ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting tumour necrosis factor-α (TNF-α) and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Preclinical and clinical evidence indicate that anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol and etanercept) is associated with a two-to four-fold increase in the risk of active tuberculosis and other granulomatous conditions (mostly resulting from the reactivation of a latent infection). In addition, it may lead to the occurrence of other serious infections (bacterial, fungal, opportunistic and certain viral infections). These associated risks seem to be lower for etanercept than other agents. Screening for latent tuberculosis infection should be performed before starting anti-TNF-α therapy, followed by anti-tuberculosis therapy if appropriate. Screening for chronic hepatitis B virus (HBV) infection is also recommended, and antiviral prophylaxis may be warranted for hepatitis B surface antigen-positive individuals. No benefit is expected from the use of antibacterial, anti-Pneumocystis or antifungal prophylaxis. Pneumococcal and age-appropriate antiviral vaccinations (i.e. influenza) should be administered. Live-virus vaccines (i.e. varicella-zoster virus or measles-mumps-rubella) may be contraindicated in people receiving anti-TNF-α therapy, although additional data are needed before definitive recommendations can be made. IMPLICATIONS: Prevention measures should be implemented to reduce the risk of latent tuberculosis or HBV reactivation among individuals receiving anti-TNF-α therapy.

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib. METHODS: Phase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05). RESULTS: We identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)). CONCLUSIONS: Within the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.

Leptin in joint and bone diseases: new insights.

Leptin is an adipokine with pleiotropic actions that regulates food intake, energy metabolism, inflammation and immunity, and also participates in the complex mechanism that regulates skeleton biology, both at bone and cartilage level. Leptin is increased in obesity and contributes to the "low-grade inflammatory state" of obese subjects causing a cluster of metabolic aberrations that affects joints and bone. In this review, we report the most recent research advances about the role of leptin in bone and cartilage function and its implication in inflammatory and degenerative joint diseases, such as osteoarthritis, rheumatoid arthritis and osteoporosis.

Oleocanthal inhibits proliferation and MIP-1α expression in human multiple myeloma cells.

Multiple myeloma (MM) is a plasma cell malignancy that causes devastating bone destruction by activating osteoclasts in the bone marrow milieu. MM is the second of all hematological malignancies. Thus, the search for new pharmacological weapons is under intensive investigation being MM a critically important public health goal. Recently, it has been demonstrated that macrophage inflammatory protein 1- alpha (MIP-1 α) is crucially involved in the development of osteolytic bone lesions in MM. Phenolic components of extra virgin olive oil are reported to have anti tumor activity. However, the underlying mechanisms and specific targets of extra virgin olive oil remain to be elucidated. In the present study, we investigated the effects of a recently isolated novel extra virgin olive oil polyphenol, oleocanthal, on the human multiple myeloma cell line ARH-77. Here we report that this natural compound has a remarkable in vitro activity by inhibiting MIP-1 α expression and secretion in MM cells. In addition, we also demonstrated that oleocanthal inhibits MM cells proliferation by inducing the activation of apoptosis mechanisms and by down-regulating ERK1/2 and AKT signal transduction pathways. This in vitro study suggests a therapeutic potential of oleocanthal in treating multiple myeloma.

Deep sequencing of GDF5 reveals the absence of rare variants at this important osteoarthritis susceptibility locus.

