臨床研究等提出・公開システム

Efficacy and safety of hydroxychloroquine for Japanese patients with rheumatoid arthritis

Hydroxychloroquine for Japanese patients with rheumatoid arthritis

60

Patients with RA who fulfilled all the following criteria were enrolled: age 18 over years, diagnosed with RA according to the 1987 American College of Rheumatology (ACR) criteria or the 2010 ACR/European League Against Rheumatism (EULAR) criteria; active disease defined as a disease activity score for 28 joints using erythrocyte sedimentation rate (DAS28-ESR) over 2.6 despite methotrexate treatment or two or more csDMARDs and with poor prognostic factors , for more than 3 months, with stable doses used for at least 4 weeks. These poor prognostic factors include high disease activity; positivity for rheumatoid factor (RF) and/or anti-citrullinated protein antibodies; erosion; one or more swollen joints; and one or more tender joints. Prior use of b/tsDMARDs was allowed as long as it had been suspended for more than 3 months.

Sixty patients were enrolled and received HCQ. Seven patients withdrew during the 24-week period due to AEs (N = 6; skin rash in two patients, arthritis exacerbation in two patients, diarrhea in one patient, and tremor in one patient) and limited transportation to the hospital because of the Covid-19 pandemic (N = 1). Therefore, 53 patients completed HCQ therapy for 24 weeks and were considered candidates for propensity score matching. By using propensity score matching, 46 patients in each group were selected for further analysis.

Fifty nine adverse events (AE) were observed in 36 patinets among 60 patients treated with HCQ. The most frequent AEs were infections and infestations, which occurred in 15 patients (25.0%), followed by gastrointestinal disorders in 11 patients (18.3%). Serious AEs occurred in two patients (cataract operation with one-night hospitalization, and cerebral hemorrhage) during the 8-week post-observation period. Six patients withdrew from the study before week 24 due to AEs (one diarrhea, one tremor, two arthritis exacerbation, two drug-related eruptions). No HCQ retinopathy was observed during the study.

1)Primary endpoint of the proportion of ACR20 achievement at week 24 was significantly higher in the HCQ group than that in the control group (54.4 % vs. 28.3 %, P = 0.007) 2) Secondary endpoint (Improvement in one or more DAS28-ESR category) HCQ group: 29 (63%,95%CI 47.5-76.8) at week 4, 28 (60.9%,95%CI 45.4-74.9) at week 8, 38 (82.6%,95%CI 68.6-92.2) at week 12 and 36 (78.3%,95%CI 63.6-89.1) at 24 week. Improvement in one or more DAS28-ESR categories at week 24 was higher in the HCQ group than that in the control group (78.3% vs. 50.0%, P = 0.009) (The rate of low disease activity (plus remission) achievement) HCQ group: 18 (39.1%,95%CI 25.1-54.6) at week 4, 18 (39.1%,95%CI 25.1-54.6) at week8, 26 (56.5%,95%CI 41.1-71.1) at week 12 and 26 (56.5%,98%CI 41.1-71.1) at week 24. The rate of low disease activity (plus remission) achievement was not different between HCQ and control group (56.5% vs. 43.5%, P = 0.264) (Clinical DAS28-ESR remission achievement at week 24) HCQ group: 7 (15.2%,95%CI6.3-28.9) at week 4, 12 (26.1%,95%CI 14.3-41.1) at week 8, 17 (37.0%,95%CI 23.2-52.5) at week 12 and 20 (43.5%,95%CI 28.9-58.9) at week 24. The proportion of patients showing improvement in clinical DAS28-ESR remission achievement at week 24 was higher in the HCQ group than that in the control group (43.5% vs. 17.4%, P = 0.014) (The proportion of patients with functional remission achievement) HCQ group: 28 (60.9%,95%CI 45.4-74.9) at week 4, 28(60.9%,95%CI 45.4-74.9) at week 8, 28 (60.9%,95%CI 45.4-74.9) at week 12 and 28 (60.9%,95%CI 45.4-74.9) at week 24. Functional remission achievement rates at week 24 were comparable between the HCQ and control groups (60.9% vs. 45.7%, P = 0.211). (Radiographic remission) HCQ group: 41 (89.1%, 95%CI 76.4-96.4) at week 24 (ACR 20 achievement at week 4, 8, and 12) HCQ group: 17 (37.0%,95%CI 23.2-52.5) at week 4, 18 (39.1%,95%CI 25.1-54.6) at week 8 and 24 (52.2%,95%CI 36.9-67.1) at week 12. (ACR 50 achievement) HCQ group: 3 (6.5%,95%CI 1.4-17.9) at week 4, 8 (17.4%,95%CI 7.8-31.4) at week 8, 13 (28.3%,95%CI 16.0-43.5) at week 12 and 14 (30.4%,95%CI 17.7-45.8) at week 24. ACR 50 achievement at week 24 was significantly higher in the HCQ group than that in the control group (30.4% vs. 4.3%, P = 0.006) (ACR 70 achievement) HCQ group: 0 (0%,95%CI 0-7.7) at week 4, 1 (2.2%,95%CI 0.1-11.5) at week 8, 3 (6.5%,95%CI 1.4-17.9) at week 12 and 8 (17.4%,95% CI 7.8-31.4) at week 24. ACR 70 achievement at week 24 was significantly higher in the HCQ group than that in the control group (17.4% vs. 0%, P = 0.005) (Serum cytokine and flow cytometry analysis) (Serum cytokine) Serum IFN gamma, IL-1 beta, IL-6, IL-12p70, and TNF alpha were slightly but significantly decreased at week 24 compared to those at baseline. They returned to baseline levels by 8 weeks after HCQ cessation. (Flow cytometry) The proportion of CD8 positive T cells among lymphocytes and classical monocytes among CD14 positive monocytes was decreased at week 24 when compared to that at baseline (P <0.05). They returned to baseline levels by 8 weeks after HCQ cessation. In contrast, NK cells among lymphocytes were increased at week 24 when compared to those at baseline (P < 0.05) and remained high even 8 weeks after HCQ cessation.

