scholarly journals Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial

2019 ◽  
Vol 78 (7) ◽  
pp. 899-907 ◽  
Author(s):  
Tsutomu Takeuchi ◽  
Yoshiya Tanaka ◽  
Satoshi Soen ◽  
Hisashi Yamanaka ◽  
Toshiyuki Yoneda ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Placebo Group ◽  
Structural Damage ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Mineral Density ◽  
Phase 3 ◽  
Double Blind ◽  
The Mean ◽  
Disease Modifying

ObjectiveTo evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA).MethodsThis was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated.ResultsIn total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1–L4) BMD in the placebo, Q6M and Q3M groups were −1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles.ConclusionsDenosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.

scholarly journals Effects of denosumab in Japanese rheumatoid arthritis patients treated with conventional anti-rheumatic drugs: 36-month extension of a phase 3 study

2021 ◽  
pp. jrheum.201376
Author(s):  
Yoshiya Tanaka ◽  
Tsutomu Takeuchi ◽  
Satoshi Soen ◽  
Hisashi Yamanaka ◽  
Toshiyuki Yoneda ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Type I Collagen ◽  
Joint Destruction ◽  
Term Treatment ◽  
Drug Discontinuation ◽  
Type I ◽  
Mineral Density ◽  
Phase 3 ◽  
Long Term Treatment

Objective To evaluate safety and efficacy of long-term denosumab 60 mg every 6 (Q6M) or 3 months (Q3M) in rheumatoid arthritis (RA) patients. Methods This 12-month, randomised, double-blind, placebo-controlled, multicentre phase 3 trial with an open-label extension period from 12 to 36 months (DESIRABLE) enrolled Japanese RA patients treated with placebo for 12 months then denosumab Q6M (P/Q6M) or denosumab Q3M (P/Q3M); denosumab Q6M for 36 months (Q6M/Q6M); or denosumab Q3M for 36 months (Q3M/Q3M). Efficacy was assessed by van der Heijde modified total Sharp (mTSS), bone erosion (ES), and joint space narrowing (JSN) scores. Results Long-term treatment better maintained mTSS and ES suppression in the P/Q3M and Q3M/Q3M versus P/Q6M and Q6M/Q6M groups; changes from baseline in total mTSS at 36 months were 2.8 (standard error 0.4), 1.7 (0.3), 3.0 (0.4), and 2.4 (0.3), respectively; corresponding changes in ES were 1.3 (0.2), 0.4 (0.2), 1.4 (0.2), and 1.1 (0.2). No JSN effect was observed. Bone mineral density consistently increased in all groups after denosumab initiation, regardless of concomitant glucocorticoid administration. Serum C-telopeptide of type I collagen decreased rapidly at 1-month post-denosumab administration (both in the initial 12- month [Q3M, Q6M groups] and long-term treatment [P/Q3M, P/Q6M groups] phases). Adverse event incidence leading to study drug discontinuation was similar across treatment groups. Conclusion Denosumab treatment maintained inhibition of progression of joint destruction up to 36 months. Based on effects on ES progression, higher dosing frequency at an earlier treatment stage may be needed to optimise treatment. Denosumab was generally well tolerated.

scholarly journals 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

2015 ◽  
Vol 75 (6) ◽  
pp. 983-990 ◽  
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.

scholarly journals Identifying the preferable rheumatoid arthritis subgroups for intervention with the anti-RANKL antibody denosumab to reduce progression of joint destruction

RMD Open ◽  
2020 ◽  
Vol 6 (2) ◽  
pp. e001249
Author(s):  
Yoshiya Tanaka ◽  
Satoshi Soen ◽  
Naoki Ishiguro ◽  
Hisashi Yamanaka ◽  
Toshiyuki Yoneda ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Nuclear Factor Κb ◽  
Phase Iii ◽  
Concomitant Treatment ◽  
Double Blind ◽  
Radiographic Damage ◽  
Interaction Factor

ObjectivesTo clarify which rheumatoid arthritis (RA) patients benefit most from the anti-receptor activator of nuclear factor-κB ligand antibody denosumab to reduce the progression of joint destruction.MethodsWe pooled patient data from the 12-month, double-blind, placebo-controlled DRIVE (phase II) and DESIRABLE (phase III) studies. In DRIVE, concomitant treatment was limited to methotrexate, salazosulfapyridine and bucillamine. In DESIRABLE, patients could receive any disease-modifying antirheumatic drug. RA patients were randomised to denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or placebo. Efficacy was assessed by van der Heijde-modified total Sharp score (mTSS), bone erosion score (ES) and joint space narrowing score (JSNS). Change in mTSS was assessed in subgroups stratified by risk factors for radiographic damage if the interaction factor was significant.ResultsThe pooled analysis included 909 patients. Denosumab reduced worsening of mTSS (mean (SD)) at 12 months in the Q6M (0.88 (3.30), p=0.0024) and Q3M (0.66 (2.16), p=0.0002) groups versus placebo (1.50 (3.73)). This reduction in mTSS progression was due to the change in ES (Q6M, 0.44 (1.89), p=0.0006; Q3M, 0.20 (0.86), p<0.0001) versus placebo (0.98 (2.54)); no effect was observed on JSNS. Anti-cyclic citrullinated peptide (CCP) antibodies, glucocorticoid use and baseline ES showed a significant interaction. Denosumab was particularly effective in patients who were anti-CCP antibody positive (p<0.05). Changes in mTSS versus placebo were observed in all denosumab dose groups, regardless of glucocorticoid use and baseline ES.ConclusionsDenosumab broadly reduced the progression of joint destruction in RA patients with risk factors for radiographic damage such as especially anti-CCP antibody positivity.

