TY - JOUR
AU - Makino, Shigeki
AB - Abstract Objectives: In this study, iguratimod (IGU) was added to rheumatoid arthritis (RA) patients inadequately responding to 24-week or longer treatment with biological disease-modifying antirheumatic drug (bDMARDs), its effectiveness was assessed, and factors contributing to remission were evaluated. Methods: RA patients who fulfilled the following criteria were included: (i) ≥ 24-week of bDMARDs; (ii) 2.6 < disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) < 5.1 or the presence of synovitis with a power Doppler (PD) score ≥2 in at least 1 of the 28 joints on joint ultrasonography. Disease activity and joint ultrasound findings were evaluated at baseline and at 12 and 24 weeks. Results: DAS assessing 28 joints with ESR (DAS28-ESR) decreased significantly from 3.45 ± 0.92 at baseline to 2.85 ± 1.13 at 24 weeks (p < .001). Overall, 38.3% achieved clinical remission (c-remission). The total PD score decreased significantly from 8.7 ± 6.1 at baseline to 5.5 ± 5.0 at 24 weeks (p < .001). A lower baseline DAS28-ESR was related to c-remission after 24 weeks (p =.002). Shorter duration of disease (p =.020) was related to ultrasound remission, in addition to a lower baseline DAS28-ESR (p < .001). Conclusions: IGU add-on therapy can be a therapeutic strategy to achieve remission in RA patients inadequately responding to ≥24-week treatment with bDMARDs. Biological disease-modifying antirheumatic drugs (bDMARDs), iguratimod, remission, rheumatoid arthritis, ultrasonography Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease that can cause joint damage and disability [1]. Combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as salazosulfapyridine (SASP) and methotrexate (MTX), and biological DMARDs (bDMARDs) has made it possible to achieve clinical remission (c-remission) in RA patients. However, only ∼30–50% of RA patients attain c-remission despite the use of bDMARDs [2–12], and their efficacy is unsatisfactory. According to the 2013 European League against Rheumatism (ELUAR) recommendations [13], if the therapeutic goal cannot be achieved with bDMARDs, c-remission should be pursued by switching to another bDMARD or by the addition of csDMARDs. However, the c-remission rate due to the switch from a tumor necrosis factor (TNF) inhibitor to another TNF inhibitor is only ∼6% [14,15], and the effect is attenuated; the c-remission rate with the switch from a TNF inhibitor to tocilizumab (TCZ) is also ∼30% [7]. On the other hand, with respect to csDMARD add-on therapy for RA patients not sufficiently responding to bDMARDs, there have been few reports predicting the therapeutic outcomes of csDMARDs to achieve c-remission. Iguratimod (IGU) is a csDMARD used in RA patients in Japan [16–22]. The therapeutic effects of IGU are derived from suppression of the production of inflammatory cytokines by inhibiting the activity of nuclear factor-κB (NFκB) and acting directly on B cells [23–28]. The efficacy of IGU in RA patients is not inferior to that of SASP [29], and IGU add-on MTX therapy is efficacious in patients with active RA with an inadequate response to MTX alone [30,31]. However, no report has evaluated the safety and efficacy of IGU add-on therapy in RA patients inadequately responding to bDMARDs. In addition, no report has evaluated RA disease activity using joint ultrasonography after IGU administration. Therefore, IGU add-on therapy was given to RA patients with an inadequate response to 24-week or longer treatment with bDMARDs, its efficacy including joint ultrasound findings was evaluated, and factors contributing to achieving remission were identified. Materials and methods Patients The subjects were RA patients aged 20 years or older who were treated at our hospital and met the 1987 ACR criteria [32] or 2010 ACR/EULAR classification criteria [33]. RA patients inadequately responding to 24-week or longer treatment using bDMARDs [2.6 < disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) < 5.1, or the presence of synovitis with a power Doppler (PD) score ≥2 in at least 1 of the 28 joints on joint ultrasonography] were regarded as eligible. Patients with a history of treatment with IGU, those with a contraindication to IGU, and those in whom other drugs such as prednisolone (PSL), MTX, SASP, and tacrolimus (TAC) were added or increased within 4 weeks before the add-on of IGU were excluded. Study design This study was approved by the Ethics Committee of Osaka Medical College (No. 1637) and was conducted according to the Declaration of Helsinki. RA patients who gave written, informed consent were enrolled in this study. The study period was from January 2015 to September 2016. The observation period of this study was 24 weeks. IGU was administered orally at 25 mg/day for the first 4 weeks, with the dose subsequently increased to 50 mg/day based on the physician’s discretion. Ultrasound evaluations