L. van Tuyl

Tight control and intensified COBRA combination treatment in early rheumatoid arthritis: 90% remission in a pilot trial

OBJECTIVE To investigate the efficacy and feasibility of an intensive combination treatment in early rheumatoid arthritis (RA) combined with monitoring both disease activity and cartilage degradation. METHODS In a pilot trial, 21 patients with active early RA (mean DAS28 5.3; mean disease duration 3 months) were treated with COBRA treatment comprising sulfasalazine, methotrexate and high-dose step-down prednisolone, intensified by adding hydroxychloroquine and continued low-dose prednisolone. In addition, based on measurements of disease activity or a marker of cartilage degradation (CTX-II), treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks; and with infliximab after 21 weeks. RESULTS Nineteen of 21 patients (90%) were in remission (DAS28 <2.6) after 40 weeks (8 weeks, 57%; 21 weeks, 76%). American College of Rheumatology (ACR) criteria, ACR20, 50, 70 and 90 improvements rates were 100%, 95%, 71% and 43% respectively. CTX-II excretion decreased by mean (SD) 347(292) ng/mmol creatinine, but only 50% of patients reduced their CTX-II excretion below the cut-off point. The two monitoring groups showed no significant difference in remission according to DAS score or CTX-II excretion, despite a trend towards more intensive treatment in the CTX-II group. Treatment intensification was feasible according to protocol. CONCLUSIONS This small pilot study suggests that intensified and tightly controlled COBRA treatment is uniquely effective in early RA. TRIAL REGISTRATION NUMBER ISRCTN96372677.

Treatment-specific changes in circulating adipocytokines: a comparison between tumour necrosis factor blockade and glucocorticoid treatment for rheumatoid arthritis.

Objective There is increasing evidence that adipocytokines may exert proinflammatory and destructive effects in rheumatoid arthritis (RA). Hence, the authors investigated the relationship between adipocytokines and several features associated with RA (inflammation, joint destruction and cardiovascular disease), as well as the effect of treatment with a tumour necrosis factor inhibitor or glucocorticoids (GCs) hereupon. Methods Serum levels of adiponectin, leptin, resistin, visfatin, vaspin and lipids were determined in a well-defined cohort of patients with RA before and after 16 weeks of adalimumab treatment (adalimumab cohort). The same parameters were analysed in two other cohorts of patients with RA before and after 2 weeks of high-dose prednisolone (high GC cohort) and before and after 22 weeks of treatment with a combination regimen with tapered high-dose prednisolone (COBRA -GC cohort). Radiographs of hands and feet (adalimumab and COBRA-GC cohorts) were assessed at baseline and after treatment. Results Treatment with adalimumab or GC showed opposing effects on vaspin and visfatin levels. Lipid levels improved after several months of adalimumab or GC treatment; in the adalimumab cohort, this was related to reduced visfatin levels, independent of C reactive protein levels. After long-term adalimumab or GC treatment, resistin levels declined, which was associated with a decrease in inflammation markers. In the adalimumab cohort, baseline resistin levels were predictive of baseline radiological damage, independent of anticitrullinated peptide antibodies status or C reactive protein levels. Conclusion Changes in serum adipocytokine levels were treatment specific, further strengthening the role of visfatin and resistin in several disease manifestations of RA.

IgM-rheumatoid factor and anti-cyclic citrullinated peptide decrease by 50% during intensive treatment in early rheumatoid arthritis

Decreases in rheumatoid factor (IgM-RF) during antirheumatic treatment are often reported,1 2 3 4 but the course of anti-cyclic citrullinated peptide (anti-CCP) is less conclusive, with some studies showing decrease,2 5 6 but others finding no change.4 7 8 As anti-CCP antibodies are very specific as a marker for rheumatoid arthritis (RA), decreases in anti-CCP levels on therapy may have prognostic relevance and guide further treatment decisions in patients with early RA. A total of 21 patients with active, early RA were treated for 40 weeks with intensive conventional disease-modifying antirheumatic drug (DMARD) therapy, comprising hydroxychloroquine, sulfasalazine, methotrexate and tapered high-dose prednisolone (enhanced “COBRA” (Combinatietherapie Bij Reumatoide Artritis trial) schedule, fig 1). On non-response at 8 weeks, methotrexate (MTX)was intensified to 25 mg/week; on non-response at 21 weeks, infliximab was offered to patients on high-dose MTX and MTX was intensified in the remainder. Serum was available for 18 out of 21 patients. Figure 1 Top: percentage change of …

