Conventional Disease-modifying Antirheumatic Drugs Research Articles

The effects of vitamin D supplementation on disease activity and fatigue in Libyan rheumatoid arthritis patients

ObjectivesThis study aimed to investigate the effect of vitamin D supplementation therapy on disease activity and fatigue in rheumatoid arthritis (RA) patients.Material and methodsA prospective randomized clinical trial was conducted at rheumatology clinics in Tripoli Central Hospital, Libya. The eligible patients received disease-modifying antirheumatic drugs (DMARDs) and were divided into two groups: group A received 50,000 IU of vitamin D once a week; while group B received conventional DMARDs without vitamin D supplementation. The groups were monitored for 12 weeks.ResultsThe study included 68 RA patients, with the majority being female (75%). There were no significant differences in parameters such as age, sex, duration of illness, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), calcium, and vitamin D levels, as well as DAS28 (Disease Activity Score with 28-joint count) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) levels between these two groups at baseline. After 12 weeks, group A showed a significant improvement in mean vitamin D levels and FACIT-F scores compared to group B. The increase in vitamin D levels in group A (24.21 ±4.81 nmol/l) was higher than that in group B (5.76 ±3.36 nmol/l). Furthermore, the FACIT-F score in group A was in the normal range (mean: 39.36 ±6.15), whereas group B still exhibited “abnormal” FACIT-F < 27.75 ±4.41. Correlation analysis indicated a positive correlation between FACIT-F and vitamin D levels, suggesting that higher vitamin D levels were associated with improved fatigue. Additionally, a weak inverse correlation was observed between DAS28 and vitamin D levels though the difference was not statistically significant (p > 0.05). Finally, the correlation between DAS28 and FACIT-F was positive (R = 0.557, p = 0.000).ConclusionsThe results of the recent study indicated that vitamin D3 (50,000 IU of cholecalciferol) supplementation had a positive impact in RA patients compared to conventional DMARDs drugs, as was clear from the significant FACIT-F.

Sex-Related Differences in Dispensation of Rheumatic Medications in Older Patients With Inflammatory Arthritis: A Population-Based Study.

The aim of our study was to compare dispensation of rheumatic medications between older male and female patients with early rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This retrospective cohort study was performed using health administrative data from Ontario, Canada (years 2010-2017), on patients with incident RA and PsA, who were aged ≥ 66 years at the time of diagnosis. Yearly dispensation of rheumatic drugs was compared between older male and female patients for 3 years after diagnosis using multivariable regression models, after adjusting for confounders. The groups of drugs included in the analysis were disease-modifying antirheumatic drugs (DMARDs) classified as conventional synthetic DMARDs (csDMARDs) and advanced therapy (biologic DMARDs and targeted synthetic DMARDs), nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and oral corticosteroids. Results were reported as odds ratios (ORs) with 95% CIs. We analyzed 13,613 patients (64% female) with RA and 1116 patients (57% female) with PsA. Female patients with RA were more likely to receive opioids (OR 1.39, 95% CI 1.22-1.58 to OR 1.51, 95% CI 1.32-1.72) and NSAIDs (OR 1.14, 95% CI 1.04-1.25 to OR 1.16, 95% CI 1.04-1.30). Dispensation of DMARDs showed no sex difference in either group. Subgroup analyses showed more intense use of advanced therapy in the RA cohort and of csDMARDs in the PsA cohort when patient and physician sex was concordant. This study did not identify any sex difference in the use of DMARDs among older patients with RA and PsA. The reasons for the higher use of opioids and NSAIDs among female patients with RA warrant further research.

Cost of Illness and Out-of-pocket Expenditure of Ankylosing Spondylitis and Rheumatoid Arthritis at a Tertiary Care Hospital in North India Using Conventional Disease-modifying Antirheumatic Drugs

Background: The economic burden of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in India is significant. Aim: To estimate the cost of illness (COI) and out-of-pocket expenditure of AS and RA among patients on conventional disease-modifying antirheumatic drugs. Methodology: A retrospective, cross-sectional study on 87 participants using a prevalence-based, bottom-up approach and the human capital method was adopted to calculate the direct and indirect costs of RA and AS. Results: The average COI for patients with RA was estimated to be ₹51,741 person per year, whereas the COI for patients with AS was ₹41,379 per person per year (Consumer Price Index 2021: 134.44). Direct cost was the major contributor to COI constituting 65.21% [₹33,743] and 58.84% [₹24,348] of the total COI of RA and AS, respectively. Increasing disease severity, longer duration of illness and increasing impairment of daily activities were significantly associated with increasing COI of both RA and AS. The main expense towards annual direct costs per year in patients with RA was medication expenses, whereas for patients with AS, it was investigation expenses. Out-of-pocket spending was significant as nearly half (54.95%) of the direct expenditure on health for both RA [₹18,544] and AS (39.2%) [₹9,544] was borne by patients themselves. RA and AS caused catastrophic health expenditure in 14.92% and 6.67% of households, respectively. Indirect costs of RA and AS were ₹17,998 and ₹17,030, respectively. Indirect costs of RA and AS increased as productivity at work decreased. Average overall work productivity impairment and overall activity impairment reached close to 50% and was comparable for RA and AS. Conclusion: The economic burden of RA and AS is significant. There is an urgent need to prioritise policies and interventions for management of rheumatological conditions.

