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ID PMID Title PublicationDate abstract
32649623 Vascular consequences of inflammation: a position statement from the ESH Working Group on 2020 Sep : Inflammation is a physiological response to aggression of pathogenic agents aimed at eliminating the aggressor agent and promoting healing. Excessive inflammation, however, may contribute to tissue damage and an alteration of arterial structure and function. Increased arterial stiffness is a well recognized cardiovascular risk factor independent of blood pressure levels and an intermediate endpoint for cardiovascular events. In the present review, we discuss immune-mediated mechanisms by which inflammation can influence arterial physiology and lead to vascular dysfunction such as atherosclerosis and arterial stiffening. We also show that acute inflammation predisposes the vasculature to arterial dysfunction and stiffening, and alteration of endothelial function and that chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis are accompanied by profound arterial dysfunction which is proportional to the severity of inflammation. Current findings suggest that treatment of inflammation by targeted drugs leads to regression of arterial dysfunction. There is hope that these treatments will improve outcomes for patients.
33221805 Hematological Manifestations among Patients with Rheumatic Diseases. 2021 BACKGROUND: Rheumatic diseases have many hematological manifestations. Blood dyscrasias and other hematological abnormalities are sometimes the first sign of rheumatic disease. In addition, novel antirheumatic biological agents may cause cytopenias. SUMMARY: The aim of this review was to discuss cytopenias caused by systemic lupus erythematosus and antirheumatic drugs, Felty's syndrome in rheumatoid arthritis, and autoimmune hemolytic anemia, thrombosis, and thrombotic microangiopathies related to rheumatological conditions such as catastrophic antiphospholipid syndrome and scleroderma renal crisis. Key Message: The differential diagnosis of various hematological disorders should include rheumatic autoimmune diseases among other causes of blood cell and hemostasis abnormalities. It is crucial that hematologists be aware of these presentations so that they are diagnosed and treated in a timely manner.
32627420 A Randomized, Double-Blind Study Comparing Pharmacokinetics and Pharmacodynamics of Propos 2020 Nov ABP 798 is a proposed biosimilar to rituximab reference product (RP), an anti-CD20 monoclonal antibody. Pharmacokinetics (PK), pharmacodynamics (PD), and safety results from the comparative clinical study that evaluated the PK, PD, safety, efficacy, and immunogenicity of ABP 798 versus rituximab RP are presented here. Subjects with moderate to severe rheumatoid arthritis (RA) received 2 doses of ABP 798, United States-sourced RP (rituximab US) or European Union-sourced RP (rituximab EU), each consisting of two 1000-mg infusions 2 weeks apart. For the second dose (week 24), ABP 798- and rituximab EU-treated subjects received the same treatment; rituximab US-treated subjects transitioned to ABP 798. End points included area under the serum concentration-time curve from time 0 extrapolated to infinity and maximum observed serum concentration following the second infusion of the first dose (PK) and percentage of subjects with complete CD19+ cell depletion days 1-33 (PD). Primary analysis established PK similarity between ABP 798 and rituximab RP based on 90% confidence intervals of the adjusted geometric mean ratios being within a prespecified equivalence margin of 0.8 and 1.25. Complete CD19+ B-cell depletion on day 3 among groups confirmed PD similarity. These findings demonstrated PK/PD similarity between ABP 798 and rituximab RP in subjects with moderate to severe RA.
