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ID PMID Title PublicationDate abstract
29403504 Perspective on Protein Arginine Deiminase Activity-Bicarbonate Is a pH-Independent Regulat 2018 Protein citrullination catalyzed by peptidyl arginine deiminase (PADs) is involved in autoimmune disease pathogenesis, especially in rheumatoid arthritis. Calcium is a key regulator of PAD activity, but under normal physiological conditions it remains uncertain how intracellular calcium levels can be raised to sufficiently high levels to activate these enzymes. In pursuit of trying to identify other factors that influence PAD activity, we identified bicarbonate as a potential regulator of PAD activity. We demonstrate that physiological levels of bicarbonate upregulate citrullination by recombinant PAD2/4 and endogenous PADs in neutrophils. The impact of bicarbonate is independent of calcium and pH. Adding bicarbonate to commercial PAD activity kits could increase assay performance and biological relevance. These results suggest that citrullination activity is regulated by multiple factors including calcium and bicarbonate. We also provide commentary on the current understanding of PAD regulation and future perspective of research in this area.
29726309 Distribution of Porphyromonas gingivalis fimA genotypes in patients affected by rheumatoid 2018 Oct OBJECTIVE: To determine and compare the distribution of Porphyromonas gingivalis fimA genotypes in patients affected by Rheumatoid arthritis (RA) and periodontitis (PE). MATERIALS AND METHODS: This study involved 394 subjects divided into four groups, RA, PE, RA and PE and healthy subjects. PE was diagnosed by using clinical attachment loss (CAL) and probing depth (PD) indexes. Presence of P. gingivalis and its genotypes was identified by polymerase chain reaction in subgingival biofilm. RESULTS: P. gingivalis was more frequent in patients with RA (82.69%), and fimA II genotype was the most frequent in all groups, especially in PE/RA (76.71%). There was statistical difference (p < .05) regarding the frequency of P. gingivalis genotypes such as fimA Ib, II and III. CONCLUSIONS: Distribution of P. gingivalis fimA II genotypes was different among groups, it could play a critical role in the presence of PE in RA patients.
29968400 Effectiveness of biologics in Australian patients with rheumatoid arthritis: a large obser 2018 Oct BACKGROUND: The comparative effectiveness of biologic treatment regimens in a real world Australian population is unknown. AIM: To assess the effectiveness of biological disease-modifying anti-rheumatic drugs (bDMARD) as monotherapy or in combination with methotrexate and/or other conventional DMARD (cDMARD) for the treatment of rheumatoid arthritis (RA). METHODS: A retrospective, non-interventional study was conducted that investigated the use of bDMARD in adult patients with RA in routine clinical practice. Data were extracted from the Optimising Patient Outcomes in Australian Rheumatology - Quality Use of Medicines Initiative database. Real-world effectiveness was measured using the 28-joint disease activity score (DAS28) and clinical disease activity index (CDAI) by treatment group at baseline, weeks 12 and 24. RESULTS: A total of 2970 patients was included with a median (min-max) age of 60.0 (19.0-94.0) years and median (min-max) duration of RA before first bDMARD treatment of 6.0 (0.2-58.3) years. A total of 1177 patients received more than one bDMARD during the analysis period of 1 January 1997 to 15 August 2015. Patients had 4922 treatment 'episodes' (defined as a cycle of continuous individual bDMARD prescribing in a single patient). Patients received a mean (SD) of 1.7 (1.0) episodes of treatment with median (min-max) treatment duration of 0.7 (0-11.8) years; median treatment duration was higher with the first treatment episode. bDMARD were most commonly initiated in combination with methotrexate (73.9% of episodes) and least commonly as monotherapy (9.9% of episodes). Median (min-max) baseline DAS28 decreased from 5.3 (0-8.7) with the first bDMARD to 3.7 (0-8.8) with the second. Median baseline CDAI similarly decreased. CONCLUSIONS: Patients tended to persist longer on their first bDMARD treatment. bDMARD as monotherapy or in combination appear to be accepted treatment strategies in the real world.
