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ID PMID Title PublicationDate abstract
24460011 Myeloperoxidase and its products in synovial fluid of patients with treated or untreated r 2014 Apr OBJECTIVE: Plasma and synovial myeloperoxidase (MPO) and its products were strongly associated with osteoarthritis (OA) and rheumatoid arthritis (RA). In addition, it is well known that there is a link between oxidative stress and cytokines. The present study aims at investigating the link between synovial MPO (and its products), interleukin (IL)-18, which is involved in the degradation of articular cartilage in RA, and IL-8, which is involved in recruitment and activation of neutrophils during inflammation. Effects of the treatment of RA on the biological parameters were also investigated. METHODS: Patients (n = 105) were studied including 39 patients with OA, 33 with RA and 33 with RA receiving a specific treatment. Disease activity score (DAS-28) was calculated whereas MPO antigen/activity, neutrophils, chloro-tyrosine (Cl-Tyr), homocitrulline (Hcit), IL-8, and IL-18 were measured in synovial fluid (SF) and CRP was measured in serum. RESULTS: DAS-28 and CRP levels were not significantly different between groups. MPO activity, and MPO, Cl-Tyr, and Hcit levels were significantly higher in SF of RA patients than OA patients. MPO specific activity (MPO activity/antigen ratio) was significantly lower in treated than in untreated RA patients as was IL-8. MPO activity and concentration were correlated with IL-8 and IL-18 in untreated but not in treated RA patients. CONCLUSIONS: MPO level is related to IL-8 and IL-18 levels in untreated RA patients. A link has been shown between treatment and decrease of IL-8, MPO specific activity and Hcit in SF. The causal role of MPO in SF inflammation and how treatment can affect MPO specific activity need further investigations.
25550337 Maintenance of remission following 2 years of standard treatment then dose reduction with 2015 Mar OBJECTIVES: To evaluate maintenance of response while reducing intravenous abatacept dose from ~10 mg/kg to ~5 mg/kg in patients with early rheumatoid arthritis (RA) who achieved disease activity score (DAS)28 (erythrocyte sedimentation rate, ESR) <2.6. METHODS: This 1-year, multinational, randomised, double-blind substudy evaluated the efficacy and safety of ~10 mg/kg and ~5 mg/kg abatacept in patients with early RA with poor prognosis who had reached DAS28 (ESR) <2.6 at year 2 of the AGREE study. The primary outcome was time to disease relapse (defined as additional disease-modifying antirheumatic drugs, ≥2 courses high-dose steroids, return to open-label abatacept ~10 mg/kg, or DAS28 (C reactive protein) ≥3.2 at two consecutive visits). RESULTS: 108 patients were randomised (~10 mg/kg, n=58; ~5 mg/kg, n=50). Three and five patients, respectively, discontinued, and four per group returned to open-label abatacept. Relapse over time and the proportion of patients relapsing were similar in both groups (31% (~10 mg/kg) vs 34% (~5 mg/kg); HR: 0.87 (95% CI 0.45 to 1.69)). Mean steady-state trough serum concentration for the ~10 mg/kg group was 20.3-24.1 µg/mL, compared with 8.8-12.0 µg/mL for the ~5 mg/kg group. CONCLUSIONS: This exploratory study suggests that abatacept dose reduction may be an option in patients with poor prognosis early RA who achieve DAS28 (ESR) <2.6 after ≥1 year on abatacept (~10 mg/kg). TRIAL REGISTRATION NUMBER: NCT00989235.
23297340 Novel small molecule therapeutics in rheumatoid arthritis. 2013 Jul A new wave of emerging therapies for the treatment of autoimmune and inflammatory diseases is under development. These therapies interrupt intracellular signalling through kinase inhibition. By interrupting one or more kinases it is possible to modulate the function of cellular structures such as surface receptors, signalling proteins and transcription of nuclear proteins and thus influence the behaviour of the cell types targeted. With these advances comes the significant potential to develop highly effective orally bioavailable therapeutics. The targets generating the greatest enthusiasm at this time for the treatment of autoimmune and inflammatory diseases include Janus-associated kinase, spleen tyrosine kinase, phosphodiesterase-4, Bruton's tyrosine kinase and phosphatidylinositol-3 kinase. Ultimately human trials will help us understand the potential risks and benefits of these novel approaches across a number of diseases.
