Moderate Rheumatoid Arthritis Research Articles

P108 Filgotinib for Rheumatoid Arthritis: an observational cohort to assess clinical effectiveness in a single centre

Abstract Background/Aims Filgotinib, a Janus-kinase (JAK) 1 preferential inhibitor, was approved for use in the UK in moderate or severe rheumatoid arthritis (RA) in 2021, as monotherapy or in combination with Methotrexate. Evidence of real-world effectiveness is currently limited. Methods Patients prescribed Filgotinib between December 2021 and August 2022 in NHS Lothian were identified from pharmacy registration data. All underwent clinical efficacy assessment at three months. Electronic patient records (EPR) were reviewed to record baseline data including previous and current treatments. Duration of Filgotinib treatment was recorded, and discontinuation reason if applicable. DAS-28 scores within six months prior to starting Filgotinib were recorded, along with available subsequent scores. Pre-existing interstitial lung disease (ILD), venous thromboembolism (VTE), major adverse cardiovascular events (MACE) and malignancy were recorded, along with incident events during treatment. Results 145 patients were prescribed Filgotinib; 106 (73.1%) females and 39 (26.9%) males, with median age 64 years. Median treatment duration was 447 days. 35 (24.1%) were treated with the reduced 100mg dose. 81 (55.9%) received conventional disease-modifying anti-rheumatic drugs (DMARDs) alongside Filgotinib. 41 (28.3%) patients discontinued treatment: 10 (6.9%) due to loss of effect; 16 (11.0%) due to lack of efficacy; six (4.1%) experienced side effects leading to cessation; five (3.4%) stopped for alternative reasons; one (0.7%) experienced a severe allergic drug reaction; three (2.1%) developed lung cancer and treatment was stopped in each case. 12 (8.3%) patients had ILD prior to treatment. 10 (6.9%) had prior major cardiovascular events, eight (5.5%) had previously treated malignancy, and six (4.1%) had previous VTE. During treatment, 1 (0.7%) patient developed ILD and two (1.4%) developed VTE. There were three (2.1%) new malignancies, all lung cancer. No new MACE occurred. 120 (82.8%) patients were previously treated with biologic or targeted synthetic DMARDs. 59 (40.7%) had failed multiple biologic DMARDs of different classes. 19 (13.1%) switched to Filgotinib from another JAK inhibitor. Pre-treatment DAS-28 scores were recorded in 55 (37.9%) patients with mean 5.1, and during treatment in 44 patients (30.3%) with mean 3.5. 17 (11.7%) patients had DAS-28 recorded both before and during treatment, with pre-treatment mean 5.0 and subsequent mean 2.9. Of these, 10 (58.8%) were classified as a good response by EULAR disease activity criteria, and four (23.5%) as a moderate response. Three (17.6%) were non-responders. Conclusion Our cohort includes 40.7% difficult-to-treat RA. Drug survival as a clinical efficacy surrogate was 71.7% at median duration 447 days, demonstrating patient acceptability and clinical effectiveness. Our service is poor at DAS-28 recording in the EPR, which may partly reflect imaging use at response assessment. Since this cohort was established, the European Medicines Agency has issued guidance advising caution using JAK inhibitors in high-risk groups to minimise the chance of serious side effects. Disclosure C.D. Box: None. S. Ramsay: None. N.D. McKay: Other; N.D.M. has received funding for conference registrations from Abbvie, UCB and Novartis, fees for lecturing from Gilead, and has taken part in advisory board meetings for UCB and Gilead.

Focus on Filgotinib in Rheumatoid Arthritis: A Trial-Based Review.

Janus kinases (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is involved in pathophysiologic cascade of a notable number of rheumatic diseases. The development of JAK inhibitors has expanded treatment choices in rheumatoid arthritis (RA) with a sustained class-effect efficacy. Filgotinib is a novel selective inhibitor of JAK1 isoform licensed for use in RA and ulcerative colitis. In this review we aim to present an analysis of filgotinib's efficacy and drug-specific safety warnings. Patients with RA with or without concomitant conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) (naïve or experienced) and those who have failed biologic Disease-Modifying Antirheumatic Drugs (bDMARDs) were examined in randomised clinical trials. Filgotinib was also tested against placebo, methotrexate, or adalimumab. Long-term extension trials provide insights for up to four years of continuous filgotinib administration. Beneficial effects are depicted in both disease activity parameters and quality of life indexes in moderate or severe RA with a longitudinal efficacy. In head-to-head comparison with adalimumab, filgotinib 200 mg was non-inferior. Adverse effects alerts are marked by the elevated risk of infectious adverse effects with the exception of herpes zoster infection, which has a low incidence.

Real-World Treatment and Care Patterns in Patients With Rheumatoid Arthritis Initiating First-Line Tumor Necrosis Factor Inhibitor Therapy in the United States.