30988125 Patient Preferences for Disease-modifying Antirheumatic Drug Treatment in Rheumatoid Arthr 2020 Feb OBJECTIVE: To summarize patients' preferences for disease-modifying antirheumatic drug (DMARD) therapy in rheumatoid arthritis (RA). METHODS: We conducted a systematic review to identify English-language studies of adult patients with RA that measured patients' preferences for DMARD or health states and treatment outcomes relevant to DMARD decisions. Study quality was assessed using a published quality assessment tool. Data on the importance of treatment attributes and associations with patient characteristics were summarized across studies. RESULTS: From 7951 abstracts, we included 36 studies from a variety of countries. Most studies were in patients with established RA and were rated as medium- (n = 19) or high-quality (n = 12). The methods to elicit preferences varied, with the most common being discrete choice experiment (DCE; n = 13). Despite the heterogeneity of attributes in DCE studies, treatment benefits (disease improvement) were usually more important than both non-serious (6 of 8 studies) and serious adverse events (5 of 8), and route of administration (7 of 9). Among the non-DCE studies, some found that patients placed high importance on treatment benefits, while others (in patients with established RA) found that patients were quite risk averse. Subcutaneous therapy was often but not always preferred over intravenous therapy. Patient preferences were variable and commonly associated with the sociodemographic characteristics. CONCLUSION: Overall, the results showed that many patients place a high value on treatment benefits over other treatment attributes, including serious or minor side effects, cost, or route of administration. The variability in patient preferences highlights the need to individualize treatment choices in RA.
32468892 Impact of immunogenicity on efficacy and tolerability of tumour necrosis factor inhibitors 2020 Sep Objective: SB4, SB2, and SB5 are biosimilars of etanercept (ETN), infliximab (INF), and adalimumab (ADA), respectively. This pooled analysis evaluated the immunogenicity of these treatments across three phase III randomized controlled trials of patients with rheumatoid arthritis (RA). Methods: Patients had to have at least one anti-drug antibody (ADAb) assessment up to the time of the primary endpoint from each study (week 24 in SB4 and SB5 studies; week 30 in SB2 study). The effect of ADAbs on American College of Rheumatology 20% (ACR20) response and the incidences of injection-site reactions (ISRs)/infusion-related reactions (IRRs) were evaluated. Results: The study included 1709 patients. The cumulative incidences of ADAbs were 30.3% in the all-treatments-combined group, 29.1% in the biosimilars combined group, and 31.5% in the reference products combined group. ACR20 response rates were significantly lower in ADAb-positive patients in the all-treatments-combined [odds ratio (95% confidence interval) 1.77 (1.37, 2.27), p < 0.0001], biosimilars combined [2.24 (1.53, 3.30), p < 0.0001], and reference products combined [1.49 (1.06, 2.09), p = 0.0225] groups. ADAb-positive patients also had a higher likelihood of developing ISRs/IRRs in the all-treatments-combined group [0.56 (0.31, 1.01), p = 0.0550], predominantly due to the results observed with SB2 + INF combined rather than with SB4 + ETN or SB5 + ADA combined. Conclusion: In this pooled analysis, ADAbs were associated with reduced efficacy in patients with RA treated with biosimilars (SB4, SB2, and SB5) or their reference products (ETN, INF, and ADA). ADAbs were associated with an increased incidence of ISRs/IRRs in those treated with SB2 + INF. Clinical trial registration numbers: NCT01936181 (SB2 study), NCT01895309 (SB4 study), and NCT02167139 (SB5 study).
32559820 Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the rece 2021 Feb AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance.