'A morass of considerations': exploring attitudes towards ethnicity-based haemoglobinopathy-carrier screening in primary care

Background. The Netherlands does not have a national haemoglobinopathy (HbP)-carrier screening programme aimed at facilitating informed reproductive choice. HbP-carrier testing for those at risk is at best offered on the basis of anaemia. Registration of ethnicity has proved controversial and may complicate the introduction of a screening programme if based on ethnicity. However, other factors may also play a role. Objective. To explore perceived barriers and attitudes among GPs and midwives regarding the registration of ethnicity and ethnicity-based HbP-carrier screening. Methods. Six focus groups in Dutch primary care, with a total of 37 GPs (n = 9) and midwives (n = 28) were conducted, transcribed and content analysed using Atlas-ti. Results. Both GPs and midwives struggled with correctly identifying ethnicities at risk for HbP. Ethical concerns regarding privacy seemed to originate from World War II experiences, when ethnic and religious registration facilitated deportation of Jewish citizens, coupled with the political climate at the time focus groups were held. Some respondents thought the ethnicity question might undermine the relationship with their clients. Software programmes prevented GPs from registering ethnicity of patients at risk. Financial implications for patients were also a concern. Despite this, respondents seemed positive about screening and were familiar with identifying ethnicity and used this for individual patient care. Conclusions. Although health professionals are generally positive about screening, ethical, financial and practical issues surrounding ethnicity-based HbP-carrier screening need to be clarified before introducing such a programme. Primary care professionals can be targeted through professional organizations but they need national policy support.

FRI0377 The relationship between remission and health related quality of life in a cohort of sle patients

Background a treat-to-target approach for SLE was suggested by an international board of experts to further improve outcome in SLE. Remission was specifically identified as a suitable target. The Definition of Remission in SLE (DORIS) task force recently achieved international consensus on criteria for remission. Objectives to investigate the relationship between remission and health-related quality of life (HRQoL) in patients with systemic lupus erythematosus (SLE) in a longitudinal observational cohort. Methods retrospective analysis of prospectively obtained data. HRQoL was assessed using the physical and mental component score (PCS and MCS, respectively) of the Short Form 36 (SF-36) questionnaire. DORIS remission categories (no remission/remission on therapy/remission off therapy) were applied. Determinants of PCS and MCS were identified with simple linear regression analyses. Association between remission and HRQoL was assessed using Generalised Estimating Equation (GEE) models. Results Data from 154 patients with 2 years of follow-up were analysed. At baseline 70/154 (45.5%) of patients were in either form of remission. Patients in remission had higher SF-36 scores in all subdomains compared to patients not in remission (figure 1). PCS was positively associated with remission and having employment and negatively associated with erythrocyte sedimentation rate, patient global assessment, SLICC damage index, prednisone use, immunosuppressant use, and body mass index. MCS was positively associated with Caucasian ethnicity and negatively associated with patient global assessment. In GEE analysis, a gradual and significant increase of PCS was observed from patients not in remission (mean PCS 36.0) to remission on therapy (41.8) to remission off therapy (44.8) (table 1). No significant difference in MCS was found between remission states.Abstract FRI0377 – Table 1 GEE analysis of the association between PCS or MCS and remission in patients with SLE A. PCS Unadjusted Adjusted* Mean PCS (±SD) B (95% CI) p-value B (95% CI) p-value No remission 36.0 (10.9) Ref. Ref. Remission on therapy 41.8 (10.0) 6.3 (3.2–9.3) <0.001 6.2 (3.3–9.0) <0.001 Remission off therapy 44.8 (10.4) 8.2 (5.3–11.2) <0.001 8.3 (5.4–11.1) <0.001 *Adjusted for age and SDI B. MCS Unadjusted Adjusted** Mean MCS (±SD) B (95% CI) p-value B (95% CI) p-value No remission 46.1 (10.6) Ref. Ref. Remission on therapy 49.3 (10.5) 2.9 (0.1–5.7) 0.041 2.3 (−0.5–5.1) 0.112 Remission off therapy 46.8 (10.1) 0.8 (−1.7–3.4) 0.52 0.4 (−2.1–3.0) 0.739 **Adjusted ethnicityAbstract FRI0377 – Figure 1 Mean SF-36 subdomain scores in 154 patients at baseline, categorised between SLE patients in remission (n=60) or not in remission (n=94). Patients in remission at baseline have higher mean scores in all SF-36 subdomains compared to patients not in remission. Conclusions we show a strong and persistent association between remission and PCS, but not MCS. These results support the relevance (construct validity) of the DORIS remission definitions and the further development of a treat-to-target approach in SLE. Disclosure of Interest None declared

