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ID PMID Title PublicationDate abstract
24017968 Clinical correlations with Porphyromonas gingivalis antibody responses in patients with ea 2013 INTRODUCTION: Prior studies have demonstrated an increased frequency of antibodies to Porphyromonas gingivalis (Pg), a leading agent of periodontal disease, in rheumatoid arthritis (RA) patients. However, these patients generally had long-standing disease, and clinical associations with these antibodies were inconsistent. Our goal was to examine Pg antibody responses and their clinical associations in patients with early RA prior to and after disease-modifying antirheumatic drug (DMARD) therapy. METHODS: Serum samples from 50 DMARD-naïve RA patients were tested using an enzyme-linked immunosorbent assay with whole-Pg sonicate. For comparison, serum samples were tested from patients with late RA, patients with other connective tissue diseases (CTDs), age-similar healthy hospital personnel and blood bank donors. Pg antibody responses in early RA patients were correlated with standard RA biomarkers, measures of disease activity and function. RESULTS: At the time of enrollment, 17 (34%) of the 50 patients with early RA had positive immunoglobulin G (IgG) antibody responses to Pg, as did 13 (30%) of the 43 patients with late RA. RA patients had significantly higher Pg antibody responses than healthy hospital personnel and blood bank donors (P < 0.0001). Additionally, RA patients tended to have higher Pg antibody reactivity than patients with other CTDs (P = 0.1), and CTD patients tended to have higher Pg responses than healthy participants (P = 0.07). Compared with Pg antibody-negative patients, early RA patients with positive Pg responses more often had anti-cyclic citrullinated peptide (anti-CCP) antibody reactivity, their anti-CCP levels were significantly higher (P = 0.03) and the levels of anti-Pg antibodies correlated directly with anti-CCP levels (P < 0.01). Furthermore, at the time of study entry, the Pg-positive antibody group had greater rheumatoid factor values (P = 0.04) and higher inflammatory markers (erythrocyte sedimentation rate, or ESR) (P = 0.05), and they tended to have higher disease activity scores (Disease Activity Score based on 28-joint count (DAS28)-ESR and Clinical Disease Activity Index) and more functional impairment (Health Assessment Questionnaire). In Pg-positive patients, greater disease activity was still apparent after 12 months of DMARD therapy. CONCLUSIONS: A subset of early RA patients had positive Pg antibody responses. The responses correlated with anti-CCP antibody reactivity and to a lesser degree with ESR values. There was a trend toward greater disease activity in Pg-positive patients, and this trend remained after 12 months of DMARD therapy. These findings are consistent with a role for Pg in disease pathogenesis in a subset of RA patients.
25154839 [Effects of Dickkopf-1 on synovitis of rheumatoid arthritis]. 2014 Jun 17 OBJECTIVE: As an important feature of rheumatoid arthritis (RA), an excessive amount of pro-inflammatory cytokines in RA synovial lesions induces the proliferation of synovial fibroblasts, cartilage erosion and systemic inflammatory immune response. Wnt inhibitor, Dkk-1, contributes to joint remodeling. This study was conducted to explore the role of Dkk-1 in the regulation of pro-inflammatory cytokine secretion. METHODS: Rheumatoid arthritis synovial fibroblasts (RASF) were cultured from surgical synovial specimens and utilized at passages 4-8. For Dkk-1 silencing assay, Dkk-1-specific siRNA and control scrambled siRNA were transfected into RASF respectively. For Dkk-1 over-expression assay, Dkk-1 plasmid and control vector were transfected into RASFs respectively. Production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8), were measured by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR) at pre- and post-transfection respectively. Differences between various groups were evaluated by Wilcoxon signed-rank test. RESULTS: After a treatment of Dkk-1-specific siRNA, RASF exhibited decreased production of pro-inflammatory cytokines in association with down-regulated Dkk-1 levels while Dkk-1 over-expression could up-regulate the production of pro-inflammatory cytokines. The effects were marked when RAFS was activated by TNF-α and IL-1β after transfection. CONCLUSION: Dkk-1 promotes the production of pro-inflammatory cytokines in RASF so as to exacerbate synovitis of RA. And targeting Dkk-1 may provide a novel therapeutic strategy for RA.