31964950 Positive and negative cooperativity of TNF and Interferon-γ in regulating synovial fibrob 2020 Jan 21 Synovial fibroblasts (SF) were reported to produce B cell activating factor (BAFF) in response to stimulation with interferon-γ (IFN-γ) or tumor necrosis factor (TNF). However, the influence of these pro-inflammatory cytokines on other receptors/ligands of the TNF superfamily or associated cytokine receptors in SF has not been investigated yet. Here we show the differential regulation of BAFF (CD257), Fn14 (CD266), TACI (CD267), BAFF-R (CD268), BCMA (CD269), CD40 ligand (CD40L, CD154), IFN-γR (CD119), Leptin receptor (ObR, CD295), VCAM-1 (CD106) and membrane TGF-β in isolated SF and the impact of IFN-γ/TNF co-incubation on proliferation, IL-6 and IL-8 production. In addition, the impact of differentially stimulated SF on B cell survival in co-cultures was assessed. Surface cytokines and cytokine receptors were detected by flow cytometry. Soluble cytokine receptors and cytokines were quantified by ELISA. Proliferation was assessed by cell titer blue. Murine B cell survival in fibroblast/ B cell co-cultures was determined by annexin V/propidium iodide staining and flow cytometry. IFN-γ together with TNF synergistically and significantly increased the cell surface levels of BAFF, Fn14, TACI, BAFF-R, BCMA, CD40L, ObR and IFN-γR in rheumatoid arthritis SF after 72 h incubation. Soluble BAFF was only induced by IFN-γ and inhibited by TNF. Addition of TWEAK had no influence on proliferation or IL-8 production but decreased TNF-induced IL-6 production, whereas APRIL, BAFF and leptin did not modulate TNF or TNF/IFN-γ-induced proliferation or cytokine production. Proliferation was increased by TNF and further enhanced by the addition of IFN-γ. In co-culture experiments, SF stimulated with TNF/IFN but not TNF or IFN-γ alone increased shedding of VCAM-1 and expression of membrane TGFβ, which was associated with reduced survival of murine B cells. IFN-γ and TNF regulate the expression of TNF family member cytokines and associated receptors. Ligation of IFN-γR and Fn14 under pro-inflammatory conditions modulated IL-6/IL-8 production and proliferation. In B cell/SF co-cultures, the combination of TNF/IFN reduced B cell survival possibly via enhanced VCAM-1 shedding and/or increased TGF-β production. IFN-γ is necessary for the observed effects on B cell survival and SF cytokine production and emphasizes its anti-inflammatory role in rheumatoid arthritis.
32061080 Network Pharmacology-Based Prediction and Verification of Qingluo Tongbi Formula to Reduce 2020 Feb 15 BACKGROUND The hepatotoxicity of Tripterygium wilfordii Hook. f. (TWHF) limits its clinic utilization. Qingluo Tongbi formula (QTF) was formulated based on a basic Chinese medicine theory. Previous studies have confirmed the safety and efficacy of QTF in treating rheumatoid arthritis. Therefore, we considered that TWHF could be detoxified based on its reasonable compatibility with QTF. We investigated the detoxicity mechanism of QTF in reducing the liver toxicity of TWHF. MATERIAL AND METHODS We used network pharmacology to determine the relevant metabolism targets of TWHF, focusing on the phase II metabolic enzymes uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1), UGT1A6, and UGT2B7. Based on the molecular mechanisms of these predictions and the results of the network analysis, we designed experiments to verify our hypothesis in vivo. We used western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), double immunofluorescence, and laser confocal microscopy to detect the expression of UGTs. Finally, we used transmission electron microscopy to observe the endoplasmic reticulum structure. RESULTS The results confirmed that QTF reversed the TWHF-induced reduction of UGT content in liver microsomes, upregulated UGT1A1 and UGT1A6 but not UGT2B7 in the liver tissue. UGT2B7 expression in the liver and liver microsomes was inconsistent. QTF upregulated the expression of UGT2B7 in the endoplasmic reticulum, and QTF upregulated UGT2B7 expression levels in the endoplasmic reticulum compared with TWHF, which reduced liver toxicity. Structural changes were observed in the endoplasmic reticulum. CONCLUSIONS The Chinese traditional medicine compound QTF can achieve the effect of detoxification by upregulating the expression of UGT2B7 in the endoplasmic reticulum.
33105665 Vitamin D Binding Protein (VDBP) and Its Gene Polymorphisms-The Risk of Malignant Tumors a 2020 Oct 22 Vitamin D is an important component of the endocrine system that controls calcium homeostasis and bone mineralization. Because of the very short half-life of free serum vitamin D it is stabilized and transported to target tissues by being bound to the vitamin D binding protein (VDBP). The most common polymorphisms: rs4588 and rs7041 in the vitamin D binding protein gene may correlate with differences in vitamin D status in the serum. This review presents data that relate to the presence of genetic variants in the VDBP gene in correlation with certain diseases, mostly concerning cancers (breast, prostate, pancreatic, lung, colorectal, basal cell carcinoma cancer and cutaneous melanoma) or other related diseases (thyroid autoimmunity disorders, obesity, diabetes mellitus, bone metabolism, rheumatoid arthritis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, tuberculosis and coronary artery diseases).