Treatment guidelines for rheumatoid arthritis (RA) recommend targeting low disease activity or remission and switching therapies for patients not reaching those targets. We evaluated real-world use of disease activity measures, treatment discontinuation, and switching patterns among patients with RA initiating a first-line tumor necrosis factor inhibitor (TNFi). Data from adult patients with RA initiating a first-line TNFi were collected from the American Rheumatology Network (January 2014-August 2021). The proportion of patients with recorded disease activity scores (Clinical Disease Activity Index [CDAI] or Routine Assessment of Patient Index Data 3 [RAPID3]) at TNFi initiation was assessed. Among patients with moderate or severe RA at TNFi initiation, reasons for discontinuation and subsequent advanced therapy were evaluated. Among TNFi initiators (n=15,182), 44.8% recorded a CDAI/RAPID3 score at treatment initiation; of those who did not, 47.0% had recorded a tender and/or swollen joint count or pain score. Among patients with moderate or severe RA (n=1,651), 52% discontinued their initial TNFi during follow-up, of which 15%, 46%, 28%, and 12% initiated the same TNFi, another TNFi, a non-TNFi biologic, or a Janus kinase inhibitor, respectively. The proportion of patients restarting the same TNFi or initiating another TNFi varied according to TNFi discontinuation reason. In clinical practice, over half of patients with RA initiating a first-line TNFi did not have baseline disease activity assessments. Many patients cycled through TNFi despite citing lack of efficacy as the most common reason for discontinuation. Consistent, objective monitoring of treatment response and timely switch to effective therapy is needed in patients with RA.

Cost-effectiveness analysis of upadacitinib as a treatment option for patients with rheumatoid arthritis in the Kingdom of Saudi Arabia

Aim To evaluate cost-effectiveness of upadacitinib (targeted synthetic-disease modifying anti-rheumatic drug [ts-DMARD]) as first-line (1 L) treatment versus current treatment among patients with rheumatoid arthritis (RA) in the Kingdom of Saudi Arabia (KSA), who had an inadequate response to prior conventional-synthetic (csDMARDs) and/or biologic-DMARDs (bDMARDs). Methods This Excel-based model included patients with moderate (Disease Activity Score [DAS28]: >3.2 to ≤5.1) or severe RA (DAS28 > 5.1). Cost-effectiveness of current treatment (1 L: adalimumab-originator/biosimilar; second-line (2 L): other bDMARDs/tofacitinib) was compared against a new treatment involving two scenarios (1 L: upadacitinib, 2 L: adalimumab-biosimilar [scenario-1]/adalimumab-originator [scenario-2]) for a 10-year time-horizon from societal perspective. Model outcomes included direct and indirect costs, quality-adjusted life-years (QALYs), hospitalization days, number of orthopedic surgeries, and incremental cost-utility ratio (ICUR) per QALY. Results With the current pathway, estimated total societal costs for 100 RA patients over 10-year period were Saudi Riyal (SAR) 50,450,354 (United States dollars [USD] 13,453,428) (moderate RA) and SAR50,013,945 (USD13,337,052) (severe RA). New pathway (scenario-1) showed that in patients with moderate-to-severe RA, upadacitinib led to higher QALY gain (+8.99 and +15.63) at lower societal cost (cost difference: -SAR2,023,522 [-USD539,606] and -SAR3,373,029 [-USD899,474], respectively). Thus, as 1 L, upadacitinib projects “dominant” ICUR per QALY over current pathway. Moreover, in alternate pathway (scenario-2), upadacitinib also projects “dominant” ICUR per QALY for patient with severe RA (QALY gain: +15.63; cost difference: -SAR 164,536 [-USD43,876]). However, moderate RA was associated with additional cost of SAR1,255,696 (USD334,852) for improved QALY (+8.99) over current pathway (ICUR per QALY: SAR139,742 [USD37,264]). Both scenarios resulted in reduced hospitalization days (scenario-1: −14.83 days; scenario-2: −11.41 days) and number of orthopedic surgeries (scenario-1: −8.36; scenario-2: −6.54) for moderate-to-severe RA over the current treatment pathway. Conclusion Upadacitinib as 1 L treatment in moderate-to-severe RA can considerably reduce healthcare resource burden in KSA, majorly due to reduced drug administration/monitoring/hospitalization/surgical and indirect costs.

Ultrasound imaging of the dorsalis pedis artery as an early indicator of the precursory changes for rheumatoid vasculitis: A case series.

Clinical verification of rheumatoid vasculitis (RV) persists as a mid-to-late diagnosis with medical imaging or biopsy. Early and subclinical presentations of RV, in particular, can remain underdiagnosed in the absence of adequate diagnostic testing. In this study, the research demonstrated the precursory changes for RV in patients with rheumatoid arthritis (RA) using non-invasive ultrasound imaging of a peripheral vessel. Six participants were recruited: three participants with (RA) and three age- and gender-matched healthy controls. All participants completed a Foot Health Survey Questionnaire (FHSQ), and participants with RA completed a Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5). Bilateral B-mode and Doppler ultrasound of the dorsalis pedis artery (DPA) was performed. The degree of inflammation, lumen and artery diameters, lumen diameter-to-artery diameter ratio and peak systolic velocity in the proximal DPA were compared between the two groups. The mean RADAI-5 score (5.4 ± 0.8 out of 10) indicated moderate disease activity amongst participants with RA. Inflammation was observed in the DPA wall in all participants with RA, compared to no inflammation observed in the control group (Friedmans two-way analysis: χ2 = 15.733, P = 0.003). Differences between groups for inflammation, lumen diameter and lumen diameter-to-artery diameter ratio were found (P < 0.034), without differences for artery diameter and peak systolic velocity (P > 0.605). DPA wall inflammation did not correlate with FHSQ scores (r = -0.770, P = 0.073). Despite moderate RA disease activity, this is the first study to demonstrate the use of ultrasound to observe inflammation in small vessel disease. Our findings suggest ultrasound imaging may be a viable screening tool to demonstrate arterial wall inflammation, indicating the precursory changes of RV.

