A genome-wide association study identifies a new locus associated with the response to anti-TNF therapy in rheumatoid arthritis.

Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept (P<1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.

Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis.

Psoriasis is a prevalent autoimmune disease of the skin that causes significant psychological and physical disability. Tumor necrosis factor (TNF)-blocking agents have proven to be highly efficacious in the management of moderate-to-severe psoriasis. However, a significant percentage of patients do not respond to this treatment. Recently, variation at the PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus has been robustly associated with anti-TNF response in rheumatoid arthritis. Using a cohort of 130 psoriasis patients treated with anti-TNF therapy, we sought to analyze the association of this locus with treatment response in psoriasis. We found a highly significant association between PDE3A-SLCO1C1 and the clinical response to TNF blockers (P=0.0031). Importantly, the allele that was previously associated with the lack of response to rheumatoid arthritis (G allele, single-nucleotide polymorphism rs3794271) was associated with a higher anti-TNF efficacy in psoriasis. The results of this study are an important step in the characterization of the pharmacogenetic profile associated with anti-TNF response in psoriasis.

Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers.

Cancer cells frequently express genes normally active in male germ cells. ATAD2 is one of them encoding a conserved factor harbouring an AAA type ATPase domain and a bromodomain. We show here that ATAD2 is highly expressed in testis as well as in many cancers of different origins and that its high expression is a strong predictor of rapid mortality in lung and breast cancers. These observations suggest that ATAD2 acts on upstream and basic cellular processes to enhance oncogenesis in a variety of unrelated cell types. Accordingly, our functional studies show that ATAD2 controls chromatin dynamics, genome transcriptional activities and apoptotic cell response. We could also highlight some of the important intrinsic properties of its two regulatory domains, including a functional cross-talk between the AAA ATPase domain and the bromodomain. Altogether, these data indicate that ATAD2 overexpression in somatic cells, by acting on basic properties of chromatin, may contribute to malignant transformation.

Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor alpha therapy in rheumatoid arthritis.

OBJECTIVE: To investigate the clinical significance of lymphoid neogenesis (LN) in rheumatoid arthritis (RA), the clinicopathological correlates of this process and its evolution after anti-tumour necrosis factor (TNF)alpha therapy in a large series of synovial tissues were analysed. METHODS: Arthroscopic synovial biopsies from 86 patients with RA were analysed by immunohistochemistry. LN was defined as the presence of large aggregates of lymphocytes with T/B cell compartmentalisation and peripheral node addressin (PNAd) positive high endothelial venules. Clinical variables at baseline and after prospective follow-up were compared in LN positive and negative RA subsets. The evolution of LN and its correlation with the clinical course in a subgroup of 24 patients that underwent a second arthroscopic biopsy after anti-TNFalpha therapy was also analysed. RESULTS: LN was present in 49% of RA synovial tissues. Patients with LN had a significantly higher disease duration and a higher previous use of anti-TNFalpha agents. During prospective follow-up, the proportion of patients achieving good or moderate European League Against Rheumatism (EULAR) 28-joint Disease Activity Score (DAS28) responses was significantly lower in patients who were LN positive despite a significantly higher use of anti-TNFalpha agents. By multivariate logistic regression analysis, LN remained as an independent negative predictor of response to therapy. In the subgroup of patients rebiopsied after anti-TNFalpha therapy, reversal of LN features occurred in 56% of the patients and correlated with good clinical responses. CONCLUSIONS: Synovial LN in RA predicts a lower response to therapy. LN features can be reversed after a short period of anti-TNFalpha therapy in parallel to good clinical responses.

Two different beta3 cysteine substitutions alter alphaIIb beta3 maturation and result in Glanzmann thrombasthenia.

We report the defects responsible for Glanzmann thrombasthenia in two patients showing traces of abnormally migrating platelet beta3 in immunoblotting. Using PCR-SSCP and direct sequencing, we identified a novel homozygous mutation in exon 10 of the beta3 gene of patient 1 which gave a C457 to Y amino acid substitution. A C542 to R substitution in beta3 of patient 2 was previously reported by us. These cysteines are present in EGF-domains 1 and 3 respectively of beta3. We therefore constructed mutants carrying substitutions on cysteine residues in each of the first three EGF domains of beta3, C457, C495 and C542 respectively. Transient expression of these mutants in COS-7 cells, including the C542 and C547 double mutant, proved that disulfide disruption directly affects cell surface expression of the integrin. We then showed by metabolic (35S) labeling and Endo-H glycosidase treatment that these substitutions strongly affected complex maturation within the cell.

Clinical, radiographic and HLA associations as markers for different patterns of psoriatic arthritis.

OBJECTIVE: The aim of this study was to examine whether the five clinical forms of psoriatic arthritis (PsA) identified by Moll and Wright (Semin Arthritis Rheum 1973;3:55-78) could be clearly distinguished, especially as the disease evolved over time, to analyse whether radiographic features or HLA associations could define subsets with greater precision and to identify predictors of disease outcome. METHODS: Seventy-three patients (37 males and 36 females) were followed for a median time of 8 yr (range 1-16 yr). A standard clinical protocol was used to assess patients at each visit and two clinical scores. based on the joint areas involved, were defined to evaluate the mode of onset and the evolution of arthritis. X-ray films of the hands, feet and sacroiliac joints were taken and the patients were divided into two categories according to the presence or absence of erosions and an X-ray erosion score was also used. Three classification methods were used to define the different clinical subsets. HLA-A, B and DR antigens were tested by standard microlymphocytotoxicity assays. A multiple linear regression model was used in the statistical analysis. RESULTS: The five classical clinical subsets defined by Moll and Wright did not remain since distinct peripheral arthritis patterns tended to evolve over time. Only two discrete groups were identified, axial disease (AD) (sacroilitis with or without peripheral arthritis) in 29% of cases and peripheral disease (PD) without sacroilitis in 71%. AD was positively associated with the duration of arthritis (P < 0.04), presence of mutilation (P < 0.02) and the joint area score over disease evolution (JASE) (P < 0.02). There were erosions in 71% of the patients. Erosions correlated with the presence of mutilation (P < 0.007) and with the JASE (P < 0.0005). HLA-B27 was found in 43% of patients with AD, but only in 11% of PD patients (P < 0.01). No other clear HLA correlations were found. CONCLUSIONS: Despite the relatively small number of patients, this longitudinal study suggests that only two clinical subsets can be clearly defined in PsA, AD and PD; these are primarily determined on clinical grounds although HLA-B27 is strongly associated with AD. The evolution of PD pattern with time means that narrower peripheral arthritis subsets are of little clinical use.

Pigmented villonodular synovitis of the knee in a patient with Paget's disease of the adjacent femoral bone.

A 49-year-old male patient, diagnosed as having Paget's disease involving the lumbar vertebrae and both femora, felt persistent pain and swelling in the left knee after trauma. A synovectomy was performed. Clinical and histological findings led to the diagnosis of pigmented villonodular synovitis of the knee joint. Only one previous case of this association has been reported. A common aetiology for both diseases is discussed, and traumatic factors should be considered in the aetiology of the association.