30400666 Rituximab Therapy in Renal Amyloidosis Secondary to Rheumatoid Arthritis. 2018 Nov 5 Secondary amyloid A (AA) amyloidosis is a late and serious complication of poorly controlled, chronic inflammatory diseases. Rheumatoid arthritis (RA) patients with poorly controlled, longstanding disease and those with extra-articular manifestations are under risk for the development of AA amyloidosis. Although new drugs have proven to be significantly effective in the treatment of secondary AA amyloidosis, no treatment modality has proven to be ideal. To date, only in small case series preliminary clinical improvement have been shown with rituximab therapy for AA amyloidosis secondary to RA that is refractory to TNF-α inhibitors (TNF-i) therapy. In these case series, we assessed the efficacy and safety of rituximab therapy for patients with RA and secondary amyloidosis. Hacettepe University Biologic Registry was developed at 2005. The data of the RA patients who were prescribed a biological drug were recorded regularly. Patients with biopsy proven AA amyloidosis patients were screened. Of 1022 RA patients under biologic therapy, 0.7% patients had clinically apparent histologically confirmed amyloidosis. Four of seven patients who were prescribed rituximab at least one infusion enrolled to those case series. Two of four patients showed significant clinical improvement and one of them also had decrease in proteinuria and the other one had stable renal function and proteinuria. The main goal for the treatment of AA amyloidosis is to control the activity of the underlying disorder. In this study, we showed that rituximab may be an effective treatment in RA patients with amyloidosis who were unresponsive to conventional disease modifying anti-rheumatic drugs (DMARDs) and/or TNFi.
30146149 [Berger's disease associated to an adalimumab-treated rheumatoid arthritis]. 2018 Nov Berger's disease is characterized by deposits of immunoglobulin A in the glomerular mesangium. We report a case of a patient who was treated by adalimumab for a rheumatoid arthritis (RA). The patient is 45 years old and is treated for RA since 1996. Adalimumab was started after the failure of several treatments. Biological and clinical response to adalimumab were excellent. A nephrotic syndrome was diagnosed during the patient follow-up. Adalimumab was stopped since it was suspected to be responsible of these symptoms. Berger's disease was diagnosed thanks to a renal biopsy. The nephrotic syndrome was treated with corticosteroids, then tocilizumab was used to treat RA. TNF-alpha inhibitors are well known for inducing kidneys' adverse reactions (ADR). Usually, they appear shortly after the beginning of a treatment. Adalimumab has already been described in studies for inducing similar kidneys' adverse drug reactions. These ADR are often associated with systemic disease outbreak. It is difficult to assert that adalimumab or RA was responsible of the ADR that we noticed in our patient. It is usually admitted that these ADR are uncommon when the RA is controlled.
29606667 Origins of Discordant Responses among 3 Rheumatoid Arthritis Improvement Criteria. 2018 Jun OBJECTIVE: We examined agreement between the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) response criteria in rheumatoid arthritis (RA) and tested whether discordant responses were associated with patients' baseline characteristics or changes in RA activity encapsulated by the different criteria. METHODS: In a prospective longitudinal study, we examined responses of 243 patients with active RA to escalation of antirheumatic treatment. We computed agreement between pairs of response criteria using κ coefficients and identified patient characteristics associated with unique responses to individual criteria. RESULTS: We found that 110 patients (45.3%) had an ACR 20% improvement (ACR20) response, 135 (55.5%) had a EULAR moderate/good response, and 83 (34.1%) had an SDAI50 response. Agreement was moderate to good (ACR20/EULAR κ 0.57; ACR20/SDAI50 κ 0.64; EULAR/SDAI50 κ 0.59). All who had SDAI50 response also had a EULAR response. Patient characteristics at baseline generally did not distinguish those who responded to both, 1, or neither criterion. Discordance was most often because of improvements in the erythrocyte sedimentation rate or C-reactive protein level among EULAR and SDAI50 responders, which were not as common among ACR20 responders. Based on receiver-operating characteristic curves, SDAI35 response had a better balance of sensitivity and specificity relative to ACR20 and EULAR moderate/good responses than SDAI50. CONCLUSION: Discordant responses to RA improvement criteria are most often because of differences in responses of acute-phase reactants. SDAI35 response had higher sensitivity for improvement, as reflected by other response criteria, than SDAI50 response.
29616303 Serum drug levels of biologic agents in the management of rheumatoid arthritis and spondyl 2018 Jun The utility of monitoring drug levels in rheumatoid arthritis and spondyloarthritis patients on biological therapy is called into question. The objective was to study relevant clinical questions on the topic, i.e., (1) whether drug levels predict relapse in patients whose biologic was optimized because of remission or low disease activity; (2) whether information about drug levels influences the prognosis of patients with primary or secondary failure to a biological therapy; and (3) whether methotrexate (MTX) influences the association between drug levels and response. Medline, Embase, Cochrane databases were screened, from inception to December 2016 in search for all studies related to the three research questions about. Overall characteristics and outcomes of the studies were collected in a table of evidence and the quality of the studies was assessed with the Newcastle-Ottawa scale or the GRADEpro. Two studies responded the first question, 5 the second, and 7 the third. Studies were small and with limitations, but suggest that measurement drug levels may be useful in patients in remission; that higher drug levels predict a longer relapse-free optimization, and in patients with failure to a biological agent, treatment may need individual adjustment according to the presence of drug levels or antidrug-antibodies. In addition, MTX influences the association between response and drug levels. Monitoring drug levels would allow optimal use of current biological therapies, but more studies and of better quality are needed to draw definitive conclusions.
