Evaluation of the efficacy and safety of a herbal formulation for rheumatoid arthritis - A non-inferiority randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a diverse disease characterized by a variable, progressive course of articular and extra-articular symptoms that are linked with pain, disability, and mortality. The exact cause of rheumatoid arthritis is still being investigated, and there is no cure for this debilitating, persistent, painful disease. Qurs-e-Mafasil, a herbal Unani preparation, is regarded as a potent treatment for Waja'al-Mafasil, a condition clinically similar to rheumatoid arthritis, but scientific evidence is scarce. AIM OF THE STUDY: This study aimed to assess the non-inferiority of Qurs-e-Mafasil compared to celecoxib in the treatment of patients with rheumatoid arthritis. MATERIALS AND METHODS: This randomized controlled trial was conducted on seventy patients diagnosed with rheumatoid arthritis between the ages of 35 and 55 years. The participants were randomly allocated in a ratio of 3:2, with 42 participants in the test group and 28 participants in the control group. The test group was administered 2 tablets (each having 500 mg) of Qurs-e-Mafasil, while the control group was administered 1 capsule of Celecoxib 100 mg. Both medications were delivered for four weeks. The primary outcome measure was European League Against Rheumatism (EULAR) response criteria based on Disease Activity Score-28 (DAS28) assessed before and after therapy, whereas the secondary outcome measure was the change in joint pain severity as determined by a 100 mm Visual Analog Scale (VAS) at baseline and each follow-up. The safety of the interventions was evaluated based on adverse event monitoring at each follow-up and laboratory tests including hemogram, Liver Function Tests (LFTs), Kidney Function Tests (KFTs), and a complete urine examination performed at baseline and after four weeks of treatment. RESULTS: The per-protocol analysis was done on 50 participants (30 in test group and 20 in control group) who completed the study duration. Thus, at the conclusion of the trial, participants in the test and control groups had either a moderate or no response based on EULAR response criteria. The odds ratio for no response versus moderate response between the test and the control groups was 0.71 (95% CI: 0.20-2.55) with p = 0.744. Moreover, the observed mean differences in VAS scores between the test and the control groups at 1st, 2nd, 3rd, and final follow-up were -0.33 (95% CI: -6.65 to 5.99, p = 0.916), 0.50 (95% CI: -5.63 to 6.63, p = 0.870), 2.42 (95% CI: -2.95 to 7.78, p = 0.370), and 3.00 (95% CI: -1.82 to 7.84, p = 0.219), respectively. CONCLUSIONS: The differences in primary and secondary outcomes between the two groups indicate that Qurs-e-Mafasil, a herbal Unani formulation containing Zingiber officinale Roscoe rhizome, Colchicum luteum Baker root, Piper nigrum L. fruit, and Withania somnifera (L.) Dunal. root, is comparable to celecoxib in the treatment of rheumatoid arthritis.

Impact of biological therapy in reducing the risk of arthritis development in inflammatory bowel diseases.

OBJECTIVE: Evaluate spondyloarthritis (SpA) incidence in inflammatory bowel diseases (IBD) between patients treated with biological disease-modifying antirheumatic drugs (bDMARDs) and conventional DMARDs (cDMARDs) and define risk factors associated with SpA development. METHODS: Retrospective cohort study was conducted on patients with Crohn's disease (CD) or ulcerative colitis (UC) and divided into two cohorts: cDMARDs or bDMARDs/targeted synthetic (ts) DMARDs treated patients. Rheumatological assessment was performed in patients presenting musculoskeletal symptoms. Multivariate analysis and Kaplan-Meier curves were used to evaluate the adjusted SpA risk development. RESULTS: 507 patients were included in the study. 176 patients with CD received bDMARDs, 112 cDMARDs and 106 new SpA diagnosies were formulated. Females (OR 1.7 (95% CI 1.1 to 3), adjusted p=0.04), non-stricturing/non-penetrating phenotype (OR 2 (95% CI 1.1 to 3.4), adjusted p=0.01), psoriasis (OR 2.1 (95% CI 1 to 4.6), adjusted p=0.04) and non-infectious uveitis (OR 6.8 (95% CI 1.4 to 33.4), adjusted p=0.01) were associated with increased SpA risk development, while bDMARDs usage was protective (OR 0.4 (95% CI 0.2 to 0.8), adjusted p=0.01), statistically higher than cDMARDs throughout the entire follow-up (effect size 0.47). 98 patients with UC received b-tsDMARDs, 121 cDMARDs and 56 new SpA diagnoses were formulated. Females (OR 2.1 (95% CI 1 to 4.3), adjusted p=0.02) and psoriasis (OR 2.7 (95% CI 1 to 6.8), adjusted p=0.03) were associated with increased SpA risk development, while bDMARDs were protective for SpA development for up to 12 months of treatment compared with cDMARDs (p=0.03). CONCLUSIONS: bDMARDs treatment had an impact in reducing SpA development and clinical associated risk factors to transition from IBD to IBD-SpA emerged.

