4 months in 65% of the patients. ACPA-positive patients less often had sustained DFR than ACPA-negative patients (58% vs 80%, P = 0.013).nnnCONCLUSIONnAfter 1 year of remission-steered treatment, 32% of the patients who had achieved early remission after 4 months were able to taper medication and achieved DFR. Neither the presence of ACPA nor any other baseline characteristics were independently associated with achieving DFR1 year, but in ACPA-positive patients DFR was less often sustained.

OP0182 Drug Free Remission After One Year of Treatment in Patients with Early Rheumatoid Arthritis: Also Possible for ACPA Positive Patients?

Background In rheumatoid arthritis (RA) remission is a realistic treatment goal. Is tapering medication to drug free remission (DFR) possible for all patients? Objectives To assess which patients with early (rheumatoid) arthritis achieve DFR after one year (DFR1year) of early remission induction therapy. Methods By protocol of the IMPROVED study, patients who achieved remission (DAS<1.6) after 4 months (early remission, n=375) of combination therapy with methotrexate 25 mg/wk and a tapered high dose of prednisone (60 mg/day tapered in 7 weeks to 7.5 mg/day, continued up to 4 months) had to taper stepwise and finally discontinue these drugs as long as remission was maintained. Characteristics of patients achieving and not achieving DFR1year were compared and predictors of DFR were identified using logistic regression. Follow up data of 16 months were included to investigate in how many patients DFR1year was sustained for 4 more months. Results 119 patients (32%) achieved DFR1year, while 245 (65%) flared and restarted medication over time. Eleven patients had insufficient data. Of patients in DFR1year, 51 (28%) at baseline fulfilled the 1987 and 2010 classification criteria for RA, 34 (35%) only fulfilled the 2010 criteria and 20 (35%) patients had UA and fulfilled neither criteria (p=0.4). In 77 (65%) DFR1year was sustained up to 16 months. Patients in DFR1year were more often rheumatoid factor (RF) negative than patients not achieving DFR1year, (50% versus 62%, p=0.04). There were no differences in baseline DAS (2.9 (0.9) versus 3.1 (0.8), p=0.12), symptom duration (16 (8-29) versus 17 (9-32), p=0.52) or ACPA positivity (56% versus 61% respectively, p=0.27). Univariable predictors were positive RF (OR 95%CI 0.6 (0.4-0.99)) and high baseline tender joint count (TJC) (OR 95%CI 0.9 (0.9-1.0). Baseline DAS, positive ACPA, age, male sex, being classified as RA according to the 2010 ACR/EULAR criteria or short symptom duration were not predictive for DFR1year. The only independent predictor was RF negativity (OR 95%CI 0.6 (0.4-0.97, adjusted for baseline TJC). Conclusions Of 375 early (rheumatoid) arthritis patients who achieved remission after 4 months of initial combination therapy with methotrexate and prednisone, 32% maintained in remission despite having tapered and discontinued all drugs at 1 year. DFR was sustained up to 16 months in 65% of these. With this treatment strategy, presence of ACPA appears not to preclude drug discontinuation, but patients with positive RF achieved DFR after 1 year somewhat less often than RF negative patients. Disclosure of Interest None Declared

Lung Density and Pulmonary Artery Diameter are Predictors of Pulmonary Hypertension in Systemic Sclerosis

Purpose: The aim was to evaluate computed tomography (CT)-measured pulmonary artery diameter (PAD) and lung density as predictors of pulmonary hypertension (PH) in subjects with systemic sclerosis (SSc). We compared these PAD values with normal values and between SSc subgroups with PH and/or interstitial lung disease (ILD). We investigated whether PAD predicts PH and whether lung densitometry, by using the 85th percentile density value (Perc85) as a measure for ILD, can predict PH. Materials and Methods: PAD and Perc85 were measured in axial CT scans and compared between 54 SSc and 76 control subjects. Four SSc subgroups were defined on the basis of PH (systolic PA pressure ≥35 mm Hg) and/or ILD (fibrosis score ≥7): PH−/ILD−, PH−/ILD+, PH+/ILD−, and PH+/ILD+. The association of PAD with age, body mass index, Perc85, lung function, and hemodynamic measures was investigated using univariate correlation along with the predictive value of these measures with respect to PH. Results: PAD in SSc was larger than that in controls (30.1±4.9 vs. 26.9±2.7 mm, P<0.001). PH+ patients showed increased PAD compared with PH− patients (34.2±4.2 vs. 28.6±4.3 mm, P<0.001), where PH+/ILD+ subjects showed the widest diameter (34.6±4.1 mm). In SSc patients, hemodynamic measures, age, body mass index, Perc85, and lung function correlated with PAD. PAD was best explained by Perc85, together with age (R2=0.358). PAD best predicted PH (AUC, 0.877; P<0.001), and PAD≥30.7 mm showed 80% sensitivity and 87% specificity. Perc85 also predicted PH (AUC, 0.733; P=0.024). Conclusions: In subjects with SSc, lung density and PAD are CT markers, each with predictive value for PH.