29512532 [Homeostasis and Disorder of Musculoskeletal System.Progress in the treatment of rheumatoi 2018 Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammation and joint damage that causes significant morbidity and mortality. Rapid and appropriate intervention using disease-modifying anti-rheumatic drugs(DMARDs)is prerequisite to halt joint destruction and long-term functional disabilities. Recent progress in the treatment strategy has brought about paradigm shift for the management of the disease, namely, the combined use of methotrexate, a synthetic DMARD, and a biologic DMARD targeting TNF, IL-6 and T cells has revolutionized treatment of rheumatoid arthritis. Clinical remission is now realistic targets for the treatment, achieved by a large proportion of rheumatoid arthritis patients, which leads to structural remission without damage in bone and cartilage as well as functional remission. Furthermore, orally available small but strong molecules targeting Janus kinase(JAK)are emerging. When DMARDs are prescribed, appropriate selection of DMARDs, adequate screening, regular monitoring and systemic management are required.
30148175 Influence of Biological Therapeutics, Cytokines, and Disease Activity on Depression in Rhe 2018 PURPOSE: Rheumatoid arthritis (RA) is an often debilitating autoinflammatory disease. Patients with rheumatoid arthritis are often troubled by co-occurring depression or other psychological manifestations. RA patients have a variety of treatment options available, including biologicals that inhibit cytokines or immune cells. If these cytokines influence the psychological symptoms, then the use of cytokine inhibitors should modulate these symptoms. METHODS: A cohort of 209 individuals was recruited. This group included 82 RA patients, 22 healthy subjects, 32 depressed control subjects, and 73 subjects with systemic lupus erythematosus. Of the RA patients, 51% were on a biological therapeutic. ELISA was used to measure cytokine levels. A variety of psychological assessments were used to evaluate depression, anxiety, sleep, fatigue, and relationship status. Clinical values were obtained from medical records. RESULTS: IL-10 concentration was associated with depressive symptoms in the RA patients, healthy controls, and the lupus patients. In the patients with primary depression, depressive symptoms were associated with IL-6 and TNF-alpha. In RA patients, Tocilizumab use was associated with decreased depressive symptoms. 14 RA patients who were not using biologicals began using them by a one-month follow-up. In these patients, there was no significant change to any value except for fatigue. CONCLUSIONS: A variety of both biological and social factors influences depressive symptoms in RA. IL-10 and IL-6 are likely to be involved, since IL-10 concentration was associated with depression and Tocilizumab decreased depressive symptoms in the RA patients. The roles of these cytokines are different in RA and lupus, as high IL-10 in RA is associated with increased depressive symptoms, but high IL-10 in the lupus patients is associated with decreased depression. IL-6 was also associated with depressive symptoms in the patients with primary depression. These results strongly indicate that disease activity, including cytokine levels, has a strong impact on depressive symptoms.
30306802 Transdermal delivery system of nanostructured lipid carriers loaded with Celastrol and Ind 2018 Co-encapsulation of drugs provides a convenient means for treating different symptoms of a disease. Celastrol (Cel) shows potent anti-arthritic activity and Indomethacin (Indo) is effective in relieving inflammatory pain. Nanostructured lipid carriers loaded with Celastrol and Indomethacin (Cel-Indo-NLCs) were prepared by emulsification evaporation-solidification method, optimized by the Box-Behnken design and characterized by transmission electron microscopy (TEM), Fourier transform infrared (FTIR) and powder X-ray diffraction analysis (PXRD). Visualization of transdermal translocation of Cel-Indo-NLCs was achieved by confocal laser scanning microscope (CLSM). Further, Cel-Indo-NLCs were incorporated into Carbopol 940 for transdermal delivery. The in vitro studies were evaluated by using the Franz diffusion cells. Cel-Indo-NLCs depicted small particle size (26.92 ± 0.62 nm) and PDI (0.201 ± 0.01), high entrapment efficiency (96.56 ± 1.41%) and drug load (3.65 ± 0.05%). Moreover, Cel-Indo-NLCs showed prominent effect of decreasing paw oedema, inhibiting inflammation and pain by regulating the levels of IL-1β, TNF-α, β-endorphin and Substance P. After the administration of Cel-Indo-NLCs-gel, no skin irritation was observed in rats. There was no difference of gastrointestinal tract between different groups of rats when they were sacrificed. The histological analysis showed no renal and reproductive toxicity. Therefore, it can be concluded that co-encapsulation strategy based NLCs have the potential to provide safe transdermal delivery and are promising in treatment of pain and inflammation associated with rheumatoid arthritis.