We investigated the efficacy and safety of hydroxychloroquine (HCQ) in patients with rheumatoid arthritis (RA). HCQ was administered to active RA despite conventional synthetic disease-modifying antirheumatic drugs for 24 weeks, in addition to prior treatment. The primary endpoint, the proportion of ACR20 achievements at week 24, was significantly higher in HCQ group compared to that of a propensity score matched control group. Neither hydroxychloroquine retinopathy nor any new safety signal was observed.

April. 23, 2023

No

There is no plan to share IPD.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180050

Kaneko Yuko

Keio University Hospital

35 Shinanomachi, Shinjuku-ku, Tokyo

ykaneko.z6@keio.jp

Takei Hiroshi

Keio University Hospital

35 Shinanomachi, Shinjuku-ku, Tokyo

+81-3-5363-3786

takei_hiroshi7@hotmail.com

Complete

Feb. 01, 2017

Interventional

non-randomized controlled trial

open(masking not used)

historical control

single assignment

treatment purpose

Rheumatoid arthritis patients with active disease (DAS28 greater than or equal to 2.6) over 18 years old

Contraindication to HCQ, e.g. history of retinopathy and hypersensitivity to 4-aminoquinoline

Both

Rheumatoid arthritis

Treatment with hydroxychloroquine for 24 weeks

D001172

D006886

Achievement rate of ACR20 at week 24

Achievement rate of improving DAS28 category at weeks 4, 8, 12 and 24
Achievement rate of low disease activity in DAS 28 at weeks 4, 8, 12 and 24
Achievement rate of clinical remission in DAS 28 at weeks 4, 8, 12 and 24
Achievement rate of functional remission in HAQ at weeks 4, 8, 12 and 24
Achievement rate of structural remission in modified total Sharp score at week 24
Achievement rate of ACR 20 at at weeks 4, 8, and 12
Achievement rate of ACR 50/70 at weeks 4, 8, 12 and 24
Adverse effects during whole study

+81-3-5363-3503

Oct. 16, 2018

None