Efficacy and safety of the modified Zhiwang decoction combined with methotrexate in early rheumatoid arthritis: study protocol for a randomised controlled trial.

INTRODUCTION: Rheumatoid arthritis (RA) is a progressive inflammatory autoimmune disease characterised by chronic systemic inflammation, which can cause swelling, stiffening and destruction of articular cartilage and bone. Early diagnosis and treatment of RA can improve outcomes and slow the progression of joint damage. Preliminary exploratory research had hinted an expected effect of modified Zhiwang decoction (MZWD) in treating early RA. However, few randomised clinical trials have evaluated the effectiveness of MZWD in early RA. Therefore, a parallel-group randomised controlled trial was designed to evaluate the efficacy and safety of MZWD combined with methotrexate (MTX) on early RA. METHODS AND ANALYSIS: This is a prospective, parallel-group, single-centre randomised controlled clinical study. A total of 150 patients will be randomly assigned to either the treatment (n=75) or control group (n=75). The treatment group will receive MZWD and MTX, and the control group will receive MTX for 12 weeks. The primary outcome of this study is Disease Activity Score-28, and the secondary outcomes are Fatigue Scale-14, Visual Analogue Scale pain scores and traditional Chinese medicine symptom scores. Safety outcomes, including adverse events and results of ECG and laboratory tests, will be monitored. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Clinical Research Ethics Committee of the China-Japan Friendship Hospital (no. 2022-KY-124) on 8 July 2022. The findings will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05508815).

Delayed low-dose methotrexate excretion in a rheumatoid arthritis patient: A case report and literature review.

RATIONALE: Low-dose methotrexate has a relatively good safety profile. However, in cases where patients with multiple risk factors, a delayed excretion has been observed, resulting in the occurrence of severe adverse reactions. It is necessary to supervise and intervene throughout the entire process of treating patients with multiple risk factors for methotrexate, and to strengthen the rational application of methotrexate. PATIENT CONCERNS AND DIAGNOSES: A 66-year-old male patient was admitted to our hospital with rheumatoid arthritis and underlying conditions such as chronic obstructive pulmonary disease (COPD). This patient received treatment with low-dose MTX (10 mg/week) and experienced adverse reactions including anemia. He was diagnosed with methotrexate-induced bone marrow suppression. INTERVENTIONS AND OUTCOMES: The therapeutic drug monitoring revealed that the serum drug concentration of methotrexate was at a critical level and the patient was rescue with calcium folinate and other adjuvant therapy such as transfusions of red blood cells, plasma, platelets, oral Yixuesheng tablets and Leucogen tablets. We conducted a 1-month follow-up, and there was no recurrence of bone marrow suppression and anemia. LESSONS: To ensure rational administration of methotrexate, it is important to fully evaluate the clinical manifestations and physical condition of patients and regularly detecting the serum drug concentration of methotrexate when patients with multiple risk factors, Otherwise, even low-dose methotrexate administration may cause delayed excretion, resulting in severe adverse reactions.

Safety of esthetic procedures in rheumatic patients: single-center survey of patients.

The popularity of esthetic medicine is growing every year, also among patients with autoimmune inflammatory rheumatic diseases (AIRD). The objective of this study was to evaluate the safety of esthetic medicine (AM) procedures in patients with AIRD. A semi-structured, anonymous questionnaire regarding rheumatic and concomitant diseases and AM procedures was distributed among adult patients hospitalized in the rheumatology department or attending outpatient clinic in the National Institute of Geriatrics, Rheumatology, and Rehabilitation, Warsaw. The main outcome was the occurrence of an adverse event. A number of 512 patients took part in the survey and 15 were excluded (AM procedure preceded the diagnosis of AIRD). The study group consisted of 497 patients, of whom 47 had undergone AM procedures. The procedures performed included: tattooing (22 patients), piercing (16 patients), hyaluronic acid (7 patients), botulinum toxin (5 patients) injections, laser procedures (6 patients), plastic surgery (4 patients), mesotherapy (3 patients) and others. The vast majority of patients had these performed during remission or low disease activity. 70.2% of patients received treatment with disease-modifying antirheumatic drugs (DMARDs) during the AM procedure, with TNF-alfa inhibitors being the most common (63.6%). Adverse events occurred in 15% of patients. All were mild and transient site reactions. Most patients would like to repeat the AM procedure in the future. The use of esthetic medicine procedures in patients with AIRD, including those treated with biologic DMARDs, was associated with a risk of mild site reactions. Most of the patients expressed satisfaction with the results of the AM procedure.