Ultrasound evaluations were performed using the Aplio 300 platinum series (Toshiba Medical Systems Corporation, Tochigi, Japan) with a multi-linear 12-MHz (or 7.5-MHz in some shoulder and knee joint assessments) hockey stick probe. According to the Outcome Measures in Rheumatoid Arthritis Clinical Trial (OMERACT) [34], 28 joints (bilateral shoulders, elbows, wrists, first to fifth metacarpophalangeal joints, first to fifth proximal interphalangeal joints, and knee joints) were evaluated by a systematic multiplanar gray-scale (GS) and PD examination. Ultrasonography was performed by sonographers (A.Y. and Y.K.) registered with the Japan College of Rheumatology who were blinded to the clinical information and laboratory data at baseline and at 12 and 24 weeks. Each patient was examined by the same sonographer, and the clinical examination and joint ultrasonography were performed on the same days. The κ-value of the total PD score between examiners A.Y. and Y.K. was 0.83 (0.78–0.87). The κ-values within each examiner were 0.76 (0.71–0.81) for A.Y. and 0.75 (0.69–0.80) for Y.K. The inter-rater intraclass correlation coefficient (ICC) for the total PD scores between examiners A.Y. and Y.K. was 0.92 (p < .001). The intrarater ICC was 0.92 (p < .001) for A.Y. and 0.90 (p < .001) for Y.K. The sums of the GS and PD scores of the 28 joints are expressed as the total GS and total PD scores [35]. A total PD score <3 was defined as ultrasound remission (u-remission) [36]. Evaluations for efficacy RA disease activity was evaluated at baseline and 12 and 24 weeks later by two rheumatologists (S.Y. and N.T.) blinded to the ultrasound findings. Each patient was evaluated by the same rheumatologist. RA disease activity was evaluated according to the following measures: the tender joint count (TJC) in 28 joints; the swollen joint count (SJC) in 28 joints; the patient’s global assessment of disease activity with a visual analog scale (Pt-VAS); the physician’s global assessment of disease activity with a visual analog scale (Ph-VAS); the levels of matrix metalloproteinase-3 (MMP-3), C-reactive protein (CRP), and ESR; DAS28-ESR: disease activity score assessing 28 joints with ESR (DAS28-ESR); and the degree of disability on the modified health assessment questionnaire (HAQ). Disease activity was categorized as follows: c-remission (DAS28-ESR <2.6), low disease activity (2.6 ≤ DAS28-ESR <3.2), and moderate disease activity (3.2 ≤ DAS28-ESR <5.1) [37]. Ultrasound findings of GS and PD were defined according to the OMERACT definitions [34]. The primary endpoints were DAS28-ESR and the total PD score response at 24 weeks. Safety was evaluated by unfavorable symptoms and laboratory data during study treatment. Statistical analysis All statistical analyses were performed using JMP for Windows, version 12.0 (SAS Institute Inc., Cary, NC). Continuous variables are presented as means ± standard deviation (SD). Efficacy variables were calculated using the last-observation-carried-forward (LOCF) method. Analysis was performed using the data of 47 patients, excluding the date of three patients who stopped or changed bDMARDs. The data at each observation point were compared with baseline data by the Wilcoxon signed-rank test. To identify factors related to achievement of c-remission and u-remission at 24 weeks, multiple logistic regression analysis was performed. Receiver operating characteristic (ROC) curves were generated to determine the best cut-off point for DAS28-ESR at baseline. The cut-off point was identified as the one closest to the (0,1) point and taken to be the cut-off point that best differentiated between patients with and without c-remission at 24 weeks. A p value <0.05 was considered significant. Results Patients’ characteristics A total of 50 RA patients (42 women, 8 men) were enrolled in this study (Table 1). The mean age was 65.3 ± 12.8 years, mean disease duration was 9.1 ± 8.5 years, mean duration of bDMARD treatment was 2.0 ± 1.7 years, and mean DAS28-ESR was 3.45 ± 0.92 at baseline. The mean dose of MTX was 6.1 ± 4.2 mg/week, the percentage of patients administered a TNF inhibitor was 52.0%, and 22.0% of the patients were previous bDMARD users. There was no difference in the baseline DAS28-ESR between the IGU 25 mg/day administration group (n = 13, 3.3 ± 0.8) and the IGU 50 mg/day administration group (n = 34, 3.5 ± 0.8) (p = .426). The observation duration of MTX, SASP and TAC treatment before IGU administration was 8.6 ± 5.8, 4.0 ± 3.7, and 2.1 ± 2.1 years, respectively. In this study, one patient was increased from MTX 8 mg/week to 10 mg/week at 10 weeks before IGU administration, one patient was increased from PSL 2 mg/day to 4 mg/day at 8 weeks before IGU administration, and one patient was increased from PSL 2 mg/day to 4 mg/day at 5 weeks before IGU administration. The mean rheumatoid factor (RF) level was 101.0 ± 121.8 (0–526) IU/mL, and