Sema4D as a biomarker for Predicting rheumatoid arthritis disease activity.

The semaphorins are membrane or secreted proteins first identified in neural development. Semaphorin 4D (Sema4D) is the first family member found to have immune properties. We evaluated the potential of Sema4D as a marker for rheumatoid arthritis (RA) disease activity, singly and in combination with other known biomarkers including rheumatoid factor (RF) and C-reactive protein (CRP). Three hundred and eleven RA patients were enrolled. The patients were divided into three groups based on their disease activity in 28 joints (DAS28): mild, moderate, and severe. The healthy group included 40 healthy individuals. SerumSema4D was measured by quantitative ELISA and the specificity and sensitivity of biomarkers were evaluated by generating a receiver operating characteristic (ROC) curve to analyze their diagnostic accuracy. Serum Sema4D levels in the moderate and severe RA groups were elevated significantly above those of the controls (P < 0.01), while levels in the mild RA and control groups did not differ significantly (P > 0.05). The Sema4D cutoff threshold was 15.7ng/ml when the DAS28 was applied as a reference. Compared to the erythrocyte sedimentation rate (ESR and CRP, Sema4D had the highest specificity (96.8%) and area under the curve (0.80) for diagnosing RA activity. The highest specificity (100%) for the biomarker combinations was obtained when Sema4D was combined with CRP and anti-CCP, the combination of the Sema4D combined with ESR and anti-CCP had the highest sensitivity (99.35%). According to this result, a new model for jointly calculating RA activity of Sema4D,anti-CCP and CRP was constructed. Meanwhile another model is established by using the method of multivariate analysis.Model comparison results showed the the multiple regression algorithm method fitted the patients' disease activity better. The serum Sema 4D level effectively reflects moderate to severe RA activity. Sema4D levels can be used together with conventional RA biomarkers to increase the diagnostic power of RA activity. The multiple regression algorithm method is promising in disease activity calculation.

Psychometric Properties of Frailty Instruments in Adults With Rheumatoid Arthritis: A Systematic Review.

Examine psychometric properties of frailty instruments used in adults with rheumatoid arthritis (RA) to inform selection of frailty instruments for clinical and research use. A systematic review was registered in PROSPERO. Studies measuring frailty in adults with RA published before May 25, 2022, were searched in six electronic databases. Level of evidence of psychometric properties were synthesized and graded for each frailty instrument using Consensus-Based Standards for the Selection of Health Measurement Instruments methodology. There were 22 articles included in the review, and psychometric properties of 16 frailty instruments were examined. RA cohorts were predominantly female with moderate RA disease activity, mean age was 60.1 years, and frailty prevalence ranged widely from 10% to 85%. Construct validity was the only psychometric property routinely examined for frailty instruments in RA, and nearly all (14/16) performed favorably in this domain. Frailty correlated most frequently with older age, higher RA disease activity, and worse physical function. Internal consistency, measurement error, and content validity were examined infrequently. Reliability and responsiveness data were not reported. Six frailty instruments were rated highest in adults with RA: three adaptations of Fried's Criteria, 32-Item and 45-Item Frailty Indexes, and the Comprehensive Rheumatologic Assessment of Frailty. Six frailty instruments possessed the highest-rated psychometric properties in RA. These instruments demonstrated construct validity of frailty with important outcomes in RA. Frailty assessment shows promise to inform risk stratification in RA, but studies are needed to evaluate reliability, responsiveness, and validity to support accuracy of frailty measurement in adults with RA who may have disease-related features that differentially impact outcomes.

Investigation of the effect of oral selenium on the reduction of clinical symptoms and joint pain in patients with rheumatoid arthritis in the Iranian population.

Rheumatoid arthritis (RA) is a common inflammatory joint disease. Since inflammation and nitrosative stress play an important role in the pathogenesis of RA, drugs that have antioxidant and anti-inflammatory effects can be effective as adjuvant treatment in these patients. Selenium is a compound that has been shown in recent studies to have anti-inflammatory and antioxidant effects. Therefore, the aim of this study was to investigate the effect of oral selenium on the reduction of clinical symptoms and joint pain in patients with RA. Fifty one patients with moderate and severe RA were randomly divided into selenium and placebo groups. The first group of patients received century Selenium drug at a dose of 200 micrograms twice a day for 12 weeks along with standard RA interventions and treatments, and the second group received standard treatments of RA along with a placebo. Clinical symptoms were evaluated with standard indicators to evaluate disease activity before and after the intervention in the 12th week. Examination of clinical symptoms at the end of the study showed that in the selenium group and after 12 weeks, a reduction in clinical symptoms and joint pain were observed, which was statistically significant compared to before the study began. Meanwhile, no significant changes were observed in the patients of the placebo group in terms of reducing symptoms and joint pains. A dose of 200 micrograms of oral selenium twice a day for 12 weeks can significantly reduce clinical symptoms and joint pain in patients with RA. This article is protected by copyright. All rights reserved.