Factors determining resistance to conventional disease-modifying anti-rheumatic drug treatment in oligoarticular juvenile idiopathic arthritis.

Our study was designed to investigate the reasons for starting the conventional disease-modifying anti-rheumatic drugs (DMARDs) and the variables that impact the response to DMARD treatment in oligoarticular juvenile idiopathic arthritis (JIA) patients. Oligoarticular JIA patients (n = 187) were categorized into two groups: Group A consisted of patients who achieved remission with DMARD, and Group B comprised those who did not respond to DMARD therapy. DMARDs were initiated for various reasons: 68 (36.4%) due to active disease despite nonsteroidal anti-inflammatory drugs (± intra-articular corticosteroid) treatment, 59 (31.6%) due to uveitis, 49 (26.2%) due to extended oligoarticular JIA, and 11 (5.9%) due to inflammatory bowel disease. One hundred twenty-three patients (65.8%) achieved remission with DMARDs (Group A), while 64 patients (34.2%) did not respond to DMARD therapy (Group B). In Group B, patients had higher C-reactive protein (CRP) levels as well as higher Juvenile Idiopathic Arthritis Disease Activity Scores-71 (JADAS-71) at diagnosis (both p < 0.001). Moreover, extended oligoarticular JIA subtype (p = 0.017) and involvement of small joints at diagnosis (p = 0.043) were more prevalent among these patients. Group A exhibited a higher frequency of antinuclear antibody positivity (p = 0.014). Elevated CRP levels (> 1.1mg/dL) (OR 1.308, 95% CI 1.203-3.574; p < 0.001) and high JADAS-71 at diagnosis (> 15.8) (OR 1.659, 95% CI 1.179-2.941; p < 0.001) were associated with DMARD resistance. Elevated CRP and high JADAS-71 at diagnosis were the main factors associated with DMARD resistance in oligoarticular JIA. Prospective long-term studies may help verify the role of these factors associated with DMARD resistance in oligoarticular JIA. Key Points • Conventional DMARDs were most commonly started due to active disease despite NSAID (± intra-articular corticosteroids). • Remission was achieved with DMARD in 65.8% of oligoarticular JIA patients. • Elevated CRP and high JADAS-71 at diagnosis were associated with DMARD resistance.

Interferon-γ Release Assay in the Assessment of Cellular Immunity-A Single-Centre Experience with mRNA SARS-CoV-2 Vaccine in Patients with Juvenile Idiopathic Arthritis.

Background: As the SARS-CoV-2 virus remains one of the main causes of severe respiratory system infections, the Food and Drug Administration strongly advises the continuation of current vaccination programs, including the distribution of updated boosters, especially in high-risk groups of patients. Therefore, there is an unceasing need for further research on the safety and, no less importantly, the clinical effectivity of the vaccines, with an extra focus on cohorts of patients with underlying health problems. This study aimed to assess the efficacy of the SARS-CoV-2 vaccine in possibly immunocompromised children with rheumatic disease while utilizing the interferon-gamma release assay (IGRA) as a marker for COVID-19 immunity in the study follow-up. Methods: This prospective study was performed in a group of 55 pediatric patients diagnosed with juvenile idiopathic arthritis. Eight participants were immunized with the Comirnaty mRNA vaccine before the research commenced, while the rest of the group (n = 47) had not been vaccinated against SARS-CoV-2. At the study baseline, the cellular response to the virus antigen was measured using a specific quantitative IGRA in whole blood; subsequently, the anti-SARS-CoV-2 test was performed, marking the antibodies' levels in serum. Around four months after the enrollment of the last patient in the study, a follow-up survey regarding the events of COVID-19 infection within the cohort was conducted. Results: The study confirmed that all the vaccinated children developed specific T-cell (p = 0.0016) and humoral (p = 0.001 for IgA antibodies, p = 0.008 for IgG antibodies) responses to the inoculation, including those receiving biological treatment and those on conventional disease-modifying anti-rheumatic drugs. The study also showed the different patterns of immunity elicited both after infection and post-vaccination, with higher levels of antibodies and T-cell response after inoculation than after natural exposure to the pathogen. According to the follow-up survey, six children developed PCR-confirmed SARS-CoV-2 infection, whereas the additional 10 patients admitted to having COVID-like symptoms with no laboratory verification. Conclusions: SARS-CoV-2 vaccinations elicit valid immune responses in pediatric rheumatic patients. Including the assessment of T-cell immunity in the evaluation of inoculation-induced immunization can enhance the accuracy of sole humoral response assays.