31863865 Development and validation of a Level A in-vitro in-vivo correlation for tofacitinib modif 2020 Apr 30 PURPOSE: To determine if a validated Level A in-vitro in-vivo correlation (IVIVC) could be achieved with the extrudable core system (ECS) osmotic tablet platform. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. METHODS: Fast-, medium-, and slow-release modified-release formulations of 11 mg tofacitinib ECS tablets, and one formulation of 22 mg tofacitinib ECS tablet, were manufactured. In vitro dissolution of the tofacitinib ECS tablets was performed using USP Apparatus 2 (paddles) and in vivo pharmacokinetic (PK) data were obtained from a Phase 1 study in healthy volunteers. A 5 mg immediate-release formulation tablet was included to support deconvolution of the tofacitinib ECS PK tablet data to obtain the in vivo absorption profiles. A linear, piecewise correlation and a simple linear correlation were used to build and validate two IVIVC models. RESULTS: The prediction errors (PEs) for the linear, piecewise correlation met the Food and Drug Administration's criteria for establishing a Level A IVIVC, with a maximum absolute individual internal PE of 4.6%, a maximum absolute average internal PE of 3.9%, and a maximum absolute external PE of 8.4% obtained. CONCLUSIONS: This study demonstrates that the tofacitinib ECS osmotic tablet platform can achieve a Level A IVIVC, similar to other osmotic delivery systems.
31600392 Outcomes of acute cardiovascular events in rheumatoid arthritis and systemic lupus erythem 2020 Jun 1 OBJECTIVES: Patients with RA and SLE have an excess cardiovascular risk. We aimed to evaluate outcomes of acute cardiovascular events in these patients. METHODS: Using a nationwide database of Taiwan, we identified adult patients who experienced first-time acute myocardial infarction (n = 191 008), intracranial haemorrhage (n = 169 923) and ischaemic stroke (n = 486 890) over a 13-year period. Odds ratios (ORs) of in-hospital mortality and hazard ratios (HRs) of overall mortality and adverse outcomes during long-term follow-up in relation to RA and SLE were estimated with adjustment for potential confounders. RESULTS: In each cohort, 748, 410 and 1419 patients had established RA; 256, 292 and 622 patients had SLE. Among acute myocardial infarction patients, RA and SLE were associated with in-hospital mortality (RA: OR 1.61, 95% CI 1.33, 1.95; SLE: OR 2.31, 95% CI 1.62, 3.28) and overall mortality. Additionally, RA (HR 1.28, 95% CI 1.18, 1.38) and SLE (HR 1.46, 95% CI 1.27, 1.69) increased the risk of major adverse cardiac events. After intracranial haemorrhage, patients with RA and SLE had higher risks of in-hospital mortality (RA: OR 1.61, 95% CI 1.26, 2.06; SLE: OR 3.00, 95% CI 2.33, 3.86) and overall mortality. After ischaemic stroke, RA and SLE increased in-hospital mortality (RA: OR 1.45, 95% CI 1.15, 1.83; SLE: OR 2.18, 95% CI 1.57, 3.02), overall mortality and recurrent cerebrovascular events (RA: HR 1.10, 95% CI 1.002, 1.21; SLE: HR 1.31, 95% CI 1.14, 1.51), among which ischaemic stroke (HR 1.39, 95% CI 1.19, 1.62) was more likely to recur in SLE patients. CONCLUSION: Both RA and SLE are consistently associated with adverse outcomes following acute cardiovascular events, highlighting the necessity of integrated care for affected patients.