Peculiarities of immunological manifestations in patients with rheumatoid arthritis in the presence of chronic infection with &lt;i&gt;Helicobacter pylori&lt;/i&gt; variant encoding cytotoxin-associated gene A

The study aimed to evaluate the association between cyclic citrullinated peptide antibody seropositivity and chronic Helicobacter pylori (H. pylori) infection in patients with rheumatoid arthritis (RA). We examined 92 women with moderate RA activity. Serum antibodies to cyclic citrullinated peptide (antiCCP), antibodies to H. pylori (anti-H. pylori-IgG), and total antibodies to H. pylori CagA antigen (antiCagA) were determined by enzyme immunoassay; the presence of anti-CagA-IgG positivity was confirmed by immunoblot. 68.5% of RA patients were positive for anti-H. pylori-IgG, and 44.4% of patients in this group were positive for anti-CagA-IgG. All the study participants were divided into three groups: I – H. pylori seronegative (H. pylori- ); II – H. pylori positive, CagA negative (H. pylori+/CagA- ); III – H. pylori positive and CagA positive (CagA+). The anti-CCP values in RA patients with CagA+ (group III) were significantly higher not only in comparison with patients seronegative for H. pylori (p &lt; 0.001), but also in comparison with patients from group II (H. pylori+/CagA- ) (p = 0.041). A study of the influence of the RA activity, the presence of RF and H. pylori on anti-CCP content demonstrated a small proportion of anti-CCP variability (R2 = 0.09), with a high contribution of H. pylori (beta = 0.25). The addition of the CagA(+) index (beta = 0.503) to the presented model allowed us to describe the variability of anti-CCP in almost 30% of cases (R2 = 0.29). In the group of RA patients with anti-CCP values exceeding the established threshold value of 20 U/mL (normal index), there was an increase in the proportion of patients infected with H. pylori (p &lt; 0.001), but not the proportion of CagA-positive patients (p = 0.06). When the threshold level was increased to 60 U/mL (three times the upper limit of normal) in patients with significantly high anti-CCP, the association with positivity for CagA became significant (p = 0.005). CagA is highly immunogenic and is capable of inducing an inflammatory response in the host that goes beyond the effect of H. pylori itself. Additional experimental studies are needed to investigate possible clinical and laboratory associations that may influence the treatment tactics of CagA+ patients with RA who are seropositive for anti-citrullinated antibodies, as well as to evaluate the possible effects of therapeutic intervention aimed at the eradication of H. pylori in this group.

Biologics initiation in moderate versus severe rheumatoid arthritis: real-world experience from a Canadian registry.

To evaluate the treat-to-target experience, and quality of life measures of moderate and severe rheumatoid arthritis (RA) patients initiating a biologic in a real-world setting of a publicly funded payer system. Biologic naive RA patients who had initiated their first biologic while enrolled in the Ontario Best Practices Research Initiative registry from 2008 to 2020 were selected if they had moderate (DAS28 >3.2 to ≤5.1) or severe (DAS28 >5.1) RA. Remission, LDA, DAS28, HAQ-DI, fatigue, sleep, drug persistence and characteristics associated with remission were assessed at 12 months post biologic initiation. Overall, 838 patients initiated their first biologic, 264 had moderate RA and 219 had severe RA. After 12 months, 44% moderate RA vs. 21% severe RA achieved remission (p<0.0001), and 59% moderate RA vs. 35% severe RA reached LDA (p<0.0001). Mean change (SD) from baseline in DAS28 was 2.2 (1.5) in severe RA vs. 1.4 (1.3) in moderate RA (p<0.0001), in fatigue score was 1.11 (3.2) in severe RA vs. 0.98 (3.2) in moderate RA (p<0.0001). Moderate disease at a biologic initiation was positively associated with remission (p=0.0016). Female gender (p=0.0170), and a higher HAQ-DI score at baseline (p=0.0042) were negatively associated with remission. Biologic persistence was 77% for moderate, and 73% for severe (p=0.2444). Severe RA patients had higher mean score improvements in DAS28, sleep and fatigue. Moderate RA was more likely to reach remission or LDA. Both groups had similar biologic persistence at 12 months. These findings highlight the importance of the treat-to-target approach and its potential underutilisation in the real-world setting.

