D. Opris

To be or not to be, ten years after: evidence for mixed connective tissue disease as a distinct entity.

OBJECTIVES To determine if mixed connective tissue disease (MCTD) can be considered an independent clinical entity, to compare 3 different classification criteria for MCTD (Kasukawa, Alarcón-Segovia, and Sharp), and to define predictors (clinical features and autoantibodies) of potential evolution toward other connective tissue diseases (CTDs). METHODS One hundred sixty-one MCTD patients were evaluated retrospectively at the diagnosis and in 2008. They were classified, at the diagnosis, according to the 3 classification criteria of MCTD (Sharp, Alarcón-Segovia, and Kasukawa) and reclassified in 2008 according to their evolution. Statistical analyses were performed to find out predictors (clinical features and autoantibodies) of evolution into other CTDs. RESULTS After a mean of 7.9 years of disease, 57.9% of patients still satisfied MCTD classification criteria of Kasukawa; 17.3% evolved into systemic sclerosis, 9.1% into systemic lupus erythematosus, 2.5% into rheumatoid arthritis, 11.5% was reclassified as affected by undifferentiated connective tissue disease, and 1.7% as suffering from overlap syndrome. Kasukawas criteria were more sensitive (75%) in comparison to those of Alarcón-Segovia (73%) and Sharp (42%). The presence of anti-DNA antibodies (P = 0.012) was associated with evolution into systemic lupus erythematosus; hypomotility or dilation of esophagus (P < 0.001); and sclerodactyly (P = 0.034) with evolution into systemic sclerosis. CONCLUSIONS MCTD is a distinct clinical entity but it is evident that a subgroup of patients may evolve into another CTD during disease progression. Initial clinical features and autoantibodies can be useful to predict disease evolution.

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.

Monitoring Drug and Antidrug Levels: A Rational Approach in Rheumatoid Arthritis Patients Treated with Biologic Agents Who Experience Inadequate Response While Being on a Stable Biologic Treatment

Clinical response in patients with rheumatoid arthritis (RA) treated with biologic agents can be influenced by their pharmacokinetics and immunogenicity. The present study evaluated the concordance between serum drug and antidrug levels as well as the clinical response in RA patients treated with biological agents who experience their first disease exacerbation while being on a stable biologic treatment. 154 RA patients treated with rituximab (RTX), infliximab (IFX), adalimumab (ADL), or etanercept (ETN) were included. DAS28, SDAI, and EULAR response were assessed at baseline and reevaluated at precise time intervals. At the time of their first sign of inadequate response, patients were tested for both serum drug level and antidrug antibodies level. At the next reevaluation, patients retreated with RTX that had detectable drug level had a better EULAR response (P = 0.038) with lower DAS28 and SDAI scores (P = 0.01 and P = 0.03). The same tendency was observed in patients treated with IFX and ETN regarding EULAR response (P = 0.002 and P = 0.023), DAS28 score (P = 0.002 and P = 0.003), and SDAI score (P = 0.001 and P = 0.026). Detectable biologic drug levels correlated with a better clinical response in patients experiencing their first RA inadequate response while being on a stable biologic treatment with RTX, IFX, and ETN.

Statins Do Not Influence Long-Term Rituximab Clinical Efficiency in Rheumatoid Arthritis Patients

Objective. This longitudinal study aims to determine if statins inhibit the response to rituximab in rheumatoid arthritis (RA) patients. Methods. 41 patients initiating rituximab were included; 17 patients were exposed to the combination of statins and rituximab. The total cholesterol, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were assessed. The clinical response was evaluated using Disease Activity Score (DAS28) and European League against Rheumatism (EULAR) response at 6 and 18 months. Results. A tendency of increasing in DAS28 was observed in statin-exposed group but the correlation was very weak (at 18 months: r = 0.013, P = 0.952). The statin-exposed status was negatively and very weakly correlated with EULAR response at 6 months (r = −0.073, P = 0.661) and 18 months (r = −0.197, P = 0.244). There was a negative correlation between statin-exposed status and inflammatory markers values (ESR and CRP); however, the correlation was very weak. The use of statin did not influence the cardiovascular risk measured by modified Systematic Coronary Risk Evaluation (mSCORE). Conclusions. Long-term significant inhibitory effects of statins on rituximab treatment in RA have not been proved using clinical response scores or biologic markers.

Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study

BACKGROUND Guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, has been approved for the treatment of moderate-to-severe psoriasis. Psoriatic arthritis is a common comorbidity of psoriasis with an umet need for novel treatments. We assessed the efficacy and safety of guselkumab in patients with active psoriatic arthritis. METHODS We did a randomised, double-blind, placebo-controlled, phase 2a trial at 34 rheumatology and dermatology practices in Canada, Germany, Poland, Romania, Russia, Spain, and the USA. Eligible participants were aged 18 years or older with active psoriatic arthritis and plaque psoriasis affecting at least 3% of their body surface area, with three or more of 66 tender joints and three or more of 68 swollen joints, who had an inadequate response or intolerance to standard treatments. We randomly assigned patients (2:1) via a central interactive web-response system using computer-generated permuted blocks with a block size of six, stratified by previous anti-tumour necrosis factor-α use, to receive subcutaneous guselkumab 100 mg or placebo at week 0, week 4, and every 8 weeks thereafter for 24 weeks. Patients, investigators, and site staff were masked to treatment assignment until final database lock at week 56. At week 16, patients with less than 5% improvement in swollen and tender joint counts were eligible for early escape to ustekinumab. At week 24, the remaining placebo-treated patients crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 and guselkumab-treated patients received a placebo injection at week 24, followed by guselkumab injections at weeks 28, 36, and 44. The primary endpoint was the proportion of patients with at least 20% improvement at week 24 in signs and symptoms of psoriatic arthritis according to American College of Rheumatology criteria (ACR20) in the modified intention-to-treat population (ie, all randomly assigned patients who received at least one dose of study treatment). Safety analyses included patients according to the study drug received. This study is registered with ClinicalTrials.gov, number NCT02319759. FINDINGS Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39·7% [95% CI 25·3-54·1]; p<0·0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred. INTERPRETATION Guselkumab, a novel anti-interleukin 23p19 antibody, significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 44 weeks of treatment. The results of this study support further development of guselkumab as a novel and comprehensive treatment in psoriatic arthritis. FUNDING Janssen Research & Development.

Assessment of skin involvement in systemic sclerosis

Skin involvement in SSc is an important marker of disease activity, severity and prognosis, making the assessment of skin a key issue in SSc clinical research. We reviewed the published data assessing skin involvement in clinical trials and summarized the major conclusions important in SSc clinical research. A systematic literature review identified randomized controlled trials using skin outcomes in SSc. Analysis examined the validity of the different skin measures based on literature findings. Twenty-two randomized controlled trials were found. The average study duration was 10.2 (s.d. 4.5) months, mean (s.d.) sample size 32.4 (32.6) and 26.7 (27.8) in intervention and control arms, respectively. The 17-site modified Rodnan skin score is a fully validated primary outcome measure in diffuse cutaneous SSc. Skin histology seems to be an appropriate method for evaluation of skin thickness. These findings have important implications for clinical trial design targeting skin involvement in SSc.

FRI0107 Romanian Registry of Rheumatic Diseases: Efficacy and Safety of Biologic Therapy in Rheumatoid Arthritis