24839355 Bone remodelling markers in rheumatoid arthritis. 2014 Bone loss in rheumatoid arthritis (RA) patients results from chronic inflammation and can lead to osteoporosis and fractures. A few bone remodeling markers have been studied in RA witnessing bone formation (osteocalcin), serum aminoterminal propeptide of type I collagen (PINP), serum carboxyterminal propeptide of type I collagen (ICTP), bone alkaline phosphatase (BAP), osteocalcin (OC), and bone resorption: C-terminal telopeptide of type 1 collagen (I-CTX), N-terminal telopeptide of type 1 collagen (I-NTX), pyridinolines (DPD and PYD), and tartrate-resistant acid phosphatase (TRAP). Bone resorption can be seen either in periarticular bone (demineralization and erosion) or in the total skeleton (osteoporosis). Whatever the location, bone resorption results from activation of osteoclasts when the ratio between osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) is decreased under influence of various proinflammatory cytokines. Bone remodeling markers also allow physicians to evaluate the effect of drugs used in RA like biologic agents, which reduce inflammation and exert a protecting effect on bone. We will discuss in this review changes in bone markers remodeling in patients with RA treated with biologics.
24838475 Brief report: rheumatoid arthritis response criteria and patient-reported improvement in a 2014 Sep OBJECTIVE: To examine the association of the American College of Rheumatology (ACR) response criteria (20% improvement [ACR20], ACR50, and ACR70) and the European League Against Rheumatism (EULAR) response criteria with patient-reported improvement in rheumatoid arthritis (RA) activity. METHODS: Two hundred fifty patients with active RA were studied prospectively, before and after escalation of antirheumatic treatment. Patients were asked to report if they subjectively judged that they had experienced important improvement with treatment, and the proportion of patients who reported improvement was compared with the proportion who met the ACR20, ACR50, ACR70, and EULAR response criteria. RESULTS: Improvement in overall arthritis status was reported by 167 patients (66.8%), while 107 patients (42.8%) had an ACR20 response, 52 (20.8%) had an ACR50 response, 24 (9.6%) had an ACR70 response, and 136 (54.4%) had a EULAR moderate/good response. ACR20 response had a sensitivity of 0.57 and a specificity of 0.85 for clinically important improvement as judged by patients. Sensitivities of the ACR50, ACR70, and EULAR moderate/good responses were 0.30, 0.14, and 0.68, respectively, while their specificities were 0.97, 0.99, and 0.73, respectively. The ACR hybrid score with the highest sensitivity and specificity for important improvement was 19.99. CONCLUSION: Among patients with active RA, ACR20 responses are highly specific measures of improvement as judged by patients, but exclude a substantial proportion of patients who consider themselves improved. Response criteria are associated with, but not equivalent to, patient-perceived improvement.
24448626 Which patients improve the most after arthritis rehabilitation? A study of predictors in p 2014 Mar OBJECTIVE: To study health-related quality of life (HRQoL) in arthritis rehabilitation performed by multidisciplinary teams in patients with chronic inflammatory arthritis. Predictors of change in health-related quality of life and the proportion of patients with clinical improvement were investigated. DESIGN: Multicentre prospective observational study in 4 European countries. METHODS: HRQoL was measured with the European Quality 5 Dimensions (EQ-5D) and the Short Form 36 Health Survey (SF-36) in 731 patients who underwent multidisciplinary rehabilitation. Potential predictors were physical functioning (Health Assessment Questionnaire (HAQ)), self-efficacy (Arthritis Self Efficacy Scale (ASES)), psychological health (Hopkins Symptom Check List (HSCL-25)), pain/fatigue (numeric rating scales (NRS)), age, sex, diagnosis, comorbidity, education, clinical setting and change of medication during rehabilitation. Analysis of covariance (ANCOVA) was used to assess for potential predictors and interactions. The minimal important differences for HRQoL were analysed. RESULTS: Reporting worse function (b 0.05, p = 0.01), less psychological well-being (b 0.09, p = 0.000), and experiencing more pain (b 0.03, p = 0.000) or fatigue (b 0.02, p = 0.000) at admission predicted improved HRQoL. Change in medication during rehabilitation (b 0.08, p = 0.013) was associated with greater improvement in HRQoL. These EQ-5D findings were supported by SF-36 findings. Positive minimal important differences were noted in 46% (EQ-5D) and 23-47% (SF-36 subscales) of the patients. CONCLUSION: Patients with more severe symptoms experienced the largest gain in HRQoL post-intervention. The results of this study are of value for selecting the right patients for rheumatological team rehabilitation.