Efficacy and safety of Duhuo-Jisheng decoction in rheumatoid arthritis: A systematic review and meta-analysis of 42 randomized controlled trials.

BACKGROUND: Duhuo-Jisheng decoction (DJD) is a Chinese herb formula. Previous studies have reported that the clinical symptoms and laboratory indicators of rheumatoid arthritis (RA) patients could be improved by DJD. However, the existing evidence was not robust enough and controversial. METHODS: Randomized controlled trials of DJD for RA were retrieved from Chinese and English databases from their inception to April 16, 2023. Meta-analysis was performed by Stata 17 software. We used subgroup analysis, meta-regression, and sensitivity analysis to identify potential sources of heterogeneity. The subgroup analysis and meta-regression were conducted from 6 aspects, including age, course of disease, course of treatment, interventions used in the experimental or control group, and random sequence generation. Galbraith plot was used to find studies with possible heterogeneity. Publication bias was assessed by Egger's test and funnel plots when the number of relevant studies was greater than or equal to 10. RESULTS: Forty-two studies were included, involving 3635 patients and 19 outcome indicators. Meta-analysis showed that, compared with the routine disease-modifying antirheumatic drugs (rDMARDs), DJD could better improve the level of laboratory indicators, main symptoms and signs, and questionnaire scores of RA patients. The laboratory indicators included rheumatoid factor, T lymphocyte subpopulation (including CD4+, CD8+, and CD4+/CD8+), and inflammatory biomarkers (including erythrocyte sedimentation rate, C-reactive protein, tumor necrosis factor-α, interleukin 6, interleukin 1ß, and interleukin 1). The main symptoms and signs included the duration of morning stiffness, the number of joint tenderness, the number of swollen joints, and the grip strength of both hands. The questionnaire included visual analogue scale, health assessment questionnaire, and disease activity score in 28 joints. In addition, the adverse events of DJD treatment were significantly lower than those of rDMARDs. However, the results of a few subgroup analyses differed from the overall results. Furthermore, the publication bias assessment showed that, out of 11 evaluated results, 4 had publication bias. CONCLUSION: DJD could be a satisfactory complementary and alternative therapy for RA. However, due to a small number of subgroup analysis results being different from the overall results, it should be verified by further studies.

Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study.

BACKGROUND: Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study. METHODS: Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported. RESULTS: Of 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population. CONCLUSIONS: Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure. TRIAL REGISTRATION: NCT02049138.

Biologic therapy is associated with malignancies among Israeli patients with rheumatoid arthritis: A population-based study.

AIMS: To examine whether biologic disease-modifying anti-rheumatic drugs (bDMARDs) are associated with increased risk of malignancy among Israeli patients with rheumatoid arthritis (RA). METHODS: We identified RA patients meeting specified inclusion and exclusion criteria from the Leumit healthcare services database between the years 2000 and 2017. Data were collected regarding bDMARD and conventional DMARD consumption, types of malignancies, and their temporal relation to RA diagnosis. The association between baseline variables and occurrence of malignancies was examined by Cox regression. RESULTS: Among 4268 eligible RA patients, 688 (16.12%) were diagnosed with any malignancy. Melanoma skin cancer (MSC) was the most prevalent malignancy (148/688, 21.5%). The proportions out of all malignancies of MSC and non-melanoma skin cancer (NMSC) were higher after than before RA diagnosis (24.7% vs 19.1%, p = .025 and 24.7% vs 13.0%, p = .021, respectively). A higher proportion of RA patients diagnosed with malignancy used bDMARDs in comparison with RA patients who were malignancy-free (40.2% vs 17.5%, p < .001). After adjusting for demographic and clinical variables, bDMARDs were associated with an increased risk of malignancy (hazard ratio 1.42, 95% confidence interval 1.10-1.78). CONCLUSIONS: Biologic DMARDs are associated with increased risk of malignancy among Israeli RA patients, presumably contributed by MSC and NMSC. MSC was the most prevalent type of malignancy in this cohort and may indicate a predisposition state among Israeli RA patients.