Background Romania fully reimburses through the National Insurance Health House (NIHH) six biological products for patients with active rheumatoid arthritis (RA), non-responders to at least 2 conventional remissive drugs: infliximab (IFX) original and biosimilars: inflectra (IFN), remsima (REM), etanercept (ETA), adalimumab (ADA), rituximab (RTX). All RA patients treated with biologics are registered in the national electronic database of the Romanian Registry of Rheumatic Diseases (RRBR) - application developed in 2013. Currently, 39.000 cases of RA are treated in Romania, according to NIHH data. Objectives Characteristics of RA population treated with biological agents in Romania, efficacy and safety data from RRBR, after 2 years of initiation. Methods Observational cross sectional study, which included all RA patients treated with biologics. Results 4470 RA patients were included, mean age 57.11 years (±12.02), 85.5% women, mean RA duration 13.51 years (±7.97), 64.8% living in urban areas, 77.4% retired (50% of them permanently work disabled due to RA), 33% with elementary education; mean body mass index (BMI) 26.09 (±4.60). Current treatment: 7.27% IFX, 0.08% IFN, 0.23% REM, 20,74% ADA, 27.21% ETA, 39.91% RTX. Methotrexate is used in 56.3% cases, leflunomide in 41.2%, sulphasalasine in 12.6% and hydroxychloroquine in 9.4%. 23% patients use steroids (20.8% <10mg prednisone daily). The current mean DAS28 is 2.86 (±1.32) and SDAI 6.88 (±7.98); 52.4% cases are in remission (according to DAS28), but only 41.4% according to SDAI; 21.5% cases are in LDA (according to DAS28) and 41.8% (SDAI). Mean EuroQoL 5D (EQ-5D) is 0.73 (±0.26). There is a strong negative association between EQ-5D and DAS28 (r = - 0.7, p<0.01). DAS28 levels correlate positively with BMI (r =0.2, p<0.05). On safety issues, 105 severe adverse events have been reported (2.34%), 21 infections, other than tuberculosis (TB), 21 cases of TB, 15 solid malignancies, 1 case of Hodgkin lymphoma, 11 major cardiovascular events; 13 cases were fatal. Conclusions In Romania, the use of biologics in RA is on a positive trend (11.5% of all RA treated cases). 1/3 of patients have low education and 38.7% are permanently work disabled. Overall treatment efficacy of biological class in terms of T2T strategy (remission) reaches 52.4% (DAS28) and 41.4% (SDAI). Compared with other patients Registries from Europe or USA (1) in Romania there is a higher proportion of women treated and the percentage of steroids use is lower; DAS28 value is significantly lower (near-remission) compared to literature data (1), probably due to the strict evaluations imposed by the NIHH, while the adverse events seem less common (perhaps a lack of registration of all clinical situations). The impact of active disease on quality of life (EQ-5D) is major. References Curtis JR, Jain A, AsklingJ et al. A Comparison of Patient Characteristics and Outcomes in Selected European and U.S. Rheumatoid Arthritis Registries, Semin Arthritis Rheum. Aug 2010; 40(1): 2–14.e1., doi: 10.1016/j.semarthrit.2010.03.003, PMCID: PMC2958101, NIHMSID: NIHMS234142 Disclosure of Interest None declared

A10.06 Detecting adalimumab serum level and anti-drug antibodies – future tool in monitoring spondyloarthritis patients?

Background and objectives Anti-TNF agents have highly proved their efficacy in spondylarthritis (SpA) patients, with a good rate of response of approximately 70%. However a third of patients lose response to treatment. Measuring the drug serum level and anti-drug antibodies might lead to identifying the cause of non-response, followed by adjusting the therapeutic scheme. The aim was to determine the utility of determining drug serum adalimumab (ADL) and anti-ADL antibodies in assessing disease activity in SpA patients. Methods Over a period of 11 months we included 54 SpA patients on ADL, with further exclusion of those who had delayed drug administration or suffered a concomitant infection. Demographic, clinical (disease activity scores) and laboratory (ESR, CRP) data were collected. We measured the determination of interest using Promonitor kits, using the ELISA technique and the statistical analysis was performed with SPSS 20.0. Results Out of the total 35 patients, 74% were males, the mean age was 40 years old with a mean disease duration of 102 months. HLA B27 was positive in 91% of patients and 28% required sacroiliac joint MRI at diagnosis, being a non-radiographic form. 28% of patients tested positive for Quantiferon and underwent chemoprophylaxis. 22% had history of uveitis before diagnosis and 9% had recurrences while on ADL. 82% of patients had detectable ADL levels. The BASDAI score was significantly higher in patients with undetectable ADL (P < 0.001), with a mean value of 6.3 indicating an inadequate disease control. Furthermore, both ASDAS-ESR and ASDAS-CRP were higher in these patients (P < 0.001). 25% had positive anti-ADL antibodies. Patients with no identified antibodies had lower disease activity scores (BASDAI, ASDAS-VSH and ASDAS-CRP, P < 0.001). Acute phase reactants (ESR, CRP) had a higher value in patients with positive anti-ADL antibodies (P = 0.015 and P < 0.001, respectively). Serum level ADL negatively correlated to the presence of anti-ADL antibodies (r = -0.360, P = 0.034) and to disease activity scores. Conclusions Undetectable serum drug level together with the presence of anti-drug antibodies and the increase of SpA activity scores indicate the impact of immunogenicity throughout secondary non-responder patients. Prompt identification of these patients might lead to a better adapted therapeutic scheme.