29381085 Gum acacia stabilized silver nanoparticles based nano-cargo for enhanced anti-arthritic po 2018 Nanomedicines anticipate drug delivery to inflamed tissues in rheumatoid arthritis (RA) with greater efficacy and lesser side effects. This study investigates the anti-arthritic potentials of Hesperidin (HP) loaded in gum acacia (GA) stabilized green silver nanoparticles (AgNPs). Synthesized GA-AgNPs were characterized through UV-vis spectrophotometer, zetasizer and atomic force microscope (AFM). The HP and its loaded NPs were tested for RA in Complete Freund's adjuvant (CFA) induced arthritis model. GA-AgNPs were found in nano-range size with negative charge, spherical shape and loaded increased HP amount. HP loaded GA-AgNPs showed minimal arthritic score exhibiting mild to moderate tissue swelling, reduced degenerative changes along with mild articular changes. Histopathological analysis revealed comparatively lesser influx of inflammatory cells and diminished granulamatous inflammation in ankle joints tissues in the presence of HP loaded GA-AgNPs. RT-PCR revealed that HP loaded GA-AgNPs significantly reduced the TLRs mRNA expression. Results validate GA stabilized green AgNPs as stable nano-cargos for targeted delivery of HP for restoring the progression of RA.
29526956 Rhabdomyolysis Induced by Isoniazid in a Patient with Rheumatoid Arthritis and End-stage R 2018 Aug 15 A 76-year-old man complicated with end-stage renal disease had latent tuberculosis infection (LTBI), and isoniazid (INH) 300 mg daily was started to prevent reactivation of LTBI before using biologic agents for rheumatoid arthritis. On the 8th day after administration of INH, he presented with a fever, petechiae, and myalgia. Serological studies revealed elevated myogenic enzymes and creatinine level. Based on the exclusion of other etiologies, rapid improvement with cessation of INH, and the recurrence of the fever and myalgia with re-administration of a reduced dose of INH, we diagnosed him with INH-induced rhabdomyolysis. Physicians should be aware of rhabdomyolysis induced by INH at a therapeutic dose as an infrequent but potentially fatal adverse drug reaction.
29387991 Smoking and susceptibility to rheumatoid arthritis in a Swedish population-based case-cont 2018 Apr Smoking is one of the most established risk factors for rheumatoid arthritis (RA). The aim of this study was to estimate how age at smoking debut, smoking cessation, duration, intensity, and cumulative dose of smoking influence the risk of developing anti-citrullinated peptide antibodies (ACPA) positive and ACPA negative RA. The present report is based on a Swedish population-based, case-control study with incident cases of RA (3655 cases, 5883 matched controls). Using logistic regression models, subjects with different smoking habits were compared regarding risk of developing the two variants of RA, by calculating odds ratios (OR) with 95% confidence intervals (CI). Smoking increased the risk of developing both ACPA positive (OR 1.9, 95% CI 1.7-2.1) and ACPA negative RA (OR 1.3, 95% CI 1.2-1.5). For both subsets of RA, there seemed to be a threshold (~ 2.5 pack years for ACPA positive RA and ~ 5 pack years for ACPA negative RA) below which no association between smoking and RA occurred. A dose-response association was observed between cumulative dose of smoking and risk of developing ACPA positive RA (p value for trend < 0.0001). Duration of smoking had a higher influence on the association between smoking and RA than did intensity of smoking. For both subsets of RA, the detrimental effect of smoking decreased after smoking cessation. Twenty years after smoking cessation, there was no longer an association between smoking and risk of ACPA negative RA, whereas the association between smoking and ACPA positive RA risk persisted and was dependent on the cumulative dose of smoking. Smoking increases the risk of both subsets of RA with a more pronounced influence on the risk of ACPA positive RA. Preventive measures in order to reduce smoking are essential and may result in a decline in RA incidence.
