Sophie Pouplin

Gene profiling predicts rheumatoid arthritis responsiveness to IL-1Ra (anakinra)

OBJECTIVESnThe overall non-response rate to biologics remains 30-40% for patients with RA resistant to MTX. The objective of this study was to predict responsiveness to the anakinra-MTX combination by peripheral blood mononuclear cell gene profiling in order to optimize treatment choice.nnnMETHODSnThirty-two patients treated with anakinra (100u2009mg/day s.c.) and MTX were categorized as responders when their 28-joint DAS (DAS-28) had decreased by ≥1.2 at 3 months. Pre-treatment blood samples had been drawn.nnnRESULTSnFor seven responders and seven non-responders, 52 microarray-identified mRNAs were expressed as a function of the response to treatment, and unsupervised hierarchical clustering correctly separated responders from non-responders. The levels of seven of these 52 transcripts, as assessed by real-time, quantitative RT-PCR, were able to accurately classify 15 of 18 other patients (8 responders and 10 non-responders), with 87.5% specificity and 77.8% negative-predictive value for responders. Among the 52 genes, 56% were associated with IL-1β.nnnCONCLUSIONnThis predictive gene expression profile was obtained with a non-invasive procedure. After further validation in other cohorts of patients, it could be proposed and used on a large scale to select likely RA responders to combined anakinra-MTX. Trial registration. Clinical Trials; NCT00213538 (http://www.clinicaltrials.gov).

Diagnostic and prognostic values of anti glucose-6-phosphate isomerase antibodies in community-recruited patients with very early arthritis.

The objective of this study was to determine the diagnostic and prognostic values of antiglucose‐6‐phosphate isomerase (GPI) antibodies in patients with very early arthritis. Anti‐GPI antibodies were measured by ELISA using purified GPI from rabbit muscle in: (i) 383 sera from healthy blood donors (nu2003=u2003120), well‐established rheumatoid arthritis (RA) (nu2003=u200399) and non‐RA differentiated arthritis (NRADA) (nu2003=u2003164) patients; (ii) 195 sera obtained from community‐recruited patients with very early inflammatory arthritis (VErA cohort) that were studied for 1u2003year and classified as having RA (nu2003=u2003116), NRADA (nu2003=u200341), and undifferentiated arthritis (UA) (nu2003=u200338) after the follow‐up period. The criterion for severity was the progression of radiographic damage. Prevalence of anti‐GPI antibodies was significantly higher in well‐established RA patients (45·4%) compared to healthy subjects (2·5%). Anti‐GPI antibodies were also present in sera from NRADA: systemic lupus erythematosus 53%, polymyositis 45·4%, adult‐onset Stills disease 44%, systemic sclerosis 42·8%, spondylarthropathies 25% and primary Sjögren’s syndrome 5·8%. No significant association was found between the presence of anti‐GPI antibodies and the 3 diagnostic groups from the VErA cohort. No correlation was observed between anti‐GPI and autoantibodies usually associated with RA. Anti‐GPI antibodies were not predictive of radiological progression in patients with very early arthritis. Thus, anti‐GPI antibodies are not useful for discriminating RA from non‐RA rheumatic diseases and do not constitute a predictive factor of structural damage.

A 3 mg/kg starting dose of infliximab in active spondyloarthritis resistant to conventional treatments is efficient, safe and lowers costs

