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ID PMID Title PublicationDate abstract
28079193 ECG non-specific ST-T and QTc abnormalities in patients with systemic lupus erythematosus 2016 OBJECTIVES: Cardiovascular disease (CVD) is a leading cause of death in systemic lupus erythematosus (SLE) and in rheumatoid arthritis (RA). Although only explored in one study, ECG non-specific ST-T abnormalities, in addition to corrected QT-interval (QTc) prolongation, were recently reported in an SLE inception cohort. Importantly, these ECG abnormalities are known predictors of CVD mortality in the general population, yet their prevalence in patients with established SLE has not been evaluated. METHODS: We cross-sectionally investigated the presence of non-specific ST-T and QTc abnormalities in 50 patients with SLE, predominantly Hispanic and black, without CVD or SLE-related cardiac involvement and compared them with 139 patients with RA without CVD. Demographics, disease-specific characteristics and CVD risk factors were ascertained and adjusted for. RESULTS: Patients with SLE (mean age 36±13 years, 92% women, 6 years median disease duration, 96% Hispanics and blacks) had a 3.3-fold higher adjusted prevalence of non-specific ST-T abnormalities (56% vs 17%; p <0.0001) compared with RA, despite the older age and higher percentage of men in the RA group. The QTc was 26 ms longer in SLE compared with RA (p=0.002) in the setting of a higher percentage of women, blacks, Hispanics and higher C reactive protein levels in the SLE group. CONCLUSIONS: This study demonstrates a high prevalence of ECG abnormalities in predominantly Hispanic and black patients with SLE. Longitudinal evaluation of the progression to potentially life-threatening arrhythmias and/or cardiovascular events is warranted.
27826175 The use of magnetic fields in treatment of patients with rheumatoid arthritis. Review of t 2016 Magnetic fields are commonly used in therapies designed for subjects with rheumatic diseases, yet the effects of magnetotherapy are not entirely clear in these disorders. This study is designed to examine the literature investigating applications of magnetotherapy in the treatment of rheumatoid arthritis (RA). The review focused on publications related to administering magnetotherapy in patients with RA. The databases Science Direct, SpringerLink, Medline, PubMed, and Polska Bibliografia Lekarska were searched for reports published since 2005. Despite the numerous reports showing an impact of magnetic field in subjects with RA, the effectiveness of magnetotherapy has not been explicitly confirmed. Given the above, further research appears to be necessary to clarify the impact of magnetic fields on biological systems, and the relationship between magnetic field intensity and the obtained results as well as their durability. The majority of clinical trials have failed to identify any undesirable outcomes or side effects of this physical therapeutic factor.
27261178 Novel JAK1-selective benzimidazole inhibitors with enhanced membrane permeability. 2016 Jul 15 The previously identified Janus kinase 1 (JAK1)-selective inhibitor, 1-(2-aminoethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide (2), suffered from low cell permeability, which resulted in poor pharmacokinetic properties. In this study, by introducing less polar hydrogen bond donors at N(1) (a hydroxyalkyl or a methylaminoalkyl group) and C2 (a cyclohexanol group) positions, a series of novel benzimidazole derivatives were prepared, which exhibited selective JAK1 inhibitory activity (IC50 against JAK1=0.08-0.15μM; JAK1-selectivity=26-40 fold vs JAK2, 12-23 fold vs JAK3, and 38-54 fold vs Tyk2) along with significantly increased lipophilicity (3.3-15.8 times) as well as membrane permeability (6.3-12 times).
26654543 [Focusing on tissue biomarkers. Estrogens as key players in the immune response and autoim 2015 Dec 20 Estrogens modulate the immune response as well as the risk and progression of autoimmune disorders. Their effects are mediated by nuclear receptors (i.e. estrogen receptor alpha and beta), membrane receptors, and are influenced by their interactions with other hormones. Locally produced hormones and cytokines are the main factors in maintaining tissue homeostasis. The response of immune cells to estrogens is related to their developmental stage. The diverse effects of estrogens on various autoimmune disorders are the result of the versatility of their pathomechanism. In general, progression of B-cell mediated disorders is aggravated by estrogens. Their effects on T-cell mediated disorders, on the other hand, are driven by Th1 or Th2 dominance. As estrogens promote the escalation of the Th2 immune response, Th2-dominant disorders are aggravated, while Th1-dominant disorders are ameliorated upon high estrogen levels. Inflammation on its own also modulates the impact of estrogens. Inflammatory cytokines alter the expression of the alpha and beta estrogen receptors as well as the activity of estrogen metabolizing enzymes. Monitoring the local, tissue-wide interaction between hormones and immune cells would provide a better tool for identification and characterization of molecules involved in this system. To date, routinely used laboratory methods have a limited role in monitoring the local effects of estrogens. In this current paper the authors summarize the role of estrogens in immune system and overview those novel methods which are useful in the investigation of local endocrine milieu.