24112707 Detection of a latent soluble form of membrane type 1 matrix metalloprotease bound with t 2013 Dec Membrane type 1 matrix metalloproteinase (MT1-MMP) is implicated in pericellular proteolysis, and, together with tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), in the activation of pro-matrix metalloproteinase-2 on the cell surface. It is expressed on the cell surface either activated or as a proenzyme. A soluble form of MT1-MMP (sMT1-MMP) has been previously identified in periprosthetic tissues and fluid of patients with loose arthroplasty endoprostheses. The aim of this study was to examine periprosthetic tissues and fluids from patients with loose arthroplasty endoprostheses, as well as tissues and fluids from patients with other disorders, for the presence of sMT1-MMP, and to investigate its activation state and possible role. With antibody against MT1-MMP, a protein with molecular mass of ~ 57 kDa was detected by western blotting in all samples tested, representing a soluble form of MT1-MMP, which cannot be ascribed to alternative splicing, as northern blotting showed only one transcript. With various biochemical methods, it was shown that this species occurs in a latent form bearing the N-terminal prodomain, and, additionally, it is bound to TIMP-2, which appeared to be bound via its C-terminal domain to a site different from the active site. Cell ELISA and immunohistochemical analysis revealed that, besides fibroblasts, all other cells, such as inflammatory, epithelial, endothelial, giant and cancer cells, express MT1-MMP on their plasma membrane as a proenzyme. Taking into account the proteolytic abilities of MT1-MMP, the latent sMT1-MMP-TIMP-2 complex could be considered as a new interstitial collagenase. However, the exact role, the production mechanism and the cell origin of this complex remain to be elucidated.
22985493 Common genetic variants associated with disease from genome-wide association studies are m 2013 Jun WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits. The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention. OBJECTIVES: To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA). MATERIALS AND METHODS: The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls. In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni). RESULTS: In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10(-4) ; odds ratio [OR] = 1.15, 95% CI: 1.06-1.24); this has also been associated with psoriasis. However, further analyses showed that the association of this allele was due to confounding by RA-associated HLA-DRB1 alleles. CONCLUSIONS: There is currently no evidence that SNPs associated with PrCa at genome-wide significance are associated with the development of RA. Studies like this are important in determining if common genetic risk profiles might predispose individuals to many diseases, which could have implications for public health in terms of screening and chemoprevention.
25444484 Clinical and histologic findings in patients with uveal melanomas after taking tumor necro 2014 Nov OBJECTIVE: To describe the progression of uveal melanocytic lesions to melanomas after initiation of tumor necrosis factor-α (TNF-α) inhibitors. PATIENTS AND METHODS: We report 3 cases of uveal melanoma occurring after treatment with TNF-α inhibitors, 2 from Mayo Clinic and 1 from Yale University. The study took place from February 27, 2009, through July 15, 2013. RESULTS: Two women and one man with inflammatory disease who received TNF-α inhibitors had subsequent development of uveal melanomas. The 2 women had inflammatory bowel disease and had been followed up for melanocytic tumors that grew markedly within 1 year after beginning treatment with TNF-α inhibitors to the point of requiring treatment. One had histologic confirmation of the melanoma. The male patient had rheumatoid arthritis that was being treated with TNF-α inhibitors. Serial ultrasonography was performed to monitor bilateral diffuse scleritis, and within 16 months of initiation of TNF-α inhibitor therapy, a choroidal mass was detected that continued to grow over the next 3 months. The patient elected to have enucleation, which revealed uveal melanoma and thinning of the sclera from the previous scleritis. CONCLUSION: Our 3 cases of uveal melanocytic tumors occurring after the use of TNF-α inhibitors add to the growing literature suggesting a correlation between TNF-α inhibitors and the development of malignant neoplasms. Considering the association between cutaneous melanoma and TNF-α inhibitors, we recommend that patients have an eye examination before initiation of TNF-α inhibitors, and those with preexisting nevi should be followed up at regular intervals.
