A. Escudero

Can some cases of 'possible' spondyloarthropathy be classified as 'definite' or 'undifferentiated' spondyloarthropathy? Value of criteria for spondyloarthropathies

OBJECTIVESnWhen evaluating patients for spondyloarthropathy, clinicians use the possible spondyloarthropathy category to indicate that they are unsure about the diagnosis. We sought to determine whether Amors criteria or the European Spondyloarthropathy Study Group (ESSG) criteria could lift thi uncertainty.nnnPATIENTS AND METHODSnDuring a Spanish study designed to validate criteria for spondyloar thropathies, 102 patients were classified in the possible spondyloarthropathy category. We divided these patients into subgroups based on whether or not they met criteria for spondyloarthropathy. We compare baseline characteristics (N = 102) and five-year outcomes (N = 52) in these subgroups.nnnRESULTSnThe following features were significantly more common in the subgroups of patients who met Amors criteria for spondyloarthropathy: oligoarthritis, heel pain, uveitis, balanitis, family history of spondyloarthropathy, an presence of the HLA B27 antigen. No differences were found for age at symptom onset, disease duration, buttock pain, gender, dactylitis, diarrhea, or psoriasis. Of the 52 patients followed up for five years, 17 me Amors criteria at baseline and 13 were subsequently found to have definite spondyloarthropathy, whic was undifferentiated in six cases. There were only three cases of spondyloarthropathy among the 2 patients who did not meet Amors criteria at baseline. Of the 28 patients who met ESSG criteria at baseline, 13 had spondyloarthropathy versus three of the 17 patients who did not meet ESSG criteria at baselinennnCONCLUSIONnAmors criteria or the ESSG criteria allow early classification of most patients with possible spondyloarthropathy and early identification of undifferentiated spondyloarthropathy corresponding to minimal-symptom or incipient disease. In this study, Amors criteria performed better than the ESSG criteria.

Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα.

IntroductionThe advent of anti-tumor necrosis factor alpha (anti-TNFα) drugs has considerably improved medical management in rheumatoid arthritis (RA) patients, although it has been reported to be ineffective in a fraction of them. MicroRNAs (miRNAs) are small, non-coding RNAs that act as fine-tuning regulators of gene expression. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various disease models. The aim of this study was to investigate serum miRNA levels as predictive biomarkers of response to anti-TNFα therapy in RA patients.MethodsIn total, 95 RA patients undergoing anti-TNFα/disease-modifying antirheumatic drugs (anti-TNFα/DMARDs) combined treatments were enrolled. Serum samples were obtained at 0 and 6xa0months and therapeutic efficacy was assessed. miRNAs were isolated from the serum of 10 patients before and after anti-TNFα/DMARDs combination therapy, cDNA transcribed and pooled, and human serum miRNA polymerase chain reaction (PCR) arrays were performed. Subsequently, selected miRNAs were analyzed in a validation cohort consisting of 85 RA patients. Correlation studies with clinical and serological variables were also performed.ResultsNinety percent of RA patients responded to anti-TNFα/DMARDs combination therapy according to European League Against Rheumatism (EULAR) criteria. Array analysis showed that 91% of miRNAS were overexpressed and 9% downregulated after therapy. Functional classification revealed a preponderance of target mRNAs involved in reduction of cells maturation - especially on chondrocytes - as well as in immune and inflammatory response, cardiovascular disease, connective tissue and musculoskeletal system. Six out of ten miRNAs selected for validation were found significantly upregulated by anti-TNFα/DMARDs combination therapy (miR-16-5p, miR-23-3p, miR125b-5p, miR-126-3p, miRN-146a-5p, miR-223-3p). Only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNFα, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP). Correlation studies demonstrated associations between validated miRNAs and clinical and inflammatory parameters. Further, we identified a specific plasma miRNA signature (miR-23 and miR-223) that may serve both as predictor and biomarker of response to anti-TNFα/DMARDs combination therapy.ConclusionsmiRNA levels in the serum of RA patients before and after anti-TNFα/DMARDs combination therapy are potential novel biomarkers for predicting and monitoring therapy outcome.