26384287 Highly potent and selective pyrazolylpyrimidines as Syk kinase inhibitors. 2015 Oct 15 A series of pyrazolylpyrimidine scaffold based Syk inhibitors were synthesized and evaluated for their biological activities and selectivity. Lead optimization efforts provided compounds with potent Syk inhibition in both enzymatic and TNF-α release assay.
26202066 Expression and activity of NOD1 and NOD2/RIPK2 signalling in mononuclear cells from patien 2016 Jan OBJECTIVES: The aim of this study was to analyse the expression and function of nucleotide-binding oligomerization domain (NOD)1 and NOD2 in isolated cells of patients with rheumatoid arthritis (RA). METHOD: mRNA expression levels of NOD1, NOD2, and receptor-interacting serine/threonine kinase 2 (RIPK2) genes were determined by quantitative polymerase chain reaction (qPCR) in peripheral blood mononuclear cells (PBMCs) and synovial fluid T cells (SFTCs) isolated from RA and osteoarthritis (OA) patients. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA) in plasma and cell culture supernatants. The stimulatory effect of RA SF was assessed by an in-vitro NOD2 activation assay using nuclear factor kappa B (NF-κB) luciferase-transfected cells. RESULTS: A significantly higher level of NOD2 and RIPK2 mRNA expression, but not NOD1, was observed on PBMCs and SFTCs isolated from RA patients compared to the OA control group. In addition, the NOD2 pathway up-regulation was functional, as stimulation of PBMCs with muramyl dipeptide (MDP) induced the production of higher amounts of tumour necrosis factor (TNF)-α, interleukin (IL)-8, and IL-1β compared with OA PBMCs. Incubation of PBMCs from healthy donors with recombinant TNF-α or RA serum induced the expression of NOD2 mRNA. Finally, SF isolated from RA patients is able to activate the NF-κB signalling pathway in HEK293T-transfected cells in a NOD2-dependent manner. CONCLUSIONS: Our findings suggest that NOD2/RIPK2 signalling is up-regulated in immune cells of RA patients. Moreover, it seems that there is a NOD2 agonist in the SF of RA patients. Therefore, NOD2/RIPK2 activation can modulate the innate immune response and may play a role in the perpetuation of the inflammatory response in RA.
25846605 Gene expression of cultured human chondrocytes as a model for assessing neutralization eff 2015 May Tumor necrosis factor-alpha (TNFα) antagonists are efficacious in the treatment of various immune-mediated inflammatory diseases. Because of rapidly growing demand for developing new or biosimilar versions of these biologicals, the need to create in vitro testing models that best represent physiological conditions is increasing. Primary human chondrocytes were used for potency evaluation and comparison between the molecular effects of anti-TNFα biologicals. Infliximab and etanercept were chosen to assess the suitability of chondrocyte cell culture for determination of anti-TNFα neutralization efficacy employing quantitative reverse transcription-polymerase chain reaction (qRT-PCR) technology. Use of both anti-TNFα biologics resulted in decrease of TNFα-stimulated expression of various matrix metalloproteinases, interleukins and other inflammation-related genes in our cell model. Significant differences in inhibition efficacy of etanercept and infliximab were observed, which were confirmed also on protein level. To evaluate the potency of anti-TNFα biologicals, a selection of TNFα-responsive target genes was made from the gene array data. The selected genes were employed in development of statistical model, which enables comparability of anti-TNFα biologicals. The presented analytical approach is suitable for assessment of the neutralization efficacy of various anti-TNFα biologicals. As such, it can be used for additional comprehensive characterization and comparability of TNF antagonists in preclinical drug testing.
