AB0904 PERSISTENCE AND REASONS FOR DISCONTINUATION OF DENOSUMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background:Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B ligand, which inhibits osteoclast differentiation, activation and survival, not only increases bone mineral density but also inhibits the progression of bone erosion in patients with rheumatoid arthritis (RA)1-3). Therefore, denosumab have been preferably prescribed for patients with RA recently. The persistence with denosumab, which is administered subcutaneously once every 6 months, was reported higher than with oral bisphosphonates4), and in the prospective cohort studies, the persistence rate for one year was reported to be 82-95%5-6). However, there have been no report about the persistence in patients with RA treated with denosumab, moreover the reasons for discontinuation of denosumab.Objectives:The aims of this single center retrospective cohort study were 1) to assess the persistence with denosumab in a routine clinical setting and 2) to identify the reasons of discontinuation in patients with RA. And we also reviewed the clinical outcomes of osteonecrosis of the jaw in patients with RA during denosumab treatment.Methods:The present study is based on databases from our hospital, which include age, gender, date of injection of denosumab, as well as information on patients’ characteristics. Patients were included in this study when denosumab were newly started at our department during the period from June 1, 2013 and September 30, 2017. In this study, persistence was defined as patients with an interval between injections of no longer than 6 months plus 8 weeks. Patients were followed until censoring (death, transferring to another hospital) or the end of the study (August 3, 2018).We investigated reasons for the discontinuation of denosumab. Major reasons for the discontinuation of denosumab were classified as adverse event, anxiety over adverse events, patient’s transfer or request, doctor’s careless lack of refilling an injection, and other reason.We identified patients who had been diagnosed as osteonecrosis of the jaw, and demographic, pharmacological, and clinical data were collected from medical records.Results:One hundred and seventy-five patients were identified. Kaplan–Meier analysis showed a slow decline of persistence after initiating denosumab therapy, dropping to 80.4 and 61.9 % after 1 and 2 years of follow-up. When analyzing the reason of discontinuation as adverse events, the persistence rate of denosumab was at 89.4, and 79.4% at 1, and 2 years of follow-up, respectively.During 2-year period, 72 patients discontinued denosumab. A total of 27 adverse events occurred, of which five events were osteonecrosis of the jaw. The other reasons for adverse event included death in four, fracture in three, and so on. Six patients discontinued due to anxiety over dental adverse event. Thirteen patients were in doctor’s careless lack of refilling an injectionAll five patients who were diagnosed as osteonecrosis of the jaw had received the treatment with prednisolone, and four were treated with biologic drugs. All patients stopped denosumab and switched to other drugs including teriparatide. All patients underwent surgical curettages of necrotic bone and cured.Conclusion:Persistence of denosumab in patients with RA is comparable to that in postmenopausal women with osteoporosis. Dental screening and care should be important to continue denosumab treatment.References:[1]Cohen SB.Arthritis Rheum. 2008;58:1299–1309.[2]Takeuchi T.Ann Rheum Dis. 2019;78:899–907.[3]Ebina K.Osteoporos Int. 2018;29:1627–1636.[4]Hadji P.Osteoporos Int. 2016;27:2967–2978.[5]Silverman SL.Arch Osteoporos. 2018;13:85. doi:10.1007/s11657-018-0491-z[6]Hadji P.Osteoporos Int. 2015;26:2479–2489.Disclosure of Interests:Shinichi Mizuki Speakers bureau: AbbVie, Asahi Kasei, Chugai, Eli Lilly, Janssen, Mitsubishi Tanabe, Ono, Tatsuya Kai: None declared, Koji Mishima: None declared, Hiroko Ikeuchi: None declared, Kensuke Oryoji: None declared

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AB0206 DESCRIPTION AND FOLLOW-UP OF RHEUMATOID ARTHRITIS PATIENTS WHO STOPPED B/TSDMARD THERAPY, STRATIFIED BY CESSATION REASON

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.898 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1128.1-1128

Author(s):

T. Burkard ◽

E. Vallejo-Yagüe ◽

T. Hügle ◽

A. Finckh ◽

A. M. Burden

Keyword(s):