Gender-Specific Effects of Genetic Variants within Th1 and Th17 Cell-Mediated Immune Response Genes on the Risk of Developing Rheumatoid Arthritis

The present study was conducted to explore whether single nucleotide polymorphisms (SNPs) in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA) in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of Dectin-2 rs4264222T allele had an increased risk of RA (ORu200a=u200a1.47, 95%CI 1.10–1.96) whereas patients harboring the DC-SIGN rs4804803G, MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of developing the disease (ORu200a=u200a0.66, 95%CI 0.49–0.88; ORu200a=u200a0.66, 95%CI 0.50–0.89; ORu200a=u200a0.73, 95%CI 0.55–0.97 and ORu200a=u200a0.68, 95%CI 0.51–0.91). Interestingly, significant gender-specific differences were observed for Dectin-2 rs4264222 and Dectin-2 rs7134303: women carrying the Dectin-2 rs4264222T and Dectin-2 rs7134303G alleles had an increased risk of RA (ORu200a=u200a1.93, 95%CI 1.34–2.79 and ORu200a=u200a1.90, 95%CI 1.29–2.80). Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of RA (ORu200a=u200a0.61, 95%CI 0.43–0.87; ORu200a=u200a0.67, 95%CI 0.47–0.95 and ORu200a=u200a0.60, 95%CI 0.42–0.86). In men, carriers of the DC-SIGN rs2287886A allele had an increased risk of RA (ORu200a=u200a1.70, 95%CI 1.03–2.78), whereas carriers of the DC-SIGN rs4804803G had a decreased risk of developing the disease (ORu200a=u200a0.53, 95%CI 0.32–0.89). In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2 rs4264222, MCP-1 rs1024611, MCP-1 rs13900 and DC-SIGN rs4804803 polymorphisms in the pooled sample (ORu200a=u200a1.38, 95%CI 1.08–1.77; ORu200a=u200a0.74, 95%CI 0.58–0.94; ORu200a=u200a0.76, 95%CI 0.59–0.97 and ORu200a=u200a0.56, 95%CI 0.34–0.93). SNP-SNP interaction analysis of significant SNPs also showed a significant two-locus interaction model in women that was not seen in men. This model consisted of Dectin-2 rs4264222 and Dectin-2 rs7134303 SNPs and suggested a synergistic effect between the variants. These findings suggest that Dectin-2, MCP-1 and DC-SIGN polymorphisms may, at least in part, account for gender-associated differences in susceptibility to RA.

Diagnostic potential of NETosis-derived products for disease activity, atherosclerosis and therapeutic effectiveness in Rheumatoid Arthritis patients

OBJECTIVESn1) To assess the association of NETosis and NETosis-derived products with the activity of the disease and the development of cardiovascular disease in RA; 2) To evaluate the involvement of NETosis on the effects of biologic therapies such as anti-TNF alpha (Infliximab) and anti-IL6R drugs (Tocilizumab).nnnMETHODSnOne hundred and six RA patients and 40 healthy donors were evaluated for the occurrence of NETosis. Carotid-intimae media thickness was analyzed as early atherosclerosis marker. Inflammatory and oxidative stress mediators were quantified in plasma and neutrophils. Two additional cohorts of 75 RA patients, treated either with Infliximab (nxa0=xa055) or Tocilizumab (nxa0=xa020) for six months, were evaluated.nnnRESULTSnNETosis was found increased in RA patients, beside myeloperoxidase and neutrophil elastase protein levels. Cell-free nucleosomes plasma levels were elevated, and strongly correlated with the activity of the disease and the positivity for autoantibodies, alongside inflammatory and oxidative profiles in plasma and neutrophils. Moreover, ROC analyses showed that cell-free nucleosomes levels could identify RA patients showing early atherosclerosis with high specificity. RA patients treated either with IFX or TCZ for six months exhibited decreased generation of NETs. Concomitantly, clinical parameters and serum markers of inflammation were found reduced. Mechanistic inxa0vitro analyses showed that inhibition of NETs extrusion by either DNase, IFX or TCZ, further abridged the endothelial dysfunction and the activation of immune cells, thus influencing the global activity of the vascular system.nnnCONCLUSIONSnNETosis-derived products may have diagnostic potential for disease activity and atherosclerosis, as well as for the assessment of therapeutic effectiveness in RA.

