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.

Insulin and Leptin Signaling in Placenta from Gestational Diabetic Subjects.

Insulin and leptin receptors are known to share signaling pathways, such as JAK2/STAT-3 (Janus kinase2/signal transduction and activator of transcription3), MAPK (Mitogen activated protein kinase), and PI3K (phosphoinositide 3-kinase). Both positive and negative cross-talk have been previously found in different cellular systems. Gestational diabetes (GDM) is a pathophysiological state with high circulating levels of both insulin and leptin. We have previously found that these 3 signaling pathways are activated in placenta from GDM patients to promote translation, involving the activation of leptin receptor. Now, we have tested the hypothesis that both leptin and insulin receptors might contribute to this activation in a positive way that may become negative when the system is overactivated. We studied the activation of leptin and insulin receptors in placenta from GDM and healthy pregnancies. We have also performed in vitro studies with insulin and leptin stimulation of trophoblast explants from healthy placenta. We have found that both leptin and insulin receptors are activated in placenta from GDM. In vitro stimulation of trophoblast explants with both leptin and insulin at submaximal doses (0.1 nM) potentiated the activation of signaling, whereas preincubation with maximal concentrations of insulin (10 nM) and further stimulation with leptin showed negative effect. Trophoblastic explants from GDM placenta, which presented high signaling levels, had a negative signaling effect when further incubated in vitro with leptin. In conclusion, insulin and leptin receptors have positive effects on signaling, contributing to high signaling levels in GDM placenta, but insulin and leptin have negative effects upon overstimulation.

Repair of erosions in patients with rheumatoid arthritis treated with etanercept: magnetic resonance imaging findings after 1 year of follow-up.

OBJECTIVES: To monitor repair of bone erosions using magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA) during etanercept combination therapy. METHOD: The study population comprised 29 RA patients [biologic-naïve, 28-joint Disease Activity Score (DAS28) ≥ 3.2] starting etanercept combination therapy with disease-modifying anti-rheumatic drugs (DMARDs) and completing the 1-year study period with the same treatment. Clinical and laboratory assessments and MRI of the hand were performed at baseline and at 1 year. MRI findings were scored by two readers using the Rheumatoid Arthritis MRI Scoring System (RAMRIS). Both readers were blind to the chronological order of the MRI scans, the identity of the patients, and clinical and other imaging data. Tenosynovitis was also scored. The intra- and inter-reader intraclass correlation coefficients (ICCs) were calculated, along with the sensitivity to change with the smallest detectable difference (SDD). Repair of erosions was defined as a RAMRIS score of at least 1 point lower than baseline. RESULTS: The mean RAMRIS score for erosions did not change but all other inflammatory MRI parameters decreased significantly. In 19 patients, the RAMRIS score for erosions remained unchanged after 1 year. In five patients the score decreased after 1 year, although the decrease exceeded the SDD in only one patient (3.4%). CONCLUSIONS: Etanercept combined with DMARDs stopped the progression of erosions, as measured by the RAMRIS, in 82.8% of our RA patients and occasional repair of bone erosions occurred after 1 year of treatment.

Activated translation signaling in placenta from pregnant women with gestational diabetes mellitus: possible role of leptin.

Placentas from gestational diabetes (GDM) suffer from structural and functional changes including overgrowth. That is why we aimed to study [³H]-leucine incorporation into protein in addition to translation signaling in placenta from GDM. Thus, we investigated the expression of leptin and leptin receptor (LEPR), as well as the activation state of signaling proteins regulating protein synthesis, such as mTOR, S6 Kinase, EIF4E-BP1, EIF4E, and eEF2 by measuring protein phosphorylation by immunoblot. [³H]-Leucine incorporation into protein also was determined in trophoblastic placenta explants from GDM and control pregnancy. We found that leptin and LEPR expression are increased in placentas from GDM and the translation machinery activity as well as [³H]-leucine incorporation into protein were higher in placentas from GDM compared with placentas from control pregnancy. In conclusion, protein synthesis rate is increased in placenta from GDM patients, and this may be due, at least in part, by the activation of translation signaling. The increased expression of leptin and LEPR may contribute to these effects. These results may provide a possible mechanism for the previously observed increase in placenta growth in GDM.

Elsevier Trophoblast Research Award lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression.

The steroid hormone 17ß-estradiol is an estrogen that influences multiple aspects of placental function and fetal development in humans. During early pregnancy it plays a role in the regulation of blastocyst implantation, trophoblast differentiation and invasiveness, remodeling of uterine arteries, immunology and trophoblast production of hormones such as leptin. Estradiol exerts some effects through the action of classical estrogen receptors ERα and ERß, which act as ligand-activated transcription factors and regulate gene expression. In addition, estradiol can elicit rapid responses from membrane-associated receptors, like activation of protein-kinase pathways. Thus, the cellular effects of estradiol will depend on the specific receptors expressed and the integration of their signaling events. Leptin, the 16,000MW protein product of the obese gene, was originally considered an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy. The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblastic cells. Expression of leptin in placenta is highly regulated by key pregnancy molecules as hCG and estradiol. The aim of this paper is to review the molecular mechanisms underlying estrogen functions in trophoblastic cells; focusing on mechanisms involved in estradiol regulation of placental leptin expression.