The predictors of paradoxical reactions, especially psoriasis, to biologic therapy-findings from the TReasure database: a 5-year follow-up study.

OBJECTIVES: The objectives of this study were to assess the clinical characteristics, predictive factors, and practical algorithms of paradoxical reactions (PRs), specifically paradoxical psoriasis (PP). METHODS: The TReasure database is a web-based prospective observational cohort comprised of patients with RA and SpA from 17 centres around Turkey since 2017. A cohort study and a case-control study nestled within the cohort were identified. RESULTS: In total, 2867 RA and 5316 SpA patients were evaluated. The first biologic agent was found to have caused PRs in 60% of the 136 patients (1.66%) who developed the PRs. The median time interval between the PRs and biological onset was 12 months (range 1-132 months, mean 21 months). The most common types of PP, constituting 92.6% of PRs, were pustular (60.3%) and palmoplantar (30.9%). Adalimumab (30.9%), infliximab (19%) and etanercept (17.4%) were the most common agents causing the PP. In the treatment of most PP patients (73.2%), switching biologic agents was favoured, with TNF inhibitor (TNFi) chosen in 46.03% and non-TNFi in 26.9% of cases. The three most frequently selected drugs were etanercept (24.6%), secukinumab (9.5%) and adalimumab (8.7%). Only 5.17% of patients who switched to another TNFi showed progression. The odds ratios (s) for SSZ, HCQ, and LEF use were significantly higher in RA controls than in PP patients (P = 0.033, OR = 0.15; P = 0.012, OR = 0.15; and P = 0.015, OR = 0.13, respectively). In the PP group with SpA, the number of smokers was significantly higher (P = 0.003, OR: 2.0, 95% CI: 1.05, 3.81). CONCLUSION: Contrary to expectations based on earlier research suggesting that paradoxical reactions develop with the class effect of biological agents, the response of patients who were shifted to another TNFi was favourable.

Relationship between frailty and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients.

INTRODUCTION: Methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA). Frailty is the intermediate condition between being healthy and disabled, and can lead to negative health outcomes. Adverse events (AEs) due to RA drugs are expected to be higher in frail patients. The present study aimed to investigate the relationship between frailty and MTX discontinuation due to AEs in RA patients. METHODS: Of 538 RA patients who visited us between June and August 2020 as part of the retrospective T-FLAG study, 323 used MTX. After 2 years of follow-up, we investigated AEs leading to MTX discontinuation. Frailty was defined as a Kihon Checklist (KCL) score ≥ 8. Cox proportional hazards regression analysis was performed to identify factors associated with MTX discontinuation due to AEs. RESULTS: Of the 323 RA patients (251 women, 77.7%) who used MTX, 24 (7.4%) discontinued MTX due to AEs during the 2-year follow-up period. Mean ages in the MTX continuation/discontinuation groups were 64.5 ± 13.9/68.5 ± 11.7 years (p = 0.169), Clinical Disease Activity Index was 5.6 ± 7.3/6.2 ± 6.0 (p = 0.695); KCL was 5.9 ± 4.1/9.0 ± 4.9 points (p < 0.001); and the proportion of frailty was 31.8%/58.3% (p = 0.012). MTX discontinuation due to AEs was significantly associated with frailty (hazard ratio 2.34, 95% confidence interval 1.02-5.37) even after adjusting for age and diabetes mellitus. AEs included liver dysfunction (25.0%), pneumonia (20.8%), and renal dysfunction (12.5%). CONCLUSIONS: Because frailty is a significant factor contributing to MTX discontinuation due to AEs, the latter should be carefully monitored in frail RA patients who use MTX. Key Points • Of the 323 rheumatoid arthritis (RA) patients (251 women, 77.7%) who used methotrexate (MTX), 24 (7.4%) discontinued MTX due to adverse events (AEs) during the 2-year follow-up period. • MTX discontinuation due to AEs was significantly associated with frailty (hazard ratio 2.34, 95% confidence interval 1.02-5.37) even after adjusting for age and diabetes mellitus, and neither the MTX dose, folic acid supplementation, nor GC co-therapy were factors in MTX discontinuation. • Frailty is a predominant factor in MTX discontinuation among established, long-term pretreated RA patients, and the occurrence of AEs due to MTX should be carefully monitored when frail RA patients use MTX.

Effectiveness of Yishen Tongbi decoction versus methotrexate in patients with active rheumatoid arthritis: A double-blind, randomized, controlled, non-inferiority trial.