24955803 Tuberculosis of the tongue in a patient with rheumatoid arthritis treated with methotrexat 2014 Jun In recent years Tumor Necrosis Factor alpha (TNF alfa) inhibitors have been highly effective in treating rheumatoid arthritis (RA). However, patients receiving these inhibitors have an increased risk of developing tuberculosis (TB). We describe a rare case of tuberculosis of the tongue in an RA patient treated with methotrexate (MTX) and the TNF alfa inhibitor adalimumab (ADA) for the previous six years. Pretreatment tuberculin skin test (TST) was negative. The patient was admitted to our division complaining of a sore throat for months. Clinical examination revealed a swollen non-healing ulcer at the base of the tongue, which was suspected to be a squamous cell carcinoma. Histopathological assessment unexpectedly revealed a chronic granulomatous inflammation compatible with tuberculosis. TST was strongly positive and the T Spot TB test was also reactive. MTX and ADA were discontinued and the patient received antituberculous treatment with complete healing of the lesion. After three months our patient had a worsening RA that was treated with MTX and rituximab with no TB related adverse events. This case highlights the importance of considering tuberculosis in the differential diagnosis of ulcerative lesions of the oral cavity, especially in immunocompromised patients treated with TNF alfa inhibitors. Rituximab can be a valid alternative therapy in such patients.
24441153 Effects of tofacitinib on lymphocytes in rheumatoid arthritis: relation to efficacy and in 2014 May OBJECTIVES: To assess the effects of tofacitinib on T lymphocytes in RA patients with a special focus on efficacy and infectious adverse events (iAEs). METHODS: Forty-four RA patients participated in 12-month phase II/III randomized clinical trials and an open-label extension trial. Peripheral lymphocyte subsets and in vitro CD4(+) T lymphocyte proliferation were measured in 23 patients of 44 at baseline and at the end of the 12-month trial. RESULTS: Forty-four patients [35 females, age 54.3 years, disease duration 84.3 months, simplified disease activity index (SDAI) 36.5, CRP 24.9 mg/l, ESR 53 mm/h, MMP-3 284 pg/ml, RF 172.6 IU/ml, neutrophil count 4842 per μl, lymphocyte count 1410 per μl] were treated with tofacitinib. At the end of the study, the SDAI improved to 6.2, but the peripheral lymphocyte count and absolute numbers of CD4(+) and CD8(+) subpopulations did not change during this period. However, CD4(+) T lymphocyte proliferation was suppressed, which correlated with the improvement in SDAI, but not with iAEs (n = 19) during the 12-month treatment. Receiver operating characteristic analysis identified a CD8(+) T lymphocyte count ≤ 211 per μl at baseline as a significant predictor of clinically significant iAEs. CONCLUSION: The efficacy of tofacitinib is mediated through the suppression of CD4(+) T lymphocyte proliferation without affecting the absolute number of these cells in the periphery. A low CD8(+) T cell count at baseline correlated with the development of iAEs during the treatment of RA patients.
25517733 Therapeutic vaccination with TNF-Kinoid in TNF antagonist-resistant rheumatoid arthritis: 2014 OBJECTIVES: Active immunization, or vaccination, with tumor necrosis factor (TNF)-Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA. METHODS: This was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 µg TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection. RESULTS: The highest anti-TNF antibody response was detected in patients immunized with 360 µg TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not. CONCLUSIONS: TNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order to establish the best conditions for clinical improvement. TRIAL REGISTRATION: ClinicalTrials.gov NCT01040715.
