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ID PMID Title PublicationDate abstract
27538766 Utility of ultrasonography in guiding modification of disease modifying anti-rheumatic dru 2018 Jan OBJECTIVE: To determine the utility of ultrasonography in guiding modification of disease-modifying anti-rheumatic drug (DMARD) and steroid therapy for inflammatory arthritis (IA) in routine clinical practice. METHODS: In this retrospective study, we analyzed DMARD and steroid use in IA patients referred to a rheumatologist-led ultrasound clinic. Power Doppler (PD) vascularity and greyscale (GS) synovial hypertrophy joint findings were categorized as positive/negative for each patient. The erythrocyte sedimentation rate (ESR) was used as a measure of disease activity. RESULTS: We assessed single visit data for 46 adult IA patients: 67.4% (n = 31) rheumatoid arthritis (RA), 15.2% (n = 7) psoriatic arthritis, 10.9% (n = 5) spondyloarthritis, and 6.5% (n = 3) undifferentiated IA. The mean ESR was 28.8 mm/h. Thirty-seven patients with both GS and PD ultrasound results were subsequently analyzed. All patients (n = 10) escalated and/or initiated on DMARD and 9/10 patients escalated or initiated on steroids were PD and GS positive. Six of seven patients with dose reduction and/or cessation of DMARDs and five of seven patients with dose reduction or cessation of steroids were PD negative. Of six patients who were GS positive and PD negative, three had dose reduction and/or cessation of DMARDs, while four had dose reduction of steroids; none of the six patients had DMARD/steroid escalation. CONCLUSION: By clarifying joint inflammation in an IA cohort with overall low ESR, ultrasonography of physician-selected joints can improve clinical assessment, resulting in treatment modification. Positive PD findings were particularly influential, while the clinical significance of GS positivity alone requires further investigation.
27942537 Risk of Herpes Zoster in Individuals on Biologics, Disease-Modifying Antirheumatic Drugs, 2016 Oct BACKGROUND: Studies examining the risk of herpes zoster (HZ) associated with immunosuppressants, such as biologics, nonbiological disease-modifying antirheumatic drugs (nbDMARDs), or corticosteroids, have generated conflicting results. METHODS: We conducted a systematic literature search from January 1946 to February 2016. Search terms related to HZ, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematous, or inflammatory bowel disease, biologics, nbDMARDS, and corticosteroids were used. We included randomized controlled trials (RCTs) and observational studies reporting associations between immunosuppressants and HZ outcomes in adults. For RCTs, we used the Mantel-Haenszel fixed-effects model to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for HZ risk. For observational studies, adjusted ORs were pooled separately using random-effects inverse variance models. RESULTS: Data were pooled from 40 eligible RCTs (20136 patients) and 19 observational studies (810939 patients). Biologics were associated with a greater risk of HZ than control (RCTs: OR = 1.71, 95% CI = 1.11-2.64; observational studies: OR = 1.58, 95% CI = 1.39-1.81). In RCTs, the OR of non-tumor necrosis factor (TNF) blockers was 2.19 (95% CI 1.20-4.02), but that of TNF blockers was not significantly different from control. Increased risks of HZ with nbDMARDs (OR = 1.21; 95% CI = 1.15-1.28) and corticosteroids (OR = 1.73; 95% CI = 1.57-1.89) were observed in observational studies, but few RCTs examined these comparisons. CONCLUSIONS: Immunocompromised patients receiving biologics were associated with an increased risk of HZ. The risk is also increased with corticosteroids and nbDMARDs. These findings raise the issue of prophylaxis with zoster vaccine in patients initiating immunosuppressive therapy for autoimmune diseases.