THU0703 Systematic review of rheumatoid arthritis clinical studies: suboptimal statistical analysis of radiological data

Background Radiography is an inexpensive, reliable and reproducible method to detect and quantify progression of damage, an important outcome in rheumatoid arthritis (RA) trials and observational studies. However, the distribution of progression scores is skewed with many low or zero scores. Analysis of such data is challenging, and the choice of analysis technique may influence the result. Current analysis practice is unknown. Objectives We systematically searched the literature to identify current practice for the analysis of radiographic progression in clinical trials and observational studies of RA. Methods PubMed Embase and Cochrane databases were searched (2006–2016) to identify studies that described analysis techniques to compare radiographic progression in at least two groups. Studies in animals, children as well as conference abstracts and studies not written in English were excluded. Titles and abstracts were screened by one researcher (SM); a second investigator (LvT) evaluated the included cases, doubtful cases and a random sample of the excluded cases. Information on study design, sample size, assessment methods and analysis technique was extracted by one researcher (SM), in consultation with 3 others (LvT; MB and JT). Results Of 5980 identified papers, 252 were eligible. 226 of these reports were on a single study while 26 were on multiple studies in one paper. Of the 226 studies, 75 studies used parametric techniques, such as t-tests, ANOVA or linear regression to analyze the data. Of these only 12% took the skewed distribution into account. In 78 studies, the continuous data was categorized into two or more groups and analyzed with binomial or ordinal methods, such a chi-square tests or logistic regression analyses. 4 studies treated the outcome as a “count” outcome variable (2 studies applied a Poisson regression, 1 a negative binomial regression and 1 a zero-inflated binomial regression). 43% compared more than two groups. Median (IQR) sample size was 351 (range 163–608). 30% had one reader, 57% two readers, and 2% more than two; in 10% the number of readers was not recorded. Order of reading was random in 43%, sequential in 31%, and unknown in 26%. Most applied the Sharp van der Heijde scoring method (75%); 9% the Genant modification, and 16% other methods. Conclusions There is large heterogeneity in the analysis strategy of radiographic progression in recent RA clinical trials and observational studies: a large number of studies apply simple, suboptimal or inappropriate methods. In addition, key information (i.e. number of readers and order of readings) is poorly documented. Disclosure of Interest S. Mahmood: None declared, L. van Tuyl: None declared, L. Schoonmade: None declared, R. Landewé Employee of: director of Rheumatology Consultancy BV, D. van der Heijde Employee of: director of Rheumatology Consultancy BV, J. Twisk: None declared, M. Boers: None declared

THU0064 Short and Sustained Periods of ACR/EULAR Remission Predict Good Functional Outcome, but Not Stable Radiographic Outcome in Early Rheumatoid Arthritis