Dual X-ray absorptiometry whole body composition of adipose tissue in rheumatoid arthritis

Abstract Aim. Rheumatoid arthritis (RA) may influence not only abdominal fat, but also whole body adiposity, since it is associated with chronic inflammation and disability. The study aims to evaluate the whole body adiposity of RA patients and to assess potential influences of disease specific measures. Methods. The study was designed to include Caucasian postmenopausal female RA patients and age-matched postmenopausal female controls. Each subject underwent on the same day clinical examination, laboratory tests, whole body dual X-ray absorptiometry (DXA) composition and physical activity estimation using a self-administered questionnaire. Results. A total of 107 RA women and 104 matched controls were included. Compared to controls, the RA group had less physical activity and a higher prevalence of normal weight obesity. Overfat RA women had a significantly higher toll of inflammation, disease activity, glucocorticoid treatment and sedentary behavior. RA women with inflammation, glucocorticoid treatment and higher disease activity class had higher whole body and trunk adipose tissue indices and higher prevalence of overfat status. Glucocorticoid treatment, inflammation, disease duration and severity correlated with whole body adipose tissue and significantly predicted high adiposity content and overfat phenotypes. Conclusions. RA disease duration and severity are associated with higher whole body and regional adiposity. Low-dose glucocorticoid treatment seems to contribute to adiposity gain and redistribution. Clinicians may need to assess body composition and physical activity in RA patients in order to fully manage cardiovascular outcomes and quality of life.

How Useful is Anti-TNF Serum Level and Anti-drug Antibodies Detectionin Evaluating Patients with Spondyloarthritis?

Objective: The aim of this study was to assess whether infliximab and adalimumab drug serum levels and the detection of anti-drug antibodies can be of use in better observing disease activity in patients with spondyloarthritis, besides classical tools such as BASDAI, ASDAS and inflammatory markers. We proposed to evaluate the influence of ADA in non-responders and in drug-related adverse events. Methods: Over one year, we enrolled 115 patients with SpA, treated with infliximab or adalimumab. Patients who delayed prescribed drug administration were excluded from the study cohort. The population comprised 69 patients - 33 on IFX and 35 on ADA. NSAIDs administration was recommended “on demand”. Demographic, clinical (BASDAI, ASDAS) and laboratory (ESR, CRP) data was collected together with drug serum level and anti-drug antibodies using ELISA. The statistical analysis was performed using the SPSS software, version 20.0 with the aid of Student t-test, Spearman and Pearson tests. Results: Detectable IFX serum levels were identified in 60% of patients while 40% had undetectable drug titers. The IFX-negative had significantly higher disease activity scores: BASDAI (P=0.023), ASDAS-ESR (P<0.001) and ASDAS-CRP (P<0.001). Significant differences were found in the same subgroups regarding inflammatory markers, with higher ESR (P<0.001) and CRP (P=0.032) in patients with undetectable IFX levels. When measuring ADL serum levels, 82% had detectable drug concentrations, with lower BASDAI (P<0.001), ASDAS-ESR and ASDASCRP (P<0.001) and higher ESR and CRP at collection time when compared to ADL-negative patients. NSAID consumption correlated to undetectable levels of IFX and ADL as well as with anti-drug antibodies for both IFX and ADL positivity. All patients who experienced drug related adverse events on both IFX and ADL had positive anti-drug antibodies. Conclusion: Serum drug level measurement and anti-drug antibody detection can be used as a completion of a clinician’s tools in assessing disease activity, leading to an optimal patient management.