BACKGROUND: Yishen Tongbi decoction (YSTB) which is an herbal formula, has been used for the treatment of rheumatoid arthritis (RA) for more than ten years with a better curative effect. Methotrexate (MTX) is an effective anchoring agent used to treat rheumatoid arthritis. There were, however, no head-to-head comparative randomized controlled trials comparing traditional Chinese medicine (TCM) to MTX, Therefore, we performed this double-blind, double-model, randomized controlled trial of the efficacy and safety of YSTB and MTX in the treatment of active RA for 24 weeks. METHODS: Patients who met the enrollment criteria were randomly selected (1:1) to receive either YSTB therapy (YSTB 150 ml once daily + MTX placebo 7.5-15 mg once weekly) or MTX therapy (MTX 7.5-15 mg once weekly + YSTB placebo 150 ml once daily) in treatment cycles lasting 24 weeks. The percentage of patients who achieve a clinical disease activity index (CDAI) response at week 24 is the primary efficacy outcome. A 10% risk differential non-inferiority margin was previously defined. The Chinese Clinical Trials Registry has recorded this trial (ChiCTR-1,900,024,902, registered on August 3rd 2019, http://www.chictr.org.cn/index.aspx). RESULTS: Out of 118 patients whose eligibility was determined from September 2019 to May 2022, 100 patients (n = 50 for each group) were enrolled in the research overall. The 24-week trial was completed by 82% (40/49) of the YSTB group's patients and 86% (42/49) of the MTX group's patients. In the intention-to-treat analysis, 67.4% (33/49) of patients in the YSTB group met the main outcome of CDAI response criteria at week 24, compared to 57.1% (28/49) in the MTX group. The risk difference was 0.102 (95% CI -0.089 to 0.293), which demonstrated the non-inferiority of YSTB to MTX. After further testing for superiority, the ratio of CDAI responses achieved by the YSTB and MTX groups was not statistically significant (p = 0.298). At the same time, in week 24, secondary outcomes such as the ACR 20/50/70 response, the European Alliance of Associations for Rheumatology good or moderate response, remission rate, simplified disease activity index response, and low disease activity rate all showed similar statistically significant patterns. There was statistically significant attainment of ACR20 (p = 0.008) and EULAR good or moderate response (p = 0.009) in two groups at week 4. The intention-to-treat analysis results and the per-protocol analysis results were in agreement. The incidence of drug-related adverse events was not statistically different between the two groups (p = 0.487). CONCLUSIONS: Previous studies have used TCM as an adjunct to conventional therapy, and few of them have directly compared it with MTX. In order to lessen disease activity in RA patients, this trial demonstrated that YSTB compound monotherapy was non-inferior to MTX monotherapy and had superior efficacy following short-term treatment. This study provided evidence-based medicine in the treatment of RA with compound prescriptions of TCM and contributed to promoting phytomedicine use in RA patients.

Hydroxychloroquine Dose and Risk for Incident Retinopathy : A Cohort Study.

BACKGROUND: Hydroxychloroquine is recommended for all patients with systemic lupus erythematosus and is often used for other inflammatory conditions, but a critical long-term adverse effect is vision-threatening retinopathy. OBJECTIVE: To characterize the long-term risk for incident hydroxychloroquine retinopathy and examine the degree to which average hydroxychloroquine dose within the first 5 years of treatment predicts this risk. DESIGN: Cohort study. SETTING: U.S. integrated health network. PARTICIPANTS: All patients aged 18 years or older who received hydroxychloroquine for 5 or more years between 2004 and 2020 and had guideline-recommended serial retinopathy screening. MEASUREMENTS: Hydroxychloroquine dose was assessed from pharmacy dispensing records. Incident hydroxychloroquine retinopathy was assessed by central adjudication of spectral domain optical coherence tomography with severity assessment (mild, moderate, or severe). Risk for hydroxychloroquine retinopathy was estimated over 15 years of use according to hydroxychloroquine weight-based dose (>6, 5 to 6, or ≤5 mg/kg per day) using the Kaplan-Meier estimator. RESULTS: Among 3325 patients in the primary study population, 81 developed hydroxychloroquine retinopathy (56 mild, 17 moderate, and 8 severe), with overall cumulative incidences of 2.5% and 8.6% at 10 and 15 years, respectively. The cumulative incidences of retinopathy at 15 years were 21.6% for higher than 6 mg/kg per day, 11.4% for 5 to 6 mg/kg per day, and 2.7% for 5 mg/kg per day or lower. The corresponding risks for moderate to severe retinopathy at 15 years were 5.9%, 2.4%, and 1.1%, respectively. LIMITATION: Possible misclassifications of dose due to nonadherence to filled prescriptions. CONCLUSION: In this large, contemporary cohort with active surveillance retinopathy screening, the overall risk for hydroxychloroquine retinopathy was 8.6% after 15 years, and most cases were mild. Higher hydroxychloroquine dose was associated with progressively greater risk for incident retinopathy. PRIMARY FUNDING SOURCE: National Institutes of Health.