Background The ACR/EULAR remission criteria were validated against their potential to predict future prognosis of rheumatoid arthritis (RA) [1]. Sustained remission was not studied, but is likely to be an even stronger predictor of RA prognosis. Furthermore, the patients in the validation study mainly had established RA, whereas results might be different for early RA patients. Objectives To investigate whether remission at single and consecutive visits predicts good outcome in early RA. Methods The presence of remission according to ACR/EULAR and other criteria (Boolean clinical, CDAI, DAS, DAS28, RAPID3) was assessed in early RA patients during the first year of the COBRA-light trial [2,3]. Likelihood ratios were used to assess whether meeting the remission criteria at single visits (13, 26, 39 or 52 weeks) and consecutive visits (13+26, 26+39 or 39+52 weeks) predicted good outcome in the second year (52–104 weeks). Good outcome was defined for function (HAQ consistently ≤0.5 and no deterioration), radiographic damage progression (no deterioration in Sharp-Van der Heijde scores) and both (“overall good outcome”). Results Of the original 164 trial patients, 144 had evaluable data. In the second year, good functional outcome was observed in 35%, good radiographic outcome in 79%, and both in 28% of the patients. Highest sustained remission rates at 13+26, 26+39, and 39+52 weeks were observed for DAS28, followed by DAS, SDAI, CDAI, RAPID3, Boolean clinical and Boolean criteria (Figure 1). Almost all criteria predicted good functional and good overall outcome, at both single and consecutive visits; only single DAS remission did not significantly predict good overall outcome (p=0.07). Sustained remission periods resulted in higher likelihood ratios than remission at single visits (Table 1). None of the criteria predicted good radiographic outcome.Table 1. Predictive value of remission at single and consecutive visits (n=144) LR+ of remission at single visits LR+ of remission at consecutive visits Good functional outcome Good radiographic outcome Good overall outcome Good functional outcome Good radiographic outcome Good overall outcome Boolean 3.6* 1.3 2.8* 29.2* 0.6 4.8* Boolean clinical 3.3* 1.2 2.6* 31.0* 0.7 5.2* CDAI 2.3* 1.2 2.0* 6.8* 0.8 3.1* SDAI 2.3* 1.3 2.1* 7.0* 0.7 3.3* DAS 1.4* 1.0 1.2* 2.4* 1.0 2.1* DAS28 1.4* 1.1 1.3* 1.8* 1.3 1.8* RAPID3† 3.5* 0.9 2.7* 12.8* 1.0 5.2* *Indicates significant predictor (p<0.05); †RAPID3 remission could only be assessed at 13, 26 and 52 weeks, not at week 39; LR+ = Positive likelihood ratio. Conclusions Early RA patients who reach remission according to ACR/EULAR and other criteria during short or sustained periods are likely to retain good physical function in the subsequent months. Sustained remission periods are a stronger predictor than remission at single visits. However, in the setting of low overall damage progression, (sustained) remission was not predictive of good radiographic outcome. References Felson, Arthritis Rheum 2011; Den Uyl, ARD 2014; Ter Wee, ARD 2015. Disclosure of Interest N. Konijn: None declared, L. van Tuyl: None declared, M. Boers Consultant for: MundiPharma, Pfizer, D. Den Uijl: None declared, M. ter Wee: None declared, P. Kerstens: None declared, A. Voskuyl: None declared, D. van Schaardenburg: None declared, M. Nurmohamed: None declared, W. Lems Grant/research support from: This study was supported by an unrestricted grant from Pfizer

OP0106 Change in Bone Mineral Density with High-Dose Prednisone in Patients with Rheumatoid Arthritis