25715850 Tibiotalocalcaneal arthrodesis using an intramedullary nail: a systematic review. 2016 Apr PURPOSE: Tibiotalocalcaneal arthrodesis is aimed to block the ankle joint motion in cases of severe osteoarthritis, avascular necrosis of the talus and/or failure of arthroplasty operations. This systematic review was carried out to evaluate the clinical outcome after tibiotalocalcaneal arthrodesis using intramedullary nail either open and arthroscopically assisted. Focus was on the success rate of the procedure in terms of union and complications and on the comparison between the techniques. METHODS: The databases PubMed (Medline), EMBASE and Cochrane Library were searched in order to retrieve relevant studies. All therapeutic level 1-4 studies involving humans with intramedullary nail fixation technique were included. Only studies written in English, Italian, French, Spanish and German were included. Data related to the type of surgery, complications and clinical outcomes were extracted and analysed. RESULTS: A total of 83 studies were identified, of which 32 studies were eligible for inclusion; 31 case series and one randomized controlled trial. The main reported outcome score was the American Orthopaedic Foot and Ankle Society scale. Almost, all the included studies reported higher than 50% union rates and a significant improvement in terms of the clinical and mechanical ankle function after treatment. CONCLUSIONS: Results suggest that satisfactory outcomes can be achieved by tibiotalocalcaneal arthrodesis using intramedullary nailing. Low complication rates contribute to make this a safe procedure. No comparison can be done between arthroscopic and open technique, due to the lack of scientific works on the first one. LEVEL OF EVIDENCE: IV.
26453509 Cucurbitacin E inhibits TNF-α-induced inflammatory cytokine production in human synoviocy 2015 Dec Increasing studies indicated that Cucurbitacin E (CuE), a compound isolated from Cucurbitaceae, has been shown anti-inflammatory effect. However, the effect of CuE on rheumatoid arthritis (RA) inflammatory response and its potential molecular mechanism are still unknown. In this study, we demonstrated that CuE significantly suppressed TNF-α-induced inflammatory cytokines production interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) mRNA and protein expression in human synoviocyte MH7A cells. Furthermore, we found that CuE also inhibited TNF-α-induced phosphorylation of NF-κBp65, IKKα/β, and IκBα in a dose-and time-dependent manner as well as NF-κBp65 nuclear translocation. Finally, we showed that CuE blocked the upstream targets of NF-κB pathway RIP1/PI3K/Akt. Interestingly, PI3K inhibitor LY294002 completely blocked the TNF-α-induced activation of p85, Akt and the whole cascade of the NF-κB signaling components and suppressed inflammatory cytokines production in mRNA and protein levels similarly as CuE. Our studies provided the first evidence that CuE inhibited TNF-α-induced inflammatory cytokine production in human synoviocyte MH7A cells via modulation of PI3K/Akt/NF-κB pathway. These findings indicated that CuE is a potential candidate for RA therapy.
27001429 The IL-1 cytokine family and its role in inflammation and fibrosis in the lung. 2016 Jul The IL-1 cytokine family comprises 11 members (7 ligands with agonist activity, 3 receptor antagonists and 1 anti-inflammatory cytokine) and is recognised as a key mediator of inflammation and fibrosis in multiple tissues including the lung. IL-1 targeted therapies have been successfully employed to treat a range of inflammatory conditions such as rheumatoid arthritis and gouty arthritis. This review will introduce the members of the IL-1 cytokine family, briefly discuss the cellular origins and cellular targets and provide an overview of the role of these molecules in inflammation and fibrosis in the lung.
26523052 Psoriatic Arthritis Registries. 2015 Nov The introduction of new biological drugs for the treatment of rheumatoid arthritis and spondyloarthritis has led to the creation of a number of registries in Europe and the United States. Most of them are sponsored by national rheumatology societies, and provide information that is useful in clinical practice concerning the clinical characteristics, efficacy, and safety of all licensed biological drugs. Their findings also help to improve our understanding of the quality of life and working ability of patients receiving biological drugs, and suggest methods for allocating resources. However, there are only a few registries for psoriatic arthritis, and efforts should be made to increase their number to obtain further reliable and useful data.