Rheumatoid Arthritis ◽

Adverse Event ◽

Family History ◽

Adverse Events ◽

Rheumatic Diseases ◽

Patient Characteristics ◽

Cohort Entry ◽

Research Support ◽

History Of

Background:Biologic or targeted synthetic disease modifying antirheumatic drugs (b/tsDMARD) may be stopped for several reasons such as non-response, adverse events, remission, or other reasons (e.g. major surgery). Understanding the reasons and consequences of b/tsDMARD therapy cessation may contribute towards therapy decision guidance. Moreover, identifying patient characteristics leading to the re-start of b/tsDMARD therapy may guide decision-making as to which patients should remain on continuous b/tsDMARD therapy versus who may potentially stop b/tsDMARD therapy.Objectives:To describe and follow rheumatoid arthritis (RA) patients who stopped b/tsDMARD therapy, stratified by cessation reason.Methods:We conducted a descriptive cohort study among adult RA patients in the longitudinal Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) between 1997 and 2019. RA patients who stopped their first b/tsDMARD therapy were eligible, with therapy stop date defining cohort entry. We followed all eligible patients from cohort entry until b/tsDMARD re-start (the outcome) or censoring due to end of patient record. All analyses were carried out stratified by cessation reason (non-response, adverse events, remission, other reasons, unknown reasons). We described patient characteristics (demographics, lifestyle factors, clinical information, other medication use, relevant comorbidities) at cohort entry. Furthermore, we estimated Kaplan Meier curves to describe differences in cumulative incidences of b/tsDMARD re-start. Finally, we assessed patient characteristics at b/tsDMARD re-start and compared them with those at cohort entry.Results:Among 2559 eligible RA patients, the majority stopped their b/tsDMARD due to non-response (982, 38%), followed by adverse events (475, 19%), other reasons (445, 17%), unknown reasons (444, 17%), and remission (213, 8%). Mean age at b/tsDMARD stop was around 56.2 years except in patients who stopped due to remission (mean age of 58.1 years). The majority of patients were women (78%), stopping due to an adverse event had the highest proportion of women (84%), stopping due to remission had the lowest proportion of women (70%). Compared to patients who stopped b/tsDMARD therapy due to non-response or adverse events, patients who stopped due to remission were generally more physically active, better educated, less likely to have a family history of rheumatic diseases, and had shorter median disease duration. A total of 2086 patients (82%) re-started b/tsDMARD therapy during follow-up. Of these, the majority did so after stopping due to non-response (94%), followed by adverse events (82%), unknown reasons (79%), other reasons (74%), and remission (47%). The median cumulative incidence of re-starting b/tsDMARD therapy was shortest after non-response (30 days), followed by unknown reasons (31 days), adverse events (94 days), other reasons (212 days), and remission (1597 days). The population who stopped b/tsDMARD therapy due to remission or other reasons yielded increased RA disease activity and an increase in proportions of women, cardiac diseases, degenerative joint disease, other auto-immune diseases, and of patients with family history of rheumatic diseases at the date of b/tsDMARD re-start. However, among patients who stopped b/tsDMARD therapy due to non-response or adverse events, patient characteristics at b/tsDMARD re-start were unchanged compared to those at b/tsDMARD stop.Conclusion:Observed differences in patient characteristics at b/tsDMARD stop may yield insight into why the patient was not responding, had an adverse event, or achieved remission. Observed changes in patient characteristics from the date of b/tsDMARD stop to re-start identified which ones may lead to a worsening of RA activity in the absence of b/tsDMARD therapy.Acknowledgements:We would like to thank Dr. Almut Scherer, Monika Hebeisen, and Eleftherios Papagiannoulis from SCQM for providing the data and answering questions thereto. A list of rheumatology offices and hospitals that are contributing to the SCQM registries can be found on www.scqm.ch/institutions. The SCQM is financially supported by pharmaceutical industries and donors. A list of financial supporters can be found on www.scqm.ch/sponsors.Disclosure of Interests:Theresa Burkard: None declared, Enriqueta Vallejo-Yagüe: None declared, Thomas Hügle Consultant of: Pfizer, Abbvie, Novartis, Grant/research support from: GSK, Jansen, Pfizer, Abbvie, Novartis, Roche, MSD, Sanofi, BMS, Eli Lilly, UCB, Axel Finckh Speakers bureau: Pfizer, Eli-Lilly, Paid instructor for: Pfizer, Eli-Lilly, Consultant of: Pfizer, BMS, Novartis, Grant/research support from: AbbVie, AB2Bio, BMS, Gilead, Pfizer, Viatris, Andrea Michelle Burden: None declared

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O06 Baseline predictors of methotrexate-related adverse events in methotrexate-naïve patients with RA