24285764 Tofacitinib: The First Janus Kinase (JAK) inhibitor for the treatment of rheumatoid arthri 2013 Nov OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy and safety, dosage administration, and adverse effects of tofacitinib for rheumatoid arthritis (RA) treatment. DATA SOURCES: Primary sources of information were obtained from clinical studies, which were identified through PubMed (1966 to June 2013) and International Pharmaceutical Abstracts (1970 to March 2013) using terms: tofacitinib, tasocitinib, CP-690550, and CP-690,550. Information was used from tofacitinib package insert, guidelines, and published abstracts from the American College of Rheumatology (ACR) and the European League Against Rheumatism. STUDY SELECTION AND DATA EXTRACTION: Data search was limited to include publications in English language and from human subjects. DATA SYNTHESIS: Tofacitinib is the first oral Janus kinase inhibitor indicated for treatment of moderate to severe RA. Tofacitinib demonstrated efficacy and safety comparable to other disease-modifying antirheumatic drugs (DMARDs). Tofacitinib was efficacious in RA patients, indicated by achievements of ACR20, ACR50, and ACR70 criteria. Similar improvements were observed in patients who met remission criteria based on the Disease Activity Scores 28 criteria and quality of life as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Tofacitinib was associated with infections and malignancies; and elevations in serum creatinine and lipids were observed. Drug interactions with inducers and inhibitors of the cytochrome P-450 3A4 and 2C9 isoenzymes were reported. CONCLUSIONS: Tofacitinib is an oral treatment option for RA patients who have inadequate response or intolerance to methotrexate. Postmarket surveillance will provide further insight to tofacitinib's role in RA therapy, especially in patients who may require different types of combination therapy with DMARDS.
23965231 SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patient 2013 Aug 21 INTRODUCTION: Our objective was to determine which one of the two function charts available in Spain to calculate cardiovascular (CV) risk, Systematic COronary Risk Evaluation (SCORE) or Framingham-REgistre GIroní del COR (REGICOR), should be used in patients with rheumatoid arthritis (RA). METHODS: A series of RA patients seen over a one-year period without history of CV events were assessed. SCORE, REGICOR, modified (m)SCORE and mREGICOR according to the European League Against Rheumatism (EULAR) recommendations were applied. Carotid ultrasonography (US) was performed. Carotid intima-media thickness (cIMT) > 0.90 mm and/or carotid plaques were used as the gold standard test for severe subclinical atherosclerosis and high CV risk (US+). The area under the receiver operating curves (AUC) for the predicted risk for mSCORE and mREGICOR were calculated according to the presence of severe carotid US findings (US+). RESULTS: We included 370 patients (80% women; mean age 58.9 ± 13.7 years); 36% had disease duration of 10 years or more; rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP) were positive in 68%; and 17% had extra-articular manifestations. The EULAR multiplier factor was used in 122 (33%) of the patients. The mSCORE was 2.16 ± 2.49% and the mREGICOR 4.36 ± 3.46%. Regarding US results, 196 (53%) patients were US+. The AUC mSCORE was 0.798 (CI 95%: 0.752 to 0.844) and AUC mREGICOR 0.741 (95% CI; 0.691 to 0.792). However, mSCORE and mREGICOR failed to identify 88% and 91% of US+ patients. More than 50% of patients with mSCORE ≥1% or mREGICOR >1% were US+. CONCLUSIONS: Neither of these two function charts was useful in estimating CV risk in Spanish RA patients.
