scholarly journals The CN-index of hnRNP-DL Predicts an Individual “Window of Treatment Success” in RA Patients

2021 ◽  
Author(s):  
Bianka Marklein ◽  
Madeleine Jenning ◽  
Zoltán Konthur ◽  
Thomas Häupl ◽  
Franziska Welzel ◽  
...  
Keyword(s):  
Treatment Success ◽  
Primary Response ◽  
Etanercept Treatment ◽  
Rheumatoid Arthritis Risk ◽  
Early Ra ◽  
Signal Value ◽  
Patients At Risk ◽  
Citrullinated Proteins ◽  
Nuclear Ribonucleoprotein ◽  
Protein Macroarray

Abstract BackgroundThere is a need for biomarker to identify patients ‘at risk’ for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers.MethodsUsing Protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry. ResultshnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. This CNDL (Citrullinated-Native-hnRNP-DL)-index identified and the bioinformatic value was explored, as a new value for an “individual window of treatment success” in early RA and for the detection of RF-IgM/α-CCP2 seronegative RA patients (24-46%). Negative CNDL-index was found in SLE patients, risk-RA- and early RA-cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CNDL-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC-analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients.ConclusionCNDL-index defines patients is a possible biomarker for develop RA and the “window of treatment success” thereby potentially closing the sensitivity gap.

scholarly journals The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Bianka Marklein ◽  
Madeleine Jenning ◽  
Zoltán Konthur ◽  
Thomas Häupl ◽  
Franziska Welzel ◽  
...  
Keyword(s):  
At Risk ◽  
Treatment Success ◽  
Primary Response ◽  
Etanercept Treatment ◽  
Rheumatoid Arthritis Risk ◽  
Early Ra ◽  
Signal Value ◽  
Patients At Risk ◽  
Citrullinated Proteins ◽  
Nuclear Ribonucleoprotein

Abstract Background There is a need for biomarker to identify patients “at risk” for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers. Methods Using protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry. Results HnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP-2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. The citrullinated/native index of autoantibodies against hnRNP-DL (CNDL-Index) was identified as a new value for an “individual window of treatment success” in early RA and for the detection of RF IgM/α-CCP-2 seronegative RA patients (24–46%). Negative CNDL-index was found in SLE patients, risk-RA and early RA cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CNDL-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients. Conclusion CNDL-index defines people at risk to develop RA and the “window of treatment success” thereby closing the sensitivity gap in RA.

scholarly journals POS0465 DIFFERENT CLINICAL RELEVANCE OF ANTI-CITRULLINATED PROTEINS ANTIBODIES IN RA PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 464-464
Author(s):  
A. Avdeeva ◽  
M. Cherkasova ◽  
E. Nasonov
Keyword(s):  
Disease Duration ◽  
Bone Destruction ◽  
Positive Correlation ◽  
Early Ra ◽  
Das 28 ◽  
Conventional Dmards ◽  
Citrullinated Proteins ◽  
Citrullinated Vimentin ◽  
Citrullinated Peptide ◽  
Treatment Table

Background:Anti-citrullinated proteins antibodies (ACPA) are a broad group of antibodies, including antibodies to citrullinated fibrinogen, antibodies to cyclic citrullinated peptide (anti-CCP), antibodies to modified citrullinated vimentin (anti-MCV), antibodies to citrullinated α-enolase.Objectives:To find a potential relationship between ACPA and disease activity, bone destruction, and ACPAs responses to various therapeutic regimens.Methods:The study included 232 patients (pts) with rheumatoid arthritis (RA); 90 pts (74 women, Me;IQR age 53.0 (38.0–58.5) years had early RA, with mean disease duration 5.0 (4.0–9.0) months, DAS 28 5.3 (4.4–6.1)); 142 pts had advanced stage of the disease (123 women, median age 51.0 (43.0–60.0) years, disease duration 56.0 (24.0–96.0) months, DAS 28 6.2 (5.5–6.8)). Pts with early RA received methotrexate (MTX) subcutaneously at average 17.5 mg dose once weekly. Pts with advanced RA received the following anti-B-cell therapy: 34 pts - rituximab (RTX); 20 pts - RTX biosimilar; 43 pts - tocilizumab (TCZ) in combination with conventional DMARDs. Serum anti-CCP and anti-MCV concentrations were measured using ELISA.Results:77 (85.6%) pts with early RA were high positive for anti-CCP, and 29 (70.7%) pts - high positive for anti-MCV. A positive correlation was found between anti-MCV and DAS 28 (r=0.4, p=0.04). As for advanced RA, 78 (80.4%) pts were high positive for anti-CCP, and 70 (79.5%) - for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r=0.4, p=0.02), as well as CDAI (r=0.4, p=0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0-122.0)) were found in pts high positive for anti-MCV (n=79), compared to low-positive/negative (57.0 (31.0–88.0), respectively, (n=27, p<0.05). anti-MCV levels dropped significantly in pts on RTX and TCZ therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment (Table 1)Conclusion:anti-MCV levels correlated with inflammatory activity and development of bone destruction, and were decreasing in pts on treatment. Anti-CCP was less responsive, showed minor changes during treatment, therefore its’ thorough monitoring was not feasible.Disclosure of Interests:None declared