27492899 S100A8/A9: From basic science to clinical application. 2016 Nov Neutrophils and monocytes belong to the first line of immune defence cells and are recruited to sites of inflammation during infection or sterile injury. Both cells contain huge amounts of the heterodimeric protein S100A8/A9 in their cytoplasm. S100A8/A9 belongs to the Ca(2+) binding S100 protein family and has recently gained a lot of interest as a critical alarmin modulating the inflammatory response after its release (extracellular S100A8/A9) from neutrophils and monocytes. Extracellular S100A8/A9 interacts with the pattern recognition receptors Toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation Endproducts (RAGE) promoting cell activation and recruitment. Besides its biological function, S100A8/A9 (also known as myeloid related protein 8/14, MRP8/14) was identified as interesting biomarker to monitor disease activity in chronic inflammatory disorders including inflammatory bowel disease and rheumatoid arthritis. Furthermore, S100A8/A9 has been tested successfully in pre-clinical imaging studies to localize sites of infection or sterile injury. Finally, recent evidence using small molecule inhibitors for S100A8/A9 also suggests that blocking S100A8/A9 activity exerts beneficial effects on disease activity in animal models of autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. This review will provide a comprehensive and detailed overview into the structure and biological function of S100A8/A9 and also will give an outlook in terms of diagnostic and therapeutic applications targeting S100A8/A9.
27472446 Prednisolone Delivery Platforms: Capsules and Beads Combination for a Right Timing Therapy 2016 In this work, a platform of alginate beads loaded with Prednisolone in hypromellose/gellan gum capsules (F6/Cps) able to delay steroidal anti-inflammatory drug (SAID) release as needed for chronotherapy of rheumatoid arthritis is proposed. Rheumatoid arthritis, showing a worsening in symptoms in the morning upon waking, is a pathology that can benefit from chronotherapy. With the aim to maximize prednisolone therapeutic action allowing the right timing of glucocorticoid therapy, different engineered microparticles (gel-beads) were manufactured using prilling (laminar jet break-up) as micro-encapsulation technique and Zn-alginate as gastroresistant carrier. Starting from various feed solutions and process parameters, the effect of the variables on particles size, morphology, solid state properties and drug release was studied. The optimization of operative and prilling/ionotropic gelation variables led to microspheres with almost spherical shape and a narrow dimensional range. The feed solution with the highest alginate (2.5% w/v) amount and drug/polymer ratio (1:5 w/w) gave rise to the highest encapsulation efficiency (78.5%) as in F6 formulation. As to drug release, F6 exhibited an interesting dissolution profile, releasing about 24% of the drug in simulated gastric fluid followed by a more sustained profile in simulated intestinal fluid. #F6, acting as a gastro-resistant and delayed release formulation, was selected for in vivo studies on male Wistar rats by means of a carrageenan-induced oedema model. Finally, this efficacious formulation was used as core material for the development of a final dosage form: F6/Cps allowed to significantly reduce prednisolone release in simulated gastric fluid (12.6%) and delayed drug release up to about 390 minutes.
27081474 Rituximab efficiently depletes B cells in lung tumors and normal lung tissue. 2016 Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab.
26612635 Total Wrist Arthroplasty: A Single-Center Study of 219 Cases With 5-Year Follow-up. 2015 Dec PURPOSE: To assess implant survival and radiographic loosening after total wrist arthroplasty (TWA) operated at a single tertiary referral center in Sweden. METHODS: In a prospective cohort study, we evaluated 189 consecutive patients with a TWA (219 wrists). The wrists were implanted between 2002 and 2013. The primary end point was revision for any reason. The mean follow-up period was 7 years (range, 2-13 years). In addition, radiological examination was done for evidence of prosthetic loosening 5 years postoperatively. Implant survival was estimated using the Kaplan-Meier method. Secondary outcome measures included range of motion, visual analog scale pain scores, hand grip strength, and patient-related outcome measures. RESULTS: Cumulative implant survival after 8 years was 81% for Biax, 94% for Remotion, and 95% for Maestro implants. Radiographic loosening was present in 26% of wrists with the Biax design, 18% of those with Remotion, and 2% of those with Maestro. Visual analog scale pain scores and patient-related outcome scores improved significantly for all TWAs. Improved hand grip strength was noted for all TWAs except for the Universal 2. Range of motion improved somewhat, especially for the Biax and Maestro TWAs. CONCLUSIONS: Good midterm to long-term results were achieved in patients undergoing TWA. Radiographic loosening did not necessarily correlate with implant survival rates, but rather to severe arthritic destruction of the wrist preoperatively. All TWA implants studied offered a high level of patient satisfaction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.