24043367 Cementless total knee arthroplasty in chronic inflammatory rheumatism. 2014 Dec INTRODUCTION: We report a short-term monocentric retrospective evaluation of cementless total knee arthroplasty (TKA) in a population suffering from chronic inflammatory rheumatism. MATERIALS AND METHODS: We have reviewed 23 patients (34 knees) with an average age of 55 years (range 26-78), bearing a TKA for chronic inflammatory rheumatisms with a 6-year follow-up (range 3-12); 78% suffered from rheumatoid arthritis and 15% from juvenile rheumatoid arthritis. We used a cementless total prosthesis sacrificing the posterior cruciate ligament and bearing an ultra-congruent rotational tibial insert, the Natural Knee (NK2™) (Zimmer(®), Warsaw, IN, USA). At last follow-up, an independent surgeon performed a clinical assessment for pain, function and quality of life using International Knee Documentation Committee score, International Knee Society (IKS) score and Devane's score. A radiographic study evaluated secondary fixation according to the radiographic index of the Knee Society and according to Ewald's score. RESULTS: The mean postoperative IKS score was 83 points (range 40-100) for the knee score and 74 points (range 20-100) for the function score. Radiographic assessment came across only one case of loosening, concerning the tibial component on an asymptomatic patient. We came across the following complications: 1 early infection, 2 important postoperative flessum deformity having needed an arthrolysis, 1 supracondylar fracture of the femur and 1 fracture of the patellar component. Survival rate at 6-year follow-up is 97% taking into account one case of revision. CONCLUSION: Non-cementation of this implant in chronic inflammatory rheumatism does not result in a higher rate of loosening. In this series, patients own satisfaction, function of the knee and survival rate are rather good. LEVEL OF EVIDENCE: Retrospective, no control group, Level IV.
25054599 Pre-operative anesthetic assessment of patients with rheumatoid arthritis. 2014 May The management and surgical interventions of problems directly or indirectly arising from rheumatoid arthritis vary drastically. Anesthesiologists and rheumatologists should be aware of the peculiarities of the anesthetic preoperative assessment of these patients, including the assessment of possible disorders of the airways, in addition to the intra-operative management and analysis of relevant pharmacological parameters. It is critical that the anesthetist is familiar with the peculiarities of the disease and the specific characteristics of drugs used in its treatment: thus, he/she will be able to plan the best possible anesthetic technique for the surgery in question, offering safety and comfort to his/her patient. It is up to the rheumatologist to know the procedure to which the patient will be submitted to and be aware of the most appropriate anesthetic technique in each case. This will allow a better interaction between the rheumatologist and the anesthesiologist in the pre-anesthetic evaluation, through the sharing of relevant information on the articular and systemic involvement by the disease that might interfere with preoperative and intraoperative management. Furthermore, the information on the pre-anesthetic assessment and the choice of anesthetic technique will enable the rheumatologist to clarify any doubts that his/her patient and family may have, as well as to guide them as to whether or not the medications in use should be maintained, and eventually about the need for a supplemental dose of corticosteroid. The objective of this review is to acquaint the rheumatologist with key concepts related to the anesthetic preoperative assessment of patients diagnosed with RA, mainly including general notions that dictate the choice of the anesthetic technique.
23472043 Risk of rheumatoid arthritis development in patients with unclassified arthritis according 2013 Jul OBJECTIVE: Early recognition and treatment of RA is associated with an improved outcome. The 2010 ACR/EULAR criteria for RA identify RA patients earlier than the 1987 ACR criteria. Nevertheless, we recently observed that 24% of the 2010 unclassified arthritis (UA) patients develop RA during follow-up. Here we studied this frequency in other cohorts and evaluated the prognostic accuracy of ACPA and the Leiden prediction rule in 2010 UA patients. METHODS: The 2010 UA patients from three Early Arthritis Clinics were studied: 776 from Leiden, 121 from Birmingham and 322 from Amsterdam. Fulfilment of the 1987 ACR criteria during follow-up was studied as the primary outcome. DMARD prescription during the year and having a persistent course of arthritis over 7 years were studied as secondary outcomes in one cohort. The presence of ACPA and the prediction score at baseline were evaluated in relation to these outcomes. RESULTS: In the three cohorts, 24%, 26% and 12%, respectively, of the 2010 UA patients fulfilled the 1987 criteria after 1 year. However, some of these patients already fulfilled the 1987 criteria at baseline. In 1987 and 2010 UA patients, 15%, 21% and 9%, respectively, developed RA (1987) at 1 year. In these patients, 0-6% of the patients were ACPA positive and 0-1% had high prediction scores. Consequently a large majority of the UA patients with an unfavourable outcome was not recognized by these prognostic tools. CONCLUSION: A proportion of 2010 UA patients progress to RA. ACPA and the Leiden prediction rule are not useful in identifying these patients. These results imply that other predictive markers should be developed for 2010 UA patients.