Rheumatology ◽

10.1093/rheumatology/keab246.005 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Ahmad A Sherbini ◽

James M Gwinnutt ◽

Kimme L Hyrich ◽

Suzanne M M Verstappen ◽

Keyword(s):

Rheumatoid Arthritis ◽

Adverse Events ◽

Health Assessment ◽

Prevalence Rates ◽

Clinical Predictors ◽

Research Support ◽

Related Data ◽

Increased Risk ◽

One Year

Abstract Background/Aims Methotrexate (MTX) is the most common treatment for rheumatoid arthritis (RA). The prevalence of adverse events (AEs) associated with MTX treatment for RA have been studied extensively, but there are limited data on the predictors of these AEs. This study aims to summarise the prevalence rates of MTX AEs, including gastrointestinal (GI), neurological, mucocutaneous, and elevated alanine transaminase (ALT) enzyme, and to identify baseline demographic and clinical predictors of these AEs. Methods The Rheumatoid Arthritis Medication Study (RAMS) is a UK multi-centre prospective cohort study of patients with RA starting MTX for the first time. Relevant demographic, medication, clinical and disease related data were collected at baseline. AEs were reported at six and twelve months follow-ups. The prevalence rates of AEs were calculated based on the proportions of patients who reported having had an AE within one year of follow-up. The associations between candidate baseline predictors and AEs were assessed using multivariable logistic regression. Results A total of 2,089 patients were included with a mean age of 58.4 (standard deviation: 13.5) years, 1390 (66.5%) were women. 1,814 and 1,579 patients completed the 6 and 12 months follow-up visits, respectively. The prevalence rates of the AEs within one year of follow-up were: GI = 777 (40.6%), mucocutaneous = 441 (23.1%), neurological = 487 (25.5%), elevated ALT (> upper limit of normal [ULN]) = 286 (15.5%). Younger age and being a woman were associated with increased risk of GI AEs, (age: OR 0.97 per year increase in age, 95% CI 0.98, 1.00; male sex: OR 0.58 vs female, 95% CI 0.46, 0.74) (Table 1). Higher baseline Health Assessment Questionnaire (HAQ) score was an independent predictor of GI, mucocutaneous, and neurological AEs. Furthermore, having ALT >1xULN at baseline or history of diabetes was associated with increased risk of subsequent ALT elevation during the study follow-up. Conclusion In patients with RA starting MTX, GI AEs were the most commonly reported AEs during the first year of follow-up. The identified predictors of AEs may facilitate discussions between clinicians and patients prior to commencing MTX, and may lead to increased adherence and consequently improved effectiveness. Disclosure A.A. Sherbini: None. J.M. Gwinnutt: Grants/research support; BMS. K.L. Hyrich: Member of speakers’ bureau; Abbvie. Grants/research support; Pfizer, UCB, BMS. S.M.M. Verstappen: Consultancies; Celltrion. Member of speakers’ bureau; Pfizer. Grants/research support; BMS.

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POS0647 EFFICACY, SAFETY AND CHARACTERISTICS OF IGURATIMOD-BASED THERAPY IN THE TREATMENT OF UA, ERA AND RA PATIENTS FOR 24 WEEKS: A PROSPECTIVE COHORT STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.91 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 561.2-562

Author(s):