30073771 Comparison of outpatient reimbursement for interstitial cystitis/bladder pain syndrome and 2019 Apr OBJECTIVE: This study compared Taiwanese public health insurance outpatient reimbursements for interstitial cystitis (IC)/bladder pain syndrome (BPS) and rheumatoid arthritis (RA) treatment. METHODS: This observational study used data from the Taiwan Longitudinal Health Insurance Database between 2002 and 2013. Patients with International Classification of Diseases, Ninth Revision, Clinical Modification codes for IC/BPS and RA were selected and matched in a ratio of 1 : 5 based on index year. After adjustment for possible confounders, including age, sex, income, hospital levels of care, and reimbursements for 24 comorbidities, yearly and per-visit pharmacy, non-pharmacy, and total claims were determined. RESULTS: In all, 1438 IC/BPS and 7190 RA patients were identified in the database. IC/BPS patients were significantly younger, and the proportion of females in this group was higher. Income levels were lower in the IC/BPS cohort, but not significantly. There were no significant differences between cohorts in terms of reimbursements for treatment for comorbidities, with the exception of end-stage renal disease, for which reimbursement was higher in the RA cohort. After adjusting for confounders, the regression coefficient for IC/BPS to RA was significantly lower for yearly total pharmacy claims, yearly total claims, per-visit pharmacy claims, and total claims per visit. CONCLUSIONS: Outpatient reimbursement was significantly lower for IC/BPS than for RA treatment, primarily with regard to pharmacy costs. This indicates less medical utilization for IC/BPS, possibly due to poor treatment outcomes and copayment polices. Further advances in the treatment of IC/BPS and health budget reallocation are encouraged.
29452300 Therapeutic strategy for rheumatoid arthritis patients who have achieved remission. 2018 Dec Once remission or low disease activity (LDA) is attained in established rheumatoid arthritis (RA) patients, attempting disease-modifying anti-rheumatic drug (DMARD) tapering appears to be a viable option to avoid patient overtreatment. Potential benefits include reduction in the treatment burden and the risk of adverse events, although the latter has not been demonstrated convincingly. The feasibility of DMARD discontinuation has been tested in numerous studies or trials. All have revealed a high risk of relapse, ranging from 56%-87% at one year. Although remission/LDA can usually be re-established by re-initiation of the previous treatment, the associated risk appears to be more harmful than beneficial. DMARD tapering, either by dose reduction or by injection spacing, is conceptually more acceptable and two superiority randomized controlled trials (RCTs) comparing half-dose etanercept to full-dose continuation demonstrated no significant difference at one year. By contrast, two equivalence RCTs that tested disease activity-guided dose optimization by progressive etanercept and adalimumab injection spacing versus continuation revealed an increased risk of acute flare. Interestingly, one of these also demonstrated the equivalence of increasing injection spacing and standard of care in terms of recurrent flare and overall disease activity over the 18-month follow-up period. The risk of structural damage progression was minimal or null. Reintroduction of DMARD at the previous dose was associated with remission being achieved in the majority of patients who flared. Tapering strategies that adhere to the Tight Control and Treat-to-Target principles appear to be suitable options for RA patients who have achieved sustained remission or low disease activity.
30036638 Anti-polysaccharide and anti-diphtheria protective antibodies after 13-valent pneumococcal 2018 Oct Immunogenicity of 13-valent pneumococcal polysaccharide (PnPS) conjugate vaccine (PCV13) was evaluated in 38 rheumatoid arthritis patients under immunosuppressive treatment and 20 healthy controls (HC). Antibodies to all PnPS and diphtheria-toxin analogue conjugate protein were measured pre- (T0), 1 (T1), 6 (T2), 12 (T3) months post-immunization. Patients and HC had similar response to individual PnPS. Mean antibody levels to all PnPS but one doubled at T1 compared with T0, with T3 persistence for only 8-7/13 PnPS. Baseline antibody levels was inversely associated with the rate of responders at T1 (T1/T0≥2) to 11/13 PnPS. Few subjects reached protective IgG levels against some serotypes frequently isolated in Italian patients with invasive pneumococcal disease. Antibody response was not influenced by therapy, except the one to PS7F, which was reduced by tumor necrosis factor-α-inhibitors. Vaccination increased also anti-diphtheria IgG. Despite this study substantially confirmed the PCV13 immunogenicity in immunocompromised patients, it also revealed some limitations.