Statin Effects on Incidence, Treatment Success, and Mortality of Clostridium difficile Infections

2019 ◽  
Vol 33 (4) ◽  
pp. 497-505
Author(s):  
Marian L. Gaviola ◽  
Emily C. Scribe ◽  
Haley N. Leverett ◽  
Meredith L. Howard
Keyword(s):  
Clostridium Difficile ◽  
Clostridium Difficile Infection ◽  
Treatment Success ◽  
Current Data ◽  
Mortality Benefit ◽  
Specific Population ◽  
Patients At Risk ◽  
Clostridium Difficile Associated Diarrhea ◽  
Statin Use ◽  
Significant Mortality

Purpose To review the effects of statin use in patients at risk for or diagnosed with Clostridium difficile infection (CDI) on CDI incidence, treatment success, and mortality. Methods A literature search was performed through January 2019 using the following terms: statins, HMG-CoA inhibitors, Clostridium difficile, Clostridium difficile associated diarrhea, and Clostridium difficile infection. Additional references were identified from a review of literature citations. Studies evaluating statin effects on C difficile-related outcomes were included. Results A total of 8 studies were identified for inclusion in this review. All studies were retrospective. Five studies reported the association between statin use and the development of CDI, suggesting that statins may decrease risk of CDI development in patients already on statin. In one study, there was an improved treatment response against CDI with the use of statin. Three retrospective studies evaluated statin use and mortality from CDI and only one study found significant mortality benefit in statin users. Conclusions Statin use may have a protective effect against the development of CDI and improve CDI treatment success; however, it is unclear if use confers a mortality benefit. Current data remain sparse and larger, prospective studies are needed to confirm current results and identify the specific population that may benefit the most from this intervention.

scholarly journals Epidemiology of tuberculosis and treatment outcomes among children in Pakistan: a 5 year retrospective study

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5253 ◽  
Author(s):  
Madeeha Laghari ◽  
Syed Azhar Syed Sulaiman ◽  
Amer Hayat Khan ◽  
Naheed Memon
Keyword(s):  
Retrospective Study ◽  
Treatment Outcomes ◽  
Urban Areas ◽  
Demographic Data ◽  
Treatment Success ◽  
Clinical Manifestations ◽  
Sputum Smear ◽  
Unsuccessful Treatment ◽  
Patients At Risk ◽  
Group 2

Background Regardless of the advancement in medical technologies, the diagnosis of tuberculosis (TB) in children has remained a challenge. Childhood TB is rampant and an important cause of morbidity and mortality. The objective of this study was to determine the trend of TB and treatment outcomes in children aged ≤14 years registered for TB treatment under DOTS course in three districts of Sindh, Pakistan. Methods For this retrospective study, records of TB children (≤14 years) registered for the treatment of TB from January 2011 to December 2015 in three districts of Pakistan, were collected. Demographic data, baseline weight, clinical manifestations, radiography, histopathology results and treatment outcomes were collected from TB unit registers. Results A total of 2,167 children were treated for TB during the study period. Of these, 1,199 (55.3%) were females and 1,242 (57.3%) were from urban areas. Over three-quarter of patients (76.9%) had pulmonary TB with 13.3% of sputum smear positive cases. The overall treatment success rate was 92.4%. In multivariate analysis, rural residents (OR: 2.146, p < 0.001), sputum smear positive cases (OR: 3.409, p < 0.001) and re-treated patients (OR: 5.919, p < 0.001), were significantly associated with unsuccessful treatment outcomes. However, age group ≤2 years, male and those who were underweight were found to have the highest risk of pulmonary tuberculosis (OR: 1.953, p < 0.001; OR: 1.262, p = 0.028; OR: 1.342, p = 0.008), respectively. Conclusion Patients at risk of treatment failure must be given particular attention. Moreover, strategies are needed to further improve the diagnosis and treatment of TB among children and improve the recording system.