Background Recently, we showed that treatment with COBRA-light therapy including prednisone with initially 30 mg/day, was as effective as the original COBRA scheme, with initially 60 mg/day [1,2], in the treatment of rheumatoid arthritis (RA). Since high-dose glucocorticoids are associated with bone loss and vertebral and nonvertebral fractures, we investigated the differences in bone mineral density (BMD) after one year of treatment in both arms. Objectives To compare 1-year changes in BMD (lumbar spine [L1-L4], total hip, and femoral neck) between the treatment groups. Methods An open-label, randomised controlled, non-inferiority trial of patients with active, newly diagnosed RA following a treat-to-target protocol. Results BMD data were determined in 144 out of 164 included RA patients, all randomized to either COBRA (n=71) or COBRA-light (n=73) therapy. Overall bone loss was very limited, and no significant difference in change in BMD between COBRA and COBRA-light was found at any site (Table 1). However, in secondary analyses, COBRA-light showed a significant decrease in BMD in the lumbar spine and total hip after 52 weeks, whereas the femoral neck and the COBRA group did not.Table 1. Changes in bone mineral density between baseline and week 52 during COBRA and COBRA-light therapy COBRA (n=71) COBRA-light (n=73) baseline week 52 change baseline week 52 change Lumbar spine 1.12 (0.17) 1.12 (0.17) 0.01% 1.10 (0.15) 1.09 (0.15) −1.02%* Total hip 0.95 (0.14) 0.95 (0.14) 0.05% 0.95 (0.12) 0.94 (0.13) −1.16%* Femoral neck 0.90 (0.16) 0.89 (0.17) −0.59% 0.88 (0.12) 0.87 (0.11) −0.98%* *Significant change between baseline and week 52 (p<0.05). Values are reported as mean (SD), unless otherwise specified. Conclusions During the trial, overall bone loss was very limited and not significantly different between the treatments. These findings strengthen the hypothesis that positive effects associated with the large reduction in disease activity as a result of combination therapy and tight control treatment counteract the negative effects of (high-dose) prednisone on bone. References Den Uyl D, et al. Ann Rheum Dis 2014; Ter Wee MM, et al. Ann Rheum Dis 2015 Disclosure of Interest L. Rasch: None declared, L. van Tuyl: None declared, M. Kremer: None declared, I. Bultink: None declared, M. Boers: None declared, W. Lems Grant/research support from: This research was performed within the framework of project T1–106 of the Dutch Top Institute Pharma, and was additionally funded by an unrestricted grant from Pfizer.

Estimation of dietary calcium intake

Dear Editor,With great pleasure we read the article by Macdonaldet al., describing the validation of a 23-item question-naire for estimating dietary calcium intake, the CaQ [1].We encourage this initiative as we are in search of aneasy, accurate, and feasible way to estimate the calciumintake of our patients as well.Recently, there has been a lot of attention for thepossible elevated cardiovascular risks of surplus calciumsupplementation on the one hand and calcium deficien-cy on the other hand in patients with osteoporosis. Tobe able to prescribe the adequate amount of calciumsupplementation, a practical tool to validly estimate thedietary intake of calcium is not available to clinicians.Most dietary assessment methods are too time-consuming for clinical practice. The gold standard ofassessing dietary calcium intake is a 7-day food diarywith weighed portion sizes, which is laborious for cli-nicians as well as for patients, and therefore not feasiblein clinical practice. Food frequency questionnaires(FFQ) are far more practical; however, they still consistof many questions and thus are not feasible in clinicalpractice either.Macdonald et al. validated their 23-item CaQ againsttwo “gold standards”: a 7-day food diary (n=33), whichis close to a real gold standard, although portion sizeswere estimated rather than weighed, and a FFQ (n=72),which is similar to the CaQ except for being moreelaborate. The authors conclude that their CaQ is anadequate tool to assess daily calcium intake when scor-ing between 700 and 1,200 mg.Although we were excited to see the work ofMacdonald et al., we missed a detailed report on thenumber of patients that has an estimated calcium intakeoutside a predefined clinically relevant area. Forexample, if an intake of 1,000 mg would be considerednormal, a difference of 250 mg between the goldstandard and the questionnaire would be clinicallyrelevant, as patients below 750 mg would benefit fromsupplementation. From a clinician’s perspective, it isimportant to know how many patients fall within theclinically relevant area, in order to judge the applicabilityof the CaQ for prescription of calcium supplements topatients.We recently validated a calcium intake list with only threeitems, which underestimated calcium intake compared toa dietary history with a clinically relevant difference ofmore than 250 mg in 56 % of patients [2]. Using ourlist to prescribe calcium supplements would mean thattoo many patients would be given too much calcium,possibly resulting in elevated cardiovascular risks.Currently, we are in the process of refining the list inorder to improve sensitivity and specificity for use inclinical practice.We look forward to validation studies of calciumintake lists in other cohorts of osteoporosis patients tosee if these lists are valid across cultures and diets andto decide on clinically relevant cutoff points for theprescription of calcium medication.