Predictors of Remission or Combined Remission and Low Disease Activity in Rheumatoid Arthritis Patients in Taiwan: A Prospective Cohort Study.

Objectives: This study aimed to identify predictors of remission or low disease activity (LDA) in patients with rheumatoid arthritis (RA) and low-ultrasound inflammation. Methods: A total of 80 patients with RA who fulfilled the 1987 ACR criteria for RA with a disease activity score of 28 joints (DAS28) > 3.2 were recruited. Over 1 year of therapy, we conducted blood tests every 6 months to examine erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP-1), neuraminidase 3 (Neu3), and α-2,3-sialyltrasnferse I (ST3Gal-1) levels in B cells and monocytes. Additionally, we evaluated physical function by using the Health Assessment Questionnaire-Disability Index (HAQ-DI). Data on demographic and clinical parameters were collected, and musculoskeletal ultrasonography was performed twice a year on 12 specific joints to assess synovial changes. One year later, we compared all collected data and laboratory or ultrasound results between patients achieving remission or LDA and those who did not in order to determine the predictors. Results: Age, the presence or absence of rheumatoid factor, and the number of conventional disease-modifying anti-rheumatic drugs used were not correlated with remission or LDA for DAS28 or Simplified Disease Activity Index formulas. However, male sex, low CRP levels, low ESR levels, and low HAQ-DI scores were associated with a higher likelihood of achieving remission or LDA for DAS28-ESR. Negative anticyclic citrullinated peptide (CCP) and low HAQ-DI scores were predictors of remission or LDA for DAS28-MCP-1. Interestingly, having less than two comorbidities is a good predictor of a combined remission/low disease activity state for SDAI and DAS28-MCP-1. Furthermore, Neu3 and ST3Gal-1 levels and ST3Gal-1/Neu3 ratios in B cells and monocytes had no significant correlation with total ultrasound scores. Nevertheless, monocyte ST3Gal-1 and Neu3 correlated significantly with DAS28-ESR >5.1 and DAS-MCP-1 >4.8 (both categories belong to high disease activity), respectively (rho = 0.609 with p = 0.012, and rho = 0.727 with p = 0.011, respectively). Monocyte ST3Gal-1/Neu3 ratios connected with DAS28-ESR >5.1 and 3.3 < SDAI ≦ 11 (low disease activity), respectively (rho = 0.662 with p = 0.005, and rho = 0.342 with p = 0.048, respectively). Conclusions: In patients with RA in Taiwan, male sex, low CRP levels, low ESR levels, and low HAQ-DI scores are predictors of remission or LDA for DAS28-ESR, which differ from the predictors for DAS28-MCP-1. Moreover, monocyte ST3Gal-1, Neu3, and their ratios correlated with different disease activity categories of DAS28-ESR, DAS28-MCP-1, and SDAI scores.

E008 Review of rheumatology care for women of childbearing age

Abstract Background/Aims Autoimmune rheumatic diseases are frequently diagnosed in women of childbearing age. Managing these conditions during pregnancy is complex because commonly used disease-modifying antirheumatic drugs (DMARDs) can pose risks. Specialized care for this patient group is crucial, necessitating adherence to established rheumatology practice standards and British Society for Rheumatology (BSR) guidelines. Our main objective is to review management of childbearing age females with rheumatic diseases attending Basildon hospital as per BSR guidelines. Methods The data for this retrospective study was collected from the electronic records of female patients attending the rheumatology outpatient clinic at Basildon Hospital between September and December 2022. We reviewed age, the specific rheumatological diagnosis, disease duration, disease activity, current medications, and whether general advice or pregnancy-specific advice was provided. Results Out of the initial cohort of 63 female patients, 48 (76%) aged between 18-55 years were selected as women of childbearing age, The median age was 46 years, with 65% in the age groups of 31-50 years, 25% in group 51-55 years and 10% 18-30 years age group. 58% of patients had inflammatory arthritis, 18.7% had connective tissue disease, 18.7% had other conditions such as hypermobility, osteoarthritis, and regional pain syndrome, 2.3% were diagnosed with vasculitis and 2.3% with polymyalgia rheumatica. Breakdown of inflammatory arthritis patients revealed rheumatoid arthritis in 64%, psoriatic arthritis 15% and ankylosing spondylitis 12%. Axial spondyloarthropathy, palindromic rheumatism, and juvenile idiopathic arthritis, each accounted for 3%. Regarding prescribed medications, 66% of the individuals were on conventional DMARDs, biologics 24%, corticosteroids 6% and 4% were on other treatments. The DMARDs prescribed were methotrexate 27%, hydroxychloroquine 19%, sulfasalazine 13%, mycophenolate 3% and leflunomide 1%. The majority of patients had disease activity in remission or mild, each accounting for 23%. Moderate and severe disease activity were reported in 21% each of the audited sample. Patients received advice specifically related to pregnancy 29%, while 71% did not have documented pregnancy-related guidance. 70% of females of reproductive age received general advice. Conclusion The study highlights a gap in pregnancy-related advice among the childbearing age patients as only 29% received guidance on pregnancy. This underpins the need for proactive counselling and education for female patients in routine practice, work in partnership with obstetric teams, and primary care to reduce potential pregnancy related complications and improve outcomes. Disclosure M. Mohareb: None. S. Ahmed: None. A. Bharadwaj: None. A. Nandagudi: None.