Discontinuation of biologic therapy in patients with rheumatoid arthritis and ankylosing spondylitis: analysis from multicenter cohort study.

Despite of the availability of several effective bDMARDs, a significant proportion of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients discontinued bDMARDs. The aims of this study were to analyze causes of bDMARDs discontinuation in RA and AS included in the Moroccan registry RBSMR. A historical prospective multicenter cohort study based on the RBSMR database at 12 months of follow-up, which included 225 RA and 170 AS. Using T student, Mann-Whitney U, chi-squared or Fischer exact tests, baseline demographic and clinical features were compared between patients discontinuing bDMARDs and patients remaining on initiated bDMARDs or switching bDMARDs. Logistic regression models were used to identify factors associated with drugs discontinuation. 61 RA discontinued bDMARDs and 47 AS interrupted anti-TNF. The most common reasons for drugs discontinuation were adverse events (7.5%) in RA patients and social security reimbursement problems (16.8%) in AS. RA patients discontinuing bDMARDs were more frequently first-line biological drugs users, more frequently female and had more comorbidities and lower DAS28 CRP than RA patients remaining on initiated bDMARDs or switching bDMARDs (p < 0.001, p = 0.01, p < 0.001 and p < 0.001 respectively). Female sex and comorbidities were the significant predictors of bDMARDs discontinuation in RA patients. Higher baseline BASDAI had a protective role on anti-TNF interruption in AS patients. Adverse events and social security reimbursement problems were the main reasons for drugs discontinuation in RA and AS patients respectively. Female sex and comorbidities in RA patients, baseline BASDAI in AS patients impacted bDMARDs discontinuation in real-life settings.

Unusual Presentation of Acute Hydroxychloroquine Retinopathy.

PURPOSE: To report a rare case of cystoid macular edema (CME) as a presentation of acute hydroxychloroquine-related retinal toxicity. OBSERVATIONS: A 37-year-old female patient visited our ophthalmology department in October 2019 complaining of bilateral blurred vision and metamorphopsia for 3 days. Best-corrected visual acuity (BCVA) was 6/6 in the right eye and 6/7.5 in the left eye under the Snellen E chart. Before presentation, she had taken hydroxychloroquine as a "reproduction-facilitating medication" prior to the in vitro fertilization (IVF) procedures with the daily dose of 200 mg for 1 week in March 2019 and 400 mg for 1 month in September 2019. She also took a combination of several herbal medicine including "Angelica sinensis" for 6 months in this period. On examination, typical signs of hydroxychloroquine maculopathy such as bilateral paracentral retinal pigment epithelium (RPE) change in blue autofluorescence and loss of the paracentral ellipsoid zone in optical coherence tomography ("flying saucer sign") were noted. CME was also found in fluorescein angiography. Her symptoms improved gradually after cessation of hydroxychloroquine and herb medicine without any further treatment. Resolution of bilateral CME was revealed at 16 weeks with final bilateral BCVA 6/6. CONCLUSIONS AND IMPORTANCE: Although rare, acute hydroxychloroquine maculopathy could occur in patients with concomitant usage of medications that could interfere with P450 enzymes system. Careful acquisition of drug history and serial ophthalmological examinations are advised in using hydroxychloroquine for disease management even for a short period of time.

Efficacy and safety of upadacitinib for active ankylosing spondylitis refractory to biological therapy: a double-blind, randomised, placebo-controlled phase 3 trial.