33021133 Updates on management strategies of hepatitis B virus reactivation in patients with resolv 2021 Jul With the introduction of methotrexate, biological disease-modifying antirheumatic drugs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), the disease activity of patients with rheumatoid arthritis has been dramatically ameliorated. However, these drugs have strong immunosuppressive effects and can cause reactivation of hepatitis B virus (HBV) in patients with resolved HBV infection. Corticosteroids or immunosuppressants used for other connective tissue diseases or vasculitis also carry a risk of inducing reactivation of HBV. Therefore, every rheumatologist should know how to detect the resolved infection of HBV in patients with rheumatic diseases receiving immunosuppressive therapy and how to monitor it when resolved infection is revealed. Of note, the cut-off index was changed from 2.1 log copies/ml to 20 IU/ml (1.3 Log IU/ml) in 2017. Rheumatologists should start nucleic acid analog administration at reactivation of HBV while performing ongoing immunosuppressive therapy in order to prevent severe or fulminant hepatitis. A low titer of HBs antibody (Ab) or lack of HBs Ab is a risk factor of reactivation of HBV. However, the reactivation of HBV cannot be prevented by HBs Ab titers at baseline or changes overtime. Rheumatologists should recognize that every immunosuppressive therapy, regardless of the mode of action, has a potential risk of reactivation. To facilitate proper management of patients with HBV infection, collaboration between rheumatologists and hepatologists is strongly encouraged. Patients' education, systems for checking electronic medical charts, and multidisciplinary efforts are considered important for detecting HBV reactivation.
31969328 EULAR recommendations for the management of rheumatoid arthritis with synthetic and biolog 2020 Jun OBJECTIVES: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. METHODS: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. RESULTS: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. CONCLUSIONS: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.
32457323 A 3'UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates th 2020 May 26 Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, involved in Alzheimer's disease pathogenesis. Anti-TNF-α therapeutic approaches currently used in autoimmune diseases have been proposed as a therapeutic strategy in AD. We have previously examined the role of TNF-α and anti-TNF-α drugs in AD, using 5XFAD mice, and we have found a significant role for peripheral TNF-α in brain inflammation. Here we investigated the role of mouse TNF-α on the AD-like phenotype of 5XFAD mice using a knock-in mouse with deletion of the 3'UTR of the endogenous TNF-α (TNF(ΔARE/+)) that develops rheumatoid arthritis and Crohn's disease. 5XFAD/TNF(ΔARE/+) mice showed significantly decreased amyloid deposition. Interestingly, microglia but not astrocytes were activated in 5XFAD/ TNF(ΔARE/+) brains. This microglial activation was associated with increased infiltrating peripheral leukocytes and perivascular macrophages and synaptic degeneration. APP levels and APP processing enzymes involved in Aβ production remained unchanged, suggesting that the reduced amyloid burden can be attributed to the increased microglial and perivascular macrophage activation caused by TNF-α. Peripheral TNF-α levels were increased while brain TNF-α remained the same. These data provide further evidence for peripheral TNF-α as a mediator of inflammation between the periphery and the brain.