OBJECTIVE: The common single nucleotide polymorphism (SNP) rs143383 in the 5' untranslated region (5'UTR) of growth and differentiation factor 5 (GDF5) is strongly associated with osteoarthritis (OA) and influences GDF5 allelic expression in vitro and in the joint tissues of OA patients. This effect is modulated in cis by another common SNP, also located within the 5'UTR, whilst a common SNP in the 3'UTR influences allelic expression independent of rs143383. DNA variants can be common, rare or extremely rare/unique. To therefore enhance our understanding of the allelic architecture of this very important OA susceptibility locus we sequenced the gene for potentially functional and novel rare variants. METHOD: Using the Sanger method we sequenced GDF5 in 992 OA patients and 944 controls, with DNA changes identified by sequencing software. We encompassed the protein-coding region of the two GDF5 exons, both untranslated regions and approximately 100 bp of the proximal promoter of the gene. RESULTS: We detected 13 variants. Six were extremely rare with minor allele frequencies (MAFs) of ≤ 0.0006. One is in a predicted transcription factor binding site in the GDF5 promoter whilst two substitute conserved amino acids. The remaining seven variants were common and are previously known variants, with MAFs ranging from 0.025 to 0.39. There was a complete absence of variants with frequencies in-between the extremely rare (n=6) and the common (n=7). CONCLUSIONS: This is the first report of the deep sequencing of an OA susceptibility locus. The absence of rare variants informs us that within the regions of the gene that we have sequenced GDF5 does not harbour any novel variants that are able to contribute, at a population level, to the OA association signal mediated by rs143383 nor does it harbour, at a population level, any novel variants that can influence OA susceptibility independent of rs143383.

Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study.

OBJECTIVES: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. METHODS: The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent. RESULTS: None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. CONCLUSIONS: Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement.

Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-γ release assays or, as an alternative in individuals without a history of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-γ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly reduces the risk of progression to TB. This TBNET consensus statement summarises current knowledge and expert opinions and provides evidence-based recommendations to reduce the TB risk among candidates for TNF antagonist therapy.

Common variations in estrogen-related genes are associated with severe large-joint osteoarthritis: a multicenter genetic and functional study.

OBJECTIVE: Several lines of evidence suggest that estrogens influence the development of osteoarthritis (OA). The aim of this study was to explore the association of two common polymorphisms within the aromatase (CYP19A1) and estrogen receptor (ER) alpha (ESR1) genes with severe OA of the lower limbs. METHODS: The rs1062033 (CYP19A1) and rs2234693 (ESR1) single nucleotide polymorphisms were genotyped in 5528 individuals (3147 patients with severe hip or knee OA, and 2381 controls) from four centres in Spain and the United Kingdom. Gene expression was measured in femoral bone samples from a group of patients. RESULTS: In the global analysis, both polymorphisms were associated with OA, but there was a significant sex interaction. The GG genotype at rs1062033 was associated with an increased risk of knee OA in women [odds ratio (OR) 1.23; P=0.04]. The CC genotype at rs2234693 tended to be associated with reduced OA risk in women (OR 0.76, P=0.028, for knee OA; OR=0.84, P=0.076 for hip OA), but with increased risk of hip OA in men (OR 1.28; P=0.029). Women with unfavourable genotypes at both loci had an OR of 1.61 for knee OA (P=0.006). The rs1062033 genotype associated with higher OA risk was also associated with reduced expression of the aromatase gene in bone. CONCLUSIONS: Common genetic variations of the aromatase and ER genes are associated with the risk of severe OA of the large joints of the lower limb in a sex-specific manner. These results are consistent with the hypothesis that estrogen activity may influence the development of large-joint OA.

Role of European mitochondrial DNA haplogroups in the prevalence of hip osteoarthritis in Galicia, Northern Spain.

OBJECTIVE: To analyse the mitochondrial DNA (mtDNA) haplogroups of patients with hip osteoarthritis (OA) and those of healthy controls in a Spanish population. METHODS: mtDNA haplogroups were assigned to 550 cases of hip OA and 505 clinically asymptomatic controls. Sets of controls with healthy knees and hips (n = 179) and patients with knee and/or hip OA (n = 977) were also analysed in a multivariate analysis after adjusting for sex, age and smoking. RESULTS: Individuals carrying haplogroup J showed a significantly decreased risk of developing hip OA (OR 0.661; 95% CI 0.440 to 0.993; p = 0.045). In addition to haplogroup J, smoking protected against the development of hip OA (OR 0.543; 95% CI 0.311 to 0.946; p = 0.031). However, no relationship was found between rheumatoid arthritis and mtDNA haplogroups. CONCLUSION: The results of this study support the hypothesis that the mtDNA haplogroups have a role in the complex osteoarthritic process.

Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study.

BACKGROUND: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. OBJECTIVE: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed. METHODS: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24. RESULTS: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol > or =240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs 2.5%), respectively. CONCLUSION: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit-risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.

Testing the druggable endothelial differentiation gene 2 knee osteoarthritis genetic factor for replication in a wide range of sample collections.

OBJECTIVES: To replicate a previously reported association with osteoarthritis (OA) of the promoter single nucleotide polymorphism (SNP) rs10980705 in the endothelial differentiation gene 2 (EDG2). METHODS: Five collections of samples, four from Europe and one from China, were studied. They included patients with 3 OA phenotypes: 1501 with knee OA, 1497 with hip OA and 376 with generalised OA. A total of 2521 controls were also studied. Allele and genotype frequencies of the rs10980705 SNP were analysed in each individual sample collection and in pooled data. In addition, a meta-analysis to incorporate results from the original Japanese report was performed. RESULTS: The association of the rs10980705 SNP with knee OA was not replicated in any of the five sample collections studied or in their combined analysis (odds ratio (OR) 1.10, 95% CI 0.98 to 1.22; p = 0.10). Meta-analysis of all data, including the original Japanese study, did show association with knee OA (OR 1.15, 95% CI 1.06 to 1.26; p = 0.002) but the effect was accounted for by the Japanese data and was less significant than the original report. No association was found with hip OA or with generalised OA. CONCLUSIONS: The original report of a promising genetic association between a druggable G-protein coupled receptor, EDG2, and knee OA has not been replicated. This lack of replication could be due to a modest effect of the promoter polymorphism that will require even larger studies (the winners curse) although a more pronounced effect in the Asian population vs Europeans cannot be excluded.

Association of a nsSNP in ADAMTS14 to some osteoarthritis phenotypes.

OBJECTIVE: To investigate the effect in OA (Osteoarthritis) susceptibility of putative damaging changes in ADAM (A Disintegrin And Metalloprotease) and ADAMTS (ADAM with ThromboSpondin motif) proteases. METHODS: Non-synonymous single nucleotide polymorphisms (nsSNP) in 18 ADAMTS and 31 ADAM genes were analyzed with two software applications for prediction of functional damage. Four putative damaging nsSNP were found in ADAMTS2, ADAMTS14, ADAMTS16 and ADAM12, respectively. These nsSNPs were analyzed in case-control sample collections with a variety of phenotypes totalling 3217 OA patients and 2214 healthy controls, all of them Caucasians. RESULTS: No statistically significant differences were found in ADAMTS2, ADAMTS16 and ADAM12 nsSNPs. Conversely, the rare allele of the rs4747096 nsSNP in ADAMTS14 was overrepresented in women requiring joint replacement because of knee OA (O.R.(M-H) (odds ratio. Mantel-Haenszel)=1.41, 95% C.I.=1.1-1.8; P=0.002) and in patients with symptomatic hand OA (O.R.=1.37, 95% C.I.=1.0-1.9; P=0.047). A non significant increase in the frequency of the same allele was also found in patients with hip OA requiring prosthesis (O.R.(M-H)=1.14, 95% C.I.=1.0-1.3; P=0.08). No association was found with other OA phenotypes. CONCLUSION: Our findings implicate ADAMTS14 in OA, specifically in knee OA requiring joint replacement in women and, possibly, in hand OA. Independent association of ADAMTS14 genetic variation to knee OA in women has been communicated. ADAMTS14 involvement, if confirmed, will open a new area of interest in OA pathogenesis because of its role in the maturation of collagen fibers.

Genetic variation in the nuclear factor kappaB pathway in relation to susceptibility to rheumatoid arthritis.