Candidate’s single-nucleotide polymorphism predictors of treatment nonresponse to the first anti-TNF inhibitor in ankylosing spondylitis

AbstractThe objective of this study is to identify single-nucleotide polymorphisms (SNPs) predictors of treatment nonresponse to the first anti-TNF-alpha agent in ankylosing spondylitis (AS). Patients were classified as “nonresponders” if they failed to achieve improvement ≥50xa0% of the initial BASDAI. We selected candidate SNPs previously reported, associated with susceptibility or pathogenesis of AS and with other spondylarthropaties (SpAs). The predictors of nonresponse were modeled with multiple logistic regression. The predictive power of the genetic model of nonresponse to treatment was tested with AUC-ROC. One hundred and twenty-one (121) AS patients fulfilled the inclusion criteria. Of the candidate SNPs tested for association with treatment effectiveness, five independent predictors were identified: rs917997, rs755622, rs1800896, rs3740691, and rs1061622. The genetic model of nonresponse to treatment had a predictive power of 0.77 (95xa0% CI 0.68–0.86). Our study identified several polymorphisms which could be the useful genetic biomarkers in predicting nonresponse to anti-TNF-alpha therapy.n

Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response. Materials and methods To test this hypothesis, we carried out a comprehensive two-stage case–control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response. Results Logistic regression analyses showed that carriers of the IL4rs2070874T and IL4rs2243250T and IL8RBrs1126580A alleles or the IL8RBrs2230054C/C genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13–1.67, P=0.0016; OR=1.24, 95% CI 1.03–1.49, P=0.020; OR=1.23, 95% CI 1.08–1.41, P=0.002 and OR=1.19, 95% CI 1.04–1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene–gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNGrs2069705C allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075). Conclusions Our data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.

Unusual and aggressive thrombotic onset in two children with antiphospholipid-antibody syndrome and systemic lupus erythematosus

We report two pediatric patients with unusual, aggressive initial manifestation of antiphospholipid antibody syndrome secondary to systemic lupus erythematosus. The first patient, a 13-year-old girl, presented with bilateral amaurosis and ischemic cerebral lesions. The second, another 13-year-old girl, presented with cerebral venous sinus thrombosis and membranous glomerulonephritis. Both patients improve after treatment with anticoagulants and immunosuppressive drugs, two therapies that are aimed at modulating the immune response or towards preventing thromboembolic events. However, there is no consensus regarding the duration and intensity of oral anticoagulation in children with antiphospholipid antibody syndrome.

Certaines spondylarthropathies dites « possibles » peuvent-elles être classées en spondylarthropathies certaines ou indifférenciées ? Interêt des critères de spondylarthropathies

Resume Objectifs. Le classement d’un patient en spondylarthropathie possible temoigne de l’embarras du clinicien. L’usage des criteres de spondylarthropathies a entrees multiples (Amor) ou de l’ESSG permet-il de lever cet embarrasxa0? Patients et methodes. Lors de l’etude espagnole de validation des criteres de spondylarthropathies, 102 patients ont ete classes en spondylarthropathies possibles. La methodologie de l’etude permettait de sous classer ces patients en deux sous-groupes selon qu’ils satisfaisaient ou non aux criteres de spondylarthropathies, permettant la comparaison des caracteristiques de deux sous-groupes. De plus, 52 patients ayant ete suivis cinq ans, leur devenir a pu etre compare a ce sous classement. Resultats. Les items suivants sont significativement plus frequents dans le sous-groupe des spondylarthropathies satisfaisant aux criteres a entrees multiplesxa0: oligoarthrite, talalgie, uveite, balanite, antecedents familiaux de spondylarthropathie, presence de l’antigene HLA B27. Les items suivants ne different pasxa0: âge au premier symptome, duree d’evolution, douleurs fessieres, sexe, dactylite, diarrhee, psoriasis. Sur les 52 patients suivis cinq ans, 17 satisfaisaient des l’entree dans l’etude aux criteres a entrees multiples, 13 se reveleront comme d’authentiques spondylarthropathies dont six toujours indifferenciees. Sur les 28 patient qui ne satisfaisaient pas a ces criteres, trois se reveleront etre des spondylarthropathies. Sur les 28 patients qui satisfaisaient aux criteres de l’ESSG, 13 se reveleront etre des spondylarthropathies et sur les 17 qui n’y satisfaisaient pas, trois se reveleront etre des spondylarthropathies. Conclusion. Les criteres de spondylarthropathies a entrees multiples (Amor) ou de l’ESSG permettent de classer precocement la plupart des patients ranges dans le cadre d’attente que constituent les spondylarthropathies possibles. Ils permettent la reconnaissance des spondylarthropathies indifferenciees qu’elles soient des formes frustes ou des formes debutantes de la maladie. Dans cette etude, les performances des criteres a entrees multiples se revelent superieures a celles des criteres de l’ESSG.

