Disease activity score-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis: data from the GUEPARD trial and ESPOIR cohort

International audienceOBJECTIVES: To compare the efficacy of disease activity score in 28 joints (DAS28ESR)-driven therapy with anti-tumour necrosis factor (patients from the GUEPARD trial) and routine care in patients with recent-onset rheumatoid arthritis (patients of the ESPOIR cohort). RESULTS: After matching GUEPARD and ESPOIR patients on the basis of a propensity score and a 1:2 ratio, at baseline all patients had comparable demographic characteristics, rheumatoid factor, anticyclic citrullinated peptide antibody positivity and clinical disease activity parameters: erythrocyte sedimentation rate, C-reactive protein, mean DAS (6.26±0.87), Sharp/van der Heijde radiographic score (SHS), health assessment questionnaire (HAQ). Disease duration was longer in GUEPARD patients (5.6±4.6 vs 3.5±2.0 months, p<0.001). After 1 year, the percentage of patients in remission with an HAQ (<0.5) and an absence of radiological progression was higher in the tight control group (32.3% vs 10.2%, p=0.011) as well as the percentage of patients in low DAS with an HAQ (<0.5) and an absence of radiological progression (36.1% vs 18.9%, p=0.045). However, there was no difference in the decrease in DAS, nor in the percentage of EULAR (good and moderate), ACR20, ACR50 and ACR70 responses. More patients in the tight control group had an HAQ below 0.5 (70.2% vs 45.2%, p=0.005). Overall, pain, patient and physician assessment and fatigue decreased more in the tight control group. The mean SHS progression was similar in the two groups as was the percentage of patients without progression. CONCLUSIONS: In patients with recent onset active rheumatoid arthritis, a tight control of disease activity allows more patients to achieve remission without disability and radiographic progression

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis

Background. Recent works have suggested a possible link between IL-33 and B-cell biology. We aimed to study in different cohorts and with an accurate ELISA assay the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients. Method. Serum IL-33, rheumatoid factor (RF), anti-citrullinated cyclic peptide antibodies (anti-CCP), high serum IgG level were assessed in 111 RA patients receiving a first course of 2 grams RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Uni and multivariate analyzes identified factors associated with a European League Against Rheumatism response at 24 weeks. Results. At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in the cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33,5% of the patients. In the combined cohorts, presence of RF or anti-CCP (OR 3.27, 95%CI [1.13-9.46]; p=0.03), high serum IgG (OR 2.32, 95%CI [1.01-5.33]; p=0.048) and detectable serum IL-33 (OR 2.40, 95%CI [1.01-5.72]; p=0.047) were all associated with RTX response in multivariate analysis. Combination of these 3 factors increased the likelihood to response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the 3 risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the 3 risk factors = 29.61; 95% CI [1.30-674.79] p=0.034) Conclusion. Detectable serum IL-33 may predict clinical response to RTX, independently of and synergistically with autoantibodies and serum IgG level

ACE as a Mechanosensor to Shear Stress Influences the Control of Its Own Regulation via Phosphorylation of Cytoplasmic Ser1270

Objectives: We tested whether angiotensin converting enzyme (ACE) and phosphorylation of Ser(1270) are involved in shear-stress (SS)-induced downregulation of the enzyme. Methods and Results: Western blotting analysis showed that SS (18 h, 15 dyn/cm(2)) decreases ACE expression and phosphorylation as well as p-JNK inhibition in human primary endothelial cells (EC). CHO cells expressing wild-type ACE (wt-ACE) also displayed SS-induced decrease in ACE and p-JNK. Moreover, SS decreased ACE promoter activity in wt-ACE, but had no effect in wild type CHO or CHO expressing ACE without either the extra-or the intracellular domains, and decreased less in CHO expressing a mutated ACE at Ser(1270) compared to wt-ACE (13 vs. 40%, respectively). The JNK inhibitor (SP600125, 18 h), in absence of SS, also decreased ACE promoter activity in wt-ACE. Finally, SS-induced inhibition of ACE expression and phosphorylation in EC was counteracted by simultaneous exposure to an ACE inhibitor. Conclusions: ACE displays a key role on its own downregulation in response to SS. This response requires both the extra- and the intracellular domains and ACE Ser(1270), consistent with the idea that the extracellular domain behaves as a mechanosensor while the cytoplasmic domain elicits the downstream intracellular signaling by phosphorylation on Ser(1270).Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[01/00009-0]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[03/14115-2]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[06/52053-7]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)[480120/2007-2

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Background: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. Methods: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. Results: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, Ptrend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, Ptrend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, Ptrend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, Ptrend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. Conclusion: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. O M Sinilnikova1,2, A C Antoniou3, J Simard4, S Healey5, M Léoné1, D Sinnett6,7, A B Spurdle5, J Beesley5, X Chen5, kConFab8, M H Greene9, J T Loud9, F Lejbkowicz10, G Rennert10, S Dishon10, I L Andrulis11,12, OCGN11, S M Domchek13, K L Nathanson13, S Manoukian14, P Radice15,16, I Konstantopoulou17, I Blanco18, A L Laborde19, M Durán20, A Osorio21, J Benitez21, U Hamann22, F B L Hogervorst23, T A M van Os24, H J P Gille25, HEBON23, S Peock3, M Cook3, C Luccarini26, D G Evans27, F Lalloo27, R Eeles28, G Pichert29, R Davidson30, T Cole31, J Cook32, J Paterson33, C Brewer34, EMBRACE3, D J Hughes35, I Coupier36,37, S Giraud1, F Coulet38, C Colas38, F Soubrier38, E Rouleau39, I Bièche39, R Lidereau39, L Demange40, C Nogues40, H T Lynch41, GEMO1,2,42, R K Schmutzler43, B Versmold43, C Engel44, A Meindl45, N Arnold46, C Sutter47, H Deissler48, D Schaefer49, U G Froster50, GC-HBOC43,44,45,46,47,48,49,50, K Aittomäki51, H Nevanlinna52, L McGuffog3, D F Easton3, G Chenevix-Trench5 and D Stoppa-Lyonnet42 on behalf of the Consortium of Investigators of Modifiers of BRCA1/