27110385 Reductions in disease activity in the AMPLE trial: clinical response by baseline disease d 2016 OBJECTIVES: To evaluate clinical response by baseline disease duration using 2-year data from the AMPLE trial. METHODS: Patients were randomised to subcutaneous abatacept 125 mg weekly or adalimumab 40 mg bi-weekly, with background methotrexate. As part of a post hoc analysis, the achievement of validated definitions of remission (Clinical Disease Activity Index (CDAI) ≤2.8, Simplified Disease Activity Index (SDAI) ≤3.3, Routine Assessment of Patient Index Data 3 (RAPID3) ≤3.0, Boolean score ≤1), low disease activity (CDAI <10, SDAI <11, RAPID3 ≤6.0), Health Assessment Questionnaire-Disability Index response and American College of Rheumatology responses were evaluated by baseline disease duration (≤6 vs >6 months). Disease Activity Score 28 (C-reactive protein) <2.6 or ≤3.2 and radiographic non-progression in patients achieving remission were also evaluated. RESULTS: A total of 646 patients were randomised and treated (abatacept, n=318; adalimumab, n=328). In both treatment groups, comparable responses were achieved in patients with early rheumatoid arthritis (≤6 months) and in those with later disease (>6 months) across multiple clinical measures. CONCLUSIONS: Abatacept or adalimumab with background methotrexate were associated with similar onset and sustainability of response over 2 years. Patients treated early or later in the disease course achieved comparable clinical responses. TRIAL REGISTRATION NUMBER: NCT00929864, Post-results.
26809798 Clinical characteristics and follow-up analysis of adult-onset Still's disease complicated 2016 May We evaluated clinical characteristics and prognosis for adult-onset Still's disease (AOSD) complicated by hemophagocytic lymphohistiocytosis (HLH). We retrospectively identified cases of AOSD with (n = 10) and without (n = 305) HLH complications. We reviewed their medical records, completed follow-up through outpatient clinic and telephone interviews, and analyzed their clinical symptoms, signs, laboratory test results, treatments, and prognosis. More AOSD patients with HLH developed hepatomegaly, bleeding, serositis, and neurologic symptoms than those without HLH, and they more commonly presented with leukopenia, thrombocytopenia, severe anemia, severe liver function abnormalities, decreased fibrinogen, elevated immunoglobulin, and bone marrow hemophagocytosis. The ten patients with AOSD complicated by HLH were treated with high-dose steroids or pulse steroid therapy, and eight of them also received cytotoxic drugs, while biological agents showed poor response. Follow-up results indicated that AOSD patients overall had good prognosis, while those with HLH showed worse prognosis, including higher relapse and readmission rates and increased mortality. In patients with AOSD, unexplained decreased blood cells, severe liver dysfunction, and/or hemophagocytosis in the bone marrow should be considered as signs of HLH complication. Patients with AOSD complicated by HLH have worse prognosis and higher relapse rates compared to AOSD patients without HLH complications. Thus, these patients should undergo frequent and careful follow-up.
27142093 Sjögren's syndrome-associated microRNAs in CD14(+) monocytes unveils targeted TGFβ signa 2016 May 3 BACKGROUND: Sjögren's syndrome (SjS) monocytes have a pro-inflammatory phenotype, which may influence SjS pathogenesis. MicroRNAs (miRNAs) are small endogenously expressed molecules that can inhibit protein expression of their targeted genes and have important functions in regulating cell signaling responses. We profiled miRNAs in SjS monocytes to identify a SjS-specific miRNA profile and determine the potential roles of miRNAs in SjS pathogenesis. METHODS: Total RNA was extracted from healthy control (HC, n = 10), SjS (n = 18), systemic lupus erythematosus (SLE, n = 10), and rheumatoid arthritis (RA, n = 10) peripheral blood CD14(+) monocytes for miRNA microarray analysis. To validate select miRNAs from the microarray analysis, the original cohort and a new cohort of monocyte RNA samples from HC (n = 9), SjS (n = 12), SLE (n = 8), and RA (n = 9) patients were evaluated by quantitative reverse transcription (RT)-PCR. Functional predictions of differentially expressed miRNAs were determined through miRNA target prediction database analyses. Statistical analyses performed included one-way analysis of variance with Bonferroni post tests, linear regression, and receiver operating characteristic curve analyses. RESULTS: MiRNAs were predominantly upregulated in SjS monocytes in comparison with controls. Quantitative RT-PCR confirmations supported co-regulation of miR-34b-3p, miR-4701-5p, miR-609, miR-300, miR-3162-3p, and miR-877-3p in SjS monocytes (13/30, 43.3 %) in comparison with SLE (1/17, 5.8 %) and RA (1/18, 5.6 %). MiRNA-target pathway predictions identified SjS-associated miRNAs appear to preferentially target the canonical TGFβ signaling pathway as opposed to pro-inflammatory interleukin-12 and Toll-like receptor/NFkB pathways. CONCLUSIONS: Our results underscore a novel underlying molecular mechanism where SjS-associated miRNAs may collectively suppress TGFβ signaling as opposed to pro-inflammatory interleukin-12 and Toll-like receptor/NFκB pathways in SjS pathogenesis.