OA20 Serious infections hospital admissions and mortality in patients with early inflammatory arthritis: results from the National Early Inflammatory Arthritis Audit

Abstract Background/Aims To identify the risk of serious infections (SI) according to initial treatment strategy, using conventional synthetic disease modifying anti-rheumatic drugs (csDMARD) and corticosteroids, in patients recruited to the National Early Inflammatory Arthritis Audit (NEIAA). Methods An observational cohort study design was used. The population included adults in England with a new onset rheumatoid arthritis (RA), fulfilling ACR/EULAR 2010 criteria, between April 2018-March 2021. Outcomes studied were SI, defined by infections requiring hospitalisation (primary admission diagnosis/nosocomial acquisition) or death (SI stated on death certificate), identified using NHS Digital linkage. Patients' characteristics were tabulated by treatment strategies. Hazard ratios (HR) were calculated using single failure Cox proportional-hazards models, with confounders-adjusted models (age, gender, smoking status, comorbidities, social deprivation) and fully-adjusted models including disease factors (seropositivity, DAS28). Individuals were considered at risk from the date of RA diagnosis, and censored at SI event, death, or March 2021 (whichever was earliest). Results 20,060 patients with RA were included. Initial DMARD therapy was known for 19,572 patients, of whom 11,966 were on methotrexate/MTX based strategies (mono or combo), 5,059 on csDMARD combination strategies (other than MTX) and 2,547 on no DMARD strategy. 15,319 patients were on corticosteroids at baseline. Mean age 59.5 years (+/-15); 63% female; smoking status (20% current; 30% ex-smokers); comorbidities (21% hypertension; 10% diabetes; and 12% lung disease). Rheumatoid Factor/CCP antibodies were positive in 68%. At presentation, median disease scores were 5.1 (interquartile range [IQR]: 4.0-5.9) for DAS28, 1.1 (IQR: 0.6-1.7) for health assessment questionnaire (HAQ) and 24 (IQR: 16.0-33.0) for musculoskeletal health questionnaire (MSKHQ).There were 519 SI admissions and 17 SI deaths, corresponding to incidence rates per 100 person-years for admissions: 3.19 (95% CI: 2.93-3.48) and deaths: 0.10 (95% CI: 0.06-0.16). In fully-adjusted models, increasing age predicted both SI admissions and deaths. Being a smoker, having a comorbidity, higher disease activity (DAS28), symptom burden (MSKHQ) and disability (HAQ) at presentation associated with more SI admissions. For each 1 unit increase in DAS28, the risk of SI increased by 8% (HR 1.08 [95% CI:1.01-1.16]). Seropositivity did not associate with SI. MTX-based strategies 0.75 (95% CI:0.62-0.91) and csDMARD combination therapy 0.70 (95% CI:0.53-0.94) associated with fewer SI admissions compared to no DMARD. In unadjusted models, corticosteroid associated with more SI admissions 1.29 (95% CI:1.10 -1.62); however, in fully-adjusted models this association was no longer statistically significant. csDMARD strategies did not associated with SI deaths in any of the models. Conclusion Patient and disease factors at diagnosis appear to be important predictors of admissions and mortality for serious infections. Infection risk appears to be greatest in those with higher RA disease activity. An important limitation is that NEIAA does not capture data on treatment changes over time and steroid use beyond baseline. Disclosure M. Adas: None. K. Bechman: None. M. Russell: Honoraria; Lilly and Menarini. Other; upport for attending conferences from Lilly, Pfizer, Janssen, and UCB, and advisory board fees from Biogen.. I. Karafotias: None. D. Nagra: None. S. Patel: None. S. Gallagher: None. E. Price: None. M. Garton: None. A. Rutherford: None. A. Cope: None. S. Norton: None. J. Galloway: Honoraria; from Abbvie, Biovitrum, Bristol Myers Squib (BMS), Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, and UCB.