P127 Baricitinib Efficacy in Moderate Rheumatoid Arthritis - A Post-hoc Analysis from two Phase III Trials

Abstract Background/Aims Baricitinib, an oral selective JAK 1/2 inhibitor, is approved for treating adults with moderate-to-severe active rheumatoid arthritis (RA). This analysis aims to report the efficacy of baricitinib in patients with moderate RA at weeks (W)12 and 24 from two phase III studies, RA-BEAM (NCT01710358) and RA-BUILD (NCT01721057). Methods This post-hoc analysis included patients from RA-BEAM (inadequate responders to methotrexate) and RA-BUILD (inadequate responders to conventional synthetic DMARDs) with moderate RA at baseline (defined as Disease Activity Score (DAS)-28 with C-reactive protein (CRP) of &amp;gt; 3.2 and ≤5.1). This analysis reports treatment response as low disease activity (LDA) defined by DAS28-CRP ≤3.2 and &amp;gt;2.6 or remission defined by &amp;lt; 2.6 and presents descriptive data at W12 and W24, including pain (visual analogue scale [VAS]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), physical functioning (Health Assessment Questionnaire-Disability Index [HAQ-DI]), Work Productivity and Activity Impairment (WPAI), duration and severity of morning stiffness, joint pain, and fatigue using daily diaries. Continuous variables are presented as median with interquartile range and categorical variables as frequencies and percentages. Results At baseline, moderate RA was observed in 117 patients on baricitinib 4-mg, 80 on adalimumab, and 133 on placebo in RA-BEAM; and 80 on baricitinib 2-mg, 63 on baricitinib 4-mg, and 73 on placebo in RA-BUILD. In RA-BEAM at W12, 46.2%, 37.5%, and 9.0% of patients on baricitinib 4-mg, adalimumab, and placebo, respectively, achieved remission. In RA-BUILD at W12, 38.8%, 44.4%, and 13.7% of patients on baricitinib 2-mg, baricitinib 4-mg, and placebo, respectively, achieved remission. At W24, a further increase in the percentage of patients achieving remission was reported in both trials (Table). Improvement in pain (VAS), FACIT-F, and HAQ-DI was similar across RA-BEAM and RA-BUILD with baricitinib treatment (Table). In both trials, patients reported improvement in duration and severity of morning stiffness, worst tiredness, and worst joint pain with baricitinib treatment (Table). Additionally, baricitinib treatment yielded numerical improvement in impairment of daily activity and work productivity in RA-BEAM (Table). Conclusion In patients with moderate RA, baricitinib markedly improved signs and symptoms of RA and patient-reported outcomes (PROs) at W12 and W24. Disclosure B.W. Kirkham: Member of speakers’ bureau; B.K. has received speaker’s payments from AbbVie, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, and UCB. Grants/research support; B. K. has received research support from Eli Lilly and Company and Novartis. Other; B. K. has been an adviser for AbbVie, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, and UCB. B. W. has received meeting support payments from Eli Lilly and Company. E. Nikiphorou: Honoraria; E.N. received speaker honoraria from Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Eli Lilly and Company, and Fresenius. Grants/research support; E.N. holds grants from Pfizer and Eli Lilly and Company. Other; E.N. participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Eli Lilly and Company, and Fresenius. E. N. received travel payments from Eli Lilly and Company. C.J. Edwards: Honoraria; C.E received honoraria from Eli Lilly and Company. Grants/research support; C.E. received grant payments from Abbvie, Pfizer, Roche, Biogen, and Eli Lilly and Company. Other; C.E. received personal fees from Abbvie, Astra-Zeneca, BMS, Celltrion, Fresenius, Galapagos, Gilead, GSK, Janssen, Roche, Pfizer, and Sanofi and travel and meeting payments from Eli Lilly and Company. M. Sheesh: Corporate appointments; M. S. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; M. S. is a minor shareholder at Eli Lilly and Company. E. Haladyj: Corporate appointments; E. H. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; E. H. is a minor shareholder at Eli Lilly and Company. J. Gerwien: Corporate appointments; J. G. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; J. G. is a minor shareholder at Eli Lilly and Company. L. Zaremba-Pechmann: Corporate appointments; L. Z-P is a contractor at HaaPACS gmbH. P.C. Taylor: Consultancies; P. T. has been a consultant for AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly and Company, BMS, Pfizer, Roche, Celltrion, Sanofi, Nordic Pharma, Fresenius, and UCB. Grants/research support; P. T. received grant/research support from Galapagos. Other; P. T. has received meeting support payments from Eli Lilly and Company.

P001 A pharmacist-based flexible approach to workforce enhancement to support implementation of National Institute for Health and Care Excellence Technology Appraisal 715, biologics in moderate rheumatoid arthritis