Genetic variants within the TNFRSF1B gene and susceptibility to rheumatoid arthritis and response to anti-TNF drugs: a multicenter study.

Background Recent research suggests that genetic variants in the tumor necrosis factor receptor 2 (TNFRSF1B) gene may have an impact on susceptibility to rheumatoid arthritis (RA) and drug response. The present population-based case–control study was carried out to evaluate whether 5 tagging single-nucleotide polymorphisms (SNPs) within the TNFRSF1B gene are associated with the risk of RA and response to antitumor necrosis factor (TNF) drugs. Methods The study population included 1412 RA patients and 1225 healthy controls. A subset of 596 anti-TNF-naive RA patients was selected to assess the association of TNFRSF1B SNPs and drug response according to the EULAR response criteria. Results We found that carriers of the TNFRSF1Brs3397C allele had a significantly increased risk of developing RA (P=0.0006). Importantly, this association remained significant after correction for multiple testing. We also confirmed the lack of association of the TNFRSF1Brs1061622 SNP with the risk of RA in the single-SNP analysis (P=0.89), but also through well-powered meta-analyses (PDOM=0.67 and PREC=0.37, respectively). In addition, our study showed that carriers of the TNFRSF1Brs3397C/C, TNFRSF1Brs1061622G/G, and TNFRSF1Brs1061631A/A genotypes had an increased risk of having a worse response to anti-TNF drugs at the level of P less than 0.05 (P=0.014, 0.0085 and 0.028, respectively). We also observed that, according to a log-additive model, carriers of the TNFRSF1Brs3397C or TNFRSF1Brs1061622G alleles showed an increased risk of having worse response to anti-TNF medications (P=0.018 and 0.0059). However, the association of the TNFRSF1Brs1061622 SNP only reached marginal significance after correction for multiple testing according to a log-additive model (P=0.0059) and it was not confirmed through a meta-analysis (PDOM=0.12). Conclusion Our results suggest that the TNFRSF1Brs3397 variant may play a role in modulating the risk of RA, but does not provide strong evidence of an impact of TNFRSF1B variants in determining response to anti-TNF drugs.

A Case of Multiple Osteonecrosis in a Patient with HIV: Effect of Joint Lavage.

A 35-year-old male former abuser of i.v. drugs, who was known to be human immunodeficiency virus (HIV) positive for 3 years, was found to have osteonecrosis (ON) involving both internal femoral condyles and humeral heads. No causes other than the HIV were evident. Joint irrigation, applied by means of an irrigation-withdrawal system, provided some relief and functional improvement. A literature search for references to the potential association of osteonecrosis with HIV infection showed a number of reports and three with multiple sites, suggesting that osteonecrosis can be considered a manifestation of HIV infection. The underlying pathogenic mechanisms remain obscure but are proposed to be related to immune alterations caused by HIV infection itself. HIV should be considered an etiological factor in patients with a diagnosis of multiple ON. Irrigation of the accessible regions of the joints involved may be an effective therapeutical choice to help control the symptoms.