the mean anti-cyclic citrullinated peptide (anti-CCP) antibody level was 107.5 ± 148.4 (0–500) U/mL. The total GS score was 14.0 ± 7.6, and the total PD score was 8.7 ± 6.1 at baseline. Table 1. Baseline characteristics of 50 RA patients receiving add-on IGU. Age (years) 65.3 ± 12.8 (32–86) Sex (male/female) 8/42 Duration of disease (years) 9.1 ± 8.5 (0.5–30) Steinbrocker stage (I/II/III/IV) 10/18/6/16 Steinbrocker class (I/II/III/IV) 34/14/2/0 MTX treatment (%)/dose of MTX (mg/week) 74.0/6.1 ± 4.2 PSL treatment (%)/dose of PSL (mg/day) 48.0/2.3 ± 3.2 SASP treatment (%) 24.0 BUC treatment (%) 18.0 TAC treatment (%) 24.0 Duration of bDMARD treatment (years) 2.0 ± 1.7 Previous bDMARD use (%) 22.0 Treatment with bDMARDs (ETN/ADA/GLM/CZP/TCZ/ABT) 10/7/8/1/6/18 TNF inhibitor treatment (%) 52.0 Positive for RF (%) 67.3 RF (IU/ml) 101.0 ± 121.8 Positive for anti-CCP antibodies (%) 78.0 Anti-CCP antibodies (U/ml) 107.5 ± 148.4 CRP (mg/dl) 0.36 ± 0.7 ESR (mm/h) 13.8 ± 11.6 MMP-3 (ng/ml) 127.2 ± 140.0 DAS28-ESR 3.45 ± 0.92 SJC 3.7 ± 2.1 TJC 2.4 ± 2.0 Pt-VAS (0–100) 39.2 ± 21.4 Ph-VAS (0–100) 32.6 ± 17.3 HAQ (0–3) 0.91 ± 0.75 Ultrasonographic data Total GS score 14.0 ± 7.6 Total PD score 8.7 ± 6.1 Age (years) 65.3 ± 12.8 (32–86) Sex (male/female) 8/42 Duration of disease (years) 9.1 ± 8.5 (0.5–30) Steinbrocker stage (I/II/III/IV) 10/18/6/16 Steinbrocker class (I/II/III/IV) 34/14/2/0 MTX treatment (%)/dose of MTX (mg/week) 74.0/6.1 ± 4.2 PSL treatment (%)/dose of PSL (mg/day) 48.0/2.3 ± 3.2 SASP treatment (%) 24.0 BUC treatment (%) 18.0 TAC treatment (%) 24.0 Duration of bDMARD treatment (years) 2.0 ± 1.7 Previous bDMARD use (%) 22.0 Treatment with bDMARDs (ETN/ADA/GLM/CZP/TCZ/ABT) 10/7/8/1/6/18 TNF inhibitor treatment (%) 52.0 Positive for RF (%) 67.3 RF (IU/ml) 101.0 ± 121.8 Positive for anti-CCP antibodies (%) 78.0 Anti-CCP antibodies (U/ml) 107.5 ± 148.4 CRP (mg/dl) 0.36 ± 0.7 ESR (mm/h) 13.8 ± 11.6 MMP-3 (ng/ml) 127.2 ± 140.0 DAS28-ESR 3.45 ± 0.92 SJC 3.7 ± 2.1 TJC 2.4 ± 2.0 Pt-VAS (0–100) 39.2 ± 21.4 Ph-VAS (0–100) 32.6 ± 17.3 HAQ (0–3) 0.91 ± 0.75 Ultrasonographic data Total GS score 14.0 ± 7.6 Total PD score 8.7 ± 6.1 Date are expressed as mean ± SD. RA: rheumatoid arthritis; MTX: methotrexate; PSL: prednisolone; SASP: salazosulfapyridine; BUC: bucillamine; TAC: tacrolimus; bDMARDs: biological disease-modifying antirheumatic drugs; ETN: etanercept; ADA: adalimumab; TCZ: tocilizumab; GLM: golimumab; CZP: certolizumab pegol; ABT: abatacept; TNF: tumor necrosis factor; CCP: cyclic citrullinated peptide; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; MMP-3: matrix metalloproteinase-3; DAS28-ESR: disease activity score assessing 28 joints with ESR; SJC: swollen joint count; TJC: tender joint count; Pt-VAS: patient’s visual analog scale; Ph-VAS: physician’s visual analog scale; HAQ: health assessment questionnaire; GS: gray-scale; PD: power-Doppler. Open in new tab Table 1. Baseline characteristics of 50 RA patients receiving add-on IGU. Age (years) 65.3 ± 12.8 (32–86) Sex (male/female) 8/42 Duration of disease (years) 9.1 ± 8.5 (0.5–30) Steinbrocker stage (I/II/III/IV) 10/18/6/16 Steinbrocker class (I/II/III/IV) 34/14/2/0 MTX treatment (%)/dose of MTX (mg/week) 74.0/6.1 ± 4.2 PSL treatment (%)/dose of PSL (mg/day) 48.0/2.3 ± 3.2 SASP treatment (%) 24.0 BUC treatment (%) 18.0 TAC treatment (%) 24.0 Duration of bDMARD treatment (years) 2.0 ± 1.7 Previous bDMARD use (%) 22.0 Treatment with bDMARDs (ETN/ADA/GLM/CZP/TCZ/ABT) 10/7/8/1/6/18 TNF inhibitor treatment (%) 52.0 Positive for RF (%) 67.3 RF (IU/ml) 101.0 ± 121.8 Positive for anti-CCP antibodies (%) 78.0 Anti-CCP antibodies (U/ml) 107.5 ± 148.4 CRP (mg/dl) 0.36 ± 0.7 ESR (mm/h) 13.8 ± 11.6 MMP-3 (ng/ml) 127.2 ± 140.0 DAS28-ESR 3.45 ± 0.92 SJC 3.7 ± 2.1 TJC 2.4 ± 2.0 Pt-VAS (0–100) 39.2 ± 21.4 Ph-VAS (0–100) 32.6 ± 17.3 HAQ (0–3) 0.91 ± 0.75 Ultrasonographic data Total GS score 14.0 ± 7.6 Total PD score 8.7 ± 6.1 Age (years) 65.3 ± 12.8 (32–86) Sex (male/female) 8/42 Duration of disease (years) 9.1 ± 8.5 (0.5–30) Steinbrocker stage (I/II/III/IV) 10/18/6/16 Steinbrocker class (I/II/III/IV) 34/14/2/0 MTX treatment (%)/dose of MTX (mg/week) 74.0/6.1 ± 4.2 PSL treatment (%)/dose of PSL (mg/day) 48.0/2.3 ± 3.2 SASP treatment (%) 24.0 BUC treatment (%) 18.0 TAC treatment (%) 24.0 Duration of bDMARD treatment (years) 2.0 ± 1.7 Previous bDMARD use (%) 22.0 Treatment with bDMARDs (ETN/ADA/GLM/CZP/TCZ/ABT) 10/7/8/1/6/18 TNF inhibitor treatment (%) 52.0 Positive for RF (%) 67.3 RF (IU/ml) 101.0 ± 121.8 Positive for anti-CCP antibodies (%) 78.0 Anti-CCP antibodies (U/ml) 107.5 ± 148.4 CRP (mg/dl) 0.36 ± 0.7 ESR (mm/h) 13.8 ± 11.6 MMP-3 (ng/ml) 127.2 ± 140.0 DAS28-ESR 3.45 ± 0.92 SJC 3.7 ± 2.1 TJC 2.4 ± 2.0 Pt-VAS (0–100) 39.2 ± 21.4 Ph-VAS (0–100) 32.6 ± 17.3 HAQ (0–3) 0.91 ± 0.75 Ultrasonographic data Total GS score 14.0 ± 7.6 Total PD score 8.7 ± 6.1 Date are expressed as mean ± SD. RA: rheumatoid