27854085 Co-Cccurrence of Guillain-Barre Syndrome and Primary Sjögren Syndrome in an Elderly Woman 2016 Sep 15 PURPOSE: Co-occurrence of Guillain-Barré syndrome (GBS) and other autoimmune diseases is rare. We present the case of a patient with co-occurrence of GBS and primary Sjögren syndrome (pSS). CASE REPORT: An 82-year-old woman presented with acute ascending flaccid paralysis and acute respiratory failure. Nerve conduction studies and cerebrospinal fluid analysis confirmed the diagnosis of GBS of acute inflammatory demyelinating polyradiculoneuropathy subtype. The initial unresponsiveness to plasma exchange therapy raised the suspicion of other potential diseases. She was later proved to have underlying pSS. Her neurological deficits and respiratory failure improved dramatically with combination therapy of intravenous immunoglobulin (IVIg) and immunosuppressive agent. CONCLUSION: pSS should be considered as a possible cause of refractory GBS, particularly in elderly women. Combination therapy with IVIg and immunosuppressive agent may be beneficial.
27599266 A Rare Ocular Manifestation of Adult Onset Still's Disease: Purtscher's-like Retinopathy. 2018 Adult-onset Still's disease (AOSD) is a rare multisystemic immune-mediated disease of unknown etiology with quotidian spiking fever, evanescent rash, arthralgia, and multiple organ involvement. The few AOSD cases that have been reported developed Purtscher's-like retinopathy associated with thrombotic microangiopathy (TMA). Here, we report Purtscher's-like retinopathy without TMA in a patient with AOSD. A 29-year-old-man who presented for evaluation of blurred vision was diagnosed with AOSD based on Yamaguchi criteria. He had Purtscher's-like retinopathy in his right eye. Lesions improved after steroid treatment. Although almost all reported AOSD cases with Purtscher's-like retinopathy are associated with TMA, in this case such a complication was not encountered.
26628988 The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis. 2015 The study aims to investigate the frequency of CD4(+)CD25(+)Foxp3(+)CD127(-) T regulatory cells (Tregs) and the expression of CCR4, CCR6 and/or other chemokine receptors on Tregs in peripheral blood (PB) in patients with rheumatoid arthritis, as well as in PB, draining lymph nodes (dLNs), lungs and spleens in collagen-induced arthritis (CIA) mice. We also study the possible role of CCR4 and CCR6 abnormal expression on Tregs in RA patients and the underlying mechanisms. The numbers of Tregs and chemokine receptors expression profile on Tregs in PB from RA patients and healthy controls were investigated by flow cytometry (FACS) using three- or four-color intracellular staining. DBA/1 Foxp3(gfp) reporter mice were immunized with collagen II (CII) emulsified with CFA. At day 60 after CII immunization, mice were sacrificed and Foxp3 (GFP) expression in PB, dLNs, Lungs and spleens was examined by FACS. The numbers of Tregs in PB were significantly lower in RA patients than in healthy controls (1.21±0.43% vs 3.50±0.98%, P<0.05). The levels of chemokine receptor CCR4 or CCR6 expression on Tregs in PB were higher in active RA patients than in healthy controls (91.13±2.98% vs 79.45±4.72%, P<0.05; or 67.33±7.53% vs 42.73±5.60%, P<0.05). The levels of CCR4 or CCR6 expression on Tregs in active RA patients were positively correlated to DAS28 scores (r=0.42, P<0.03; or