24245522 Long-term persistence and effects of fetal microchimerisms on disease onset and status in 2013 Nov 18 BACKGROUND: The discovery of a fetal cells transfer to the mother is a phenomenon with multiple implications for autoimmunity and tolerance. The prevalence and meaning of the feto-maternal microchimerism (MC) in rheumatic diseases has not been thoroughly investigated. The aim of this study was to analyze the prevalence of fetal MC in patients with inflammatory rheumatic diseases and to investigate the association of MC with disease onset and current status. METHODS: A total of 142 women who gave birth to at least one male offspring were recruited: 72 women with rheumatoid arthritis (RA), 16 women with systemic lupus erythematosus (SLE), and 54 healthy women. For the detection of fetal microchimerism a nested PCR method was used to amplify a Y chromosome specific sequence (TSPY1). For characterization of disease activity we analyzed autoantibody profiles and X-rays in RA, and in addition complement levels in SLE respectively. RESULTS: A significant higher prevalence of fetal MC was found in RA (18%) and SLE (31%) compared to controls (3.7%) (p = 0.02 and p = 0.006, resp.). The mean age at disease onset was comparable in MC + and MC- RA patients. Disease onset occurred 18.7 (MC +) and 19.8 (MC-) years post partum of the first son, respectively. The presence of anti-CCP and RF did not differ significantly, anti-CCP were found in 75% of MC + and 87% of MC- patients, RF in 75% of both MC + and MC- patients. A slightly higher mean Steinbrocker score in MC + patients was associated with longer disease duration in MC + compared to MC- RA. In SLE patients the mean age at disease onset was 42.6 years in MC + and 49.1 years in MC- patients. Disease onset occurred 24.0 and 26.4 years post partum of the first son for MC + and MC- patients, respectively. The presence of ANA and anti-dsDNA antibodies, C3, C4 and CH50 did not differ significantly. CONCLUSION: Our results indicate a higher frequency of long-term male MC in RA and SLE patients compared with controls without impact on disease onset and status in RA and SLE.
23482473 Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a r 2014 Jan OBJECTIVES: To evaluate the efficacy and safety of atorvastatin versus placebo in modifying lipids in patients with rheumatoid arthritis (RA) receiving the oral Janus kinase inhibitor, tofacitinib. METHODS: A randomised, placebo controlled, multicentre phase 2 study, open-label for tofacitinib and blinded for atorvastatin. Patients received tofacitinib 10 mg twice daily for 12 weeks; at week 6, patients were randomly assigned 1:1 to receive oral atorvastatin 10 mg once daily or placebo for 6 weeks. Main outcome measures were lipid moieties, American College of Rheumatology (ACR) response rates, disease activity score in 28 joint counts and safety. RESULTS: 111 patients meeting ACR 1987 RA criteria with active disease were enrolled. Tofacitinib-induced elevation of mean total, low-density lipoprotein (LDL) and high-density lipoprotein-cholesterol, triglycerides and apolipoprotein A-1 concentrations were sustained in placebo recipients to week 12; atorvastatin added at week 6 significantly reduced tofacitinib-associated increases in total and LDL-cholesterol, triglycerides and apolipoprotein B to below week 0 levels. Co-administration of atorvastatin resulted in a significant reduction of LDL-cholesterol versus placebo (primary endpoint; p<0.0001); from week 6 to week 12 the least squares mean reduction was 35.3% with atorvastatin, versus 5.8% increase with placebo. ACR responses were observed with tofacitinib; numerically greater rates were seen with atorvastatin versus placebo. Adverse events were consistent with phase 3 studies. CONCLUSIONS: Tofacitinib-associated elevated total and LDL-cholesterol and triglycerides were rapidly and significantly reduced by atorvastatin. Further investigation is required to explore the significance of reductions in RA disease activity in patients receiving tofacitinib and atorvastatin. (Pfizer protocol A3921109).