Abstract Background/Aims The National Institute for Health and Care Excellence Technology Appraisal 715; biologics for treating moderate rheumatoid arthritis was published in July 2021. Previously biologics have only been approved for patients with severe disease. The National Health Service is legally obliged to provide treatments recommended in technology appraisals, yet they do not attract funding for medicines or workforce enhancement. Technology Appraisal 715 is expected to expand the eligible patient cohort posing a significant challenge for the rheumatology team already operating under considerable strain. Without workforce investment clinic capacity would need to be cut for clinicians to manage the additional workload. This would result in greater delays for clinic appointments, already above national targets for new and follow up patients. The specialist pharmacist, an established member of the rheumatology team, is ideally placed to provide further flexible working roles within the team, addressing workforce issues. The aim here was to quantify additional workload associated with technology appraisal 715 and explore potential staffing models for implementation and delivery. Methods An audit of current practice was undertaken. Audit results were used to populate the modelling tool published with the technology appraisal and calculate predicted increase in workload. Three staffing models were developed and critiqued to manage this increase. A business case ranking these models in order of cost effectiveness was submitted to Trust management. Results University Hospitals Sussex rheumatology managed a cohort of around 1500 rheumatoid arthritis patients before publication of appraisal 715 with a growth rate of 14% a year since 2011. A majority of homecare prescribing was undertaken by the current specialist pharmacist and one registrar. Screening and prescribing a prescription took an average of 7 minutes. The team process around 120 prescriptions a week (approximately 14 hours work or two working days). The technology appraisal tool predicted an increase of up to 50% in the eligible patient cohort over 5 years. Increased workload was expected in the following areas; prescribing, pre-biologic and post-biologic clinics, Blueteq management, homecare and general administration workload. The staffing model of one band 8a pharmacist prescriber, one admin band 3 and half an admin band 4 (for Blueteq) was identified as most cost effective. A business case recommending this model was approved by both the Trust and commissioners. Conclusion Rheumatology teams face a growing workload and patient waiting times are increasing. Difficulties in recruitment of clinicians has been highlighted nationally. Pharmacists skilled in managing patients with acute and chronic diseases can acquire specialist competencies allowing them to take on non-traditional roles. Barriers separating professions need to be questioned as pharmacists are ideally placed to help manage increasing workload demands, including that of prescribing and implementation of technology appraisal 715. Disclosure S. Butler: Consultancies; Abbvie, Galapagos, Janssen.

Von Willebrand Factor and Intima-Media Thickness in Patients With Rheumatoid Arthritis: A Cross-Sectional Study

Background. Cardiovascular risk assessment in patients with rheumatoid arthritis (RA) is often a real challenge and requires the search for new indicators to reveal the potential threat of developing atherosclerotic vascular lesions in the early stages.&#x0D; The study aimed to analyse the association between von Willebrand factor (vWF), disease activity, and intima-media thickness (IMT) score in RA patients.&#x0D; Materials and Methods. The study involved 60 RA patients divided into three groups based on the Disease Activity Score 28 (DAS-28) activity index and 20 individuals as healthy controls. Clinical and laboratory assessments included determining the number of swollen (SJ) and painful joints (PJ), the visual analogue scale (VAS) score, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fibrinogen. The concentration of vWF in blood plasma was determined by an enzyme-linked immunosorbent assay (ELISA). The IMT was measured at the bifurcation of the external and internal carotid arteries. Asymptomatic vascular damage was identified as the IMT &gt; 0.9 mm; an atherosclerotic plaque was verified when a focal structure encroached ≥ 0.5 mm or 50% of the adjacent IMT value into the carotid lumen or the IMT &gt; 1.5 mm.&#x0D; Results. Most RA patients (39/60; 65.0%) showed an increase in the IMT (&gt; 0.9 mm); atherosclerotic plaques (IMT &gt; 1.5 mm) were confirmed in 16 (26.7%) individuals, which was significantly more as compared to the control group. VWF was positively associated with the IMT [OR 1.1 (1.06-1.2), p &lt; 0.001]. In addition, elevated levels of vWF were associated with disease activity. The highest values of vWF were found in patients with moderate RA activity (43.3 [21.2-56.9]). There was a positive correlation between vWF and ESR, CRP, DAS-28 (0.564, 0.455, and 0.573, respectively).&#x0D; Conclusions. There was a positive correlation between vWF, inflammatory markers, and disease activity. VWF appeared to be a reliable predictor of the IMT score in RA patients.