X. Liu ◽

Z. Sun ◽

W. Guo ◽

F. Wang ◽

L. Song ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cohort Study ◽

Adverse Events ◽

Disease Activity ◽

Prospective Cohort Study ◽

Early Rheumatoid Arthritis ◽

Prospective Cohort ◽

Combined Treatment ◽

Serious Adverse Events

Background:Experts emphasize early diagnosis and treatment in RA, but the widely used diagnostic criterias fail to meet the accurate judgment of early rheumatoid arthritis. In 2012, Professor Zhanguo Li took the lead in establishing ERA “Chinese standard”, and its sensitivity and accuracy have been recognized by peers. However, the optimal first-line treatment of patients (pts) with undifferentiated arthritis (UA), early rheumatoid arthritis (ERA), and rheumatoid arthritis (RA) are yet to be established.Objectives:To evaluate the efficacy and safety of Iguratimod-based (IGU-based) Strategy in the above three types of pts, and to explore the characteristics of the effects of IGU monotherapy and combined treatment.Methods:This prospective cohort study (ClinicalTrials.gov Identifier NCT01548001) was conducted in China. In this phase 4 study pts with RA (ACR 1987 criteria[1]), ERA (not match ACR 1987 criteria[1] but match ACR/EULAR 2010 criteria[2] or 2014 ERA criteria[3]), UA (not match classification criteria for ERA and RA but imaging suggests synovitis) were recruited. We applied different treatments according to the patient’s disease activity at baseline, including IGU monotherapy and combination therapies with methotrexate, hydroxychloroquine, and prednisone. Specifically, pts with LDA and fewer poor prognostic factors were entered the IGU monotherapy group (25 mg bid), and pts with high disease activity were assigned to combination groups. A Chi-square test was applied for comparison. The primary outcomes were the proportion of pts in remission (REM)or low disease activity (LDA) that is DAS28-ESR<2.6 or 3.2 at 24 weeks, as well as the proportion of pts, achieved ACR20, Boolean remission, and good or moderate EULAR response (G+M).Results:A total of 313 pts (26 pts with UA, 59 pts with ERA, and 228 pts with RA) were included in this study. Of these, 227/313 (72.5%) pts completed the 24-week follow-up. The results showed that 115/227 (50.7%), 174/227 (76.7%), 77/227 (33.9%), 179/227 (78.9%) pts achieved DAS28-ESR defined REM and LDA, ACR20, Boolean remission, G+M response, respectively. All parameters continued to decrease in all pts after treatment (Fig 1).Compared with baseline, the three highest decline indexes of disease activity at week 24 were SW28, CDAI, and T28, with an average decline rate of 73.8%, 61.4%, 58.7%, respectively. Results were similar in three cohorts.We performed a stratified analysis of which IGU treatment should be used in different cohorts. The study found that the proportion of pts with UA and ERA who used IGU monotherapy were significantly higher than those in the RA cohort. While the proportion of triple and quadruple combined use of IGU in RA pts was significantly higher than that of ERA and UA at baseline and whole-course (Fig 2).A total of 81/313 (25.8%) pts in this study had adverse events (AE) with no serious adverse events. The main adverse events were infection(25/313, 7.99%), gastrointestinal disorders(13/313, 4.15%), liver dysfunction(12/313, 3.83%) which were lower than 259/2666 (9.71%) in the previous Japanese phase IV study[4].The most common reasons of lost follow-up were: 1) discontinued after remission 25/86 (29.1%); 2) lost 22/86 (25.6%); 3) drug ineffective 19/86 (22.1%).Conclusion:Both IGU-based monotherapy and combined therapies are tolerant and effective for treating UA, ERA, and RA, while the decline in joint symptoms was most significant. Overall, IGU combination treatments were most used in RA pts, while monotherapy was predominant in ERA and UA pts.References:[1]Levin RW, et al. Scand J Rheumatol 1996, 25(5):277-281.[2]Kay J, et al. Rheumatology 2012, 51(Suppl 6):vi5-9.[3]Zhao J, et al. Clin Exp Rheumatol 2014, 32(5):667-673.[4]Mimori T, et al. Mod Rheumatol 2019, 29(2):314-323.Disclosure of Interests:None declared

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Efficacy, Safety and Tolerability Of Valsartan Plus HCTZ in Patients With Essential Hypertension: A Multicentre Observational Study in Bangladesh

Cardiovascular Journal ◽

10.3329/cardio.v3i1.6425 ◽

1970 ◽

Vol 3 (1) ◽

pp. 37-44

Author(s):

MN Islam

Keyword(s):