arthritis; MTX: methotrexate; PSL: prednisolone; SASP: salazosulfapyridine; BUC: bucillamine; TAC: tacrolimus; bDMARDs: biological disease-modifying antirheumatic drugs; ETN: etanercept; ADA: adalimumab; TCZ: tocilizumab; GLM: golimumab; CZP: certolizumab pegol; ABT: abatacept; TNF: tumor necrosis factor; CCP: cyclic citrullinated peptide; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; MMP-3: matrix metalloproteinase-3; DAS28-ESR: disease activity score assessing 28 joints with ESR; SJC: swollen joint count; TJC: tender joint count; Pt-VAS: patient’s visual analog scale; Ph-VAS: physician’s visual analog scale; HAQ: health assessment questionnaire; GS: gray-scale; PD: power-Doppler. Open in new tab Efficacy evaluation Of the 50 patients given add-on IGU therapy, seven patients discontinued by 24 weeks. Of these patients, four patients discontinued IGU administration due to adverse events, and three patients discontinued administration of bDMARDs or switched to another bDMARD. Two patients discontinued abatacept (ABT) during the 12 weeks after IGU administration, and one patient was changed to TCZ for insufficient efficacy at 12 weeks. The DAS28-ESR was significantly improved, from 3.45 ± 0.92 at baseline to 3.10 ± 1.16 at 12 weeks’ administration of IGU and 2.85 ± 1.13 at 24 weeks’ (p = .017 and p < .001, respectively) (Figure 1(a)). The rate of c-remission and low disease activity at 12 weeks was 34.0 and 19.1%, respectively, and the rate of c-remission and low disease activity at 24 weeks was 38.3 and 21.3%, respectively (Figure 1(b)). The c-remission rate with 24-week IGU administration was 46.2% in the IGU 25 mg/day group and 35.3% in the IGU 50 mg/day group (p = .521). The DAS28-ESR was significantly improved, from 3.42 ± 0.73 at baseline to 2.87 ± 1.24 at 24 weeks’ administration of IGU in the patients with TNF inhibitor (p = .02), from 3.51 ± 0.89 at baseline to 2.82 ± 1.01 at 24 weeks’ with non-TNF inhibitor (p < .001), respectively. There was no difference in the c-remission rate with 24-week IGU administration between the TNF inhibitor group (34.6%) and the non-TNF inhibitor group (42.9%) (p = .76). The baseline DAS28-ESR was significantly lower in the group that achieved c-remission after 24-week IGU administration compared with the non-c-remission group (p = .001), while the duration of disease, duration of bDMARD treatment, TNF inhibitor/non-TNF inhibitor, previous bDMARD use/non-previous bDMARD use, IGU dose, total GS score at baseline, and total PD score at baseline were not related to c-remission (Table 2). On multivariate analysis, lower DAS28-ESR at baseline was a predictor for achieving c-remission after 24 weeks (Table 3). ROC curve analysis indicated that the possibility of c-remission after 24-week IGU administration was high if IGU were added with a baseline DAS28-ESR ≤3.59 ± 0.31 [AUC: 0.79, cut-off: 3.59, sensitivity: 0.89, specificity: 0.62, positive predictive value (PPV): 0.59, negative predictive value (NPV): 0.90] (Figure 2). Figure 1. Open in new tabDownload slide (a) The DAS28-ESR is significantly decreased at 24 weeks (LOCF). Asterisk (*) indicates a significant difference compared with the DAS28-ESR at baseline. (b) The DAS28-ESR at baseline and at 12 and 24 weeks (LOCF). (c) The total GS score and total PD score at baseline and at 12 and 24 weeks (LOCF). Asterisk (*) indicates a significant difference compared with the total PD score at baseline. Figure 1. Open in new tabDownload slide (a) The DAS28-ESR is significantly decreased at 24 weeks (LOCF). Asterisk (*) indicates a significant difference compared with the DAS28-ESR at baseline. (b) The DAS28-ESR at baseline and at 12 and 24 weeks (LOCF). (c) The total GS score and total PD score at baseline and at 12 and 24 weeks (LOCF). Asterisk (*) indicates a significant difference compared with the total PD score at baseline. Figure 2. Open in new tabDownload slide ROC curves of the DAS28-ESR at baseline for predicting the achievement of c-remission at 24 weeks after addition of IGU. Figure 2. Open in new tabDownload slide ROC curves of the DAS28-ESR at baseline for predicting the achievement of c-remission at 24 weeks after addition of IGU. Table 2. Univariate analysis of predictive factors for achievement of c-remission at 24 weeks in RA patients receiving add-on IGU (LOCF). Variables c-remission (n = 18) Non-c-remission (n = 29) p value Age 65.0 ± 15.3 65.7 ± 11.4 .870 Female (%) 83.3 86.2 1.000 Duration of disease (years) 8.5 ± 8.6 9.3 ± 8.2 .693 Duration of bDMARD treatment at baseline (years) 2.1 ± 2.0 2.0 ± 1.5 .673 TNF inhibitor treatment (%) 50.0 58.6 .763 Previous bDMARD use (%) 16.7 27.6 .492 MTX treatment (%) 77.8 69.0 .739 MTX (mg/week) 6.3 ± 4.1 5.8 ± 4.4 .814 PSL treatment (%) 33.3 58.6 .135 PSL (mg/day) 1.2 ± 1.9 3.0 ± 3.5 .062 Positive for RF (%) 50.0 79.3 .055 RF (IU/ml) 73.4 ± 108.7 121.2 ± 130.5 .086 Positive for anti-CCP antibodies (%) 72.2 82.8 .473 anti-CCP antibodies (U/ml) 89.6 ± 152.4 111.1 ± 134.8 .210 HAQ (0–3) 0.79 ± 0.8 1.02 ± 0.7 .287 Total GS score at baseline 15.8 ± 10.6 13.0 ± 5.5 .436 Total PD score at baseline 8.9 ± 8.4 8.8 ± 4.5 .328 DAS28-ESR at baseline 3.0 ± 0.8 3.7 ± 0.6 .001 Variables c-remission (n = 18) Non-c-remission (n = 29) p value Age 65.0 ± 15.3 65.7 ± 11.4 .870 Female (%) 83.3 86.2 1.000 Duration of disease (years) 8.5 ± 8.6 9.3 ± 8.2 .693 Duration of bDMARD treatment at baseline (years) 2.1 ± 2.0 2.0 ± 1.5 .673 TNF inhibitor treatment (%) 50.0 58.6 .763 Previous bDMARD use (%) 16.7 27.6 .492 MTX treatment (%) 77.8 69.0 .739 MTX (mg/week) 6.3 ± 4.1 5.8 ± 4.4 .814 PSL treatment (%) 33.3 58.6 .135 PSL (mg/day) 1.2 ± 1.9 3.0 ± 3.5 .062 Positive for RF (%) 50.0 79.3 .055 RF (IU/ml) 73.4 ± 108.7 121.2 ± 130.5 .086 Positive for anti-CCP antibodies (%) 72.2 82.8 .473 anti-CCP antibodies (U/ml) 89.6 ± 152.4 111.1 ± 134.8 .210 HAQ (0–3) 0.79 ± 0.8 1.02 ± 0.7 .287 Total GS score at baseline 15.8 ± 10.6 13.0 ± 5.5 .436 Total PD score at baseline 8.9 ± 8.4 8.8 ± 4.5 .328 DAS28-ESR at baseline 3.0 ± 0.8 3.7 ± 0.6 .001 RA: rheumatoid arthritis; c-remission: clinical remission; bDMARDs: biological disease-modifying antirheumatic drugs; TNF: tumor necrosis factor; CCP: cyclic citrullinated peptide; MTX: methotrexate; PSL: prednisolone; HAQ: health assessment questionnaire; GS: gray-scale; PD: power-Doppler; DAS28-ESR: disease activity score assessing 28 joints with erythrocyte sedimentation rate. Open in new tab Table 2. Univariate analysis of predictive factors for achievement of c-remission at 24 weeks in RA patients receiving add-on IGU (LOCF). Variables c-remission (n = 18) Non-c-remission (n = 29) p value Age 65.0 ± 15.3 65.7 ± 11.4 .870 Female (%) 83.3 86.2 1.000 Duration of disease (years) 8.5 ± 8.6 9.3 ± 8.2 .693 Duration of bDMARD treatment at baseline (years) 2.1 ± 2.0 2.0 ± 1.5 .673 TNF inhibitor treatment (%) 50.0 58.6 .763 Previous bDMARD use (%) 16.7 27.6 .492 MTX treatment (%) 77.8 69.0 .739 MTX (mg/week) 6.3 ± 4.1 5.8 ± 4.4 .814 PSL treatment (%) 33.3 58.6 .135 PSL (mg/day) 1.2 ± 1.9 3.0 ± 3.5 .062 Positive for RF (%) 50.0 79.3 .055 RF (IU/ml) 73.4 ± 108.7 121.2 ± 130.5 .086 Positive for anti-CCP antibodies (%) 72.2 82.8 .473 anti-CCP antibodies (U/ml) 89.6 ± 152.4 111.1 ± 134.8 .210 HAQ (0–3) 0.79 ± 0.8 1.02 ± 0.7 .287 Total GS score at baseline 15.8 ± 10.6 13.0 ± 5.5 .436 Total PD score at baseline 8.9 ± 8.4 8.8 ± 4.5 .328 DAS28-ESR at baseline 3.0 ± 0.8 3.7 ± 0.6 .001 Variables c-remission (n = 18) Non-c-remission (n = 29) p value Age 65.0 ± 15.3 65.7 ± 11.4 .870 Female (%) 83.3 86.2 1.000 Duration of disease (years) 8.5 ± 8.6 9.3 ± 8.2 .693 Duration of bDMARD treatment at baseline (years) 2.1 ± 2.0 2.0 ± 1.5 .673 TNF inhibitor treatment (%) 50.0 58.6 .763 Previous bDMARD use (%) 16.7 27.6 .492 MTX treatment (%) 77.8 69.0 .739 MTX (mg/week) 6.3 ± 4.1 5.8 ± 4.4 .814 PSL treatment (%) 33.3 58.6 .135 PSL (mg/day) 1.2 ± 1.9 3.0 ± 3.5 .062 Positive for RF (%) 50.0 79.3 .055 RF (IU/ml) 73.4 ± 108.7 121.2 ± 130.5 .086 Positive for anti-CCP antibodies (%) 72.2 82.8 .473 anti-CCP antibodies (U/ml) 89.6 ± 152.4 111.1 ± 134.8 .210 HAQ (0–3) 0.79 ± 0.8 1.02 ± 0.7 .287 Total GS score at baseline 15.8 ± 10.6 13.0 ± 5.5 .436 Total PD score at baseline 8.9 ± 8.4 8.8 ± 4.5 .328 DAS28-ESR at baseline 3.0 ± 0.8 3.7 ± 0.6 .001 RA: rheumatoid arthritis; c-remission: clinical remission; bDMARDs: biological disease-modifying antirheumatic drugs; TNF: tumor necrosis factor; CCP: cyclic citrullinated peptide; MTX: methotrexate; PSL: prednisolone; HAQ: health assessment questionnaire; GS: gray-scale; PD: power-Doppler; DAS28-ESR: disease activity score assessing 28 joints with erythrocyte sedimentation rate. Open in new tab Table 3. Multivariate analysis of predictive factors for achievement of c-remission at 24 weeks in RA patients receiving add-on IGU (LOCF). Variables Odds ratio (95% CI) p value Age 1.008 (0.942–1.081) .824 Duration of disease 0.987 (0.874–1.109) .825 Duration of bDMARD treatment <1 year 0.867 (0.104–6.393) .889 TNF inhibitor 0.277 (0.021–2.721) .270 Previous bDMARD use 0.434 (0.048–3.054) .406 RF (IU/ml) 0.995 (0.987–1.001) .115 Anti-CCP antibodies (U/ml) 1.000 (0.994–1.006) .927 MTX (mg/week) 1.112 (0.870–1.465) .403 PSL (mg/day) 0.803 (0.510–1.099) .196 DAS28-ESR at baseline 0.170 (0.029–0.575) .002 Variables Odds ratio (95% CI) p value Age 1.008 (0.942–1.081) .824 Duration of disease 0.987 (0.874–1.109) .825 Duration of bDMARD treatment <1 year 0.867 (0.104–6.393) .889 TNF inhibitor 0.277 (0.021–2.721) .270 Previous bDMARD use 0.434 (0.048–3.054) .406 RF (IU/ml) 0.995 (0.987–1.001) .115 Anti-CCP antibodies (U/ml) 1.000 (0.994–1.006) .927 MTX (mg/week) 1.112 (0.870–1.465) .403 PSL (mg/day) 0.803 (0.510–1.099) .196 DAS28-ESR at baseline 0.170 (0.029–0.575) .002 RA: rheumatoid arthritis; c-remission: clinical remission; bDMARDs: biological