OBJECTIVE: To examine genetic association between rheumatoid arthritis (RA) and known polymorphisms in core genes of the nuclear factor (NF)kappaB pathway, the major intracellular pathway in RA pathogenesis. METHODS: Discovery and replication sample sets of Spanish patients with RA and controls were studied. A total of 181 single nucleotide polymorphisms (SNPs) uniformly spaced along the genomic sequences of 17 core genes of the NFkappaB pathway (REL, RELA, RELB, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, IKBKA, IKBKB, IKBKE, IKBKAP, KBRAS1, KBRAS2, MAP3K1, MAP3K14, TAX1BP1) were studied by mass spectrometry analysis complemented with 5'-nuclease fluorescence assays in the discovery set, 458 patients with RA and 657 controls. SNPs showing nominal significant differences were further investigated in the replication set of 1189 patients with RA and 1092 controls. RESULTS: No clear reproducible association was found, although 12 SNPs in IKBKB, IKBKE and REL genes showed significant association in the discovery set. Interestingly, two of the SNPs in the IKBKE gene, weakly associated in the discovery phase, showed a trend to significant association in the replication phase. Pooling both sample sets together, the association with these two SNPs was significant. CONCLUSION: We did not find any major effect among the explored members of the NFkappaB pathway in RA susceptibility. However, it is possible that variation in the IKBKE gene could have a small effect that requires replication in additional studies.

Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus.

This study aimed to test the functional effects of the PD1.3 single nucleotide polymorphism (SNP) (rs11568821), which were proposed based on its association to systemic lupus erythematosus (SLE) susceptibility and in electrophoretic mobility shift assays (EMSA) results. We analysed transcriptional effects of the PD1.3 locus by enhancer reporter assays. Results were against the hypothesis that the PD1.3 locus acts as enhancer in transcriptional regulation of PDCD1. In addition, they excluded a differential effect of the PD1.3 alleles. EMSA results confirmed that oligonucleotides with the PD1.3 G allele bind RUNX1 but not those with the A allele. However, binding to PD1.3 G oligonucleotides was much lower than binding to positive control oligonucleotides. Criss-cross experiments showed that this was due to flanking nucleotides in the PD1.3 sequence that negatively affect RUNX1 binding. These results cast doubts on the functional relevance of the PD1.3 SNP and, together with the lack of association in several studies, put into question its role as an SLE susceptibility factor. Investigation of other PDCD1 polymorphisms is needed to uncover the possible effect of this gene on SLE susceptibility.

A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes.

OBJECTIVE: Recent studies revealed a close connection between adipose tissue, adipokines and articular degenerative inflammatory diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). The goal of this work was to investigate the activity of adiponectin in human and murine chondrocytes and to study its functional role in the modulation of nitric oxide synthase type II (NOS2). For completeness, interleukin (IL)-6, IL-1beta, matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, prostaglandin E2 (PGE2), leukotriene B4 (LTB4), tumor necrosis factor alpha (TNF)-alpha and monocyte chemoattractant protein-1 (MCP-1) accumulation have been evaluated in adiponectin-stimulated chondrocytes cell culture supernatants. METHODS: Murine ATDC5 cell line, C28/I2, C20A4, TC28a2 human immortalized chondrocytes, and human cultured chondrocytes were used. Nitrite accumulation was determined by Griess reaction. Adiponectin receptors (AdipoRs) expression was evaluated by immunofluorescence microscopy and confirmed by reverse transcriptase-polymerase chain reaction. NOS2 expression was evaluated by Western blot analysis whereas cytokines, prostanoids and metalloproteinases production was evaluated by specific enzyme-linked immunosorbent assays. RESULTS: Human and murine chondrocytes express functional AdipoRs. Adiponectin induces NOS2. This effect is inhibited by aminoguanidine, dexamethasone and by a selective inhibitor of phosphatidylinositol 3-kinase. In addition, adiponectin is able to increase IL-6, MMP-3, MMP-9 and MCP-1 by murine cultured chondrocytes whereas it was unable to modulate TNF-alpha, IL-1beta, MMP-2, TIMP-1, PGE2 and LTB4 release. CONCLUSIONS: These results bind more closely the interactions between fat-derived adipokines and articular inflammatory diseases, and suggest that adiponectin is a novel key element in the maintenance of cartilage homeostasis which might be considered as a potential therapeutical target in joint degenerative diseases.