r=0.58, P<0.02). Similarly, the numbers of CCR6 expression on GFP(+) cells in the spleens, dLNs, lungs and blood of CIA were all increased than those of normal mice (P<0.01). Frequency of CCR4 expression on GFP(+) cells in dLNs of CIA was somehow higher but slightly lower in the spleens of CIA compared to normal mice without significant differences (P>0.05). Frequency of CCR5 expression on GFP(+) cells in the spleens and dLNs of CIA were both increased than those of normal mice, but there were no significant differences (P>0.05). CCR7 or CCR9 expression on Tregs from spleen and dLN of either normal or CIA mice was undetectable. Although the frequency of CD4(+)Foxp3(+)Tregs in peripheral blood was decreased in active rheumatoid arthritis patients, the levels of chemokine receptors such as CCR4 and CCR6 among the Tregs were increased, implicating that Tregs in active RA have obtained the ability migrating to inflammatory joints and may reflect the feedback regulation of the body to local inflammation. Furthermore, CCR4 and CCR6 expressed on Tregs may be related to the activity and severity of RA.
27658491 Tocilizumab as monotherapy or combination therapy for treating active rheumatoid arthritis 2016 Sep 22 BACKGROUND: Previous studies in patients with rheumatoid arthritis (RA) have shown that switching to tocilizumab (TCZ) monotherapy (TCZ(MONO)) or combination therapy (TCZ(COMBI)) with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) is efficacious in reducing disease activity in patients with inadequate response to csDMARDs. However, hitherto there is no consensus on whether TCZ(MONO) is as effective as TCZ(COMBI). The objective of this study was therefore to evaluate the efficacy and safety of TCZ(MONO) versus add-on TCZ(COMBI) and both TCZ therapies versus continuing the current csDMARD therapy, by performing a systematic review and meta-analyses. METHOD: The MEDLINE, EMBASE and CENTRAL databases were searched until February 2016 for relevant randomized controlled trials (RCTs). We performed meta-analyses of Disease Activity Score in 28 joints (DAS28 < 2.6), American College of Rheumatology (ACR) 20/50/70 responses, adverse events (AEs) and serious AEs (SAEs) to compare the three different strategies, whereas a random-effect model was used for pooling relative risks (RR) and 95 % confidence intervals (CI). In addition, sensitivity analyses were performed for evaluating differences in study duration. RESULTS: In total, 13 RCTs were included in the meta-analysis, involving 6679 patients. When comparing both TCZ strategies, a marginally greater proportion of patients achieving DAS28 < 2.6 (RR 1.21; 95 % CI 1.09, 1.36) and ACR50 response (RR 1.14; 95 % CI 1.03, 1.26) was found in favor of the TCZ(COMBI) strategy. However, the risk of SAEs was also significantly higher using this strategy (RR 1.40; 95 % CI 1.03, 1.92, p = 0.03). Pooled effect estimates showed statistical superiority of switching to either TCZ strategy compared to continuing csDMARD therapy. CONCLUSIONS: In the management of active RA, almost similar efficacy can be expected in patients unable to tolerate csDMARDs, who switch to TCZ(MONO) compared to inadequate responders switching to add-on TCZ(COMBI). Although TCZ(COMBI) is marginally superior to TCZ(MONO) in achieving DAS28 < 2.6 and ACR50 response, this is at the cost of an increased risk of SAEs.