OBJECTIVES: To evaluate the efficacy and safety of upadacitinib, a Janus kinase inhibitor, in patients with active ankylosing spondylitis (AS) with an inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: Adults with active AS who met modified New York criteria and had an IR to one or two bDMARDs (tumour necrosis factor or interleukin-17 inhibitors) were randomised 1:1 to oral upadacitinib 15 mg once daily or placebo. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Sequentially tested secondary endpoints included Ankylosing Spondylitis Disease Activity score, Spondyloarthritis Research Consortium of Canada MRI spine inflammation score, total back pain, nocturnal back pain, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and Maastricht Ankylosing Spondylitis Enthesitis Score. Results are reported from the 14-week double-blind treatment period. RESULTS: A total of 420 patients with active AS were randomised (upadacitinib 15 mg, n=211; placebo, n=209). Significantly more patients achieved the primary endpoint of ASAS40 at week 14 with upadacitinib vs placebo (45% vs 18%; p<0.0001). Statistically significant improvements were observed with upadacitinib vs placebo for all multiplicity-controlled secondary endpoints (p<0.0001). Adverse events were reported for 41% of upadacitinib-treated and 37% of placebo-treated patients through week 14. No events of malignancy, major adverse cardiovascular events, venous thromboembolism or deaths were reported with upadacitinib. CONCLUSION: Upadacitinib 15 mg was significantly more effective than placebo over 14 weeks of treatment in bDMARD-IR patients with active AS. No new safety risks were identified with upadacitinib. TRIAL REGISTRATION NUMBER: NCT04169373.

Adalimumab or etanercept as first line biologic therapy in enthesitis related arthritis (ERA) - a drug-survival single centre study spanning 10 years.

OBJECTIVES: To analyse and compare drug-survival of adalimumab and etanercept (and their biosimilars) in biologic-naïve patients with ERA (Enthesitis-Related Arthritis). METHODS: In this retrospective observational study, conventional statistics and machine-learning were applied to compare drug-survival (adalimumab, etanercept and their biosimilars initiated: 2009-2019) in ERA and identify determinants. The primary outcome was discontinuation of treatment due to primary- or secondary-failure and adverse drug-reactions. RESULTS: During the observation period, 99 of 188 patients with ERA on first-line TNF inhibitors (etanercept-n=108, adalimumab-n=80) discontinued their treatment (median survival-time 3.9years, 95%CI 2.6-4.9years). Adalimumab was associated with longer drug-survival compared to etanercept especially after an initial positive response, with the median time to treatment discontinuation 4.9years (95% CI 3.9-5.7) for adalimumab, compared to 2years (95%CI 1.4-4.0) for etanercept (HR of treatment-discontinuation-0.49, 95%CI 0.32--0.75, p=0.001). Adjusted by propensity-score, adalimumab-methotrexate combination was associated with longer drug survival, compared to adalimumab-monotherapy (HR-0.41, 95%CI 0.20-0.85), etanercept-monotherapy (HR-0.28, 95%CI 0.15-0.53), and etanercept-methotrexate combination (HR-0.39, 95%CI 0.21-0.73). The presence of HLA-B27 was associated with longer drug-survival (HR-0.50, 95%CI 0.29-0.87) following an initial positive response. Higher-CRP at baseline was associated with higher rate of primary-failure (HR-1.68, 95%CI 1.08-2.62). Axial-ERA (sacroiliitis±spinal-involvement) was associated with poorer drug-survival for both primary- and secondary-failure (overall HR-2.03, 95%CI 1.22-3.40). Adjusted by propensity-score, shorter drug-survival was observed in patients with baseline-CRP≥12.15 mg/L, but only in the context of axial-ERA, not in peripheral-ERA (no sacroiliitis/spinal-involvement) (HR-2.28, 95%CI 1.13--3.64). CONCLUSION: Following an initial positive primary response, continuing methotrexate with adalimumab was associated with the longest drug-survival compared to adalimumab-monotherapy or etanercept-based regimens. Axial-ERA was associated with a poorer drug-survival. A CRP >12.15 in patients with axial-ERA was associated with a higher rate of primary-failure. Further prospective studies are required to confirm these findings.

[Biological therapy in juvenile idiopathic arthritis].

During the past 20 years of the biologic era, remission has become a realistic goal when treating children and adolescents with juvenile idiopathic arthritis (JIA). Studies describing long-term effects and safety are now available for several biologic agents, overall being well tolerated and with acceptable adverse events. No significant association between treatment with biologics and malignancy has been detected. This review finds that although biologics have been a success for most JIA patients, some fail to respond leaving the need for new treatment options and optimal switching between biologics most relevant.

Biotherapy in juvenile idiopathic arthritis Moroccan patients: a single-center experience.