23457383 Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumul 2013 Jun OBJECTIVE: To assess the longterm safety and efficacy of tocilizumab (TCZ) in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patient data were from 5 randomized controlled TCZ trials (n = 4211), their open-label extension phases (n = 3512), and a drug interaction study (n = 23). All randomly assigned patients, regardless of previous RA treatment, were analyzed. Measures of safety included number of adverse events (AE), serious AE (SAE), AE leading to treatment discontinuation, laboratory tests, and deaths. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 responses, tender joint count (TJC), swollen joint count (SJC), ACR core set components, and low disease activity (LDA) or Disease Activity Score in 28 joints (DAS28) remission. ACR/European League Against Rheumatism (EULAR) disease remission was a posthoc exploratory analysis. RESULTS: Total duration of observation was 12,293 patient-years (PY). No new safety signals were identified; infections were the most common AE and SAE. The rate of serious infections was 4.5/100 PY. Improvements from baseline in clinical efficacy, measured as ACR20/50/70 responses, TJC, SJC, ACR core set components, and LDA and DAS28 remission, were generally sustained through at least 216 weeks of followup. ACR/EULAR disease remission was attained by 16.5% (Boolean) and 22.7% (index) of patients at Week 216. CONCLUSION: TCZ has to date been studied for up to 4.6 years (240 weeks) of treatment in patients with RA. Our analysis reveals a longer-term safety profile consistent with previous observations, no new safety signals, and durable efficacy of TCZ in a large clinical trial program.
23466017 Sensibility of five at-work productivity measures was endorsed by patients with osteoarthr 2013 May OBJECTIVE: To examine and compare the sensibility attributes (face/content validity and feasibility) of five at-work productivity measures from the perspective of patients with osteoarthritis (OA) or rheumatoid arthritis (RA). STUDY DESIGN AND SETTING: Workers with OA or RA (n = 250) completed a survey that includes five at-work productivity (presenteeism) measures and questions asking about their comprehensiveness, understandability, length, and suitability of response options. A final question asked respondents which single measure was considered "best" overall. Measures compared included the Workplace Activity Limitations Scale (WALS), Stanford Presenteeism Scale, Endicott Work Productivity Scale, Work Instability Scale for Rheumatoid Arthritis (RA-WIS), and Work Limitations Questionnaire (WLQ-25). Sensibility performance was assessed quantitatively (% respondent endorsement) and qualitatively via written feedback. RESULTS: The WLQ-25 was considered most comprehensive (endorsed by 92.8%), the WALS performed best in terms of understandability (97.6%) and suitability of response options (97.9%), and the RA-WIS was favored in terms of length (91.6%). Consistent sensibility performance between OA and RA was found. The WALS (32.6%) and WLQ-25 (30.0%) were moderately preferred in the final overall appraisal. CONCLUSION: Sensibility criteria were generally met by all five at-work productivity measures. Variable endorsement levels across specific sensibility attributes were also revealed across the measures compared.
23592053 Superior performance of the CCP3.1 test compared to CCP2 and MCV in the rheumatoid factor- 2013 Jul Anti-citrullinated protein/peptide antibodies (ACPAs) have recently been identified as sensitive and specific diagnostic and prognostic markers in rheumatoid arthritis (RA). In this study, we wished to assess the diagnostic performance of the third-generation anti-CCP3.1 assay, but with special focus on the rheumatoid factor (RF)-negative RA population. Anti-CCP as well as anti-MCV was tested in 119 RA patients and 118 control patients using second and third-generation assays. Using these optimal cut-off levels, the diagnostic sensitivity of anti-CCP2, CCP3, and CCP3.1 was 74.8, 78.8, and 83.0%, respectively, while the specificity was 95.7, 96.6, and 98.3%, respectively. The diagnostic performance of the CCP3.1 test was significantly better than that of CCP2 (p = 0.041). In addition, the CCP3.1 test performed significantly better than the MCV test as well (p = 0.0003). When the diagnostic performance of the CCP3.1, CCP2, and MCV tests was compared in the 35 RF-negative patients, the CCP3.1 test exerted significantly better performance than the MCV test (p = 0.006), and it also showed a tendency of better performance in comparison with the CCP2 test (p = 0.131). In conclusion, the CCP3.1 assay can significantly increase the sensitivity of ACPA testing in RF-negative RA, as well as in the total RA population.