27721905 Combination therapy with biologic agents in rheumatic diseases: current and future prospec 2016 Oct Strategies in rheumatoid arthritis (RA) based on 'treat to target' aim to control disease activity, minimize structural damage, and promote longer life. Several disease-modifying antirheumatic drugs (DMARDs) have been shown to be effective including biological DMARDs (bDMARDs). Treatment guidelines and recommendations for RA have also been published. According to those guidelines, conventional synthetic DMARDs (csDMARDs), as monotherapy or combination therapy, should be used in DMARD-naïve patients, irrespective of the addition of glucocorticoids (GCs). Combination therapies with bDMARDs are also essential for conducting treatment strategies for RA, because in every recommendation or guideline for the management of RA, combination therapies of csDMARDs with bDMARDs are recommended for RA patients with moderate or high disease activity after failure of csDMARD treatment. bDMARDs are more efficacious if used concomitantly with methotrexate (MTX) than with MTX monotherapy or bDMARD monotherapy. Thus, retention has been reported to be longer when combined with MTX. The superior efficacy of combination therapy compared with MTX monotherapy or bDMARD monotherapy could be because: (1) it could help to minimize MTX toxicity by reducing the dose of MTX, thus retention rate of the same therapeutic regimen would become high; (2) anti-bDMARD antibodies are observed at lower concentrations when using MTX concomitantly, so less clearance of bDMARDs via less formation of bDMARD and an anti-bDMARD immune complex; (3) of the additive effects of MTX to bDMARD, especially the combination of tumor necrosis factor inhibitors (TNFis) with MTX. Hence, evidence suggests that combination therapy with bDMARDs is more efficacious than monotherapy using a csDMARD or bDMARD, and that MTX is the best drug for this purpose (if MTX is not contraindicated). Finding the most effective drug regimen at the lowest cost will be the aim of RA treatment in the future.
27313530 Recombinant Human Endostatin Suppresses Mouse Osteoclast Formation by Inhibiting the NF-κ 2016 Rheumatoid arthritis is an autoimmune disease characterized by synovial hyperplasia and progressive joint destruction. As reported previously, recombinant human endostatin (rhEndostatin) is associated with inhibition of joint bone destruction present in rat adjuvant-induced arthritis; however, the effect of rhEndostatin on bone destruction is not known. This study was designed to assess the inhibitory effect and mechanisms of rhEndostatin on formation and function of osteoclasts in vitro, and to gain insight into the mechanism underlying the inhibitory effect of bone destruction. Bone marrow-derived macrophages isolated from BALB/c mice were stimulated with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor to establish osteoclast formation. Osteoclast formation was determined by TRAP staining. Cell viability of BMMs affected by rhEndostatin was determined using a MTT assay. Bone resorption was examined with a bone resorption pits assay. The expression of osteoclast-specific markers was analyzed using quantitative real-time PCR. The related signaling pathways were examined using a Luciferase reporter assay and western blot analysis. Indeed, rhEndostatin showed a significant reduction in the number of osteoclast-like cells and early-stage bone resorption. Moreover, molecular analysis demonstrated that rhEndostatin attenuated RANKL-induced NF-κB signaling by inhibiting the phosphorylation of IκBα and NF-κB p65 nuclear translocation. Furthermore, rhEndostatin significantly inhibited the activation of RANKL-dependent mitogen-activated protein kinases, such as ERK1/2, JNK, and p38. Hence, we demonstrated for the first time that preventing the formation and function of osteoclasts is an important anti-bone destruction mechanism of rhEndostatin, which might be useful in the prevention and treatment of bone destruction in RA.
25856795 Acacetin inhibits expression of matrix metalloproteinases via a MAPK-dependent mechanism i 2015 Aug It is well known that rheumatoid arthritis (RA) is an autoimmune joint disease in which fibroblast-like synoviocytes (FLSs) play a pivotal role. In this study, we investigated the anti-arthritic properties of acacetin in FLSs. The expression of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-13 were investigated by quantitative RT-PCR and western blot at gene and protein levels. At the same time, the phosphorylation of mitogen-activated protein kinases (MAPK) was investigated. The DNA-binding activity of NF-κB was investigated by electrophoretic mobility shift assay. We found that acacetin inhibits p38 and JNK phosphorylation and reduces MMP-1, MMP-3 and MMP-13 expression in interleukin-1β-induced FLSs. Our results suggest that acacetin has antiarthritic effects in FLSs. Thus, acacetin should be further studied for the treatment of arthritis.