29449195 Neutrophil Microvesicles from Healthy Control and Rheumatoid Arthritis Patients Prevent th 2018 Mar Microvesicles (MVs) are emerging as a novel means to enact cell-to-cell communication in inflammation. Here, we aimed to ascertain the ability of neutrophil-derived MVs to modulate target cell behaviour, the focus being the macrophage. MVs were generated in response to tumour necrosis factor-α, from healthy control neutrophils or those from rheumatoid arthritis patients. MVs were used to stimulate human monocyte-derived macrophages in vitro, or administered intra-articularly in the K/BxN mouse model of arthritis. A macrophage/fibroblast-like synoviocyte co-culture system was used to study the effects of vesicles on the crosstalk between these cells. We demonstrate a direct role for phosphatidylserine and annexin-A1 exposed by the MVs to counteract classical activation of the macrophages, and promote the release of transforming growth factor-β, respectively. Classically-activated macrophages exposed to neutrophil MVs no longer activated fibroblast-like synoviocytes in subsequent co-culture settings. Finally, intra-articular administration of neutrophil MVs from rheumatoid arthritis patients in arthritic mice affected the phenotype of joint macrophages. Altogether these data, with the identification of specific MV determinants, open new opportunities to modulate on-going inflammation in the synovia - mainly by affecting macrophage polarization and potentially also fibroblast-like synoviocytes - through the delivery of autologous or heterologous MVs produced from neutrophils.
29664818 Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis Is Associated With Chang 2018 Jun PURPOSE: This study reports the effect of disease-modifying therapies for rheumatoid arthritis (RA) on systolic and diastolic blood pressure (SBP, DBP) over 6 months and incident hypertension over 3 years in a large administrative database. METHODS: We used administrative Veterans Affairs databases to define unique dispensing episodes of methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, tumor necrosis factor inhibitors, and prednisone among patients with RA. Changes in SBP and DBP in the 6 months before disease-modifying antirheumatic drug initiation were compared with changes observed in the 6 months after initiation. The risk of incident hypertension within 3 years (new diagnosis code for hypertension and prescription for antihypertensive) was also assessed. Multivariable models and propensity analyses assessed the impact of confounding by indication. RESULTS: A total of 37,900 treatment courses in 21,216 unique patients contributed data. Overall, there were no changes in SBP or DBP in 6 months prior to disease-modifying antirheumatic drug initiation (all P > 0.62). In contrast, there was a decline in SBP (β = -1.08 [-1.32 to -0.85]; P < 0.0001) and DBP (β = -0.48 [-0.62 to -0.33]; P < 0.0001) over the 6 months following initiation. The greatest decline was observed among methotrexate and hydroxychloroquine users. Methotrexate users were 9% more likely to have optimal blood pressure (BP) after 6 months of treatment. Patients treated with leflunomide had increases in BP and a greater risk of incident hypertension compared with patients treated with methotrexate (hazard ratio, 1.53 [1.21-1.91]; P < 0.001). CONCLUSIONS: Blood pressure may improve with treatment of RA, particularly with methotrexate or hydroxychloroquine. Leflunomide use, in contrast, is associated with increases in BP and a greater risk of incident hypertension.
27698401 Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF 2018 Jan Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case-case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort (N=469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00-1.77, P-value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60-0.94, P=0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB (CHUK, MYD88, NFKBIB, and NLRP3).
29879987 Discriminating phenotypic signatures identified for tocilizumab, adalimumab, and tofacitin 2018 Jun 7 BACKGROUND: Clinical trials have shown combinations of anti-tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals. However, co-treatment with the anti-interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy. Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity. METHODS: TCZ, ADA, and TOF, alone and in combination with MTX, were profiled in BioMAP systems at concentrations close to clinical exposure levels: TCZ, 200 μg/ml; TOF1, 1.1 μM; TOF2, 0.12 µM; MTX, 10 μM. Changes in biomarkers were evaluated by statistical methods to determine whether combinations differed from the individual agents. RESULTS: Although the BioMAP activity profile for TCZ + MTX was not significantly different from that for TCZ alone, profiles for ADA + MTX and TOF1 + MTX or TOF2 + MTX had a greater number of statistically significant different activities (P < 0.01) than did agents profiled individually. CONCLUSIONS: These data support the comparable efficacy of TCZ as monotherapy and as combination therapy and suggest that TOF, like ADA, may be more beneficial in combination with MTX. Taking an orthogonal approach to directly compare monotherapy and combination therapies indicates that MTX contributes to the efficacy of some, but not all, RA therapies and can be affected by factors additional to reduced immunogenicity.