Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
23755969 Therapies for active rheumatoid arthritis after methotrexate failure. 2013 Jul 25 BACKGROUND: Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate--a common scenario in the management of rheumatoid arthritis. METHODS: We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48. RESULTS: Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications. CONCLUSIONS: With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT ClinicalTrials.gov number, NCT00405275.)
25482674 Davallia bilabiata inhibits TNF-α-induced adhesion molecules and chemokines by suppressin 2014 Davallia bilabiata (D. bilabiata) is also called GuSuiBu in Taiwan and is used as a substitute for Drynaria fortunei J. Sm. It is often used for trauma and bone repair. The inhibitory effect of D. bilabiata on inflammatory activity has not been reported. In the present study, we aimed to study the mechanism of anti-inflammation of D. bilabiata on the adhesion of leukocytes to vascular endothelial cells. The results showed that D. bilabiata, at concentrations without cytotoxic effect, inhibited the adhesion of monocytes (THP-1) to the TNF-α-stimulated human umbilical vascular endothelial cells (HUVECs). D. bilabiata suppressed the expression of the adhesion molecules ICAM, VCAM, and E-selectin at both the mRNA and protein level. In addition, both of the TNF-α-induced mRNA and protein expression of chemokines including fractalkine/CX3CL1, MCP-1 and RANTES as well as the level of secreted soluble fractalkine were decreased by D. bilabiata. We also verified that D. bilabiata inhibited the TNF-α-induced nuclear translocation of NF-κB through the inhibitory process on the TNF-α-activated phosphorylation of IKKα, IKKβ, IκB and NF-κB. All together, we concluded that the D. bilabiata affected the canonical pathway of TNF-α-induced NF-κB activation and down-regulated cell adhesion molecules and chemokine expression through inhibition of the NF-κB/IκBα/IKK signaling pathway. These findings strongly indicated that D. bilabiata might be a promising alternative/adjunct treatment for inflammatory diseases, such as rheumatoid arthritis and osteoarthritis.
24936585 Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid 2015 Oct OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)-GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA. METHODS: We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. RESULTS: GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils. CONCLUSIONS: The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.
23872401 Enhancement of PLGF production by 15-(S)-HETE via PI3K-Akt, NF-κB and COX-2 pathways in r 2013 Aug 15 Metabolites from arachidonic acids play the pivotal roles in inflammatory arthritis. Arachidonic acid could be metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) to produce the bioactive eicosanoids. Although the down-stream products of COX including prostaglandin E2 are well-known inflammatory stimulators, the role of LOX products in inflammatory arthritis is still unclear. Here we found that the downstream product of 15-LOX, 15-S-hydroxyeicosatetraenoic acid (15-(S)-HETE), can enhance the expression of placenta growth factor (PLGF), which is recently considered to play an important role in rheumatoid arthritis. 15-(S)-HETE increased the expression of PLGF in human rheumatoid arthritis synovial fibroblasts in a time-dependent and concentration-dependent manner. PI3K-Akt, NF-κB signaling pathways were involved in the potentiation effects of 15-(S)-HETE. In addition, COX-2 was up-regulated by the treatment of 15-(S)-HETE and the increase of COX-2 expression participated in 15-(S)-HETE-induced PLGF expression, which was confirmed by COX-2 shRNA or pharmacological COX-2 inhibitor. Moreover, it was found that treatment of prostaglandin E2 (PGE2), which was the main down-stream metabolite of COX-2, increased the expression of PLGF. EP1, EP2, EP3 and EP4 agonists could up-regulate PLGF as well. In animal studies, we found that the adjuvant-induced expression of PLGF and COX-2 was inhibited in 15-LOX knockout mice. These results indicated that PLGF up-regulation by 15-LOX downstream product may be involved in inflammatory arthritis.
25027437 Antiphospholipid antibodies during 6-month treatment with infliximab: a preliminary report 2014 Jul 16 BACKGROUND: The introduction of tumor necrosis factor (TNF) antagonists (adalimumab, infliximab, and etanercept) was a major advance and was highly important and beneficial in most rheumatoid arthritis (RA) patients. The adverse effects of this treatment are infrequent, but include opportunistic intracellular infection (especially the reactivation of latent Mycobacterium tuberculosis); exacerbation of demyelinating disorders; and the production of various types of antibodies such as antinuclear antibodies (ANA) or double-stranded DNA autoantibodies (dsDNA) and antiphospholipid antibodies (aPL) such as anti-cardiolipin antibodies (aCL) and anti-B2GP-I antibodies (B2GP-I). The aim of the study was to determine the prevalence of aCL and B2GP-I in IgM and IgG classes, using ELISA tests, during 6 months of follow-up in patients with refractory RA successfully treated with infliximab. MATERIAL/METHODS: We determined the prevalence of aCL and B2GP-I in IgM and IgG classes, using ELISA tests, during 6 months of follow-up in patients with refractory RA successfully treated with infliximab. RESULTS: We observed a statistically important increase only in the group of B2GP-I IgM (p<0.05). There are contradictory results concerning the ability of infliximab to induce aPL, but most authors confirm this phenomenon. CONCLUSIONS: Further investigations are needed to determine if the new aPL appears in patients with β2-GPI gene polymorphisms such as leucine-to-valine substitution at position 247, which can lead to a conformational changes in β2-GPI protein, leading to aPL synthesis. The role of aPL in pathogenesis of APS is still unclear, but we should remember the immunogenic aspect of TNF antagonist treatment. Therefore, we recommend early detection of aPL and observation of the patient, paying special attention to signs and symptoms of thromboembolism.
23919527 Designing CXCL8-based decoy proteins with strong anti-inflammatory activity in vivo. 2013 Sep 17 IL (interleukin)-8 [CXCL8 (CXC chemokine ligand 8)] exerts its role in inflammation by triggering neutrophils via its specific GPCRs (G-protein-coupled receptors), CXCR1 (CXC chemokine receptor 1) and CXCR2, for which additional binding to endothelial HS-GAGs (heparan sulphate-glycosaminoglycans) is required. We present here a novel approach for blocking the CXCL8-related inflammatory cascade by generating dominant-negative CXCL8 mutants with improved GAG-binding affinity and knocked-out CXCR1/CXCR2 activity. These non-signalling CXCL8 decoy proteins are able to displace WT (wild-type) CXCL8 and to prevent CXCR1/CXCR2 signalling thereby interfering with the inflammatory response. We have designed 14 CXCL8 mutants that we subdivided into three classes according to number and site of mutations. The decoys were characterized by IFTs (isothermal fluorescence titrations) and SPR (surface plasmon resonance) to determine GAG affinity. Protein stability and structural changes were evaluated by far-UV CD spectroscopy and knocked-out GPCR response was shown by Boyden chamber and Ca2+ release assays. From these experiments, CXCL8(Δ6F17KF21KE70KN71K) emerged with the most promising in vitro characteristics. This mutant was therefore further investigated in a murine model of mBSA (methylated BSA)-induced arthritis in mice where it showed strong anti-inflammatory activity. Based on these results, we propose that dominant-negative CXCL8 decoy proteins are a promising class of novel biopharmaceuticals with high therapeutic potential in inflammatory diseases.
24852423 Genetic deletion of Mst1 alters T cell function and protects against autoimmunity. 2014 Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4+ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1-/- B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1-/- CD4+ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4+ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.
24385683 Thrombin promotes matrix metalloproteinase-13 expression through the PKCδ c-Src/EGFR/PI3K 2013 Thrombin is a key mediator of fibrin deposition, angiogenesis, and proinflammatory processes. Abnormalities in these processes are primary features of rheumatoid arthritis and osteoarthritis. Matrix metalloproteinase-13 (MMP-13) may contribute to the breakdown of articular cartilage during arthritis. However, the role of thrombin in MMP-13 production in chondrocytes is unknown. In this study, we investigated the intracellular signaling pathways involved in thrombin-induced MMP-13 expression in human chondrocytes. We found that stimulation with thrombin led to increased secretion of MMP-13 in cultured human chondrocytes. Further, this thrombin-induced MMP-13 production was reduced after transfection with siRNAs against protease activated receptors 1 and 3 (PAR1 and PAR3), but not with PAR4 siRNA. Treatment with specific inhibitors for PKCδ, c-Src, EGFR, PI3K, Akt, or AP-1 or with the corresponding siRNAs against these signaling proteins also abolished the thrombin-mediated increase in MMP-13 production in chondrocytes. Our results provide evidence that thrombin acts through the PAR1/PAR3 receptors and activates PKCδ and c-Src, resulting in EGFR transactivation and activation of PI3K, Akt, and finally AP-1 on the MMP-13 promoter, thereby contributing to cartilage destruction during arthritis.
26280611 Primary total hip arthroplasty with hydroxyapatite coated titanium femoral stems. Does des 2014 Sep We present results of a prospective randomised controlled trial examining two cohorts of patients treated with proximally (Group A) and fully coated (Group B) femoral components with long term follow up. Patients were reviewed preoperatively and 6, 12, 26 and 52 weeks post operatively then annually. The Merle d'Aubigne Postel (MDP) hip score was used to assess clinical outcome. A Visual Analog Score (VAS) was also recorded. Statistical calculation was performed using the student's t- test and Kaplan Meier survival analysis. One hundred and four patients were included in group A and 103 patients in group B. Mean age was 60.4 years and 60.8 years respectively. Mean follow- up was 12.9 years. Mean pre-operative MDP scores were 8.8 and 9.5 in Groups A and B respectively. Mean pre-operative VAS score 7.8 and 7.4 respectively. At final follow up mean MDP and VAS were 16.9, 16.6 and 2.1, 2.4 respectively. Three femoral revisions occurred in Group A. Seven revisions occurred in Group B. Survival of the femoral component with revision for any reason as the end point was 96% in Group A and 94.8% in Group B. Both components produced symptomatic relief and similar revision rates. Thigh pain occurred only in Group A.
23503637 Oxford phase 3 unicondylar knee arthroplasty through a minimally invasive approach: long-t 2013 May PURPOSE: Surgical treatment options for medial compartment osteoarthritis of the knee include high tibial osteotomy, total knee arthroplasty or unicompartmental knee arthroplasty (UKA), depending on the patient's age, level of physical activity and the degree of deformity. METHODS: In this study, we evaluated the long-term results of patients who underwent the Oxford cemented meniscal-bearing unicondylar knee prosthesis through a minimally invasive approach including a clinical, functional and radiographic assessment. RESULTS: Favourable clinical and radiological outcomes were registered overall at ten years after surgery. Overall results of UKA according to the American Knee Society (AKS) using Insall's criteria showed an excellent or good outcome for 492 knees (96.28 %), fair for 11 (2.15 %) and poor for eight (1.57 %) in the post-operative long term. CONCLUSIONS: We believe that with appropriate surgical technique, patient selection, prosthetic design and specific training, surgeons should achieve good outcomes with the added advantages of a minimally invasive approach. High volume for this technique is important in our opinion.
24176730 A case of bilateral trochleitis in adult-onset Still's disease. 2014 Apr OBJECTIVES: We describe the first case of adult-onset Still's disease (AOSD) presenting with trochleitis and successfully treated with an interleukin-1 receptor antagonist. METHODS: This is a descriptive case report of one patient, identified in consultation with the inpatient ophthalmology consult service. RESULTS: A 23-year-old Caucasian male initially presented with complaints of sore throat, myalgias, rash, and fever. After he failed to respond to antibiotic therapy for presumed streptococcal pharyngitis and developed left eye pain with upgaze, he was admitted to the hospital. Laboratory workup revealed elevated inflammatory markers and liver enzymes. He was eventually diagnosed with AOSD. During his hospitalization he developed binocular vertical diplopia, worsening of left eye pain on upgaze, and exquisite tenderness over the region of the left trochlea, consistent with trochleitis. This diagnosis was supported by magnetic resonance imaging (MRI). Soon after onset of left eye symptoms, the right eye developed identical symptoms. He was started on intravenous corticosteroids, which led to the rapid resolution of his ocular and systemic symptoms. However, after transition to oral corticosteroids, his symptoms recurred. He was started on anakinra, an interleukin-1 (IL-1) receptor antagonist, which led to resolution of his ocular and systemic symptoms. CONCLUSIONS: Trochleitis is an unusual form of orbital inflammation localized to the superior oblique tendon and trochlea complex. It has been associated with a number of systemic inflammatory conditions including systemic lupus erythematous, rheumatoid arthritis, and juvenile idiopathic arthritis. This is the first case of a patient with AOSD presenting with trochleitis. Treatment with IV corticosteroids and anakinra resulted in rapid resolution of his ocular and systemic symptoms.
23395494 [Persistent aphthous mouth ulcers associated with tocilizumab: two cases]. 2013 Feb BACKGROUND: Tocilizumab, a humanized monoclonal antibody that blocks interleukin-6 receptor, is approved for use in rheumatological diseases. The most frequent adverse events reported are infections. We describe for the first time the occurrence of recurrent aphthous mouth ulcers in two patients on TCZ. PATIENTS AND METHODS: Two patients were treated with TCZ for rheumatological disease. A few weeks after administration of TCZ, they presented with multiple painful mouth ulcers that would not heal until TCZ had been withdrawn. In both cases, the oral ulcers resolved 6 to 7weeks after withdrawal of TCZ and readministration of the drug led to recurrence of oral ulcers within 10days in both patients. DISCUSSION: We describe for the first time the occurrence of aphthous mouth ulcers induced by TCZ. The causative role of TCZ was established by positive rechallenge. These cases were similar to a recently reported case of multiple intestinal aphthous ulcers occurring during TCZ treatment. Such mucosal side effects may be explained by similar inflammatory mechanisms but appear paradoxical because TCZ inhibits a pro-inflammatory cytokine, interleukin 6. TCZ treatment can be maintained if necessary, in combination with colchicine, as reported for one of our patients.
25514036 Inhibition of osteoclastogenesis by osteoblast-like cells genetically engineered to produc 2015 Jan 16 Bone destruction at inflamed joints is an important complication associated with rheumatoid arthritis (RA). Interleukin-10 (IL-10) may suppress not only inflammation but also induction of osteoclasts that play key roles in the bone destruction. If IL-10-producing osteoblast-like cells are induced from patient somatic cells and transplanted back into the destructive bone lesion, such therapy may promote bone remodeling by the cooperative effects of IL-10 and osteoblasts. We transduced mouse fibroblasts with genes for IL-10 and Runx2 that is a crucial transcription factor for osteoblast differentiation. The IL-10-producing induced osteoblast-like cells (IL-10-iOBs) strongly expressed osteoblast-specific genes and massively produced bone matrix that were mineralized by calcium phosphate in vitro and in vivo. Culture supernatant of IL-10-iOBs significantly suppressed induction of osteoclast from RANKL-stimulated Raw264.7 cells as well as LPS-induced production of inflammatory cytokine by macrophages. The IL-10-iOBs may be applicable to novel cell-based therapy against bone destruction associated with RA.
25433956 How to mechanistically explain the CONDOR study data. 2015 Jan Results of the CONDOR study suggest that in osteoarthritis and rheumatoid arthritis patients at elevated risk of gastrointestinal (GI) events, treatment with celecoxib, a cyclooxygenase (COX)-2 selective non-steroidal anti-inflammatory drug (NSAID), demonstrated significantly lower toxicity in the upper and lower (GI) tract when compared to the non-selective NSAID diclofenac plus a proton-pump-inhibitor (PPI), omeprazole. According to current knowledge, traditional NSAIDs (tNSAIDs) as non-selective COX-inhibitors exert their damaging effects on the upper GI tract, largely by reduction of the COX-1 related synthesis of gastro-protective prostaglandins. Thus, the question arises, how NSAIDs do exert their damaging effects especially in the lower GI tract and how to explain the reduced risk of a COX-2 selective inhibitor, celecoxib. Here we hypothesize, that the toxicity of celecoxib on enteral mucosa cells is lower than observed with other NSAIDs, and can be explained COX-independently by typical physicochemical properties of the NSAID substances (e.g., acidic, lipophilic, amphiphilic, surfactant properties). As a consequence these features account for differences in (1) uncoupling effects on mitochondria, (2) effects on cell membrane integrity, and/or (3) formation of "toxic micelles" with bile salts. The evidence for these differences is mainly based on experimental findings. However, several phenomena show differences in extent (e.g., uncoupling effects). The reduced toxicity appears to be rather a substance-specific characteristic. This is an unconditional reason to carry on investigating these phenomena in experimental and large-scale clinical trials.