disease-modifying antirheumatic drugs; TNF: tumor necrosis factor; CCP: cyclic citrullinated peptide; MTX: methotrexate; PSL: prednisolone; DAS28-ESR: disease activity score assessing 28 joints with erythrocyte sedimentation rate. Odds ratios and 95% confidence intervals (CIs) were determined with a logistic regression model. Open in new tab Table 3. Multivariate analysis of predictive factors for achievement of c-remission at 24 weeks in RA patients receiving add-on IGU (LOCF). Variables Odds ratio (95% CI) p value Age 1.008 (0.942–1.081) .824 Duration of disease 0.987 (0.874–1.109) .825 Duration of bDMARD treatment <1 year 0.867 (0.104–6.393) .889 TNF inhibitor 0.277 (0.021–2.721) .270 Previous bDMARD use 0.434 (0.048–3.054) .406 RF (IU/ml) 0.995 (0.987–1.001) .115 Anti-CCP antibodies (U/ml) 1.000 (0.994–1.006) .927 MTX (mg/week) 1.112 (0.870–1.465) .403 PSL (mg/day) 0.803 (0.510–1.099) .196 DAS28-ESR at baseline 0.170 (0.029–0.575) .002 Variables Odds ratio (95% CI) p value Age 1.008 (0.942–1.081) .824 Duration of disease 0.987 (0.874–1.109) .825 Duration of bDMARD treatment <1 year 0.867 (0.104–6.393) .889 TNF inhibitor 0.277 (0.021–2.721) .270 Previous bDMARD use 0.434 (0.048–3.054) .406 RF (IU/ml) 0.995 (0.987–1.001) .115 Anti-CCP antibodies (U/ml) 1.000 (0.994–1.006) .927 MTX (mg/week) 1.112 (0.870–1.465) .403 PSL (mg/day) 0.803 (0.510–1.099) .196 DAS28-ESR at baseline 0.170 (0.029–0.575) .002 RA: rheumatoid arthritis; c-remission: clinical remission; bDMARDs: biological disease-modifying antirheumatic drugs; TNF: tumor necrosis factor; CCP: cyclic citrullinated peptide; MTX: methotrexate; PSL: prednisolone; DAS28-ESR: disease activity score assessing 28 joints with erythrocyte sedimentation rate. Odds ratios and 95% confidence intervals (CIs) were determined with a logistic regression model. Open in new tab The total PD score was significantly improved, from 8.7 ± 6.1 at baseline to 6.4 ± 5.5 at 12-week administration of IGU and 5.5 ± 5.0 after 24 weeks (p < .001 and p < .001, respectively) (Figure 1(c)). However, the total GS score was 13.0 ± 7.9 and 13.0 ± 5.6 after 12 and 24 weeks of administration of IGU, respectively, showing no improvement (p = .12 and p = .18, respectively). In this study, a total PD score <3 was defined as u-remission [36]. The u-remission rate was 19.1 and 27.7% after 12 and 24 weeks, respectively. In addition to a lower baseline DAS28-ESR, shorter duration of disease and elderly status (p = .001, p = .020 and p = .021, respectively) were found to be predictors of achieving u-remission at 24 weeks of IGU administration (Table 4). No other factors contributed to u-remission. Table 4. Multivariate analysis of predictive factors for achievement of u-remission (total PD score <3) at 24 weeks in RA patients receiving add-on IGU (LOCF). Variables Odds ratio (95% CI) p value Age 1.099 (1.013–1.228) .021 Duration of disease 0.826 (0.657–0.974) .020 Duration of bDMARD treatment <1 year 0.254 (0.009–3.171) .304 TNF inhibitor 20.747 (0.704–1975.224) .082 Previous bDMARD use 0.268 (0.014–3.397) .317 RF (IU/ml) 1.001 (0.993–1.009) .744 Anti-CCP antibodies (U/ml) 1.004 (0.996–1.014) .314 MTX (mg/week) 0.765 (0.503–1.054) .106 PSL (mg/day) 0.602 (0.255–1.055) .083 DAS28-ESR at baseline 0.075 (0.006–0.424) .001 Variables Odds ratio (95% CI) p value Age 1.099 (1.013–1.228) .021 Duration of disease 0.826 (0.657–0.974) .020 Duration of bDMARD treatment <1 year 0.254 (0.009–3.171) .304 TNF inhibitor 20.747 (0.704–1975.224) .082 Previous bDMARD use 0.268 (0.014–3.397) .317 RF (IU/ml) 1.001 (0.993–1.009) .744 Anti-CCP antibodies (U/ml) 1.004 (0.996–1.014) .314 MTX (mg/week) 0.765 (0.503–1.054) .106 PSL (mg/day) 0.602 (0.255–1.055) .083 DAS28-ESR at baseline 0.075 (0.006–0.424) .001 RA: rheumatoid arthritis; u-remission: ultrasound remission; bDMARDs: biological disease-modifying antirheumatic drugs; TNF: tumor necrosis factor; CCP: cyclic citrullinated peptide; MTX: methotrexate; PSL: prednisolone; DAS28-ESR: disease activity score assessing 28 joints with erythrocyte sedimentation rate. Odds ratios and 95% confidence intervals (CIs) were determined with a logistic regression model. Open in new tab Table 4. Multivariate analysis of predictive factors for achievement of u-remission (total PD score <3) at 24 weeks in RA patients receiving add-on IGU (LOCF). Variables Odds ratio (95% CI) p value Age 1.099 (1.013–1.228) .021 Duration of disease 0.826 (0.657–0.974) .020 Duration of bDMARD treatment <1 year 0.254 (0.009–3.171) .304 TNF inhibitor 20.747 (0.704–1975.224) .082 Previous bDMARD use 0.268 (0.014–3.397) .317 RF (IU/ml) 1.001 (0.993–1.009) .744 Anti-CCP antibodies (U/ml) 1.004 (0.996–1.014) .314 MTX (mg/week) 0.765 (0.503–1.054) .106 PSL (mg/day) 0.602 (0.255–1.055) .083 DAS28-ESR at baseline 0.075 (0.006–0.424) .001 Variables Odds ratio (95% CI) p value Age 1.099 (1.013–1.228) .021 Duration of disease 0.826 (0.657–0.974) .020 