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.

P122 Secular trends in prescription of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in rheumatoid arthritis: Experience from a UK regional centre (2016-2022)

Abstract Background/Aims In the past two decades, biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) have substantially transformed the treatment landscape for rheumatoid arthritis (RA). With the emergence of new molecules, the introduction of cost-effective biosimilars, and the impact of the COVID pandemic, the treatment preferences might have shifted over time. We aim to explore the evolving trends in the prescription of biologic and targeted synthetic DMARDs in RA patients whose disease was refractory to conventional DMARDs. Methods A biologic registry was set up sourcing data from pharmacy and departmental records. Data of RA patients who were commenced on biologics or targeted synthetic DMARDs between January 2016 and December 2022 are presented descriptively without formal statistical assessments. Line plots depict prescription trends over the years. Data visualization done using R studio (v 2023.06). Results We have 1504 out of the 2345 patients in our biologic registry with RA; 827 of these patients commenced the treatment in the 7-year study period. Over the years, biosimilars are increasingly being preferred as the first-line agents. If a biosimilar for a biologic drug was available, all prescriptions were for the biosimilar in 2022. There was a significant drop (43.7%) in biologic prescriptions during the pandemic in 2020 compared to the previous year. However, by the next year, prescriptions rebounded to 91% of their pre-pandemic levels. TNF inhibitors and Janus kinase (JAK) inhibitors were the most common treatments initiated. There was a steady increase in the prescription of JAK inhibitors since their introduction in 2017. During the pandemic, JAK inhibitors were the most preferred agents for RA. However, a decline in their prescriptions was noted in 2022, down 36% from the previous year, possibly due to emerging concerns about their cardiovascular safety. While there was reduction in prescription of all biologics during pandemic, anti B cell therapy had the steepest decline (74.1% reduction in 2020 compared to previous year). This may be due to the increased risk of SARS-CoV-2 infection and impaired response to the vaccine with Rituximab. This trend is gradually reversing. Rates of prescription of abatacept and anti-IL6 agents remained fairly stable across the seven years. Conclusion Significant fluctuations are evident in the trend of prescription of biologic and targeted synthetic DMARDs in patients with rheumatoid arthritis in a regional centre in UK. We conclude that availability of biosimilars, safety data on JAK inhibitors and impact of the COVID pandemic had influenced the prescription trends. Disclosure H. Muhammed: None. H. Osborn: None. K. Hughes: None. A. Yau: None. G. Hirsch: None. S. Raizada: None. T. Sheeran: None. S. Venkatachalam: None.

Effects of tapering conventional synthetic disease-modifying antirheumatic drugs to drug-free remission versus stable treatment in rheumatoid arthritis (ARCTIC REWIND): 3-year results from an open-label, randomised controlled, non-inferiority trial

Tapering of disease-modifying antirheumatic drugs (DMARDs) to drug-free remission is an attractive treatment goal for patients with rheumatoid arthritis, although long-term effects of tapering and withdrawal remain unclear. We compared 3-year risks of flare between three conventional synthetic DMARD treatment strategies in patients with rheumatoid arthritis in sustained remission. In this open-label, randomised controlled, non-inferiority trial, we enrolled patients aged 18-80 years with rheumatoid arthritis who had been in sustained remission for at least 1 year on stable conventional synthetic DMARD therapy. Patients from ten hospitals in Norway were randomly assigned (2:1:1) with centre stratification to receive stable conventional synthetic DMARDs, half-dose conventional synthetic DMARDs, or half-dose conventional synthetic DMARDs for 1 year followed by withdrawal of all conventional synthetic DMARDs. The primary endpoint of this part of the study was disease flare over 3 years, analysed as flare-free survival and risk difference in the per-protocol population with a non-inferiority margin of 20%. This trial is registered with ClinicalTrials.gov (NCT01881308) and is completed. Between June 17, 2013, and June 18, 2018, 160 patients were enrolled and randomly assigned to receive stable-dose conventional synthetic DMARDs (n=80), half-dose conventional synthetic DMARDs (n=42), or half-dose conventional synthetic DMARDs tapering to withdrawal (n=38). Four patients did not receive the intervention and 156 patients received the allocated treatment strategy. One patient was excluded due to major protocol violation and 155 patients were included in the per-protocol analysis. 104 (67%) of 156 patients were women and 52 (33%) were men. 139 patients completed 3-years follow-up without major protocol violation; 68 (87%) of 78 patients in the stable-dose group, 36 (88%) of 41 patients in the half-dose group and 35 (95%) of 37 patients in the half-dose tapering to withdrawal group. During the 3-year study period, 80% (95% CI 69-88%) were flare-free in the stable-dose group, compared with 57% (41-71%) in the half-dose group and 38% (22-53%) in the half-dose tapering to withdrawal group. Compared with stable-dose conventional synthetic DMARDs, the risk difference of flare was 23% (95% CI 6-41%, p=0·010) in the half-dose group and 40% (22-58%, p<0·0001) in the half-dose tapering to withdrawal group, non-inferiority was therefore not shown. Adverse events were reported in 65 (83%) of 78 patients in the stable-dose group, 36 (90%) of 40 patients in the half-dose group, and 36 (97%) of 37 patients in the half-dose tapering to withdrawal group. One death occurred in the stable-dose conventional synthetic DMARD group (sudden death considered unlikely related to the study medication). Two conventional synthetic DMARD tapering strategies were associated with significantly lower rates of flare-free survival compared with stable conventional synthetic DMARD treatment, and the data do not support non-inferiority. However, drug-free remission was achiveable for a significant subgroup of patients. This trial provides information on risk and benefits of different treatment strategies important for shared decision making. Research Council of Norway and South-Eastern Norway Regional Health Authority.