24433430 ACPA-positive and ACPA-negative rheumatoid arthritis differ in their requirements for comb 2014 Jan 16 INTRODUCTION: UK guidelines recommend that all early active rheumatoid arthritis (RA) patients are offered combination disease-modifying antirheumatic drugs (DMARDs) and short-term corticosteroids. Anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA may differ in their treatment responses. We used data from a randomized controlled trial - the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial - to examine whether responses to intensive combination treatments in early RA differ by ACPA status. METHODS: The CARDERA trial randomized 467 early active RA patients to receive: (1) methotrexate, (2) methotrexate/ciclosporin, (3) methotrexate/prednisolone or (4) methotrexate/ciclosporin/prednisolone in a factorial-design. Patients were assessed every six months for two years. In this analysis we evaluated 431 patients with available ACPA status. To minimize multiple testing we used a mixed-effects repeated measures ANOVA model to test for an interaction between ACPA and treatment on mean changes from baseline for each outcome (Larsen, disease activity scores on a 28-joint count (DAS28), Health Assessment Questionnaire (HAQ), EuroQol, SF-36 physical component summary (PCS) and mental component summary (MCS) scores). When a significant interaction was present, mean changes in outcomes were compared by treatment group at each time point using t-tests stratified by ACPA status. Odds ratios (ORs) for the onset of new erosions with treatment were calculated stratified by ACPA. RESULTS: ACPA status influenced the need for combination treatments to reduce radiological progression. ACPA-positive patients had significant reductions in Larsen score progression with all treatments. ACPA-positive patients receiving triple therapy had the greatest benefits: two-year mean Larsen score increases comprised 3.66 (95% confidence interval (CI) 2.27 to 5.05) with triple therapy and 9.58 (95% CI 6.76 to 12.39) with monotherapy; OR for new erosions with triple therapy versus monotherapy was 0.32 (95% CI 0.14 to 0.72; P = 0.003). ACPA-negative patients had minimal radiological progression irrespective of treatment. Corticosteroid's impact on improving DAS28/PCS scores was confined to ACPA-positive RA. CONCLUSIONS: ACPA status influences the need for combination DMARDs and high-dose tapering corticosteroids in early RA. In CARDERA, combination therapy was only required to prevent radiological progression in ACPA-positive patients; corticosteroids only provided significant disease activity and physical health improvements in ACPA-positive disease. This suggests ACPA is an important biomarker for guiding treatment decisions in early RA. TRIAL REGISTRATION: Current Controlled Trials ISRCTN32484878.
24205270 Integrative pathway-based approach for genome-wide association studies: identification of 2013 Genome-wide association studies (GWAS) led to the identification of numerous novel loci for a number of complex diseases. Pathway-based approaches using genotypic data provide tangible leads which cannot be identified by single marker approaches as implemented in GWAS. The available pathway analysis approaches mainly differ in the employed databases and in the applied statistics for determining the significance of the associated disease markers. So far, pathway-based approaches using GWAS data failed to consider the overlapping of genes among different pathways or the influence of protein-interactions. We performed a multistage integrative pathway (MIP) analysis on three common diseases--Crohn's disease (CD), rheumatoid arthritis (RA) and type 1 diabetes (T1D)--incorporating genotypic, pathway, protein- and domain-interaction data to identify novel associations between these diseases and pathways. Additionally, we assessed the sensitivity of our method by studying the influence of the most significant SNPs on the pathway analysis by removing those and comparing the corresponding pathway analysis results. Apart from confirming many previously published associations between pathways and RA, CD and T1D, our MIP approach was able to identify three new associations between disease phenotypes and pathways. This includes a relation between the influenza-A pathway and RA, as well as a relation between T1D and the phagosome and toxoplasmosis pathways. These results provide new leads to understand the molecular underpinnings of these diseases. The developed software herein used is available at http://www.cogsys.cs.uni-tuebingen.de/software/GWASPathwayIdentifier/index.htm.