scholarly journals SAT0069 TUBERCULOSIS IN BIOLOGIC-NAÏVE PATIENTS WITH RHEUMATOID ARTHRITIS - RISK FACTORS AND TUBERCULOSIS CHARACTERISTICS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 969.2-969
Author(s):  
J. Sundbaum ◽  
E. Arkema ◽  
J. Bruchfeld ◽  
J. Jonsson ◽  
J. Askling ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Medical Records ◽  
Treatment Success ◽  
Population Based ◽  
Naive Patient ◽  
Rheumatoid Arthritis Risk ◽  
Quality Register ◽  
Increased Risk ◽  
Associated Risk Factors

Background:The risk of tuberculosis (TB) has decreased in biologic disease modifying anti-rheumatic drugs (bDMARDs) treated rheumatoid arthritis (RA) patients, but remains unaltered 4-fold increased in bio-naïve RA patients compared to the general population in Sweden (1). In absolute numbers, most TB cases in contemporary RA patients occur in the group of bio-naïve patients. Knowledge about risk factors for TB and TB characteristics in bio-naïve RA patients is still limited.Objectives:To investigate risk factors for TB and TB characteristics in bio-naïve RA patients.Methods:Population-based case-control study. A national bio-naïve RA cohort was identified from the National Patient Register and the Swedish Rheumatology Quality Register. RA cases with TB were identified by linkage to the Swedish Tuberculosis Register (with mandatory TB registration) 2001-2014 (n=42). For each case, four matched RA controls without TB were identified. Clinical data were obtained from medical records. Univariate and multivariable logistic regression analyses were used to estimate risk for TB expressed as adjusted (adj) odds ratio (OR) with 95% confidence intervals (CI).Results:After review of the medical records and validation of diagnoses, 31 cases with RA and TB and 122 controls remained in the study. The TB cases had a median of 3 (1-6) reported TB risk factors, and almost 90% were born before 1950. Only one case was screened for TB (with negative result of tuberculin skin test). Active TB occurred at a mean of 15 years after RA diagnosis, and all except three cases were considered as reactivation of latent TB. Exposure to leflunomide (5 cases, 4 controls) (adj OR 6.02; 95% CI 1.47-24.65) and azathioprine (5 cases, 6 controls) (adj OR 3.85; 95% CI 1.06-13.79) were associated with increased risk for TB. Methotrexate, used in 67.7% of cases and 73.9% of controls, was not associated with increased risk of TB (adj OR 0.83; 95% CI 0.34-1.98). Exposure to corticosteroids was more common among cases than controls (74.2% vs 53.8%, p= 0.04), and was associated with an adj OR for TB of 2.44 (95% CI 1.00-5.92). No significant differences were identified between prednisolone-treated cases and controls in terms of maximum dose ever of prednisolone, treatment duration before TB, or cumulative dose of prednisolone during the last year before diagnosis of TB. Obstructive pulmonary disease was the only comorbidity linked to an increased TB risk (adj OR 3.94; 95% CI 1.45-10.69). Pulmonary TB dominated (84%) followed by TB lymphadenitis (19%). Treatment success was 94%, comparable to TB patients in general.Conclusion:Several RA-associated risk factors may contribute to increased TB risk in bio-naïve RA patients (treatment with leflunomide, azathioprine, or prednisolone and concomitant obstructive lung disease). We could not confirm previous findings of an association with the use of moderate to high doses of prednisolone (≥15 mg). TB risk seems difficult to predict with precision in the individual bio-naïve patient based on RA-associated risk factors. To further decrease the TB risk in RA patients TB screening should also be considered in the group of bio-naïve patients.References:[1] Arkema EV et al. Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments? Ann Rheum Dis 2015;74:1212-17.Disclosure of Interests:Johanna Sundbaum: None declared, Elizabeth Arkema: None declared, Judith Bruchfeld: None declared, Jerker Jonsson: None declared, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma, Eva Baecklund: None declared