Duration of bDMARD treatment <1 year 0.254 (0.009–3.171) .304 TNF inhibitor 20.747 (0.704–1975.224) .082 Previous bDMARD use 0.268 (0.014–3.397) .317 RF (IU/ml) 1.001 (0.993–1.009) .744 Anti-CCP antibodies (U/ml) 1.004 (0.996–1.014) .314 MTX (mg/week) 0.765 (0.503–1.054) .106 PSL (mg/day) 0.602 (0.255–1.055) .083 DAS28-ESR at baseline 0.075 (0.006–0.424) .001 RA: rheumatoid arthritis; u-remission: ultrasound remission; bDMARDs: biological disease-modifying antirheumatic drugs; TNF: tumor necrosis factor; CCP: cyclic citrullinated peptide; MTX: methotrexate; PSL: prednisolone; DAS28-ESR: disease activity score assessing 28 joints with erythrocyte sedimentation rate. Odds ratios and 95% confidence intervals (CIs) were determined with a logistic regression model. Open in new tab Safety evaluation IGU administration was continued for 24 weeks in 46 patients, with a continuation rate of 92%. IGU administration was continued at 50 mg/day in 35 patients (76.1%) and at 25 mg/day in 11 patients (23.9%) after 24 weeks of IGU administration. Adverse events were observed in 12 patients (24%) after 24 weeks. Of these patients, seven had gastrointestinal symptoms such as diarrhea and vomiting, three had liver dysfunction, one had rash, and one had malaise. The clinical symptoms and abnormal blood test results were resolved after the dose of IGU was reduced to 25 mg/day in eight patients and discontinued in four patients (two had gastrointestinal symptoms, one had liver dysfunction, and one had a rash). None of the patients died during the study. Discussion In this study, c-remission could be achieved with IGU add-on therapy in RA patients inadequately responding to treatment with bDMARDs. In particular, lower baseline DAS28-ESR contributed to c-remission, and shorter duration of disease, in addition to lower baseline DAS28-ESR, was a contributing factor to u-remission. Additional IGU administration to RA patients inadequately responding to bDMARDs can be considered one of the therapeutic strategies. In recent years, the clinical effects of RA treatment have improved, and c-remission has become possible in RA patients. However, it is difficult for 50–70% of RA patients using bDMARDs to achieve remission [2–12]. In RA patients inadequately responding to treatment with bDMARDs, the c-remission rate decreased progressively each time there was a change to other bDMARDs [14–16]. On the other hand, according to the 2013 ELUAR recommendations [13], if the therapeutic goal cannot be achieved with bDMARDs, c-remission should be pursued by additional administration of csDMARDs. However, there have been few reports predicting the therapeutic outcomes of additional administration of csDMARDs to achieve c-remission. For non-responders [38], who show lack of efficacy to bDMARDs, changing the bDMARD is a reasonable therapeutic strategy. However, for partial responders, who show an insufficient response to bDMARDs [38], no conclusion has been reached about which is better, switching of bDMARDs or add-on of csDMARDs. There have been reports about the add-on administration of MTX and TAC for RA patients using bDMARDs [2,39,40]. In a prospective study, MTX was added to 76 RA patients treated for 3 years with etanercept (ETN) alone, and the DAS28-remission rate increased from 26.7% at baseline to 36.8% at 52 weeks after add-on MTX was started, but the improvement was not significant [2]. The lack of a significant difference may be explained by the fact that DAS28-remission was already achieved in ∼20% of the RA patients at the time of the addition of MTX. In post-marketing surveillance of TAC, TAC was added in 165 RA patients with a simplified disease activity index of >3.3 despite the use of bDMARDs, namely infliximab (IFX), ETN, adalimumab (ADA), golimumab (GLM), TCZ, or ABT, for 4–8 weeks, the DAS28-CRP decreased from 4.0 ± 1.0 at baseline to 2.9 ± 1.2 after 24-week administration of TAC, and no difference was observed in efficacy among the bDMARDs [39]. Furthermore, when TAC was added in 20 RA patients with a clinical disease activity index >2.8 despite the use of TCZ for 8 weeks or longer, the DAS28-CRP decreased from 3.3 to 2.1 after 24 weeks in 85% [40]. However, these reports did not identify factors that contributed to c-remission when additional MTX or TAC was administered to RA patients inadequately responding to bDMARDs. Moreover, there has been no substantial report evaluating the efficacy of csDMARDs other than MTX and TAC administered in addition to bDMARDs. In a double-blind, parallel-group study of IGU and SASP in RA patients with moderate or higher disease activity, the efficacy of IGU according to the ACR 20 response rate was comparable of that of SASP (61.3 and 53.1%, respectively) [29]. Concerning the add-on administration of IGU or placebo in RA patients with moderate or higher disease activity that persisted despite 12-week or longer administration