Biomarker combination predicting imminent relapse after discontinuation of biological drugs in patients with rheumatoid arthritis in remission.

Compared to conventional disease-modifying antirheumatic drugs (DMARDs), biological DMARDs demonstrate superior efficacy but come with higher costs and increased infection risks. The ability to stop and resume biological DMARD treatment while maintaining remission would significantly alleviate these barriers and anxieties. The objective of this study was to identify biomarkers that can predict an imminent relapse, hopefully enabling the timely resumption of biological DMARDs before relapse occurs. Forty patients with rheumatoid arthritis who had been in remission for more than 12 months were included in the study. The patients discontinued their biological DMARD treatment and were monitored monthly for the next 24 months. Out of the 40 patients, 14 (35%) remained in remission at the end of the 24-month period, while 26 (65%) experienced relapses at different time points. Among the relapse cases, 13 patients experienced early relapse within 6 months, and another 13 patients had late relapse between 6 months and 24 months. Seventy-three cytokines in the sera collected longitudinally from the 13 patients with late relapse were measured by multiplex immunoassay. Using cytokines at two time points, immediately after withdrawal and just before relapse, volcano plot and area under the receiver operating characteristic curves (AUC) were drawn to select cytokines that distinguished imminent relapse. Univariate and multivariate logistic regression analyses were used for the imminent relapse prediction model. IL-6, IL-29, MMP-3, and thymic stromal lymphopoietin (TSLP) were selected as potential biomarkers for imminent relapse prediction. All four cytokines were upregulated at imminent relapse time point. Univariate and multivariate logistic regression showed that a combination model with IL-6, MMP-3, and TSLP yielded an AUC of 0.828 as top predictors of imminent relapse. This methodology allows for the prediction of imminent relapse while patients are in remission, potentially enabling the implementation of on- and off-treatments while maintaining remission. It also helps alleviate patient anxiety regarding the high cost and infection risks associated with biological DMARDs, which are the main obstacles to benefiting from their superb efficacy.

The interplay of rheumatoid arthritis and osteoporosis: exploring the pathogenesis and pharmacological approaches.

Rheumatoid arthritis (RA) and osteoporosis are two chronic disorders that are often seen together. RA is an autoimmune disorder that causes pain and inflammation in the joints, while osteoporosis is a disorder in which the bones become weak and fragile. Risk factors for bone loss in RA include disease activity, longer disease duration, erosive disease, autoantibody positivity, and joint damage leading to impaired physical activity. Recent research has shown that there is a complex interplay between immune cells, cytokines, and bone remodeling processes in both RA and osteoporosis. The bone remodeling process is regulated by cytokines and immune system signaling pathways, with osteoclasts activated through the RANK/RANKL/OPG pathway and the Wnt/DKK1/sclerostin pathway. Understanding these mechanisms can aid in developing targeted therapies for treatment of osteoporosis in RA patients. Current pharmacological approaches include anti-osteoporotic drugs such as bisphosphonates, denosumab, teriparatide, abaloparatide, raloxifene, and romosozumab. Conventional disease-modifying antirheumatic drugs such as methotrexate and biologicals including TNF inhibitors, IL-6 inhibitors, rituximab, and abatacept lower disease activity in RA and can improve bone metabolism by reducing inflammation but have limited impact on bone mineral density. This review will shed light on the relationship between osteoporosis and rheumatoid arthritis as well as the various factors that influence the onset of osteoporosis in RA patients. We also explore several treatment approaches to effectively managing osteoporosis in RA patients.

Adult-Onset Still's Disease (AOSD): Advances in Understanding Pathophysiology, Genetics and Emerging Treatment Options.