24045692 Spatiotemporal analysis for indocyanine green-aided imaging of rheumatoid arthritis in han 2013 Sep Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease, with a prevalence of 0.5 to 1% in the general population. Imaging can possibly aid in early diagnosis, crucial to effective personalized therapeutic strategies and treatment follow-up. The intravenous administration of indocyanine green (ICG) has been considered for identifying synovial hyperperfusion as an RA physiological biomarker. However, while the distribution of ICG in the human hand is a time-dependent process, the particular biodistribution dynamic patterns established following intravenous administration have not yet been studied. For this reason, the dynamic relationships of ICG distribution in the human hand in RA patients using a method based on principal component analysis are analyzed. In vivo analyses were corroborated by simulations of clinical scenarios using a finite element method. Observations of spatiotemporal characteristics are contrasted to fluorescence intensity images and magnetic resonance images of the hand joints, employed as the anatomical and diagnostic reference. Processing results for 450 joints from 5 healthy volunteers and 10 patients show that image features obtained from the spatiotemporal analysis offer good congruence with synovitis and reveal better detection performance compared to observations of raw fluorescence intensity images.
23431370 SKLB023 blocks joint inflammation and cartilage destruction in arthritis models via suppre 2013 Rheumatoid arthritis (RA) is the most common arthritis and is mainly characterized by symmetric polyarticular joint disorders. Our previous study demonstrated a novel small molecule compound (Z)-N-(3-Chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acet-amide (SKLB023) showed potently anti-arthritic effects in a rat arthritis model, however, the underlying mechanisms for this are largely unknown. Both NF-κB and macrophages were reported to play important roles in the pathologic processes of RA. The purposes of this study were to indicate whether NF-κB and macrophages contributed to anti-arthritic effects of SKLB023 in two experimental arthritis models. Our results showed that SKLB023 could significantly improve joint inflammation and cartilage destruction both in adjuvant induced arthritis (AIA) and collagen-induced arthritis (CIA) models. We further found that the binding activation of NF-κB to DNA in joint tissues and RAW264.7 macrophages were suppressed by SKLB023. SKLB023 also inhibited the NF-κB activity in peritoneal macrophages by luciferase assay. Furthermore, the number of macrophages in synovial tissues was decreased after the treatment of different doses of SKLB023. The levels of TNF-α, IL-1β, and IL-6 in plasma, and the levels of TNF-α, NO, and IL-1β in peritoneal macrophages were down-regulated by SKLB023. Finally, SKLB023 attenuated the expression of iNOS and COX-2 in vivo and suppressed the phosphorylations of components of the mitogen-activated protein kinases (MAPKs). These observations identify a novel function for SKLB023 as an inhibitor of NF-κB in macrophages of RA, highlighting that SKLB023 was a potential therapeutic strategy for RA.
25100215 Elevated IgG4 serum levels among primary Sjögren's syndrome patients: do they unmask unde 2014 May OBJECTIVE: To determine IgG4 levels in a cohort of consecutive patients with primary Sjögren's syndrome (SS) and other autoimmune diseases and explore whether they associate with distinct clinical, serologic, and histopathologic features. METHODS: Serum IgG4 levels were measured in 133 primary SS patients and 49 healthy donors (HDs). Seventy-four lupus and 54 rheumatoid arthritis (RA) patients served as disease controls. Immunohistochemical IgG4 analysis was performed in paraffin-embedded minor salivary gland (MSG) tissues. RESULTS: Raised IgG4 serum levels (>135 mg/dl) were detected in 10 (7.5%) of 133 primary SS patients (high-IgG4 group), in 8 (10.8%) of 74 lupus patients, in 7 (12.9%) of 54 RA patients, and in 1 (2%) of 49 HDs. Compared to the normal-IgG4 (<135 mg/dl) primary SS group, high-IgG4 patients exhibited increased prevalence of IgG4-related features (autoimmune cholangitis, autoimmune pancreatitis, and interstitial nephritis), lower rates of antinuclear antibody positivity, and higher IgG2 and IgE levels. Positive staining for IgG4+ plasma cells with an IgG4:IgG ratio ≥40% was detected in 3 of 6 available MSG tissues in the high-IgG4 group. Criteria of possible or definite IgG4-related disease (IgG4-RD) were fulfilled by 10 (7.5%) of 133 of our primary SS cohort. CONCLUSION: Raised IgG4 serum levels were detected in 7.5% of primary SS patients in association with IgG4RD-reminiscent clinical, serologic, and histopathologic features. Whether this high-IgG4 primary SS group represents a misclassified IgG4-RD group or a distinct primary SS subtype remains to be further explored in future studies.