Remission achieved after 2 years treatment with low-dose prednisolone in addition to disease-modifying anti-rheumatic drugs in early rheumatoid arthritis is associated with reduced joint destruction still present after 4 years: an open 2-year continuation study

2008 ◽  
Vol 68 (4) ◽  
pp. 508-513 ◽  
Author(s):  
I Hafström ◽  
K Albertsson ◽  
A Boonen ◽  
D van der Heijde ◽  
R Landewé ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Low Dose ◽  
Joint Destruction ◽  
Joint Space ◽  
Mineral Density ◽  
Scoring Method ◽  
Sustained Effect ◽  
Radiological Damage ◽  
Disease Modifying ◽  
Hands And Feet

Objective:To evaluate if remission induced by low-dose prednisolone during the first 2 years of rheumatoid arthritis (RA) in the BARFOT glucocorticoid (GC) study had a sustained effect on radiological damage for a total of 4 years.Methods:A total of 150 of 211 eligible patients with RA who had been randomised to the 7.5 mg prednisolone group (P) or no prednisolone group (NoP) in addition to the initial disease-modifying antirheumatic drugs were included. Radiographs of hands and feet were scored using the Sharp–van der Heijde scoring method. A patient was considered to be in remission if the 28-joint count disease activity score was <2.6.Results:Mean (SD) age was 53 (14) and 57 (12) years for the patients in the P and NoP groups, respectively. 64% were female, 64% rheumatoid factor positive, and disease duration at baseline was 6 months. At 2 years the proportion of patients in remission in the P and NoP groups was 55 vs 30%, p = 0.003. Longitudinal analysis showed that over the entire course of the disease, patients on prednisolone had a higher probability of being in remission. Patients in remission at 2 years, compared with those not in remission, had significantly lower total Sharp score, erosion score and joint space narrowing score at 2 and 4 years. The changes in bone mineral density during the 4 years did not differ between those in remission and those with active disease, and were similar in the two treatment groups.Conclusions:Prednisolone 7.5 mg daily in addition to disease-modifying anti-rheumatic drugs increases the rate of remission in patients with early RA, which has a beneficial and sustained effect on radiological damage.

scholarly journals POS0573 IMPACT OF JOINT DESTRUCTION IN THE HANDS, THE WRISTS AND THE ANKLES ON THE ULTRASOUND ASSESSMENT AND THE FUNCTIONAL OUTCOMES IN RHEUMATOID ARTHRITIS IN REMISSION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 521.1-521
Author(s):  
R. Fakhfakh ◽  
N. El Amri ◽  
K. Baccouche ◽  
H. Zeglaoui ◽  
E. Bouajina
Keyword(s):  
Rheumatoid Arthritis ◽  
Functional Outcomes ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Power Doppler ◽  
Health Assessment ◽  
Cross Sectional ◽  
Significant Difference ◽  
The Mean ◽  
Hands And Feet

Background:Joint destruction is a strong predictive factor for residual synovitis among rheumatoid arthritis (RA) patients in clinical remission. Both of them were associated with functional impairment.Objectives:To assess the ultrasound findings and functional outcomes of RA patients in remission according to the site of joint destruction.Methods:A Cross-sectional study including RA patients in remission DAS28 ESR≤ 2.6 for at least 6 months. A B-mode and power doppler (PD) ultrasound of 42 joints was performed. Synovitis was defined and scored using the combined OMERACT-PDUS (gray scale and power doppler (PD)) scoring system graded from 0 to 3. The health assessment questionnaire (HAQ) and the radiological Sharp score of the wrists, hands and feet were calculated.Results:Thirty-seven patients were included. The sex ratio was 0.37 and the mean age was 54.2 years ± 12.7. The mean disease duration was 8.1 years±5.1. The mean remission duration was 36.5 months ± 32.7. The mean DAS28vs was 2.1 ± 0.5. Rheumatoid factor and anti-citrullinated peptide antibodies were found in 62% and 75% of patients, respectively. The mean HAQ was 0.35 ± 0.38. Bone erosion was found in 81% of patients. In patients with hands and feet erosions (54%), synovitis was found in 90% of cases associated with PD in 70% of cases. The mean total score of synovitis was 7.8 ± 5.4. The mean HAQ was 0.37 ± 0.44. In patients with only erosions in the hands or wrists (18.9%), synovitis was found in 100% of cases associated with PD in 57% of cases. The mean total score of synovitis was 4.5±4.7. The mean HAQ was 0.48 ± 0.34. In patients with only feet erosions (8.1%), synovitis was found in 100% of cases associated with PD in 66.7% of cases. The mean total score of synovitis was 4.6±3.5. The mean HAQ was 0.31 ± 0.26. RA was not erosive in 18.9% of patients. In these patients, synovitis was found in 100% of cases associated with PD in 28.6% of cases. The mean total score of synovitis was 5.6±4.3. The mean HAQ was 0.21 ± 0.23. There is no significant difference between these groups(p>0.05).Conclusion:In RA in remission, PD synovitis and functional incapacity were less frequent in the absence of erosion. PD synovitis was more frequently found in patients with erosions, especially, in the feet. The HAQ was higher in patients with hands erosions.References:[1]Hamamoto Y, Ito H, Furu M, Hashimoto M, Fujii T, Ishikawa M, et al. Serological and Progression Differences of Joint Destruction in the Wrist and the Feet in Rheumatoid Arthritis - A Cross-Sectional Cohort Study. PLoS One. 2015;10(8):e0136611.Disclosure of Interests:None declared

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