24014647 Articular adipose tissue resident macrophages in rheumatoid arthritis patients: potential 2013 Dec OBJECTIVES: The objectives of this study were to characterize macrophages resident in inflamed articular adipose tissue (AAT) and non-inflamed subcutaneous adipose tissue (ScAT) of RA patients and to evaluate the basal and cytokine-triggered secretory activities of these tissues. METHODS: Tissues were obtained from patients undergoing knee joint replacement surgery. The number of total CD68(+), CD14(+) and CD163(+) macrophages was evaluated by immunohistochemistry. The concentrations of select factors were measured in supernatants from untreated and cytokine-treated tissue explant cultures using ELISA. IL-1β and TNF were applied as the stimuli. RESULTS: Paired samples of AAT and ScAT, obtained from the same patients, contained a similar number of macrophages, displaying an M2-skewed phenotype. Both tissues released equivalent amounts of IL-1β, TNF, IL-10 and macrophage migration inhibitory factor (MIF). However, AAT secreted more chemokines (CCL2, CCL5), cytokines [IL-6, IL-8, IL-1 receptor antagonist (IL-1Ra)], hepatocyte growth factor (HGF) and MMP-3 than ScAT. Basal secretion of adipocytokines was not patient specific. Except for HGF and MIF, cytokine treatment up-regulated the release of these factors from both tissues, but also upon stimulation AAT produced more IL-6, IL-8 and IL-1Ra than ScAT. CONCLUSION: The secretory activity, reflecting cell activation status but not phenotype or the number of macrophages, discriminates rheumatoid AAT from ScAT. By releasing various factors possessing chemotactic, proinflammatory, anti-inflammatory and tissue degrading activities, AAT resident macrophages may drive and control local pathological processes.
24252040 Analysis of the factors which influence the measurement of synovial power Doppler signals 2014 May OBJECTIVES: This pilot multicenter exercise aimed to evaluate the inter-observer reproducibility of synovial power Doppler (PD) signals in rheumatoid arthritis (RA) patients and to determine the factors influencing the measurements. METHODS: Two representative RA patients were assessed by four independent experienced sonographers. The influence of machine difference, deterioration of the transducer and pulse repetition frequency (PRF) on the assessment of synovial PD signals was investigated. RESULTS: Intra-class correlation coefficient (ICC) for the scanner-reader reproducibility of semi-quantitative PD score was high (0.867). ICC for the inter-scanner reproducibility of synovial PD pixel count was higher than that of semi-quantitative PD score. The assessment of PD signals significantly differed between two machines with quantitative measurements but did not with semi-quantitative score. The assessment of PD signals with a deteriorated transducer was much less sensitive than that with an intact one. The semi-quantitative scores for PD signals were comparable between three different PRFs (500/800/1,300 Hz), whereas the pixel count was significantly lower with the highest one in the knee joint. CONCLUSIONS: Measurement of PD signal can be substantially affected by deteriorated quality of the transducer, whereas the differences are relatively modest between machines with similar specifications and also between PRF settings within a low range.
23816503 Mesangial immunoglobulin (Ig)A glomerulonephritis in a patient with rheumatoid arthritis t 2013 Dec We report observations of a 47-year-old seropositive woman with rheumatoid arthritis (RA) suffering from mesangial immunoglobulin (Ig)A glomerulonephritis (GN) after initiation of abatacept, a selective T-cell co-stimulation modulator cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig. She was initially treated by corticosteroids, followed by methotrexate associated with a TNF inhibitor (adalimumab then switched to etanercept), finally switched to abatacept monotherapy, after secondary failure of these two forms of TNF inhibitors. Due to a progressively increased hematuria and proteinuria after abatacept therapy initiation, a renal biopsy was performed highlighting GN with mesangial IgA deposits, with necrosis and extracapillary crescent formations. IgA GN as a possible adverse event to abatacept was considered. Abatacept was stopped and a treatment by corticosteroids was initiated. Proteinuria decreased a couple of months after abatacept interruption. The short term between abatacept induction and IgA GN onset, as well as GN improvement since abatacept discontinuation, lend weight to the argument that CTLA4-Ig may play a crucial role in IgA GN pathogenesis. The possibility of a drug postponed adverse event justifies a long-term renal surveillance in RA patients treated by abatacept.