27346252 Expression of the calcium-sensing receptor in monocytes from synovial fluid is increased i 2017 Mar OBJECTIVES: We assessed calcium-sensing receptor (CaSR) expression in monocytes isolated from synovial fluid of patients with different types of rheumatisms and explored whether CaSR expression was related to the inflammatory nature of synovial fluid. METHODS: Forty-one patients were included: osteoarthritis (n=10), microcristallin rheumatisms (n=10), rheumatoid arthritis (n=12) and other inflammatory rheumatisms (n=9). Surface and total CaSR expressions in monocytes isolated from synovial fluid and blood were assessed by flow cytometry analysis. U937 cells were cultured during 24hours in presence of cell-free synovial fluids. RESULTS: Every monocyte population tested express the CaSR intra- and extracellularly. Whereas similar pattern of CaSR expression exist in monocyte isolated from blood or synovial fluids, our results indicate that higher CaSR expression levels can be observed in monocytes from synovial fluids than in circulating monocytes. In both populations of monocytes, surface and total CaSR expressions were found to be significantly increased in patients with osteoarthritis compared to rheumatoid arthritis. Similar data were obtained when U937 cells were incubated with cell-free synovial fluids from osteoarthritis patients. Still present, this effect was significantly lowered when "inflammatory" synovial fluids were introduced in culture. CONCLUSIONS: Our results indicate that CaSR expression in synovial derived monocytes is higher in osteoarthritis than in inflammatory rheumatisms and that CaSR expression is modulated by the nature of the synovial fluid. Given the role played by monocytes in the pathogenesis of chronic rheumatisms, monocytes could be interesting therapeutic targets via the CaSR.
27857933 Retro-Odontoid Pseudotumor without Atlantoaxial Subluxation or Rheumatic Arthritis. 2016 Oct We present a case of retro-odontoid pseudotumor (ROP) without rheumatoid arthritis (RA) or atlantoaxial subluxation (AAS). A 76-year-old woman presented with paresthesia and weakness of both lower and upper extremities. She had no laboratory or physical findings of RA. Dynamic X-ray showed no AAS and magnetic resonance imaging (MRI) showed a retro-odontoid mass compressing the spinal cord. Transdural mass debulking and biopsy were performed via minimal left suboccipital craniectomy and C1 hemilaminectomy. Two months after surgery, her symptoms were aggravated. Follow-up MRI visualized mass re-growth and spinal cord compression due to the mass and AAS. Posterior C1-2 fixation was performed without further decompression. Twelve months after posterior fixation, no symptoms were apparent and follow-up MRI showed complete resolution of the ROP with C1-2 bony fusion. The ROP with C1-2 instability might be completely resolved only C1-2 fusion without decompression. Furthermore, we speculated that osteoarthritis of C1-2 itself causes a partial tear or degradation of the transverse ligament, that induced formation of ROP.
25657894 The Link Between Periodontitis and Rheumatoid Arthritis: A Periodontist's Perspective. 2015 In this review, we critically evaluate the case-control studies examining the relationship between rheumatoid arthritis (RA) and periodontitis, two common chronic inflammatory diseases with a similar host-mediated pathogenesis. We review the "two-hit" periodontitis model that our group previously proposed, in which we elucidate how a systemic disease such as RA can potentially exacerbate or initiate periodontitis. Furthermore, we discuss adjunctive host modulation therapy, originally developed for periodontitis (i.e., subantimicrobial-dose doxycycline alone or in combination with an anti-inflammatory agent), to simultaneously mitigate RA and periodontitis. Finally, we review studies describing periodontal treatment effects on both RA disease activity measures and systemic inflammation. Current evidence suggests that an association exists between periodontitis and RA. Well-designed multicenter longitudinal clinical trials and studies with sufficient sample sizes are needed to ascertain the temporal relationship between these two diseases and whether periodontal treatment can reduce the severity of RA or prevent its onset.