26172530 Effects of methotrexate and salazosulfapyridine on protein profiles of exosomes derived fr 2016 Feb PURPOSE: To elucidate effects of salazosulfapyridine (SASP) and methotrexate (MTX), major anti-rheumatic drugs, on exosomes derived from SW982 of a human synovial sarcoma cell line. EXPERIMENTAL DESIGN: SW982 was treated with SASP and/or MTX under interleukin-1β (IL-1β)-treated or nontreated conditions. Exosomes were isolated from the culture media, and exosomal proteome was analyzed by 2D-DIGE. Protein spots whose intensity was significantly altered by the above treatments were identified by MS. RESULTS: Two hundred ninety-four protein spots were detected in the exosome preparations by 2D-DIGE. Compared to the nontreated cells, SASP-, MTX-, and (SASP + MTX)-treated cells displayed 8, 10, and 21 exosomal protein spots with more than ±2.0-fold intensity differences (p < 0.05), respectively. Similarly, the IL-1β-treated cells displayed 58 exosomal protein spots with more than ±1.5-fold intensity differences (p < 0.05). In about half of the 58 spots, the IL-1β-induced intensity changes were suppressed by simultaneous addition of SASP and/or MTX. Most of the identified proteins were immunity- or anti-oxidation-related proteins. CONCLUSIONS AND CLINICAL RELEVANCE: The SASP and/or MTX treatments altered the protein profiles of exosomes and suppressed the effects of IL-1β on the exosomal proteome. Exosomes may play roles in the actions of these anti-rheumatic drugs.
25589459 A systematic review of post-surgical pyoderma gangrenosum: identification of risk factors 2015 Mar BACKGROUND: Post-surgical pyoderma gangrenosum (PSPG) presents as a rapidly expanding cutaneous ulcer at a site of surgery with potentially devastating consequences. We systematically reviewed the English and foreign language literature to identify risk factors for PSPG and propose a management strategy. METHODS: A systematic review was completed in PubMed, Medline, Embase, and Cochrane Database for all published reports of PSPG from January 1946 to June 2013. We manually examined bibliographies for relevant references and used Google Translate for articles in foreign languages, including Italian, Japanese, German, Dutch, Turkish, Spanish, Chinese, Dutch, Russian, Portuguese, and Czech. RESULTS: We identified 220 cases of PSPG (mean age 52.8 years, range 5-85 years). Thirty-seven patients (16.8%) had a history of pyoderma gangrenosum, nineteen (8.6%) had a hematologic disorder such as leukemia or lymphoma, thirteen (5.9%) had inflammatory bowel disease, and eight (3.6%) had rheumatoid arthritis. PSPG occurred most commonly after breast (25%), cardiothoracic (14%), abdominal (14%), and obstetric (13%) surgeries. The most common breast procedures were bilateral reduction mammoplasty (45%), breast reconstruction (25%), and lumpectomy or mastectomy (11%). Signs of wound complication occurred on average 7.0 days after surgery. Nineteen patients (8.6%) at risk for PSPG received perioperative corticosteroids during skin grafting or later surgeries with a favorable outcome. CONCLUSIONS: Patients with a history of pyoderma gangrenosum, rheumatoid arthritis, inflammatory bowel disease, or hematologic malignancy who are undergoing breast, cardiothoracic, or abdominal surgeries should be carefully observed for post-operative ulceration at incision sites. Debridement should not be performed before dermatologic consultation to assess for PSPG. Patients at risk of PSPG undergoing breast surgery may benefit from perioperative prednisone to prevent PSPG which can lead to destructive wound enlargement and significant scarring.
26314610 T-786C single nucleotide polymorphism of the endothelial nitric oxide synthase gene as a r 2015 Sep OBJECTIVES: We investigated the association of the T-786C single nucleotide polymorphism (SNP) of the endothelial nitric oxide synthase gene (NOS3), which is characterised by reduced expression of the enzyme in response to shear stress or interleukin-10 stimulation and significantly associated with coronary heart disease or rheumatoid arthritis, with the occurrence of isolated polymyalgia rheumatica. METHODS: A cohort of 78 patients who had presented at a rheumatological specialist practice in Heidelberg was tested for the T-786C SNP by means of restriction fragment length polymorphism analysis, and the result was compared with the data of a control cohort (n=2061) compiled from the genotyping of umbilical cord arteries from newborns. Patients were tested for an association with the genotype and their clinical characteristics obtained at the time of the initial presentation and during the first year of treatment. RESULTS: The T-786C SNP of the NOS3 gene was significantly associated with isolated PMR (p=0.0009; OR 2.475). The C-allele frequency in patients with PMR was higher than in patients with rheumatoid arthritis, who also showed a significant association with the T-786C SNP (PMR 0.481 vs. 0.422 RA). A significant association with clinical features of the patients could not be detected. CONCLUSIONS: The T-786C SNP of the NOS3 gene, which predisposes towards the development of endothelial dysfunction, is significantly associated with polymyalgia rheumatica manifesting itself without any clinically detectable vascular involvement.
31149453 A case report of using nivolumab for a malignant melanoma patient with rheumatoid arthriti 2016 Oct The use of antibodies against programmed cell death 1 (PD-1), which block inhibitory T cell checkpoints, is a promising new therapy for advanced malignant melanoma and NSCLC. However, patients with autoimmune diseases were excluded at the clinical trial using such immune checkpoint inhibitor, because of the possibilities to worsen an adverse event of the autoimmune disease. Thus, the efficacy and toxicity of nivolumab using such cases have not been reported yet. A 70-year-old woman with bone and duodenal metastasis of primary mucosal melanoma with complications of the rheumatoid arthritis was treated with nivolumab. After 4 weeks injection of nivolumab, bone metastasis was diminished. After receiving six courses of nivolumab therapy, she maintained a complete response for 9 months, without rheumatic exacerbation or drug-related adverse events. Establishment of the biomarker of the effect prediction of the PD-1 antibody, the adverse event prediction will be important in future.
27003097 An Update on Calcineurin Inhibitor-Free Regimens: The Need Persists, but the Landscape has 2016 Apr Calcineurin inhibitors (CNIs) have failed to improve long-term renal allograft survival. Their association with cardiovascular morbidity in addition to their suboptimal inhibition of a chronic alloimmune response has shifted investigative efforts toward CNI-free regimens. Sotrastaurin, a small molecule targeting protein kinase C isoforms, failed to provide adequate immunosuppression, whereas the Janus kinase 3 inhibitor tofacitinib's success in the treatment of rheumatoid arthritis led to biopharma's abandonment of it as a transplant agent. Like tofacitinib, tocilizumab, a biologic targeting the IL-6 pathway, has been approved for use in rheumatoid arthritis and interest in transplantation has been confined to several investigator-initiated trials. Belatacept, a second-generation, higher avidity variant of CTLA4Ig (abatacept), was approved by the Food and Drug Administration for prophylaxis of transplant rejection in 2011. Long-term follow-up of recipients on belatacept has demonstrated superior glomerular filtration rates as compared with CNIs, albeit with an increased risk of early and histologically severe rejection. Focus on optimizing belatacept-inclusive regimens has led to studies using lymphocyte depletion as induction and maintenance therapy with target of rapamycin inhibitors. ASKP1240, the most advanced of the anti-CD40 antibodies targeting the CD40/CD154 costimulatory pathway has just completed a phase II trial with a CNI-free arm. Animal models suggest that its highest efficacy may be in combination with belatacept. Finally, nonagonistic CD28 antibodies, which would allow CTLA4 and PD-LI binding of CD80/CD86 and activation of inhibitory pathways, have re-emerged with 2 anti-CD28 candidates in preclinical development. A reliable nontoxic CNI-free regimen may ultimately require the combination of biologic agents that provide efficacy as well as safety.