OBJECTIVEnWe assessed the efficacy, tolerance and cost of a 3 mg/kg starting dose of infliximab for ankylosing spondylitis (AS) and psoriatic arthritis (PsA).nnnMETHODSnWe retrospectively followed-up 45 biologic-naive consecutive patients (11 with axial AS, 24 with axial and peripheral [mixed] AS and 10 with PsA) who were treated between 2002 and 2005 with a 3 mg/kg dose of infliximab after failure of conventional therapies. The following variables were recorded: visual analog scale (VAS) scores of patients global (G) and pain (P) assessment, duration of early morning stiffness (EMS), disease activity (BASDAI) and functional disability (BASFI). Treatment responses were assessed at 6 and 12 months using the AS assessment score (ASAS)-20% and -40% criteria and BASDAI-50.nnnRESULTSnBaseline characteristics of the 29 men and 16 women were (median [range]): G-VAS, 70 [13-100]; P-VAS, 70 [13-100]; EMS, 60 [0-180] minutes; BASDAI, 64.4 [23.9-100]; BASFI, 57.2 [3.5-98.5]. All manifestations regressed significantly (p<0.0001) for 39 (86.7%) and 24 (53.5%) patients at 6 and 12 months, respectively; 26 (57.8%) had achieved ASAS-20 responses at 6 months that persisted at 1 year for 20 (44.4%); 19 (42.2%) and 12 (26.7%) satisfied BASDAI 50 criteria at 6 and 12 months, respectively. Interestingly, almost 30% still received low-dose infliximab after 4 years of follow-up.nnnCONCLUSIONnAn initial dose of 3 mg/kg of infliximab significantly attenuated AS and PsA manifestations in>40% of the patients, making use of this dose highly advantageous in terms of safety and 33% lower cost.

Combining anti-cyclic citrullinated peptide with the American College of Rheumatology 1987 criteria failed to improve early rheumatoid arthritis diagnosis in the community-based very early arthritis cohort

OBJECTIVESnTo test the performances of combining anti-CCP second generation (CCP2) with ACR 1987 classification criteria and to diagnose early RA in a community-based very early arthritis (VErA) patient cohort.nnnMETHODSnThe VErA cohort comprised 310 patients (median age 52 years; 68.1% women; median symptom duration 4.2 months; glucocorticoid- and DMARD naïve) conservatively treated during the first 2 years. At 6 years of follow-up, a three-expert committee classified the patients into three groups: RA, other classified arthritis (OCA) or unclassified arthritis (UA). We calculated the performances of the different sets, including anti-CCP2 positivity, while retaining or deleting RF and rheumatoid nodule components with ACR 1987 criteria for early RA diagnosis. Models were subjected to receiver operating characteristics curve and logistic regression analyses to try to identify relevant sets able to classify very early RA.nnnRESULTSnAt 6 years, 149 patients were diagnosed as RA and 119 as non-RA (95 OCA and 24 UA). The original ACR 1987 criteria had 77.9% sensitivity and 64.7% specificity for the RA diagnosis at 6 years. The modified set excluding rheumatoid nodules, including anti-CCP2 positivity and retaining RF performed significantly better than ACR 1987 criteria, with 79.9% sensitivity and 64.7% specificity and with a larger area under the curve. However, in the zone of interest, i.e., ≥4/7 criteria, the curves for these sets were superimposed.nnnCONCLUSIONSnAdding anti-CCP2 positivity and deleting rheumatoid nodules failed to improve the performances of ACR 1987 classification criteria for the diagnosis of early RA.

Switching from an anti-TNF monoclonal antibody to soluble TNF-receptor yields better results than vice versa: An observational retrospective study of 72 rheumatoid arthritis switchers

OBJECTIVESnTo evaluate the benefits for rheumatoid arthritis (RA) patients of switching from one tumor necrosis factor inhibitor (TNFi) to another based on reason for change (primary failure, escape or intolerance) and molecule-switching order.nnnMETHODSnBetween 2000 and 2008, 356xa0RA patients prescribed a TNFi (infliximab [IFX], etanercept [ETA] or adalimumab [ADA]) and undergoing standardized evaluation were included in this retrospective study. Detailed demographic, clinical and biological data were collected before first biologic use and ≤6xa0months later to evaluate response based on EULAR-criteria. Primary failure, escape or intolerance of first TNFi triggered switch to another TNFi, the response of which was evaluated 6xa0months later. Propensity score then measured any interaction with baseline variables.nnnRESULTSnOf the 356xa0RA patients, 38 switched from IFX/ADA to ETA, 26 from ETA to IFX/ADA, and eight from one monoclonal antibody (mAb; IFX/ADA) to another. Clinical parameters for switchers and non-switchers were comparable. Switchers changed therapies because of primary failure (36.1%), escape (33.3%), or intolerance (30.6%), with no difference found in these subgroups. More switchers responded to the second TNFi than the first (P<0.01), respectively, regardless of switch (ETA to IFX/ADA: 50 vs. 23.1% [P<0.05]; IFX/ADA to ETA: 57.9 vs. 15.8% [P<0.001]) or reason for changing. In addition, DAS28 decreased more with the second antagonist (P<0.001) and regardless of molecules switched (P<0.01). Survival of the second TNFi was significantly longer with switch from mAb to the soluble receptor than vice versa (P<0.05).nnnDISCUSSIONnOverall, any switching from one TNFi to another, especially mAb to soluble receptor, was often beneficial for RA patients.