Adult-onset Still's disease (AOSD) is a multisystemic complex disorder clinically characterised by episodes of spiking fever, evanescent rash, polyarthritis or diffuse arthralgias; multiorgan involvement may develop according to the hyper-inflammatory extent. The pathogenesis of AOSD is not completely recognised. The central role of macrophage activation, which results in T helper 1 (Th1) cell cytokine activation, is well established. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-18 play a fundamental role in disease onset and progression. The disease may develop in both children and adults with overlapping clinical features, and although several subsets depending on the clinical manifestations and the cytokines expressed have been identified, the dichotomy between systemic juvenile idiopathic arthritis (sJIA) and AOSD nowadays has been overcome, and the pathology is considered a disease continuum between ages. Various therapeutic approaches have been evaluated thus far, and different compounds are under assessment for AOSD treatment. Historically, glucocorticoids have been employed for treating systemic manifestations of Still's disease, while conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) demonstrated efficacy in controlling the articular manifestations. Currently, biological (b) DMARDs are widely employed; IL-1 inhibitors such as anakinra and canakinumab have proven to have high efficacy and an excellent safety profile and the anti-IL-6 tocilizumab is approved for sJIA, with several trials and longitudinal studies confirming its efficacy and safety. Moreover, in the light of the 'window of opportunity', new evidence showed that the earlier these treatments are initiated, the sooner clinical inactivity can be achieved. Other treatment options are being considered since several molecules involved in the disease pathophysiology can be targeted through various mechanisms. This review will provide a broad overview of AOSD pathophysiology, insights into specific organ manifestations and the currently available treatments with the identification of potential therapeutic targets involved in AOSD pathogenesis will be outlined.

Rheumatoid arthritis: pathogenesis and therapeutic advances.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the unresolved synovial inflammation for tissues-destructive consequence, which remains one of significant causes of disability and labor loss, affecting about 0.2-1% global population. Although treatments with disease-modifying antirheumatic drugs (DMARDs) are effective to control inflammation and decrease bone destruction, the overall remission rates of RA still stay at a low level. Therefore, uncovering the pathogenesis of RA and expediting clinical transformation are imminently in need. Here, we summarize the immunological basis, inflammatory pathways, genetic and epigenetic alterations, and metabolic disorders in RA, with highlights on the abnormality of immune cells atlas, epigenetics, and immunometabolism. Besides an overview of first-line medications including conventional DMARDs, biologics, and small molecule agents, we discuss in depth promising targeted therapies under clinical or preclinical trials, especially epigenetic and metabolic regulators. Additionally, prospects on precision medicine based on synovial biopsy or RNA-sequencing and cell therapies of mesenchymal stem cells or chimeric antigen receptor T-cell are also looked forward. The advancements of pathogenesis and innovations of therapies in RA accelerates the progress of RA treatments.

Drug Retention Time of Immunosuppressive Therapy in Behcet’s Uveitis

ABSTRACT Purpose Behcet’s Disease is a chronic multisystem vasculitis associated with a blinding uveitis. Few comparative studies exist between conventional disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs in Behcet’s uveitis (BU). We therefore used drug retention time (DRT), an accepted surrogate measure of pharmacological efficacy and tolerability, to compare these treatments in patients with BU. Methods Retrospective chart review of patients who met the revised International Criteria for Behcet’s Disease (ICBD) treated at the Royal Victorian Eye and Ear Hospital, Australia, between 1985–2021. DRT was analysed with Kaplan-Meier plots and defined as total time on drug in the first medication-period for each DMARD in each patient. Results Forty-eight patients (37 males) with median age of 28.6 years were followed-up for a median of 8.0 years. At initial presentation, half had bilateral disease and median logMAR visual acuity was 0.176 (Snellen 6/9) in 62 uveitic eyes (16 anterior uveitis, 11 intermediate, 2 posterior, and 33 panuveitis). Thirty-three patients met ICBD initially. Prescribed corticosteroid-sparing agents were Cyclosporin (N = 24), Mycophenolate (N = 22), Azathioprine (N = 22), Methotrexate (N = 16), and Adalimumab (N = 15). Median DRT was 14.0, 27.4, 8.3, 24.0, and 52.0 months, respectively. DMARDs were discontinued 116 times and adverse effects (N = 37) were the main reason for cessation. Over time, patients were switched from Cyclosporin to Adalimumab earlier in the disease course due to poorer tolerance of adverse events. Conclusion Adalimumab’s drug retention time was found to be similar to and possibly better than cDMARDs in patients with BU, who often suffer from vision-threatening disease at first presentation.