31967309 CP-25 inhibits PGE2-induced angiogenesis by down-regulating EP4/AC/cAMP/PKA-mediated GRK2 2020 Feb 14 G protein-coupled receptor kinase 2 (GRK2), a type of cytosolic enzyme, transiently translocates to the plasma membrane upon G protein-coupled receptors (GPCRs) activation, and it also binds to extracellular signal-regulated kinase (ERK) to inhibit the activation of ERK. GRK2 deficiency in endothelial cells (ECs) leads to increased pro-inflammatory signaling and promotes recruitment of leukocytes to activated ECs. However, the role of GRK2 in regulating angiogenesis remains unclear. Here, we show that GRK2 is a novel regulatory molecule on migration and tube formation of ECs, vessel sprouting ex vivo and angiogenesis in vivo. We identify that EP4/AC/cAMP/protein kinase A (PKA)-mediated GRK2 translocation to cells membrane decreases the binding of GRK2 and ERK1/2 to inhibit ERK1/2 activation, which promotes prostaglandin E2 (PGE2)-induced angiogenesis. GRK2 small interfering RNA (siRNA) inhibits the increase in PGE2-induced HUVECs migration and tube formation. In vivo, PGE2 increases ECs sprouting from normal murine aortic segments and angiogenesis in mice, but not from GRK2-deficient ones, on Matrigel. Further research found that Lys220 and Ser685 of GRK2 play an important role in angiogenesis by regulating GRK2 translocation. Paeoniflorin-6'-O-benzene sulfonate (CP-25), as a novel ester derivative of paeoniflorin (pae), has therapeutic potential for the treatment of adjuvant arthritis (AA) and collagen-induced arthritis (CIA), but the underlying mechanism of CP-25 on angiogenesis has not been elucidated. In our study, CP-25 inhibits the migration and tube formation of HUVECs, and angiogenesis in mice by down-regulating GRK2 translocation activation without affecting GRK2 total expression. Taken together, the present results revealed that CP-25 down-regulates EP4/AC/cAMP/PKA-mediated GRK2 translocation, restoring the inhibition of GRK2 for ERK1/2, thereby inhibiting PGE2-stimulated angiogenesis.
31915099 Incidence and temporal trends of co-occurring personality disorder diagnoses in immune-med 2020 Jan 9 AIMS: Although immune-mediated inflammatory diseases (IMID) are associated with multiple mental health conditions, there is a paucity of literature assessing personality disorders (PDs) in these populations. We aimed to estimate and compare the incidence of any PD in IMID and matched cohorts over time, and identify sociodemographic characteristics associated with the incidence of PD. METHODS: We used population-based administrative data from Manitoba, Canada to identify persons with incident inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) using validated case definitions. Unaffected controls were matched 5:1 on sex, age and region of residence. PDs were identified using hospitalisation or physician claims. We used unadjusted and covariate-adjusted negative binomial regression to compare the incidence of PDs between the IMID and matched cohorts. RESULTS: We identified 19 572 incident cases of IMID (IBD n = 6,119, MS n = 3,514, RA n = 10 206) and 97 727 matches overall. After covariate adjustment, the IMID cohort had an increased incidence of PDs (incidence rate ratio [IRR] 1.72; 95%CI: 1.47-2.01) as compared to the matched cohort, which remained consistent over time. The incidence of PDs was similarly elevated in IBD (IRR 2.19; 95%CI: 1.69-2.84), MS (IRR 1.79; 95%CI: 1.29-2.50) and RA (IRR 1.61; 95%CI: 1.29-1.99). Lower socioeconomic status and urban residence were associated with an increased incidence of PDs, whereas mid to older adulthood (age 45-64) was associated with overall decreased incidence. In a restricted sample with 5 years of data before and after IMID diagnosis, the incidence of PDs was also elevated before IMID diagnosis among all IMID groups relative to matched controls. CONCLUSIONS: IMID are associated with an increased incidence of PDs both before and after an IMID diagnosis. These results support the relevance of shared risk factors in the co-occurrence of PDs and IMID conditions.
32471903 Characteristics associated with hospitalisation for COVID-19 in people with rheumatic dise 2020 Jul OBJECTIVES: COVID-19 outcomes in people with rheumatic diseases remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 hospitalisation status in people with rheumatic disease. METHODS: Case series of individuals with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry: 24 March 2020 to 20 April 2020. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analysed. RESULTS: A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed. CONCLUSIONS: We found that glucocorticoid exposure of ≥10 mg/day is associated with a higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with rheumatic disease. Neither exposure to DMARDs nor NSAIDs were associated with increased odds of hospitalisation.
33261314 Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Sc 2020 Dec 10 Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.