Pain due to osteoarthritis may impair the early outcome of deep brain stimulation in Parkinson's disease

OBJECTIVEnTo analyse postoperative pain due to osteoarthritis in patients with Parkinsons disease submitted to bilateral subthalamic nucleus stimulation.nnnMETHODSnFifty-three parkinsonian patients (mean age, 59.9 ± 8.3 years; mean disease duration, 11.5 ± 4.2 years) referred for subthalamic nucleus stimulation were enrolled. Patients were prospectively asked to refer and describe any pain due to osteoarthritis they experienced at any time during the preoperative period and within the 6 postoperative months. Pre-existing pain due to osteoarthritis, therapeutic changes, parkinsonian motor disability and weight gain were assessed as explanatory factors for occurrence pain due to osteoarthritis after surgery.nnnRESULTSnAfter surgery, thirty patients (57%) complained of pain due to osteoarthritis whereas all demonstrated great functional improvement. Twenty (67%) among the 30 experienced similar pain sensation before surgery. Symptoms occurred rapidly, between 4 and 26 postoperative weeks. Multiple stepwise regression analysis showed that pre-existing pain due to osteoarthritis, 6-month postoperative UPDRS III motor score and axial sub-score improvements in the off-drug/on-stimulation condition were accurate independent predictors of pain due to osteoarthritis after surgery (F(8,41)=2.20, p<0.047).nnnCONCLUSIONnOur results highlight the high prevalence of pain due to osteoarthritis arising shortly after subthalamic implantation. An accurate pain and osteo-articular assessment should be performed preoperatively in parkinsonian candidates for subthalamic nucleus stimulation in order to limit occurrence of complications in the early postoperative period.

Estimated medication costs of primary TNFα antagonist failure in patients with rheumatoid arthritis.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 17 avril 2012

FRI0314 Assessment of the Ultrasonography's Efficiency as a Diagnostic Tool for Calcium Pyrophosphate Crystal Deposition Disease

Background The diagnosis of calcium pyrophosphate deposition disease (CPPD) by detection of calcium pyrophosphate crystals in the synovial fluid may be difficult or impossible for technical reasons. Currently, conventional X-rays are used with a high specificity but a low sensitivity. Objectives The aim of this study is to assess ultrasonography efficiency in the diagnosis of CPPD. The secondary objectives are to determine an ultrasound sensitive site for the diagnosis and to compare ultrasonography to conventional radiography. Methods We conducted a bicentrique transversal prospective study. Every patient with knee arthritis was included and had an arthrocentesis, conventional radiography of the knee and an ultrasound of the knee (meniscus, capitellum and trochlea) and the wrists. The ultrasound examiner was blinded of the fluid histologic findings. The final diagnosis was performed by the synovial fluid analysis which was made by various examiners. Ultrasound diagnosis of CPPD was established if there were at least one typical calcification found during the examination (hyperechoic bands parallel to the surface of the hyaline cartilage and “punctate” pattern composed of several thin hyper-echoic spots). Results 78 patients were included: 22 CPPD, 11 gouts (with no chalky gout), 16 inflammatory rheumatisms, 14 osteoarthritides and 15 undetermined arthritides. 20 patients had radiographic signs of CPPD and 39 patients had ultrasound signs (21 CPPD, 5 gouts, 4 inflammatory rheumatisms and 5 osteoarthritides). In our study ultrasound has a sensitivity of 95,4%, a specificity of 65,8%, a positive predictive value of 60% and a negative predictive value of 96,4% in the diagnosis of CPPD. Radiography of the knee has a sensitivity of 77.7%, a specificity of 92,7%, a positive predictive value of 85% and a negative predictive value of 88,8%. There was no statistical difference between ultrasound and conventional radiography regarding the sensitivity (p=0,219). The meniscus analysis in ultrasound is statistically the most sensitive site for the detection of CPPD (p=0,006). Conclusions Regarding the sensitivity of ultrasound for the CPPDs diagnosis, our results are in agreement with the literature (1,2) in contrast to our specificity which could be related to the heterogeneity of the assessers (real-life study). Ultrasound is an examination at least as efficient as conventional radiography in the diagnosis of CPPD, however it presents the benefits of being easier to carry out by the rheumatologists, cheaper and less irradiate. References Filippou G, Frediani B, Gallo A, et al. A “new” technique for the diagnosis of chondrocalcinosis of the knee: sensitivity and specificity of high-frequency ultrasonography. Ann Rheum Dis 2007;66:1126-28 Gutierrez M, Di Geso L, Salaffi F, et al. Ultrasound detection of cartilage calcification at knee level in calcium pyrophosphate deposition disease. Arthritis Care and Research. 2014; 66:69-73 Disclosure of Interest None declared