Prothrombotic state in rheumatoid arthritis

Aim. To study the indices of standard coagulogram and thrombodynamics test in native plasma and in the test with phospholipids in relation to the activity of rheumatoid arthritis (RA) and the ongoing therapy.Material and methods. We examined 28 patients with rheumatoid arthritis and eight age- and sex-matched healthy controls: 11 patients with high rheumatoid arthritis activity (DAS28&gt;5.2) (Group 1), nine patients with low and moderate rheumatoid arthritis activity (DAS28&lt;5.2) (Group 2) and eight rheumatoid arthritis patients receiving anticoagulants (Group 3). Results. Elevated fibrinogen was more common in the RA patient groups: 5/11(45%) in group 1, 3/9(33%) in group 2 and 3/8(38%) in group 3. In the control group, fibrinogen was normal, p&gt;&lt;0.05. Increased SFMC was found in all patients in all three groups (100%) and only in 2 of the controls (25%), with p&gt;&lt;0.05. Mean clot density was significantly higher in RA groups than in controls: 26811, 25437 and 24740 versus 20631 c.u. in groups 1, 2, 3 and control, respectively, p&gt;&lt;0,01. In patients with anticoagulants, lag time (1.4 minutes) was longer than without anticoagulants (1.1-1.2 minutes), with p&gt;&lt;0.05 in all cases. Spontaneous clots were detected only in patients: 3 in groups 1 and 1 each in groups 2 and 3. Hypocoagulation was detected only in group 3 in 1/8(12%) patients, and thrombotic readiness status was detected in groups 1 and 2: in 2/11(18%) and 1/9(11%) patients, respectively. The frequency of normal- and hypercoagulation did not differ between the patient and control groups. Conclusion. According to the thrombodynamics test, hypercoagulability is present in RA patients. Thrombodynamics test can be used to identify the risk of thrombosis and to individualize therapy in RA patients. Keywords: prothrombotic state, hypercoagulation, rheumatoid arthritis, thrombodynamics&gt;˂ 5.2) (Group 2) and eight rheumatoid arthritis patients receiving anticoagulants (Group 3).Results. Elevated fibrinogen was more common in the RA patient groups: 5/11(45%) in group 1, 3/9(33%) in group 2 and 3/8(38%) in group 3. In the control group, fibrinogen was normal, p˂ 0.05. Increased SFMC was found in all patients in all three groups (100%) and only in 2 of the controls (25%), with p˂ 0.05. Mean clot density was significantly higher in RA groups than in controls: 26811, 25437 and 24740 versus 20631 c.u. in groups 1, 2, 3 and control, respectively, p˂ 0,01. In patients with anticoagulants, lag time (1.4 minutes) was longer than without anticoagulants (1.1-1.2 minutes), with p˂ 0.05 in all cases. Spontaneous clots were detected only in patients: 3 in groups 1 and 1 each in groups 2 and 3. Hypocoagulation was detected only in group 3 in 1/8(12%) patients, and thrombotic readiness status was detected in groups 1 and 2: in 2/11(18%) and 1/9(11%) patients, respectively. The frequency of normal- and hypercoagulation did not differ between the patient and control groups.Conclusion. According to the thrombodynamics test, hypercoagulability is present in RA patients. Thrombodynamics test can be used to identify the risk of thrombosis and to individualize therapy in RA patients.

An Update on Biosimilars in Rheumatic and Musculoskeletal Disorders

Biosimilars contain a version of the active substance of an approved biologic medicine. They were introduced several years ago; the first biosimilar was approved by the European Medicine Agency in 2006. They are now commonly used to treat several immune-mediated conditions, and large evidence-based national and international guidelines support their use. Biosimilars are licensed for use after going through a comprehensive approval process to demonstrate clinical equivalence to the reference biologic in at least one randomized controlled trial. Once biosimilarity is demonstrated in one indication, this can be used to approve the drug for other indications if the mechanism of action is the same across different indications. Biosimilars do not have any clinically meaningful differences from the originator medicine in terms of quality, safety and efficacy but have a cost-saving benefit. NHS England supports the use of biosimilars, stating that clinicians should use the best-value biological product, including biosimilars. In 2021, the National Institute for Health and Care Excellence lowered the biologic eligibility criteria for rheumatoid arthritis by recommending the use of anti-tumour necrosis factor medications with licensed biosimilars for treating moderate rheumatoid arthritis after conventional disease-modifying anti-rheumatic drugs have failed. This recommendation has enabled more patients to access advanced therapy at an earlier stage of the disease, thus potentially increasing the likelihood of inducing remission and limiting disease progression.

Evaluating the efficacy of upadacitinib in patients with moderate rheumatoid arthritis: a post-hoc analysis of the SELECT phase 3 trials.

Moderately active RA is associated with poor patient outcomes. Despite this, some health systems have restricted access to advanced therapies to those with severe RA. There is also limited evidence of the efficacy of advanced therapies in the moderately active RA population. This post-hoc analysis from four phase 3 trials explored the efficacy of upadacitinib (UPA) for moderately active RA. Patients included in this analysis received UPA 15 mg once daily [monotherapy after switching from MTX or in combination with stable background conventional synthetic DMARDs (csDMARDs)] or placebo. Clinical, functional and radiographic outcomes were analysed separately for patients with moderate disease activity {28-joint count DAS using CRP [DAS28(CRP)] of >3.2 and ≤5.1} and severe disease activity [DAS28(CRP) >5.1]. Patients with moderate disease activity who received UPA 15 mg (combination or monotherapy) after an inadequate response to biologic DMARDs and/or csDMARDs were significantly more likely to achieve a 20% improvement in the ACR response criteria, low disease activity status [DAS28(CRP) ≤ 3.2] or clinical remission [DAS28(CRP) < 2.6] by week 12/14 vs placebo. Statistically significant improvements in patient-reported functioning and pain from baseline were observed for UPA 15 mg vs placebo at week 12/14. Radiographic progression was also significantly reduced at week 26 compared with placebo. Similar improvements were observed for severe disease. This analysis provides support for the use of UPA for the treatment of patients with moderate RA. ClinicalTrials.gov: SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847.

Assessment of risk factors in patients with rheumatoid arthritis-associated interstitial lung disease.