Evaluation of Therapeutic Response Under Biologic Therapy in Patients with Rheumatoid Arthritis

Biotherapy has revolutionized the therapeutic management of rheumatoid arthritis (RA). The objective of the study was to evaluate and compare the efficacy and tolerance of biological disease modifying antirheumatic drugs (bDMARDs) and conventional disease modifying antirheumatic drugs ( cDMARDs) used in RA.&#x0D; It was a retrospective study covering 13 years at the level of the immunology unit of the UHU Hassiba Ben Bouali Blida and functional rehabilitation service of the CHU Frantz Fanon Blida. We identified 1866 records of patients with RA, 75 receiving biotherapy and 71 receiving conventional treatment. The therapeutic response was evaluated by the DAS 28-ESR (disease activity score based on erythrocyte sedimentation rate) and interpreted according to the EULAR (European league against rheumatism) judgements criteria.&#x0D; A female predominance of 83%, the average age of RA patients was 49.3 ±13.42 years, the mean starting DAS28-ESR was 5.625± 1.4. 84% of patients initially received MTX (methotrexate) on the front line, the decrease in DAS28-ESR was non- significant, with patients exhibiting intolerance (41%), and (45%) ineffectiveness. The introduction of biotherapy mainly Actemra allowed a decrease of DAS28-ESR of - 1.842±0.3812, a significant decrease according to the criteria of the EULAR. Humira had an adverse efficacy and tolerance profile (including the occurrence of severe adverse effects (AEs)).&#x0D; In conclusion, biotherapy is more effective than conventional treatments, while in terms of tolerance data are insufficient to make a judgment on it.&#x0D; Keywords: Rheumatoid arthritis – Biotherapy.

Conventional and Biological Disease-Modifying Antirheumatic Drugs in Chro-nic Kidney Disease and Hemodialysis

Advanced chronic kidney disease and the different modalities of renal replacement therapies have been a great limitation when prescribing the different conventional and biological therapies used for the treatment of different autoimmune diseases. Many of them persist with great activity, requiring the use of other types of medications such as glucocorticoids or non-steroidal anti-inflammatory drugs, further perpetuating their adverse effects. Addditionally, most clinical studies have excluded patients with chronic kidney disease and the evidence for continuing biological treatments in this scenario is based on pharmacokinetic properties or case reports where the outcomes have been favorable. The lack of knowledge and the absence of clear guidelines for decision-making regarding starting conventional or biological therapy in this context generate a lack of continuity in the prescription of treatments, which decreases the therapeutic response and negatively affects the quality of life. from the patients. For this reason, a narrative review is carried out with the aim of establishing a practical consensus that unifies the recommendations for each of the treatments most frequently used in the control of various autoimmune diseases in patients with advanced chronic kidney disease.

Correlation Of Lipid Profile and Das28 Score of Early Rheumatoid Arthritis Patients on Conventional Synthetic Dmards

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and a higher risk of cardiovascular diseases. The relationship between RA disease activity, lipid profiles, and the impact of disease-modifying antirheumatic drugs (DMARDs) on these parameters is an area of ongoing research. Objective: This study aimed to investigate the correlation between lipid profiles and the Disease Activity Score in 28 joints (DAS-28) in patients with early RA who were on conventional synthetic DMARDs. Methods: In this cross-sectional study, 30 RA patients from a rheumatology department were enrolled over six months. The study included adults aged 30-70 years, of both genders, who had been on DMARDs for at least 6 months. Exclusion criteria included fracture of the affected joint, pregnancy, use of steroids or lipid-lowering agents, and heavy smoking. Data on demographics, disease duration, type of DMARDs, and lipid profiles were collected. The DAS-28 score was calculated for each patient. Statistical analysis was performed using SPSS Version 25, with Pearson’s Correlation coefficient used to measure relationships between variables. Results: The cohort consisted of 53.3% males and 46.7% females, with a mean age of 48.23 years. The majority (76.7%) were rheumatoid factor positive. The most commonly used DMARD was Methotrexate (46.7%). The study found strong negative correlations between DAS-28 scores and lipid levels: total cholesterol (Pearson's r = -0.837), triglycerides (r = -0.759), LDL (r = -0.720), and HDL (r = -0.689). BMI showed a significant positive correlation with DAS-28 (r = 0.711). A notable negative correlation was observed between the duration of DMARD use and DAS-28 scores (r = -0.777). Conclusion: The study indicates a significant correlation between lipid profiles and disease activity in RA patients on DMARDs. The findings suggest that effective RA management with DMARDs could influence lipid metabolism and potentially reduce cardiovascular risks. These insights are crucial for developing comprehensive RA treatment strategies that encompass both joint health and cardiovascular considerations.

Association between disease-modifying antirheumatic drugs for rheumatoid arthritis and risk of incident dementia: a systematic review with meta-analysis

BackgroundDysregulation of several inflammatory cytokines including tumour necrosis factor (TNF) in dementia patients has also been identified as a key factor in the pathogenesis of rheumatoid arthritis (RA). We aimed...