In this study, we aimed to evaluate the clinicobiological findings and the biotherapy treatment response of Moroccan patients with juvenile idiopathic arthritis (JIA), and compare our results with those of populations of the same or different ethnicity. This retrospective cross-sectional study included patients aged 1-14 years, diagnosed between 2003 and 2018 with JIA according to the International League of Associations for Rheumatology (ILAR) 2004 revised criteria, who received biologics and who followed up during the year 2018 in the day hospital of our single-center tertiary pediatric rheumatology unit. Among 59 patients, 53% had systemic JIA, 29% seronegative polyarticular JIA, 8% arthritis-related enthesitis, 5% seropositive polyarticular JIA, 3% oligoarthritis and 2% psoriatic arthritis. Tocilizumab was the most prescribed biologic (34 patients), followed by Etanercept (25 patients), Adalimumab (6 patients), Anakinra (3 patients) and biosimilar Infliximab (3 patients). Eleven patients switched biologics. Erythrocyte sedimentation rate, number of active joints and the Juvenile Arthritis Disease Activity Score 27 (JADAS 27) decreased significantly at month three for 56 patients. These results were maintained at the last visit for 31 patients, while there was a slight worsening in 15 of them and no assessment in 13 patients due to lack of data. At the end of the evaluation, 39% of the patients were exclusively on biotherapy, while 61% were still on other disease-modifying antirheumatic drugs (DMARDs). Twenty-eight patients developed lymphopenia, 4 patients had elevated transaminases, 4 patients developed moderate infection, and 2 patients developed macrophage activation syndrome. To the best of our knowledge, this is the first Moroccan study on biotherapy in JIA. Our study population was characterized by a male predominance, a high frequency of the systemic form and a low percentage of positive antinuclear antibodies. We have shown that in the era of biologics, only 67.4% patients are nearly disease-free at the end of the study with a real risk of side effects. Although effective, biotherapy must be closely monitored because of potentially severe side effects, especially with Tocilizumab use.

A Systematic Review Characterizing Psoriatic Arthritis Onset and Exacerbation in Patients Receiving Biologic Therapy.

BACKGROUND: While biologic therapies revolutionized treatment of immune-mediated inflammatory diseases (IMIDs), some adverse effects have been noted. This includes the development and exacerbation of PsA in patients on biologic agents, however the outcomes were not extensively explored. OBJECTIVE: To perform a systematic review to characterize the outcomes of PsA onset or exacerbation secondary to biologic use. METHODS: MEDLINE and EMBASE search conducted on March 23, 2021 resulted in 18 studies comprised of 64 patients. RESULTS: Of the 64 patients, 57 (89.1%) experienced new-onset PsA and 7 (10.9%) experienced exacerbation of preexisting PsA following exposure to a biologic; most commonly a TNF-α inhibitor (42.2%, n = 27/64) and IL-12/23 inhibitors (39.1%, n = 25/64). The mean durations of biologic use before PsA onset and exacerbation were 14.8 months and 5.2 months, respectively. Twenty-four patients (44.4%) subsequently switched to an alternate biologic without further reports of PsA-related adverse events. All 64 patients reported a specific treatment for PsA; most commonly discontinuation of the associated biologic agent (32.8%, n = 21/64). Complete resolution of PsA was reported in 35.9% (n = 23/64) of cases, of which 91.3% (n = 21/23) resulted after discontinuation of biologic. CONCLUSION: Although we characterized outcomes of PsA induction and exacerbation secondary to biologic use, large-scale studies are required.

Placebo-Related Adverse Events in Rheumatoid Arthritis.

Prospective, double-blind, randomized, placebo-controlled studies are considered to provide the highest quality of interventional evidence. This meta-analysis summarizes the frequencies of adverse events according to the Medical Dictionary for Regulatory Activities (MedDRA) in the placebo arms of 101 such studies in rheumatoid arthritis, including a total of 17,150 patients in the placebo arms and 37,819 patients in the verum arms. Placebo-treated patients reported more than one adverse event in a median of 55.0%, 65.5%, and 72.5% (compared to 72.3% in the verum arms), and a serious adverse event in 2.5%, 5.8%, and 8.6% (compared to 5.9% in the verum arms), with stable doses of corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs as background therapies, respectively. Odds ratios were comparable between placebo and verum arms for nausea (1.00 with 95% confidence interval (CI) 0.86-1.17), for hepatobiliary disorders (1.08 with CI 0.85-1.36), for abnormal hepatic functions (1.09 with CI 0.83-1.44), and general disorders and administration site conditions (1.39 with CI 0.95-2.03). A publication bias has to be assumed for nausea (p = 0.018; Egger's test), diarrhoea (p = 0.022), and serious infections and infestations (p = 0.009). In conclusion, patients should be aware that "adverse events" may occur even with placebo medication, independent from an additional verum medication added to the background therapy. Further studies are warranted to respect and overcome the psychological and other issues related to these placebo-related "adverse events".