FRI0502 After how many time does it become useless to try to classify an inflammatory rheumatism

Background There is several models to predict the development ofrheumatoid arthritis in patients with early undifferentiated arthritis (UA). No study have concerned the future of the patients with UA in the medium and long term. Objectives 1) to describe the population of UA at inclusion. 2) to identify predictive factors of the preservation of the status of UA. 3) to determine a time from which it is useless to try to classify a UA. Methods Community-based adults (n = 310) who had never taken disease-modifying antirheumatic drugs (DMARDs) or steroids with swelling of ≥2 joints persisting for >4 weeks and lasting <6 months were recruitedbetween 1998 and 2002. They have been followed during 10 years. The diagnoses were annually analyzed by experts’ committee. UA were defined according to 2 approaches : “academic”, that is the impossibility to classify the rheumatism according to the official criteria; “pragmatics” in which were not any more considered as unclassified the patients with a diagnostic hesitation without therapeutic impact. UA were compared with the classified arthritis (CA) at inclusion; a survival analysis of the status of UA have been made using a Cox regression. Results according to the “academic” method, there were 180 UA / 312 patients at inclusion. There was 73,9 % of women versus 60,6 % to the CA ( p=0,014 ); the number of swollen joints/ 44 ( NSJ) was lesser (7,2 vs 12,1; p < 0,001); lower limbs less often affected (50,0 % vs 72,7 %; p < 0,001); the DAS of 2,5 vs 2,9 (p < 0,001); ESR and CRP less high (p < 0,05); rheumatoid factor and anti-CCP-2 antibodies less frequent (p < 0,001), finally, the erosion Sharp score less high (0,3 vs 0,9; p=0,001). According to the “pragmatic” filter, 162/312 remained unclassified. There was no significant feminine ascendancy, the NSJ was lesser (6,8 vs 9,3; p < 0,001); the big joints (56,8 % vs 62,2 %; p=0,047) and lower limbs (50,6 % vs 59,6 %; p < 0,001) less often affected; the DAS lesser (2,4 vs 2,7; p < 0,001); rheumatoid factor and anti-CCP-2 antibodies less often positive (p < 0,01); finally, the erosion Sharp score less high (0,3 vs 0,6; p=0,002). The survival analysis of the status of UA according to the “academic” approach found, as predictive factor of classification : a rate of anti-CCP-2 > 3 times the normal (Hazard Ratio ( HR) 3,01, p < 0,001), the painful involvement of the only lower limbs - protective factor (HR=0,24; p=0,017). According to the “pragmatic” approach: a morning stiffness > 60 ′ (HR=1,64, p=0,002), a NSJ > median (HR=1,62; p=0,003), a swelling of upper limbs joints (HR=2,67; p=0,023), an involvement of the lower and upper limbs (HR=1,44; p=0,047). The protective factors were : swelling of the small joints (HR=0,17; p < 0,001) and involvement of the small and big joints (HR=0,57; p=0,002). The inventory of the diagnoses done according to time shows that after 6 years of evolution, only 3 patients lost the status of UA. Conclusions UA distinguishes from CA by a lower level of activity. The predictive factors of the preservation of the status of UA are in touch with a less important severity of the rheumatism. It seems useless to try to classify a rheumatism after 6 years of evolution. Disclosure of Interest None Declared