Adverse Event ◽

Essential Hypertension ◽

Adverse Events ◽

Global Assessment ◽

Paired Comparison ◽

Additional Treatment ◽

Serious Adverse Events ◽

Published Evidence ◽

Bangladeshi Population

Background: Valsartan is an established drug for treatment of essential hypertension. It blocks the action of Angiotensin II irrespective of its sources. A large proportion of patients need additional treatment with two or more drugs of different pharmacological classes for achieving target blood pressure. Published evidence demonstrated synergistic effect of Thiazides with ARB. Coadministration of valsartan and Hydrochlorothiazide has the potential to reverse the untoward effect of each other. Current study aimed at evaluating the efficacy, safety and tolerability of Valsartan plus Hydrochlorothiazide combination, and thus validating the regimen in the treatment of essential hypertension in Bangladeshi population, a population significantly different from Caucasian population where most studies were done. Methods: Current study is a prospective interventional study involving 404 Adult, patients, with Stage I (SBP 140-159 mmHg/DBP 90-99 mmHg) or Stage II (SBP≥160 mmHg/DBP ≥100 mmHg) essential hypertension or patients uncontrolled on current mono-therapy or other combination therapy. Valsartan plus HCTZ 80/12.5 mg once daily tablet were prescribed to continue till the following visit or for the remainder of the study. In case of inadequate control increment in dose was made on the following visit. Patients were assessed at baseline, at 4th weeks, 12th week and 24th week. One of the major outcome parameter set for the study was the percentage of participant having BP controlled that is a SBP <140 mmHg and DBP <90 mmHg or a reduction >10 mmHg for DBP and/ or >20 mmHg SBP versus baseline values at 24 weeks. At final follow-up, in addition to repetition of the baseline measurements and examinations, data on Safety of the drug was collected by enquiring and recording all adverse events or serious adverse events. Global assessment of efficacy and tolerability of treatment was also done by both the physicians and patients on a 4-point scale. Result: The percentage of participant having BP controlled at the end of the trial was 91%. Besides, Significant reduction in mean SBP and mean DBP was also evident (P<.001) through paired comparison from baseline to end of the study. Average reduction of 32.4 ± 19.5 mmHg was seen in systolic BP and 17.4 ± 9.3 mmHg in diastolic BP. Global assessment based on both physician and patients reported greater satisfaction with the efficacy of treatment modality. Total adverse event reported by only six (1.5%) participants. Of the six cases three of the adverse effect was reported at 3rd visit and another three were reported at 4th visit. Total five dropouts (1.24%) were reported of which 1 in 3rd visit and 4 in 4th visit. Among the dropout patient three were withdrawn from the study and two didn’t attend the final follow-up. Global assessment of safety and tolerability based on both physician and patient’s opinion reveals greater satisfaction level with the safety and tolerability of combination treatment. Conclusion: The combination of valsartan and hydrochlorothiazide is an effective treatment for patients with essential hypertension. The combination is also effective in patients not responding to monotherapy with either agent. The drug is found to be well tolerated with minimal adverse event during the course of treatment. Key words: Valsartan; Hydrochlorothiazide; Hypertension. DOI: 10.3329/cardio.v3i1.6425Cardiovasc. j. 2010; 3(1): 37-44

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Calcium and vitamin D supplementation with 3-year denosumab treatment is beneficial to enhance bone mineral density in postmenopausal patients with osteoporosis and rheumatoid arthritis

Therapeutics and Clinical Risk Management ◽

10.2147/tcrm.s182858 ◽

2018 ◽

Vol Volume 15 ◽

pp. 15-22 ◽

Cited By ~ 7

Author(s):

Takako Suzuki ◽

Yukio Nakamura ◽

Hiroyuki Kato

Keyword(s):

Rheumatoid Arthritis ◽

Bone Mineral Density ◽

Vitamin D ◽

Bone Mineral ◽

Vitamin D Supplementation ◽

Mineral Density ◽

Denosumab Treatment

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Long-term follow up after denosumab treatment for osteoporosis – rebound associated with hypercalcemia, parathyroid hyperplasia, severe bone mineral density loss, and multiple fractures: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-020-02401-0 ◽

2020 ◽

Vol 14 (1) ◽

Author(s):

Yves Maugars ◽

Pascale Guillot ◽

Joëlle Glémarec ◽

Jean-Marie Berthelot ◽

Benoit Le Goff ◽

...

Keyword(s):

Bone Mineral Density ◽

Case Report ◽

Bone Mineral ◽

Mineral Density ◽

Multiple Fractures ◽

Bone Mineral Density Loss ◽

Long Term Follow Up ◽

Denosumab Treatment

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Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose–response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)—a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-208052 ◽

2015 ◽

Vol 75 (6) ◽

pp. 983-990 ◽

Cited By ~ 84

Author(s):

Tsutomu Takeuchi ◽

Yoshiya Tanaka ◽

Naoki Ishiguro ◽

Hisashi Yamanaka ◽

Toshiyuki Yoneda ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Phase Ii ◽

Bone Erosion ◽

Therapeutic Option ◽

Human Monoclonal Antibody ◽

Joint Destruction ◽

Japanese Patients ◽

Apparent Difference ◽

Mineral Density ◽

Erosion Score

ObjectivesTo evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA).MethodsIn this multicentre, randomised, placebo-controlled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months.ResultsDenosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo.ConclusionsAddition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction.Trial registration numberJapicCTI-101263.

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