AB0287 High Levels of 25(OH)D Are Associated with Lower Disease Activity in Patients with Newly Diagnosed Rheumatoid Arthritis: Table 1.

Background Vitamin D deficiency is highly common in patients with rheumatoid arthritis (RA) (1). In vitro, vitamin D has anti-inflammatory effects and vitamin D has been linked to disease activity in RA due to its immuno-modulatory properties (1,2). Objectives To investigate the association between vitamin D status and disease activity in newly diagnosed RA patients before start of therapy. Methods Consecutive patients with active, newly diagnosed RA (symptom duration <2 years), were randomized for treatment with COBRA or COBRA-light therapy (3). Before start of therapy, baseline values were determined, including Disease Activity Score (44 joint; DAS) and serum 25-hydroxy vitamin D (25(OH)D) levels. Based on the widely used cut-off values, patients were stratified into three groups based on baseline serum 25(OH)D levels: <50 nmol/l, 50-74 nmol/l, and ≥75 nmol/l. Results Baseline serum 25(OH)D levels were determined in 147 of 164 included RA patients in the COBRA-light trial (90% of trial population). Serum 25(OH)D levels of the different groups are presented in Table 1. Patients with a baseline serum 25(OH)D level ≥75 nmol/l had a significant lower mean DAS compared to patients with a baseline serum 25(OH)D <75 nmol/l (p=0.001). Vitamin D deficient patients (<50 nmol/l) had a significant shorter symptom duration (p=0.003), and were more often rheumatoid factor positive (p=0.015) compared to patients with sufficient serum 25(OH)D levels.Table 1. Vitamin D status and disease related factors of patients with newly diagnosed rheumatoid arthritis before start of therapy Serum 25(OH)D Serum 25(OH)D Serum 25(OH)D <50 nmol/l 50–74 nmol/l ≥75 nmol/l (n=62; 42%) (n=50; 34%) (n=35; 24%) Disease Activity Score (DAS, 44 joints) 4.2 (0.7) 4.0 (0.9) 3.6 (0.7)* Symptom duration (weeks) 12 [8,21]* 18 [8,49] 25 [13,36] Health Assessment Questionnaire score (HAQ, 0 to 3) 1.5 (0.8) 1.3 (0.6) 1.2 (0.6) Serum 25(OH)D (nmol/l) 36 [25,46] 61 [54,67] 87 [81,100] Rheumatoid factor positive (n (%)) 44 (72)† 22 (45) 20 (57) aCCP positive (n (%)) 44 (71) 26 (53) 25 (71) Values are reported as mean (SD) or median [IQR], unless otherwise specified. *Differs significantly from both other groups (p-value<0.05); †Differs significantly from serum 50-74 nmol/l (p-value<0.05). 25(OH)D: 25-hydroxy vitamin D; aCCP: antibodies against cyclic citrullinated peptides. Conclusions Newly diagnosed RA patients with serum 25(OH)D levels ≥75 nmol/l demonstrate a significant lower disease activity than patients with a serum 25(OH)D level <75 nmol/l before start of therapy. This study cannot distinguish whether a lower DAS at baseline is caused by immuno-modulatory properties due to higher serum 25(OH)D levels, or that higher serum 25(OH)D levels are caused by more frequent outdoor activities related to a lower DAS. Since 75% of the newly diagnosed RA patients have insufficient serum 25(OH)D levels (<75 nmol/l), vitamin D supplementation should be considered in every newly diagnosed RA patient. References Grazio S, et al. Am J Med Sci 2014. Baker JF, et al. Clin Exp Rheumatol 2012. Den Uyl D, et al. Ann Rheum Dis 2013. Disclosure of Interest L. Rasch: None declared, N. Konijn: None declared, Y. Krul-Poel: None declared, L. van Tuyl: None declared, H. Raterman: None declared, M. ter Wee: None declared, D. den Uyl: None declared, S. Simsek: None declared, M. Nurmohamed: None declared, W. Lems Grant/research support from: This research was performed within the framework of project T1-106 of the Dutch Top Institute Pharma, and was additionally funded by an unrestricted grant from Pfizer.