22453529 Preliminary report on a study of health-related quality of life in patients with rheumatoi 2013 Feb There are studies about health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA), but few studies prospectively assessed HRQoL. The main purpose of this study was to analyze HRQoL in patients hospitalized due to RA exacerbation and observed over a planned 2-year follow-up in an outpatient setting. The study involved 42 women and 9 men, at mean age of 62.5 years (SD ± 12.6). The mean duration of the study was 22-23 months. The HRQoL analysis was performed using the SF-36 survey. At the beginning of the study, basic data on age, sex, selected biochemical (ESR, CRP, GFR, hemoglobin, plasma albumin, plasma protein), and clinical parameters (the duration of RA, VAS, DAS28, BMI, the presence of cardiovascular disease, diabetes, osteoporosis, osteoporotic fractures, osteoarthritis, neoplasm) were collected. Questionnaires were completed at the beginning and end of the study. Statistically significant reductions in HRQoL scores were observed in social functioning (SF; 0.42 vs 0.32, P < 0.05), whereas role-emotional health (RE; 0.48 vs 0.59, P < 0.05) and mental health (MH; 0.47 vs 0.54, P < 0.05) scores were increased. A decrease in the SF was positively correlated with the lack of osteoporosis at baseline (r = 0.35, P > 0.02). An increase in the MH was inversely correlated with BMI (r = -0.31, P < 0.05), and the level of hemoglobin (r = -0.32, P < 0.028) and positively correlated with the presence of osteoarthritis at baseline (r = 0.29, P < 0.05). In RA patients, dimensions of HRQoL as SF, RE, and MH could change within 2 years and these changes could be related to comorbidities. Although preliminary findings are promising, further studies are needed.
23313808 High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthri 2013 Oct OBJECTIVE: Phagocyte-derived myeloperoxidase (MPO) and pro-inflammatory high density lipoprotein (HDL) associate with rheumatoid arthritis (RA), but the link between MPO and HDL has not been systematically examined. In this study, we investigated whether MPO can oxidise HDL and determined MPO-specific oxidative signature by apoA-1 by peptide mapping in RA subjects with and without known cardiovascular disease (CVD). METHODS: Two MPO oxidation products, 3-chlorotyrosine and 3-nitrotyrosine, were quantified by tandem mass spectrometry (MS/MS) in in vitro model system studies and in plasma and HDL derived from healthy controls and RA subjects. MPO levels and cholesterol efflux were determined. Site-specific nitration and chlorination of apoA-1 peptides were quantified by MS/MS. RESULTS: RA subjects demonstrated higher levels of MPO, MPO-oxidised HDL and diminished cholesterol efflux. There was marked increase in MPO-specific 3-chlorotyrosine and 3-nitrotyrosine content in HDL in RA subjects consistent with specific targeting of HDL, with increased nitration in RA subjects with CVD. Cholesterol efflux capacity was diminished in RA subjects and correlated inversely with HDL 3-chlorotyrosine suggesting a mechanistic role for MPO. Nitrated HDL was elevated in RACVD subjects compared with RA subjects without CVD. Oxidative peptide mapping revealed site-specific unique oxidation signatures on apoA-1 for RA subjects with and without CVD. CONCLUSIONS: We report an increase in MPO-mediated HDL oxidation that is regiospecific in RA and accentuated in those with CVD. Decreased cholesterol efflux capacity due to MPO-mediated chlorination is a potential mechanism for atherosclerosis in RA and raises the possibility that oxidant resistant forms of HDL may attenuate this increased risk.