Poly(ADP-ribose) polymerase inhibition reduces tumor necrosis factor-induced inflammatory response in rheumatoid synovial fibroblasts.

OBJECTIVES: To investigate the effect of poly(ADP-ribose) polymerase (PARP) inhibition on the production of inflammatory mediators and proliferation in tumour necrosis factor (TNF)-stimulated fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS: Cultured FLS from patients with RA were treated with two PARP inhibitors, 3,4-dihydro-5-[4-1(1-piperidinyl)buthoxy]-1(2H)-isoquinolinona (DPQ) or 4-amino-1,8-naphthalimida (ANI) before TNF stimulation. PARP-1 expression was also suppressed in RA FLS by small interfering RNA (siRNA) transfection. Expression and secretion of inflammatory mediators were analysed by quantitative polymerase chain reaction and by enzyme-linked immunosorbent assay, respectively. Proliferation of RA FLS was also determined. Mitogen-activated protein kinase (MAPK) activity was analysed by western blot assay and activator protein (AP)-1 and nuclear factor (NF)kappaB binding by electrophoretic mobility shift assay. RESULTS: We show, for the first time, that PARP inhibition either with specific inhibitors or by siRNA transfection significantly reduced TNF-induced cytokine and chemokine expression in FLS from patients with RA. PARP inhibitors also decreased TNF-induced RA FLS proliferation. PARP inhibition reduced TNF-induced JNK phosphorylation and AP-1 and NF kappaB binding activities were partially impaired by treatment with PARP inhibitors or by PARP-1 knockdown. CONCLUSION: PARP inhibition reduces the production of inflammatory mediators and the proliferation of RA FLS (in response to TNF), suggesting that PARP inhibitors could have therapeutic benefits in RA.

Opposed independent effects and epistasis in the complex association of IRF5 to SLE.

Genetic variation in the interferon regulatory factor 5 (IRF5) gene affects systemic lupus erythematosus (SLE) susceptibility. However, association is complex and incompletely defined. We obtained fourteen European sample collections with a total of 1383 SLE patients and 1614 controls to better define the role of the different IRF5 variants. Eleven polymorphisms were studied, including nine tag single nucleotide polymorphisms (SNPs) and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility (rs10488631, P<10(-17)) and protection (rs729302, P<10(-6)). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression, a splice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5' side of the gene. In conclusion, our results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, we have found evidence for epistasis between known functional polymorphisms for the susceptibility effect.

Further evidence of the role of frizzled-related protein gene polymorphisms in osteoarthritis.

OBJECTIVE: To replicate the association of frizzled-related protein (FRZB) non-synonymous polymorphisms with osteoarthritis (OA) susceptibility. METHODS: Three groups of Spanish patients with OA were included: with total joint replacement due to primary OA in the hip (n = 310), or the knee (n = 277), or with hand OA (n = 242). Controls were more than 55 years old and did not show OA (n = 294). SNPs rs288326 (R200W) and rs7775 (R324G) were genotyped. RESULTS: There were no significant differences in allele frequencies between controls and each of the three groups of OA patients. However, allele G of the R324G SNP showed a trend to be more frequent in patients with a clinical OA syndrome at multiple joints (p = 0.07), specifically in women of the total hip replacement group (8.3% in patients without other affected joints, 13.1% with one, 15.9% with two and 24.1% with more than two additional joints, p for trend = 0.008). CONCLUSIONS: No direct replication of previous OA association findings was obtained but the results suggest that the R324G SNP of the FRZB gene may have an effect in OA development in multiple joints, with a specific severe involvement of the hip in women. This phenotype could reconcile previous studies that showed association either with generalised OA or with hip OA in women.