Review: Leptin gene expression in the placenta--regulation of a key hormone in trophoblast proliferation and survival.

Leptin is a 16000 MW protein originally described as an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy. The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblast cells. Study of the major signaling pathways known to be triggered by leptin receptor has revealed that leptin stimulates JAK/STAT, MAPK and PI3K pathways in placental cells. Leptin also exerts an antiapoptotic action in placenta and this effect is mediated by the MAPK pathway. Moreover, leptin stimulates protein synthesis by activating the translational machinery via both PI3K and MAPK pathways. Expression of leptin in placenta is highly regulated, suggesting that certain key pregnancy molecules participate in such regulation. An important hormone in reproduction, hCG, induces leptin expression in trophoblast cells and this effect involves the MAPK signal transduction pathway. Moreover, the cyclic nucleotide cAMP, which has profound actions upon human trophoblast function, also stimulates leptin expression and this effect seems to be mediated by crosstalk between the PKA and MAPK signaling pathways. Estrogens play a central role in reproduction. 17ß-estradiol upregulates leptin expression in placental cells through genomic and non-genomic actions, probably via crosstalk between estrogen receptor-α and the MAPK and PI3K signal transduction pathways. Taken together these findings give a better understanding of the function of leptin and the regulatory mechanisms of leptin expression in human placental trophoblast and further support the importance of leptin in the biology of reproduction.

Alopecia areata as another immune-mediated disease developed in patients treated with tumour necrosis factor-α blocker agents: Report of five cases and review of the literature.

BACKGROUND: Tumour necrosis factor antagonists (anti-TNF-α) have demonstrated the efficacy in different chronic immune inflammatory disorders. Within the spectrum of adverse events, autoimmune diseases have been observed, including cases of alopecia areata (AA). OBJECTIVES: The objective of the study is to characterize AA developed during anti-TNF-α therapy. METHODS: We present five new cases and review all the cases reported in the literature (eleven). RESULTS: One third of the cases had a positive (personal or family) history of AA. Most of them presented with rapid extensive AA, usually involving the ophiasis area. Prognosis was usually poor, with slight response to treatments. In the cases where anti-TNF-α therapy was maintained, the course did not seem to change. CONCLUSIONS: Although rare, AA developed during anti-TNF-α therapy might be more frequent than suggested by reports of isolated cases. Personal and family history of autoimmune disease might alert clinicians to their possible development or relapse once the anti-TNF-α therapy is started.

Predictors of the long-term outcome of early synovitis: a 5-year follow-up study.

One hundred patients who presented to an Early Synovitis Clinic in 1979-81 were called for review after a minimum of 5 years. Sufficient data for analysis were obtained in 88 cases, of whom 36 had a final diagnosis of rheumatoid arthritis (19 seropositive, 17 seronegative) and 16 human parvovirus B19 arthropathy. Outcome was assessed by persistence of symptoms greater than 24 months and functional disability by Health Assessment Questionnaire. Sixty-two patients had persistent disease, with 26 showing some functional impairment (positive HAQ FDI). A number of presenting features were assessed for their ability to predict outcome at 5 years. Polyarticular onset of disease was associated with a poor prognosis but lacked both specificity and sensitivity. Certain laboratory tests at presentation, including positive rheumatoid factor and low serum sulphydryl levels, also indicated a poor outcome. Combining these serological abnormalities gave 100% specificity for detecting persistent, disabling disease but with rather low sensitivity. Thus, other test systems are required to increase further the successful prediction of clinical outcome in patients with early synovitis.

Anticardiolipin antibodies, livedo reticularis, and major cerebrovascular and renal disease in systemic lupus erythematosus.

Increased levels of IgG anticardiolipin antibodies (ACA) were found in 23 of 98 patients (23%) with systemic lupus erythematosus. Increased levels of IgM ACA were found less frequently (5%). All four patients with major cerebrovascular events had increased IgG ACA, including the two with highest levels, both of whom were men. Six of nine patients with livedo reticularis had increased IgG ACA. In turn, this clinical feature was associated with cerebrovascular disease in two and renal disease in another six. IgG ACA were not associated with other thromboembolic events, thrombocytopenia, serum IgG, or autoantibodies to Ro(SSA), La(SSB), U1RNP, Sm, or double or single stranded DNA.

Evolution of benign rheumatoid nodules into rheumatoid arthritis after 50 years.

A patient with benign rheumatoid nodules who developed rheumatoid arthritis after 50 years is described.