of MTX at 6–8 mg/week, the ACR 20 response rate after 24 weeks was 69.5% in the IGU group and 30.7% in the placebo group, the DAS28-CRP was 3.37 ± 1.18 and 4.31 ± 1.31, and the remission (DAS28-CRP) rate was 27.4 and 9.1%, respectively, indicating the superiority of IGU [30,31]. However, no report has evaluated the efficacy and safety of add-on IGU in RA patients inadequately responding to bDMARDs. In this study, the c-remission rate according to the DAS28-ESR after 24-week administration of IGU was 38.3%, a lower baseline DAS28-ESR was identified as a factor that contributed to the attainment of c-remission, and ROC curve analysis showed that the cut-off baseline DAS28-ESR was ≤3.59. From these results, add-on IGU is considered a therapeutic strategy to achieve c-remission in partial responders in whom improvement to moderate disease activity has been achieved with bDMARDs. RA patients who achieved c-remission have also been reported to be likely to suffer destruction of joints with a residual synovial PD signal compared with joints without a residual synovial PD signal on ultrasonography [41], and the control of synovitis on joint ultrasonography is also an important issue. In the present study, a significant improvement was observed in the total PD score after 24-week add-on administration of IGU compared with the baseline value, and an improvement in the PD score was suggested to have a preventive effect against progression of joint destruction. Moreover, the RA relapse rate after the discontinuation of bDMARD administration has been reported to be significantly lower in patients who have achieved u-remission, defined as a total PD score <3 [36]. In the present study, u-remission was achieved after 24-week IGU administration in 27.7% of the patients, and, in addition to a lower baseline DAS28-ESR, a shorter duration of disease and elderly status were identified as predictors of u-remission. In this study, the addition of IGU to RA patients with a shorter duration of disease was a factor contributing to u-remission. Previous reports demonstrated that the prevalence of ultrasound PD-positive was greater for long-standing than early RA, suggesting that u-remission was difficult to achieve in long-standing RA patients [42]. Furthermore, the addition of IGU to elderly RA patients was a factor contributing to u-remission. IGU may have been effective in elderly patients because of decreased drug clearance. Based on these results, the results of the present study suggest that the addition of IGU can be a therapeutic strategy to attain u-remission in early RA patients who have responded partially to bDMARDs. There have been no reports of efficacy based on joint ultrasound findings of the add-on administration of csDMARDs including MTX in RA patients inadequately responding to bDMARDs. This study has several limitations. First, the number of subjects was small, and the observation period was short. Second, the study was not a randomized, comparative study and lacked a control group, such as add-on other csDMRDs, and a direct comparison with other csDMARDs such as MTX, or a direct comparison between IGU add-on administration and switching to other bDMARDs was not made. The present study provides a foundation for large-scale research in the treatment of RA patients who are partial responders. Third, in this study, the average MTX dose at baseline was low. One of the reasons is that, in some patients, it was difficult to increase MTX due to side effects, age, and decreased renal function. Secondly, patients with TNF inhibitor tended to have high tolerance to MTX compared to patients with non-TNF inhibitor. The patients with TNF inhibitor including IFX and GLM can have a shortened administration period or an increased dose if relapse or disease activity persists. For these reasons, the use rate of non-TNF inhibitors was relatively high in this study. In conclusion, c-remission can be achieved by IGU add-on in RA patients responding partially to 24-week or longer administration of bDMARDs. In particular, add-on IGU before switching bDMARDs is a therapeutic strategy in RA patients with a shorter duration of disease and a lower baseline DAS28-ESR, if MTX cannot be increased. Acknowledgements The authors would like to thank the RA patients in this IGU study and the staff members of the Department of Internal Medicine (IV), Osaka Medical College. Conflict of interest None. 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TI - Add-on iguratimod as a therapeutic strategy to achieve remission in patients with rheumatoid arthritis inadequately responding to biological DMARDs: A retrospective study
JF - Modern Rheumatology
DO - 10.1080/14397595.2017.1336865
DA - 2018-03-04
UR - https://www.deepdyve.com/lp/oxford-university-press/add-on-iguratimod-as-a-therapeutic-strategy-to-achieve-remission-in-Hw2eJPc79C
SP - 227
EP - 234
VL - 28
IS - 2
DP - DeepDyve
ER -