24757144 STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhi 2014 Apr OBJECTIVE: To investigate the impact of STA-21, a promising STAT-3 inhibitor, on the development and progression of inflammatory arthritis and to determine the possible mechanisms by which STA-21 has antiarthritic effects in interleukin-1 receptor antagonist-knockout (IL-1Ra-KO) mice, an animal model of rheumatoid arthritis (RA). METHODS: IL-1Ra-KO mice were treated with intraperitoneal injections of STA-21 (0.5 mg/kg) or vehicle 3 times per week for 3 weeks. The mouse joints were assessed for clinical and histologic features of inflammatory arthritis. CD4+CD25+FoxP3+ Treg cells and CD4+IL-17+ cells were defined. Human peripheral blood mononuclear cell-derived monocytes or mouse bone marrow-derived monocyte/macrophage (BMM) cells were cultured in the presence of macrophage colony-stimulating factor alone or together with RANKL and various concentrations of STA-21, followed by staining of the cells for tartrate-resistant acid phosphatase activity to determine osteoclast formation. RESULTS: STA-21 suppressed inflammatory arthritis in IL-1Ra-KO mice. The proportion of Th17 cells was decreased and the proportion of Treg cells expressing FoxP3 was markedly increased in the spleens of STA-21-treated mice. Adoptive transfer of CD4+CD25+ T cells obtained from STA-21-treated IL-1Ra-KO mice markedly suppressed inflammatory arthritis. In vitro treatment with STA-21 induced the expression of FoxP3 and repressed IL-17 expression in both mouse and human CD4+ T cells. Moreover, STA-21 prevented both mouse BMM cells and human monocytes from differentiating into osteoclasts in vitro. CONCLUSION: STA-21 improved the clinical course of arthritis in IL-1Ra-KO mice. It increased not only the number of Treg cells but also the function of the Treg cells. It also suppressed Th17 cells and osteoclast formation. These data suggest that STA-21 might be an effective treatment for patients with RA.
24864075 Defining the role of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) in rheumat 2015 Nov BACKGROUND: Antibodies to citrullinated proteins are a hallmark of rheumatoid arthritis (RA). Porphyromonas gingivalis peptidylarginine deiminase (PPAD) has been implicated in the initiation of RA by generating citrullinated neoantigens and due to its ability to autocitrullinate. OBJECTIVES: To define the citrullination status and biology of PPAD in P gingivalis and to characterise the anti-PPAD antibody response in RA and associated periodontal disease (PD). METHODS: PPAD in P gingivalis cells and culture supernatant were analysed by immunoblotting and mass spectrometry to detect citrullination. Recombinant PPAD (rPPAD), inactive mutant PPAD (rPPAD(C351S)), and N-terminal truncated PPAD (rPPAD(Ntx)) were cloned and expressed in Escherichia coli. Patients with RA and healthy controls were assayed for IgG antibodies to citrullinated rPPAD and unmodified rPPAD(C351S) by ELISA. Anti-PPAD antibodies were correlated with anti-cyclic citrullinated peptide (third-generation) antibody levels, RA disease activity and PD status. RESULTS: PPAD from P gingivalis is truncated at the N-terminal and C-terminal domains and not citrullinated. Only when artificially expressed in E coli, full-length rPPAD, but not truncated (fully active) rPPAD(Ntx), is autocitrullinated. Anti-PPAD antibodies show no heightened reactivity to citrullinated rPPAD, but are exclusively directed against the unmodified enzyme. Antibodies against PPAD do not correlate with anti-cyclic citrullinated peptide levels and disease activity in RA. By contrast, anti-PPAD antibody levels are significantly decreased in RA patients with PD. CONCLUSIONS: PPAD autocitrullination is not the underlying mechanism linking PD and RA. N-terminal processing protects PPAD from autocitrullination and enhances enzyme activity. Anti-PPAD antibodies may have a protective role for the development of PD in patients with RA.
24498770 [Case of pharyngeal laceration associated with the use of airwayscope in a patient with di 2013 Dec A 54-year-old woman with atlantoaxial subluxation in rheumatoid arthritis was scheduled for total elbow arthroplasty. Since her neck was stabilized with a cervical collar and her interincisor distance was 1.5 finger-breadth, a difficult airway was anticipated. Anesthesia was induced with propofol and fentanyl. Mask ventilation was barely achieved with difficulty Then insertion of an Intlock with Airwayscope (AWS) into the pharynx was attempted but could not be performed because of restriction of neck mobility and small mouth opening. Although only Intlock separated from AWS could be inserted into the pharynx, oropharyngeal bleeding occurred and we could not obtain an appropriate view on the monitor. Following aspiration of blood, the trachea was intubated using a flexible fiberoptic bronchoscope under AWS guidance. After the operation, a view of bronchoscopy by an otolaryngologist revealed three lacerations from the mucosa to muscle layer in the pharynx. The lacerations could have resulted from use of AWS in a patient with a small mouth opening and with vulnerable mucosa due to long-term steroid therapy.