26312914 Evaluation of carotid plaque inflammation in patients with active rheumatoid arthritis usi 2015 Feb 26 BACKGROUND: Rheumatoid arthritis is associated with a 50% increased risk in cardiovascular mortality. Inflammation is thought to accelerate atherosclerosis and might also lead to an inflammatory rupture-prone plaque phenotype. We tested the hypothesis that patients with active rheumatoid arthritis also have carotid plaque inflammation and that plaque inflammation correlates with clinical and serological markers of inflammation. METHODS: Patients with active rheumatoid arthritis, defined as the Disease Activity Score in 28 joints (DAS28) score of more than 3·2, were recruited to a single centre study in the UK. Patients with carotid plaque on ultrasound underwent carotid MRI followed by (18)F-fluorodeoxyglucose ((18)F-FDG) PET-CT. Scans were co-registered and analysed by a physicist, masked to clinical information. The maximum standardised uptake values (SUV(max)) were measured in the plaque area. The association of SUV with DAS28, C-reactive protein, and CD4+CD28- T-cell frequency was tested with non-parametric statistics. Ethics approval and informed consent were obtained. FINDINGS: Scans were done in 13 patients, nine of whom were women. Median age was 60 years (IQR 57-65), disease duration was 11 years (6-25), and DAS28 score was 4·52 (4·32-5·13). None had a history or symptoms of clinical cardiovascular disease or took statins. All plaques caused less than 70% stenosis, and tracer uptake in plaque was seen on PET in all 13 patients. Median SUV(max) was 2·18 (IQR 2·00-2·65), and all cases had an SUV(max) greater than 1·6 (the threshold for defining carotid plaque inflammation). There was a significant association with SUV(max) and C-reactive protein (r=0·58, p=0·04) and quartiles of CD4+CD28- T-cell frequency (p=0·045), but not with low-density lipoprotein concentrations (r=-0·49, p=0·09) or DAS28 score (r=0·38, p=0·20). No association was found with age (r=0·13, p=0·69) or sex (p=0·64). INTERPRETATION: In this small pilot study, plaque inflammation was seen in all patients and correlated with C-reactive protein. Whether this finding represents simultaneous joint and plaque inflammation, which might improve on treatment of joint disease, remains to be determined. CD4+CD28- T-cells are known to predict cardiovascular events in patients with angina. Their association with plaque inflammation in this study suggests a possible role in cardiovascular risk prediction in rheumatoid arthritis. Larger studies are warranted to investigate these findings further. FUNDING: North West England MRC Clinical Pharmacology and Therapeutics Clinical Research Fellowship, National Institute for Health Research, AstraZeneca-University of Manchester Strategic Alliance Fund.
26862354 Associations of MICA Polymorphisms with Inflammatory Rheumatic Diseases. 2015 Inflammatory rheumatic diseases are characterized by inflammation resulting from the immune dysregulation that usually attacks joints, skin and internal organs. Many of them are considered as complex disease that may be predisposed by multiple genes and/or genetic loci, and triggered by environmental factors such as microbiome and cellular stress. The major histocompatibility complex class I chain-related gene A (MICA) is a highly polymorphic gene that encodes protein variants expressed under cellular stress conditions, and these MICA variants play important roles in immune activation and surveillance. Recently, accumulating evidences from both genetic and functional studies have suggested that MICA polymorphisms may be associated with various rheumatic diseases, and the expression of MICA variants may attribute to the altered immune responses in the diseases. The objective of this review is to discuss potential genetic associations and pathological relevance of MICA in inflammatory rheumatic diseases that may help us to understand pathogenesis contributing to the development of these diseases.