24368514 Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid art 2015 Apr OBJECTIVES: The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA. METHODS: Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo. RESULTS: Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs -1.9%, respectively; all p<0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (>30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p<0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)). CONCLUSIONS: These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.
23286833 Rituximab versus anti-TNF in patients who previously failed one TNF inhibitor in an observ 2013 OBJECTIVE: The purpose of this study was to characterize and compare responses in patients who had failed one tumour necrosis factor (TNF) inhibitor when switching to another TNF inhibitor or rituximab (RTX). METHODS: The Stockholm TNF follow-up registry (STURE) was used. Treatment results at 6 months were analysed by (i) the biologic used, (ii) the type of anti-TNF switch, and (iii) the reason for discontinuation (inefficacy or intolerance). RESULTS: A total of 328 patients who failed an anti-TNF switched to an alternative biologic, 69 to RTX, 161 to an anti-TNF monoclonal antibody (mAb), and 98 to etanercept (ETA). Significant reductions in the 28-joint Disease Activity Score (DAS28) at 6 months were observed for all groups. The mean ± SD reduction in DAS28 was 1.70 ± 1.18 for RTX, 1.40 ± 1.51 for ETA, and 0.67 ± 1.36 for mAb, the difference being statistically significant between RTX and mAb (p < 0.0001). For patients who had failed ETA, RTX led to significantly greater DAS28 reductions than mAb (p = 0.01). When the reason for discontinuation of the previous anti-TNF was intolerance or secondary inefficacy, RTX led to significantly greater DAS28 reduction compared to mAb and ETA (p = 0.01 and p = 0.03, respectively). CONCLUSIONS: In this observational cohort, patients who failed one anti-TNF had better overall results when treated with RTX than with a subsequent anti-TNF mAb. Having failed ETA, RTX yielded greater DAS28 reductions and European League Against Rheumatism (EULAR) responses than mAb. The advantage of RTX was most clearly seen in patients who had failed anti-TNF because of intolerance or secondary inefficacy.
24942540 Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumati 2014 Nov OBJECTIVE: The efficacy and safety of subcutaneous tocilizumab (TCZ-SC) versus subcutaneous placebo (PBO-SC) was evaluated in patients with rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs in the BREVACTA study. METHODS: Patients (n = 656) were randomized 2:1 to receive TCZ-SC 162 mg every other week or PBO-SC every other week for 24 weeks; 20% previously received anti-tumor necrosis factor treatment. Escape therapy with TCZ-SC 162 mg weekly was offered from week 12 for inadequate response. The primary end point was the American College of Rheumatology 20% improvement (ACR20) response at week 24. The key secondary outcomes were radiographic progression and safety. RESULTS: TCZ-SC was superior to PBO-SC for ACR20 response at week 24 (60.9% versus 31.5%; P < 0.0001). All secondary end points showed TCZ-SC to be superior to PBO-SC, including ACR50 and ACR70 response (40% and 20% for TCZ-SC, respectively, and 12% and 5% for PBO-SC, respectively; P < 0.0001 for both) and Disease Activity Score in 28 joints (DAS28) remission (DAS28 <2.6; 32% versus 4% [P < 0.0001]). The mean change in modified Sharp/van der Heijde score was significantly lower in the TCZ-SC group than the PBO-SC group (0.62 versus 1.23; P = 0.0149). Adverse events (AEs) and serious AEs (SAEs) were comparable between the TCZ-SC and PBO-SC groups; 4.6% and 3.7% of patients had at least 1 SAE, respectively, and infection was the most common SAE in 2.1% and 1.8% of patients, respectively. More injection site reactions occurred with TCZ-SC than PBO-SC (7.1% versus 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred. There were 3 deaths in the TCZ-SC group and 0 in the PBO-SC group. CONCLUSION: TCZ-SC every other week had significantly greater efficacy, including ACR end points and inhibition of joint damage, compared with PBO-SC. TCZ-SC was well tolerated and its safety profile was comparable with that of previous intravenous TCZ studies.
23578666 The role of citrullination of an immunodominant proteoglycan (PG) aggrecan T cell epitope 2013 Apr The P70-84 peptide (also called 5/4E8 epitope) of the human cartilage proteoglycan (PG) aggrecan is the dominant/arthritogenic epitope in both humans and arthritis-prone BALB/c mice (PG-induced arthritis, PGIA). An elevated T cell reactivity was demonstrated to a citrullinated version of the P70-84 epitope in most of the patients with rheumatoid arthritis (RA). The goal of this study was to understand better how a T cell epitope, if citrullinated, may affect antigenicity/arthritogenicity in PGIA, a murine model of RA. T cell reactivity to differentially citrullinated versions of either the human PG aggrecan P70-84 peptide or the corresponding mouse sequence was assessed in peptide or aggrecan-immunized and arthritic BALB/c mice as well as in T cell receptor transgenic mice specific for peptide P70-84 sequence. Peripheral T cell responses were induced by priming BALB/c mice with either the human wild-type or its citrullinated versions. Unexpectedly, priming with the citrullinated self-peptide induced a higher T cell response compared to the wild-type sequence (p<0.001), and the citrullination of the human peptide abolished T cell reactivity in PGIA. Our data suggest that T cells reactive to the citrullinated P70-84 peptide escaped thymic selection and are present in the peripheral T cell repertoire. Results of this study provide evidence that citrullination of an immunodominant T cell epitope may substantially alter, either increase or abolish, T cell recognition at the periphery in an experimental model of arthritis.
23264551 Monoclonal anti-citrullinated protein antibodies selected on citrullinated fibrinogen have 2013 Apr OBJECTIVE: ACPAs are thought to play a pathogenic role in RA. Because of their polyclonal nature it is difficult to study characteristics of ACPAs such as cross-reactivity or affinity. This study aimed to analyse the ACPA response at clonal level. METHODS: Citrullinated fibrinogen-specific B cells were isolated from blood derived from an RA patient by fluorescent automated cell sorting (FACS). Antigen specificity was verified by ELISA of culture supernatant. RNA of antigen-specific B cells was isolated and VH and VL chains were cloned and subsequently expressed as IgG1 antibodies. RESULTS: Two human recombinant antibodies were obtained that bind to citrullinated fibrinogen peptide (cFib). Both monoclonal antibodies originate from different naive B cells, undergo extensive somatic hypermutation and bind to cFib (but not to Fib) with moderate avidity. Furthermore, they show distinct cross-reactivity patterns towards other citrullinated peptides, suggesting that both antibodies have different primary targets. CONCLUSION: Together these data suggest that ACPAs are formed by antigen-driven maturation, and that multiple citrullinated antigens are involved in activating the B-cell response.
24287449 A combination of sinomenine and methotrexate reduces joint damage of collagen induced arth 2014 Jan OBJECTIVE: To analyze the combination therapy of Sinomenine (SIN) and Methotrexate (MTX) in rheumatoid arthritis (RA), we herein demonstrated the combination effect of SIN and MTX on collagen-induced arthritis (CIA) in rats through their modulation on osteoclast-related cytokines. METHODS: CIA was induced by the immunization of type II collagen (CII) in SD rats. SIN and MTX were administrated alone or in combination after the onset of arthritis. Arthritis index and histological analysis were used to evaluate the effect of treatments. Effects of SIN and MTX on expression of receptor activator of NF-κB ligand (RANKL) and osteopontin (OPN) in synovial tissues were assayed by immunohistochemistry. RANKL, osteoprotegerin (OPG), IL-6, IL-17 and matrix metalloproteinases (MMPs) in rat serum were measured by ELISA. The expression of osteoclast-related cytokines in fibroblast-like synoviocytes (FLS) from RA patients was assayed by RT-PCR. RESULTS: SIN and MTX combination additively reduced the inflammatory symptoms and joint damage in CIA. Combination of SIN and MTX significantly repressed synovial RANKL and OPN production. SIN and MTX exhibited complementary and synergistic effect upon down-regulating RANKL, IL-6, IL-17 and MMPs in rat serum. SIN and MTX also modulated the expression of RANKL and OPG in RA-FLS. CONCLUSION: SIN and MTX have additive effects, decreasing inflammation and joint damage in CIA rats by modulating osteoclast-related cytokines. These results are indicative of the combined effect of SIN and MTX for anti-arthritic treatment in RA.