THU0047 Autoantibody Profiling of Late and Early RA Patients Against Citrullinated Proteins

2015 ◽  
Vol 74 (Suppl 2) ◽  
pp. 209.1-209
Author(s):  
A. Lueking ◽  
P. Schriek ◽  
H. Goehler ◽  
M. Gamer ◽  
K. Marquart ◽  
...  
Keyword(s):  
Early Ra ◽  
Citrullinated Proteins

scholarly journals ECIL guidelines for treatment of Pneumocystis jirovecii pneumonia in non-HIV-infected haematology patients

2016 ◽  
Vol 71 (9) ◽  
pp. 2405-2413 ◽  
Author(s):  
Georg Maschmeyer ◽  
Jannik Helweg-Larsen ◽  
Livio Pagano ◽  
Christine Robin ◽  
Catherine Cordonnier ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Treatment Success ◽  
Clinical Signs ◽  
Signs And Symptoms ◽  
Antimicrobial Treatment ◽  
Pneumocystis Jirovecii ◽  
High Dose ◽  
Pneumocystis Jirovecii Pneumonia ◽  
Laboratory Findings ◽  
Patients At Risk

Abstract The initiation of systemic antimicrobial treatment of Pneumocystis jirovecii pneumonia (PCP) is triggered by clinical signs and symptoms, typical radiological and occasionally laboratory findings in patients at risk of this infection. Diagnostic proof by bronchoalveolar lavage should not delay the start of treatment. Most patients with haematological malignancies present with a severe PCP; therefore, antimicrobial therapy should be started intravenously. High-dose trimethoprim/sulfamethoxazole is the treatment of choice. In patients with documented intolerance to this regimen, the preferred alternative is the combination of primaquine plus clindamycin. Treatment success should be first evaluated after 1 week, and in case of clinical non-response, pulmonary CT scan and bronchoalveolar lavage should be repeated to look for secondary or co-infections. Treatment duration typically is 3 weeks and secondary anti-PCP prophylaxis is indicated in all patients thereafter. In patients with critical respiratory failure, non-invasive ventilation is not significantly superior to intubation and mechanical ventilation. The administration of glucocorticoids must be decided on a case-by-case basis.

scholarly journals Treatment with etanercept and low monocyte concentration contribute to the risk of invasive aspergillosis in patients post allogeneic stem cell transplantation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tamara Zoran ◽  
Michael Weber ◽  
Jan Springer ◽  
P. Lewis White ◽  
Joachim Bauer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Invasive Aspergillosis ◽  
Ex Vivo ◽  
Antifungal Prophylaxis ◽  
Cell Transplant ◽  
Etanercept Treatment ◽  
Hematopoietic Stem ◽  
Patients At Risk

AbstractInvasive aspergillosis (IA) is a life-threatening complication among allogeneic hematopoietic stem cell transplant (alloSCT) recipients. Despite well known risk factors and different available assays, diagnosis of invasive aspergillosis remains challenging. 103 clinical variables from patients with hematological malignancies and subsequent alloSCT were collected. Associations between collected variables and patients with (n = 36) and without IA (n = 36) were investigated by applying univariate and multivariable logistic regression. The predictive power of the final model was tested in an independent patient cohort (23 IA cases and 25 control patients). Findings were investigated further by in vitro studies, which analysed the effect of etanercept on A. fumigatus-stimulated macrophages at the gene expression and cytokine secretion. Additionally, the release of C-X-C motif chemokine ligand 10 (CXCL10) in patient sera was studied. Low monocyte concentration (p = 4.8 × 10−06), severe GvHD of the gut (grade 2–4) (p = 1.08 × 10−02) and etanercept treatment of GvHD (p = 3.5 × 10−03) were significantly associated with IA. Our studies showed that etanercept lowers CXCL10 concentrations in vitro and ex vivo and down-regulates genes involved in immune responses and TNF-alpha signaling. Our study offers clinicians new information regarding risk factors for IA including low monocyte counts and administration of etanercept. After necessary validation, such information may be used for decision making regarding antifungal prophylaxis or closely monitoring patients at risk.

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