25941631 Blocking c-Met signaling enhances bone morphogenetic protein-2-induced osteoblast differen 2015 We previously demonstrated that blocking hepatocyte growth factor (HGF) receptor/c-Met signaling inhibited arthritis and articular bone destruction in mouse models of rheumatoid arthritis (RA). In the present study, we investigated the role of c-Met signaling in osteoblast differentiation using the C2C12 myoblast cell line derived from murine satellite cells and the MC3T3-E1 murine pre-osteoblast cell line. Osteoblast differentiation was induced by treatment with bone morphogenetic protein (BMP)-2 or osteoblast-inducer reagent in the presence or absence of either HGF antagonist (NK4) or c-Met inhibitor (SU11274). Osteoblast differentiation was confirmed by Runx2 expression, and alkaline phosphatase (ALP) and osteocalcin production by the cells. Production of ALP, osteocalcin and HGF was verified by enzyme-linked immunosorbent assay. Runx2 expression was confirmed by reverse transcription-PCR analysis. The phosphorylation status of ERK1/2, AKT, and Smads was determined by Western blot analysis. Both NK4 and SU11274 enhanced Runx2 expression, and ALP and osteocalcin production but suppressed HGF production in BMP-2-stimulated C2C12 cells. SU11274 also enhanced ALP and osteocalcin production in osteoblast-inducer reagent-stimulated MC3T3-E1 cells. SU11274 inhibited ERK1/2 and AKT phosphorylation in HGF-stimulated C2C12 cells. This result suggested that ERK and AKT were functional downstream of the c-Met signaling pathway. However, both mitogen-activated protein kinase/ERK kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitor suppressed osteocalcin and HGF production in BMP-2-stimulated C2C12 cells. Furthermore, SU11274, MEK, and PI3K inhibitor suppressed Smad phosphorylation in BMP-2-stimulated C2C12 cells. These results indicate that although the c-Met-MEK-ERK-Smad and c-Met-PI3K-AKT-Smad signaling pathways positively regulate osteoblast differentiation, c-Met signaling negatively regulates osteoblast differentiation, independent of the MEK-ERK-Smad and PI3K-AKT-Smad pathways. Therefore, blocking c-Met signaling might serve as a therapeutic strategy for the repair of destructed bone in patients with RA.
27638666 Cartilage damage and bone erosion are more prominent determinants of functional impairment 2016 Nov 1 Chronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted joint mobility. In this context, we investigated the impact of the distinct components, including synovial inflammation, bone erosion or cartilage damage, as well as the effect of blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA. We determined CatWalk-assisted gait profiles as objective quantitative measurements of functional impairment. We first determined body-weight-independent gait parameters, including maximum intensity, print length, print width and print area in wild-type mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 - the first clinical signs of arthritis. Moreover, we found further gait changes during chronic disease development, indicating progressive functional impairment in hTNFtg mice. By investigating the association of gait parameters with inflammation-mediated joint pathologies at different time points of the disease course, we found a relationship between gait parameters and the extent of cartilage damage and bone erosions, but not with the extent of synovitis in this chronic model. Next, we observed a significant improvement of functional impairment upon blocking TNF, even at progressed stages of disease. However, blocking TNF did not restore full functionality owing to remaining subclinical inflammation and structural microdamage. In conclusion, CatWalk gait analysis provides a useful tool for quantitative assessment of functional impairment in inflammatory destructive arthritis. Our findings indicate that cartilage damage and bone erosion, but not synovial inflammation, are the most important determinants for progressive functional impairment in this chronic erosive arthritis model.
25802697 Inflammatory Rheumatologic disorders in patients with Myelodysplastic Syndromes: A cross-s 2015 Jan 1 BACKGROUND: The aim of this study was to determine the prevalence and characteristics of rheumatologic manifestations associated with MDS. METHODS: Eighty patients with MDS were evaluated by history and physical examination for inflammatory rheumatologic disorders from Jan 2013 to May 2014. Patients who had any signs or symptoms of rheumatologic disorders underwent evaluation by laboratory tests. Patients with and without inflammatory rheumatic disorders were compared for their characteristics. RESULTS: Of 80 participants with MDS, 9 (11.3%) patients were diagnosed as having rheumatic disorders. MDS patients with or without rheumatologic disorder were similar in demographic and hematologic parameters, except age which was lower in patients with rheumatologic disorders. (p=0.016). In younger patients, refractory cytopenia and refractory cytopenia with multilinage dysplasia were more prevalent. CONCLUSION: The findings of this study indicate that rheumatologic manifestations may be present in MDS patients. Younger patients are more prone to the occurrence of MDS and rheumatic disorders.