To assess the risk factors for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and to evaluate the association of ILD with the use of methotrexate as well as with joint disease activity. A retrospective, cross-sectional study conducted between March and December 2019 at a tertiary healthcare center, in a follow-up of RA patients who had undergone pulmonary function tests (PFT) and chest computed tomography. We evaluated the tomographic characteristics, such as the presence of ILD and its extension, as well as joint disease activity. Functional measurements, such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), were also assessed. After this, a multivariate logistic regression analysis was applied in order to identify risk factors associated with ILD. We evaluated 1.233 patients, of which 134 were eligible for this study. The majority were female (89.6%), with a mean age of 61 years old and with a positive rheumatoid factor (86.2%). RA-associated ILD (RA-ILD) was detected in 49 patients (36.6%). We found an association of RA-ILD with age ≥= 62 year, male sex, smoking history and fine crackles in lung auscultation and a decreased DLCO. The indicators of being aged ≥ 62 years old and having moderate or high RA disease activity were both independent factors associated with RA-ILD, with an odds ratio of 4.36 and 3.03, respectively. The use of methotrexate was not associated with a higher prevalence of ILD. Age and RA disease activity are important risk factors associated with RA-ILD. Methotrexate was not associated with the development of RA-ILD in the present study.

Bone resorption during therapy with denosumab in patients with rheumatoid arthritis, positive for the main immunological markers

Objective. Inflammation in rheumatoid arthritis (RA) leads to the development of local and generalized bone loss. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACCP) are believed to play a negative role in the radiological progression of RA. The use of such antiresorptive therapy as denosumab – monoclonal antibodies to RANKL (receptor activator of nuclear factor kappa-B ligand), reduces the activity of osteoclasts, increases bone mineral density (BMD), and also potentially affects the erosive process at RA. The aim of the study is to evaluate the effect of denosumab therapy on BMD and erosion count in patients with RA and osteoporosis (OP) in consideration of the positivity in the RF and ACCP in serum and the baseline RA activity. Materials and methods. The 12-month prospective study of the efficacy of denosumab therapy (60 mg subcutaneously every 6 months) in patients with RA and OP included 66 postmenopausal women; age – 59.4±7.5 years, duration of RA – 17.8±10.6 years, RF-positive – 47 (72%) patients, ACCP-positive – 48 (74%) patients. At baseline and after 12 months, dual-energy X-ray absorptiometry was performed with an assessment of BMD in the lumbar spine (L1– L4), proximal femur (hip neck and total hip), distal forearm; X-ray of the hands and distal parts of the feet in direct projection, followed by assessment of erosive-destructive changes according to the Sharp/van der Heijde method. Results. A significant increase in BMD was established in all studied sites of the skeleton despite the positivity of the RF and ACCP (for the hip neck p=0.05), while a significant increase in BMD in the RF- and ACCP-negative group was detected only in L1–L4 site. The progression of the increase in erosion count was noted in the RF- and ACCP-positive group while in the RF- and ACCP-negative group this indicator did not change. Regardless of the baseline activity of RA (by DAS28 (Disease Activity Score 28)) the BMD of most parts of the skeleton were stabilized. In patients with moderate RA activity, BMD increased significantly in L1–L4 in both groups: RF- and ACCP-positive and -negative , as well as in the total hip – in RF- and ACCP-positive group. The dynamics of the erosion count in RA patients did not depend on the baseline degree of DAS28 activity, no significant changes were detected in the analyzed groups. Conclusions. RF and ACCP positivity in serum in patients with RA and OP treated with denosumab did not have a negative effect on the dynamics of BMD, while the number of erosions increased. The baseline RA activity level did not affect the dynamics of the erosion count and the dynamics of BMD in most subgroups – BMD levels have been increased or stabilized.

Сalprotectin in the blood plasma as a new biomarker for assessing the activity of rheumatoid arthritis

Aim. To study the potential use and information value of calprotectin in the blood plasma as a new biomarker for determining the activity of rheumatoid arthritis (RA).Materials and methods. The study included 113 people. The treatment group consisted of 79 patients diagnosed with RA; the average age was 58 (± 11.66) years, the median duration of the disease was 10 [6; 15] years. The control group encompassed 34 healthy volunteers; the average age was 40 (± 11.14) years. RA activity was determined according to the Disease Activity Score (DAS) 28 and the Clinical Disease Activity Index (CDAI). The concentration of calprotectin in the blood plasma was determined by the solid-phase enzyme-linked immunosorbent assay. The obtained results were compared with laboratory and clinical parameters, as well as with composite indices (DAS28, CDAI) of RA activity. For mathematical data processing, Spearman’s rank correlation coefficient, linear discriminant analysis, and ROC analysis were used.Results. In the group of patients with RA, the level of calprotectin in the blood was higher than in the control group. A statistically significant relationship was revealed between the level of calprotectin in the blood and all standard parameters of RA activity. The ROC analysis showed that the sensitivity, specificity, and diagnostic accuracy in assessing articular syndrome, as well as moderate and high RA activity according to the composite indices DAS28 and CDAI were higher for calprotectin than for erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The linear discriminant analysis showed that a combination of ESR and calprotectin levels was the most informative; following it, the probability of correct classification of RA activity, according to the DAS28 index, was 71%. For the CDAI index, only one marker, calprotectin, resulted in a statistically significant classification with a probability of 70.5 %.Conclusion. Сalprotectin in the blood plasma is a promising laboratory biomarker for assessing synovitis activity in RA demonstrating higher accuracy, sensitivity, and specificity than traditional acute-phase reactants.

Association of UGT1A1 Genetic Variants with Increases in Bilirubin Levels

Association of UGT1A1 Genetic Variants with Increases in Bilirubin Levels