THU0100 Disease Activity Flares in Early Rheumatoid Arthritis Patients are Associated with Joint Damage Progression and Disability – Analysis of 10 Year Follow-up in the Best Study

Background Disease flares frequently occur in patients with rheumatoid arthritis (RA). It has been suggested that these may spontaneously remit, in which case targeted treatment including intensification at the time of a flare could entail overtreatment. Objectives To study the occurrence and outcomes of flares during long-term follow-up in early RA patients who were treated to target over 10 years. Methods In the BeSt study, which enrolled 508 patients, targeted treatment aimed at a disease activity score (DAS) ≤2.4. A flare was defined from the 2nd year of follow-up onwards as a DAS >2.4 and an increase in DAS of ≥0.6 from the previous DAS, regardless of the height of the previous DAS, measured during 3-monthly visits. Of 480 patients sufficient follow-up data were available to apply this definition. Functional ability (health assessment questionnaire, HAQ) during a flare was compared to functional ability during the absence of a flare with a linear mixed model (LMM). Visual analogue scales (VAS) (increase of ≥20mm between 2 visits, yes/no) and radiographic progression (Sharp vd Heijde score; increase ≥0.5 during 1 year, yes/no) were analysed similarly with a generalized LMM. Results The incidence of flares was 7-11% per visit during year 2 to 4 of follow-up, and 4-6% per visit during the later years of follow-up. During year 2 to 10, 321/480 patients (67%) experienced at least one flare with a median (IQR) frequency of 2 (1 - 4) times. At the time of a flare, functional ability decreased with a mean difference of 0.25 in HAQ (p<0.001). During a flare, the odds ratio (95% confidence interval (CI)) for an increase of ≥20mm in VAS compared to the previous visit was 8.5 (7.3-9.8), 8.4 (7.2-9.7) and 5.6 (4.8-6.6) for patients assessment of disease activity, pain and morning stiffness, respectively, compared to the absence of a flare. The odds ratio for developing radiographic progression in a year a flare occurred was 1.7 (95% CI 1.1-2.8), compared to a year without a flare. In patients without any flare during follow-up, median (IQR) radiographic progression from baseline to year 10 was 1.3 (0.0-3.1). The more flares occurred, the higher progression rates were observed: median (IQR) SHS progression was 2.3 (0.5-9.6), 3.0 (0.0-10.0) and 4.3 (0.5-20.1) in patients who experienced 1, 2 and ≥3 flares during follow-up, respectively (p=0.005). A similar dose response relation was shown for functioning; in patients without any flare during follow-up, median (IQR) HAQ was 0.0 (0.0 – 0.5) at year 10, and was 0.4 (0.0-0.9), 0.6 (0.1-0.9) and 0.8 (0.4-1.3) in patients with 0, 1, 2, or ≥3 flares during follow-up, respectively (p<0.001). Conclusions DAS-defined disease flares in rheumatoid arthritis are associated with short term deterioration in functioning and pain as well as radiographic damage progression, and show a dose response relation with long term functional disability and joint damage. The captured incidence of flares was low, and with a continued treatment strategy targeted at DAS ≤2.4, the frequency of flares further decreased over time. This suggests that the disease becomes more indolent in the majority of patients. Disclosure of Interest I. Markusse: None declared, L. Dirven: None declared, H. Han: None declared, M. van Oosterhout: None declared, A. Schouffoer: None declared, P. Kerstens: None declared, W. Lems: None declared, T. Huizinga: None declared, C. Allaart Grant/research support from: The study was designed by the investigators and supported by a government grant from the Dutch Insurance Companies, with additional funding from Schering-Plough B.V. and Janssen B.V. Data collection, trial management, data analysis and preparation of the manuscript were performed by the authors.