32508063 Tocilizumab Increases Body Weight and Serum Adipokine Levels in Patients with Rheumatoid A 2020 Jun 8 BACKGROUND: Causes of weight change after tocilizumab treatment are unclear. We aimed to investigate the effects of tocilizumab treatment on body weight and serum adipokine levels in patients with rheumatoid arthritis (RA). METHODS: In this retrospective cohort study, we evaluated weight changes in patients with RA who received methotrexate (Cohort I) or tocilizumab with methotrexate (Cohorts II and III) for 24 weeks. Adipokine concentrations at baseline and 24 weeks were analyzed in Cohorts I and III. Cohorts I and II received tocilizumab therapy for an additional 48 weeks, during which weight changes were monitored (24-72 weeks). RESULTS: No significant weight change occurred after 24 weeks of methotrexate treatment (mean difference, -0.2 kg; P = 0.630), but was observed after 24 weeks of tocilizumab treatment (mean difference, +0.9 kg; P = 0.010). Weight changed regardless of the treatment response in both treatment groups. The leptin-adiponectin ratio (P = 0.015) and levels of adiponectin (P < 0.001), leptin (P < 0.001), and resistin (P = 0.003) increased significantly after 24 weeks of tocilizumab, but not methotrexate treatment. After 24, 48 and 72 weeks of tocilizumab treatment in Cohort II, mean (95% confidence interval [CI]) weight changes from baseline were +0.7 (0.0-1.4), +1.2 (0.4-2.0) and +1.1 (0.2-2.0) kg, respectively, and mean (95% CI) percent weight changes from baseline were +1.3% (0.1%-2.6%), +2.2% (0.7%-3.6%), and +2.0% (0.4%-3.7%) at 24, 48, and 72 weeks, respectively. CONCLUSION: Weight and the leptin-adiponectin ratio increased after tocilizumab treatment. Given that cardiovascular (CV) risk factors may deteriorate in patients with RA who receive tocilizumab, further studies are required to determine the effects of weight gain on CV outcomes in these patients.
31448433 Preferential Inhibition of JAK1 Relative to JAK3 by Upadacitinib: Exposure-Response Analys 2020 Feb Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed for treatment of rheumatoid arthritis. This study characterizes the relationships between upadacitinib exposure and interleukin (IL)-6-induced signal transducer and activator of transcription proteins 3 (STAT3) phosphorylation (pSTAT3) and IL-7-induced STAT5 phosphorylation (pSTAT5) in the ex vivo setting as measures for JAK1 and JAK1/JAK3 inhibition, respectively, with comparison to tofacitinib. Drug plasma concentrations and ex vivo IL-6-induced pSTAT3 and IL-7-induced pSTAT5 in blood from subjects evaluated in 2 phase 1 studies who received immediate-release 1 mg to 48 mg upadacitinib, 5 mg twice daily (BID) tofacitinib, or placebo were determined. Exposure-response models were developed, and the effects of different upadacitinib doses on ex vivo biomarker responses were simulated and compared to tofacitinib. Upadacitinib (and tofacitinib) reversibly inhibited IL-6-induced pSTAT3 and IL-7-induced pSTAT5 in a concentration-dependent manner. Model-estimated values of 50% of the maximum effect were 60.7 nM for upadacitinib and 119 nM for tofacitinib for IL-6-induced pSTAT3 inhibition, and 125 nM for upadacitinib and 79.1 nM for tofacitinib for IL-7-induced pSTAT5 inhibition. Tofacitinib 5 mg BID is estimated to have a similar magnitude of effect on IL-6-induced pSTAT3 to ∼3 mg BID of upadacitinib (immediate-release formulation), whereas a 4-fold higher dose of upadacitinib (∼12 mg BID), is estimated to show a similar magnitude of inhibition on IL-7-induced pSTAT5 as tofacitinb 5 mg BID. This study confirms that in humans, upadacitinib has greater selectivity for JAK1 vs JAK3 relative to the rheumatoid arthritis approved dose of tofacitinib, and results from these analyses informed the selection of upadacitinib IR doses evaluated in phase 2.