23457413 Selected reaction monitoring to differentiate and relatively quantitate isomers of sulfate 2013 Apr Rheumatoid arthritis is a common and debilitating systemic inflammatory condition affecting up to 1% of the world's population. This study aimed to investigate the immunological significance of O-glycans in chronic arthritis at a local and systemic level. O-Glycans released from synovial glycoproteins during acute and chronic arthritic conditions were compared and immune-reactive glycans identified. The sulfated core 1 O-glycan (Galβ1-3GalNAcol) was immune reactive, showing a different isomeric profile in the two conditions. From acute reactive arthritis, three isomers could be sequenced, but in patients with chronic rheumatoid arthritis, only a single 3-Gal sulfate-linked isomer could be identified. The systemic significance of this glycan epitope was investigated using the salivary mucin MUC7 in patients with rheumatoid arthritis and normal controls. To analyze this low abundance glycan, a selected reaction monitoring (SRM) method was developed to differentiate and relatively quantitate the core 1 O-glycan and the sulfated core 1 O-glycan Gal- and GalNAc-linked isomers. The acquisition of highly sensitive full scan linear ion trap MS/MS spectra in addition to quantitative SRM data allowed the 3- and 6-linked Gal isomers to be differentiated. The method was used to relatively quantitate the core 1 glycans from MUC7 to identify any systemic changes in this carbohydrate epitope. A statistically significant increase in sulfation was identified in salivary MUC7 from rheumatoid arthritis patients. This suggests a potential role for this epitope in chronic inflammation. This study was able to develop an SRM approach to specifically identify and relatively quantitate sulfated core 1 isomers and the unsulfated structure. The expansion of this method may afford an avenue for the high throughput investigation of O-glycans.
24334460 Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity. 2014 Jan Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity. Severely arthritic C3H mice possessed a naturally occurring hypomorphic allele, Gusbh. C57BL/6 mice congenic for the C3H Gusb allele were prone to increased Lyme-associated arthritis severity. Radiation chimera experiments revealed that resident joint cells drive arthritis susceptibility. C3H mice expressing WT Gusb as a transgene were protected from severe Lyme arthritis. Importantly, the Gusbh allele also exacerbated disease in a serum transfer model of rheumatoid arthritis. A known GUSB function is the prevention of lysosomal accumulation of glycosaminoglycans (GAGs). Development of Lyme and rheumatoid arthritis in Gusbh-expressing mice was associated with heightened accumulation of GAGs in joint tissue. We propose that GUSB modulates arthritis pathogenesis by preventing accumulation of proinflammatory GAGs within inflamed joint tissue, a trait that may be shared by other lysosomal exoglycosidases.
25128504 Serum 14-3-3η is a novel marker that complements current serological measurements to enha 2014 Nov OBJECTIVE: Serum 14-3-3η is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA). In our study, we assessed the diagnostic utility of 14-3-3η and its association with standard clinical and serological measures. METHODS: A quantitative ELISA was used to assess 14-3-3η levels. Early (n=99) and established patients with RA (n=135) were compared to all controls (n=385), including healthy subjects (n=189). The sensitivity, specificity, positive and negative predictive values of 14-3-3η, and the likelihood ratios (LR) for RA were determined through receiver-operator curve analysis. The incremental value of adding 14-3-3η to anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) in diagnosing early and established RA was assessed. RESULTS: Serum 14-3-3η differentiated established patients with RA from healthy individuals and all controls (p<0.0001). A serum 14-3-3η cutoff of ≥0.19 ng/ml delivered a sensitivity and specificity of 77% and 93%, respectively, with corresponding LR positivity of 10.4. At this cutoff in early RA, 64% of patients with early RA were positive for 14-3-3η, with a corresponding specificity of 93% (LR+ of 8.6), while 59% and 57% were positive for ACPA or RF, respectively. When ACPA, RF, and 14-3-3η positivity were used in combination, 77 of the 99 patients (78%) with early RA were positive for any 1 of the 3 markers. Serum 14-3-3η did not correlate with C-reactive protein, erythrocyte sedimentation rate, or Disease Activity Score, but patients who were 14-3-3η-positive had significantly worse disease. CONCLUSION: Serum 14-3-3η is a novel RA mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA.