Clinical efficacy,radiographic progression,and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial

Objective: To evaluate the safety and efficacy of golimumab?+?methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA).

Methods: Japanese patients with active RA despite MTX were randomized to placebo?+?MTX (Group 1, n?=?88), golimumab 50?mg?+?MTX (Group 2, n?=?86), or golimumab 100?mg?+?MTX (Group 3, n?=?87). Patients with?<20% improvement in swollen/tender joint counts entered early escape at week 16. At week 24, all remaining placebo patients crossed over to golimumab 50?mg. Efficacy assessments included ACR20, DAS28-ESR, and HAQ-DI. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score.

Results: ACR20 response rates in Group 1, Group 2, and Group 3 were 67.9, 86.1, and 82.4%, respectively, at week 52 and were maintained through week 104 (87.1, 94.0, and 88.7%) and week 156 (97.1, 94.1, and 89.5%). Proportions of patients with good/moderate DAS28-ESR response or clinically meaningful improvement in HAQ-DI were also maintained through week 156. The majority of patients did not experience radiographic progression through week 156. Among 257 golimumab-treated patients, 251 (97.7%) had?≥1 AE; 54 (21.0%) had?≥1 serious AE through week 156. Infections were the most common type of AE.

Conclusions: Response to golimumab?+?MTX was maintained over 3 years in Japanese patients with active RA despite MTX. Safety results were consistent with the known safety profile of golimumab.     

Efficacy and safety of sirukumab in Japanese patients with moderate to severe rheumatoid arthritis inadequately controlled by disease modifying anti-rheumatic drugs: Subgroup analysis of a phase 3 study

Abstract

Objective: To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs.

Methods: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints).

Results: A total of 168 (Japanese)/1670 patients received sirukumab 50?mg/4 weeks (q4w, n?=?58), 100?mg/every 2 weeks (q2w, n?=?54), or placebo (n?=?56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50?mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p?<?.001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50?mg q4w: 0.3, p?=?.024; 100?mg q2w: 0.0, p?=?.002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52.

Conclusion: Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.     

Comparison of golimumab 100-mg monotherapy to golimumab 50 mg plus methotrexate in patients with rheumatoid arthritis: Results from a multicenter,cohort study

Objective. The aim of this study was to compare the efficacy and safety of golimumab (GLM) 50 mg + methotrexate (MTX) combination therapy and GLM 100 mg monotherapy in patients with rheumatoid arthritis (RA).

Methods. The subjects were 115 RA patients (92 females and 23 males; median (range) age, 64 (17–87) years; median (range) disease duration, 8 (0.6–48) years) started on GLM. Eighty-three patients received GLM 50 mg/4 weeks + MTX (C group; median (range) MTX dosage 8 (2–16) mg/week), and 32 patients received GLM 100 mg/4 weeks (M group).

Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3, disease activity score (DAS) 28-ESR, DAS28-CRP, simplified disease activity index, and clinical disease activity index were evaluated 4, 12, and 24 weeks after starting GLM.

Results. There were no significant differences in disease activity, adverse events, and drug continuation rates at 24 weeks between the groups. The DAS28-ESR remission rate was 34% in the C group and 26% in the M group.

Conclusions. GLM 100 mg monotherapy improved disease activity as well as GLM 50 mg + MTX combination therapy. GLM 100 mg monotherapy appears to have a sufficient therapeutic effect in RA patients who cannot take MTX.     

Tocilizumab is clinically,functionally, and radiographically effective and safe either with or without low-dose methotrexate in active rheumatoid arthritis patients with inadequate responses to DMARDs and/or TNF inhibitors: A single-center retrospective cohort study (KEIO-TCZ study) at week 52

Abstract

Objectives. To explore the effectiveness and safety of tocilizumab (TCZ) with or without methotrexate (MTX) in active rheumatoid arthritis (RA) patients showing inadequate responses to DMARDs and/or TNF inhibitors in clinical practice.

Methods. We observed consecutive 115 RA patients initiating TCZ treatment in Keio University Hospital, dividing them into two groups with (TCZ + MTX group) or without MTX (TCZ group), and evaluated clinical, functional and structural outcomes besides safety at week 52.

Results. Overall mean age, RA duration, and DAS28-ESR were 55.4, 8.4 years, and 5.0, respectively. Proportions of the prior use of TNF inhibitors and concomitant MTX were 45.5% and 57.4%, respectively. Mean dose of concomitant MTX was 8.4 mg/week. Baseline characteristics were comparable between the groups. TCZ improved disease activity measured by DAS28-ESR to 2.1 at week 52 overall, without significant difference between the groups. Clinical (DAS28-ESR < 2.6), functional (HAQ-DI ≤ 0.5), and structural (ΔTSS ≤ 0.5) remission rates in the TCZ group and the TCZ + MTX group were 79.1%/63.8% (P = 0.10), 62.8%/54.4% (P = 0.40), and 70.0%/53.8% (P = 0.61), respectively. Retention rates were 81.0% in the TCZ + MTX group and 88.5% in the TCZ group (P = 0.47). The rate of serious adverse events was comparable between the groups.

Conclusions. TCZ was clinically, functionally, and radiographically effective and safe either with or without low-dose MTX.     

Golimumab reduces disease activity of rheumatoid arthritis for 1 year and strongly inhibits radiographic progression in Japanese patients: partial but detailed results of the GO-FORTH and GO-MONO studies

The objective of this study is to evaluate the efficacy of golimumab (GLM) in Japanese patients with active rheumatoid arthritis (RA) for 1 year. Nineteen patients were enrolled; 9 were randomized to the placebo (PBO) + methotrexate (MTX), GLM 50 mg + MTX, or GLM 100 mg + MTX therapy group; and 10 were randomized to the PBO, GLM 50 mg, or GLM 100 mg therapy group. One patient in the GLM 100 mg + MTX therapy group with median values from the GO-FORTH study was added. Data were evaluated by assessing the changes in DAS28-ESR, Health Assessment Questionnaire Disability Index (HAQ-DI), and total Sharp score (TSS) at week 52. Mean changes in DAS28-ESR in the MTX monotherapy, GLM 50 mg + MTX, GLM 100 mg + MTX, PBO, GLM 50 mg, and GLM 100 mg therapy groups were ?2.70, ?2.57, ?2.27, ?0.60, ?2.53, and ?2.53, respectively; the mean improvements in HAQ-DI were 0.188, 0.708, 0.377, 0.188, 1.042, and 0.625, respectively. The mean changes in TSS were 1.63, ?0.33, ?1.17, 4.25, 1.00, and 1.67, respectively. A significant difference was only observed in the mean TSS change between the PBO + MTX and the GLM 100 mg + MTX groups. However, in terms of mean changes in DAS28-ESR in the combination therapy groups, PBO + MTX therapy seemed to elicit similar results as the GLM 50 mg + MTX and GLM 100 mg + MTX therapies (no significant difference) because all four patients in the PBO + MTX therapy group may have received GLM from week 24 as a crossover. Combined GLM + MTX therapy reduced disease activity and strongly inhibited radiographic disease progression in patients with active RA at week 52.     

Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data

Abstract

Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We investigated concomitant methotrexate (MTX) dose on tofacitinib efficacy/safety in Japanese RA patients.

Methods: This post hoc analysis pooled data from a 3-month phase 2 study (NCT00603512) and a 24-month phase 3 study (NCT00847613). Patients (N= 254) received tofacitinib (low-dose (1 or 3?mg), 5?mg, 10?mg) twice daily (BID) or placebo, with low-dose (>0 to 8?mg/week) or high-dose (>8?mg/week) MTX. Efficacy (ACR20/50/70 and DAS28-4 (ESR)<2.6 response rates; changes from baseline (CFB) in DAS28-4 (ESR) and HAQ-DI) and safety (adverse events (AEs), discontinuations due to AEs, serious AEs, and deaths) were assessed through month 3.

Results: At month 3, ACR20/50/70 response rates, mean DAS28-4 (ESR) CFB and HAQ-DI CFB were similar across MTX doses and generally greater for all tofacitinib doses versus placebo. AE rates with low-dose/high-dose MTX were: placebo, 28.6%/52.9%; tofacitinib low-dose, 50.0%/66.7%; 5?mg BID, 56.5%/64.3%; 10?mg BID, 73.8%/67.7%.

Conclusion: Tofacitinib efficacy in Japanese RA patients may be unaffected by background MTX dose. AE rates with low-dose versus high-dose MTX were lower with placebo, tofacitinib low-dose or 5?mg BID, but not 10?mg BID, with no apparent differences across system organ class/laboratory parameters.     

Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized,double-blind,multicenter, phase 3 study (SIRROUND-T)

Abstract

Objective: To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy.

Methods: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed.

Results 116/878 patients received sirukumab 50?mg/4 weeks (q4w, n?=?35), 100?mg/2 weeks (q2w, n?=?44) or placebo (n?=?37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50?mg q4w:20 [57.1%]; p?<?.001, 100?mg q2w:24 [54.5%]; p?=?.001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50?mg q4w:29 [82.9%]; 100?mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs.

Conclusion: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.     

Assessment of the effectiveness of golimumab 50-mg and 100-mg regimens in patients with rheumatoid arthritis in daily practice

Abstract

Objectives. To assess the effectiveness of the golimumab (GLM) 50-mg and 100-mg regimens in patients with rheumatoid arthritis (RA) in daily practice. Methods. We retrospectively analyzed RA patients who started GLM between September 2011 and July 2012. Patients were divided into three groups: a 50-mg group; a 50/100-mg group (had a dose increase to 100 mg); and a 100-mg group (started GLM at 100 mg). We assessed Disease Activity Score 28 (DAS28) and treatment continuation rate. Risk factors associated with time to discontinuation of the 50-mg regimen were determined with proportional hazards analysis. Results. We analyzed 74 patients: 43 in the 50-mg group, 23 in the 50/100-mg group, and 8 in the 100-mg group. DAS28 improved from 4.0 ± 1.0, 4.8 ± 1.0, and 4.7 ± 1.9, respectively, at baseline to 2.4 ± 1.2, 3.3 ± 1.5, and 2.5 ± 0.7, respectively, at week 52. Treatment continuation rates at week 52 were 73.7%, 60.9%, and 87.5%, respectively. In the 50/100-mg group, the mean DAS28 improved significantly from 4.4 ± 1.2 before to 3.6 ± 1.3 12 weeks after the dose increase. Oral corticosteroid therapy ≥ 5 mg/day, previous use of two biologic agents, and DAS28 > 5.1 at initiation of GLM were significantly associated with discontinuation of the 50-mg regimen. Conclusions. Both GLM 50-mg and 100-mg regimens are effective in patients with RA in daily practice.     

Golimumab,a new human anti–tumor necrosis factor α antibody,administered intravenously in patients with active rheumatoid arthritis: Forty‐eight–week efficacy and safety results of a phase III randomized,double‐blind,placebo‐controlled study

Objective

To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA).

Methods

Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15–25 mg/week for ≥4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14.

Results

The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX).

Conclusion

The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer‐term reduction of RA signs/symptoms in MTX‐resistant patients, with no unexpected safety concerns.

     

The efficacy of abatacept in Japanese patients with rheumatoid arthritis: 104 weeks radiographic and clinical results in clinical practice

Objective: We aimed to assess the efficacy of abatacept in Japanese patients with rheumatoid arthritis (RA) in clinical practice.

Methods: We examined 92 patients who received abatacept for 104 weeks. Analysis of radiographic efficacy was conducted using van der Heijde-modified total Sharp score (mTSS). Disease activity score was assessed using disease activity score in 28 joints (DAS28) and simplified disease activity index (SDAI) by last observation carried forward.

Results: The change in mTSS was 0.61 at 52 weeks and 0.27 at 52–104 weeks. Structural remission occurred in 64.9% at 52 weeks and 76.6% at 104 weeks. The significant risk factors for joint damage progression at 52 weeks were prednisolone use, baseline C-reactive protein level (CRP), and erythrocyte sedimentation rate (ESR), as well as average DAS28-CRP and DAS28-ESR scores, SDAI, CRP, ESR, and matrix metalloproteinase-3 (MMP-3) levels. The clinical remission rates were 47.8% by DAS28-CRP, 39.1% by DAS28-ESR, and 30.4% by SDAI at 52 weeks, were 59.8% by DAS28-CRP, 48.9% by DAS28-ESR, and 43.5% by SDAI at 104 weeks.

Conclusion: This study suggested efficacy of abatacept treatment in Japanese patient with RA for 104 weeks in daily clinical practice. Abatacept lead to suppress joint destruction for 104 weeks.     

Iguratimod,a synthetic disease modifying anti-rheumatic drug inhibiting the activation of NF-κB and production of RANKL: Its efficacy,radiographic changes,safety and predictors over two years’ treatment for Japanese rheumatoid arthritis patients

Abstract

Objective: To elucidate the clinical and radiographic outcomes for rheumatoid arthritis (RA) patients treated with a synthetic disease-modifying antirheumatic drug, iguratimod (IGU).

Methods: Clinical outcomes for 213 RA patients treated with 25?mg/day oral IGU or 50?mg/day after 4 weeks of 25?mg/day treatment for one day to 104 weeks were assessed.

Results: A total of 142 active RA patients (DAS28-ESR ≥3.2) treated for more than 12 weeks showed a significant reduction in both DAS and simplified disease activity index (SDAI) scores at week 4 (p?<?.001) to week 104. Good and moderate DAS responses were achieved in 54 (38%) and 66 (46%) patients, respectively. Total Genant-modified Sharp scores (GSS) of 31 patients at week 104 showed no progression (total GSS ≤0.84: the smallest detectable change) in 16 (52%) patients with a mean score reduction (95%CI) of ?4.3 (?8.1～?0.5) (p?<?.05). Predictors were an early response, moderate disease activity at baseline, and male gender. Eleven of the 213 patients had gastric and/or duodenal ulcer. A peculiar haemorrhage was seen in two patients treated concomitantly with IGU and warfarin potassium.

Conclusion: IGU treatment shows an early and sustained efficacy. Radiographically, no progression of GSS was evident in 16 (52%) patients at week 104. Gastric bleeding or gastric perforation warrants careful attention, especially in patients with concomitant use of both a non-steroidal anti-inflammatory drug and oral prednisolone.     

Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis: A 52-week,randomized, single-blind,extension study

Objectives: The objective of this study is to evaluate the efficacy and safety of long-term (64 weeks; 52-week extension of a 12-week study) baricitinib treatment in Japanese patients with active rheumatoid arthritis (RA) despite methotrexate therapy.

Methods: Patients (N?=?145) with active RA were randomized to placebo, 1mg, 2mg, 4mg, or 8mg baricitinib for the first 12 weeks. During the 52-week extension period, patients on 4mg or 8mg baricitinib remained on the same dose and all other patients were re-randomized to 4mg or 8mg baricitinib. Most patients on 8mg baricitinib were switched to 4mg by week 64 (protocol amendment); data analysis was based on the treatment group at the beginning of the extension period.

Results: Increases in the American College of Rheumatology (ACR) response rates (ACR20, ACR50, and ACR70) observed during the first 12 weeks were maintained during the extension period, accompanied by improvements in ACR core components. At week 64, a large proportion of patients (>40%) had low disease activity. Most treatment-related adverse events were mild or moderate; herpes zoster was the most common reason (11/27 patients) for discontinuation.

Conclusions: The efficacy and safety profile of baricitinib was maintained during long-term treatment of Japanese patients with RA and background methotrexate therapy.

Clinicaltrials.gov NCT01469013; Funding: Eli Lilly and Incyte     

Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: 52-week results from an open-label extension of the J-RAPID study

Abstract

Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate.

Methods. J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate.

Results. The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules.

Conclusions. Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules.     

A randomized,double-blind,parallel-group,phase III study of shortening the dosing interval of subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis and an inadequate response to subcutaneous tocilizumab every other week: Results of the 12-week double-blind period

Objective: To determine the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) monotherapy every week (qw) versus every other week (q2w) in patients with rheumatoid arthritis who had an inadequate response to TCZ-SC q2w.

Methods: Adult patients in Japan with inadequate response to TCZ-SC q2w were randomized to either TCZ-SC 162?mg qw monotherapy or TCZ-SC 162?mg q2w monotherapy for 12 weeks (double-blind). The primary endpoint was the change from baseline in adjusted Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) at week 12. Efficacy, safety and pharmacokinetics were assessed.

Results: TCZ-SC qw was superior to TCZ-SC q2w for adjusted mean change in DAS28-ESR from baseline to week 12. The difference in the change in DAS28-ESR between TCZ-SC qw and q2w was ?1.21 (95%CI:??2.13,??0.30, p?=?.0108). A higher proportion of patients receiving TCZ-SC qw achieved DAS28-ESR remission/low disease activity than TCZ-SC q2w. Adverse events were 71.4% and 66.7% for TCZ-SC qw and q2w, respectively; infection was the most common event with one fatal case with TCZ-SC qw.

Conclusions: In patients with inadequate response to TCZ-SC q2w, shortening the dosing interval to qw improved efficacy with acceptable tolerability. Occurrence of infection for both TCZ q2w and qw is important and needs careful attention.     

Efficacy of golimumab for preventing large joint destruction in patients with rheumatoid arthritis as determined by the ARASHI score

Objectives: The objective of this study is to investigate the inhibitory effect of golimumab on large joint destruction in patients with rheumatoid arthritis.

Methods: We recruited 45 patients with rheumatoid arthritis and evaluated the radiographic severity of large joint destruction using the assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging (ARASHI) score. We evaluated 450 large joints including the elbow, shoulder, hip, knee, and ankle at baseline and 52 weeks after treatment with golimumab. Rapid radiographic progression (RRP) and rapid radiographic improvement (RRI) were calculated and the correlation between large joint destruction and clinical factors was analyzed.

Results: The mean age of the study population was 61.29?±?14.71 years old, and most patients (91.1%) were female. The mean disease duration was 12.6?±?12.48 years. The cohort included patients in all clinical stages of disease as defined by the Steinbroker criteria (I:7, II:10, III:9, IV:19) as well as clinical classes 2 (n?=?18), 3 (n?=?26), and 4 (n?=?1) and the mean disease activity score-CRP (DAS28-CRP) was 4.431?±?1.044. Patients were treated with methotrexate (mean dose 6.44?±?1.78?mg/week), prednisolone (PSL) (mean dose 1.078?±?1.871?mg/d), and golimumab (44.4% of 100?mg). RRP was evident in 20% of the large joints treated with golimumab, and, therefore, golimumab was effective at inhibiting large joint destruction in 80% of joints. RRI was evident in 33.3% of large joints following golimumab treatment. We also observed that EULAR response criteria significantly correlated with the ARASHI change score at 52 weeks after treatment. The total ARASHI status score significantly correlated with the Sharp–van der Heijde score, but not with the delta total sharp score. Multiple regression analyses revealed that the total ARASHI change score was only correlated with EULAR response criteria significantly.

Conclusions: Golimumab therapy was effective at inhibiting large joint destruction of RA patients who have good clinical response, including higher improvement of the shoulder and ankle joints than other large joints.     

Prediction of DAS28-ESR remission at 6 months by baseline variables in patients with rheumatoid arthritis treated with etanercept in Japanese population

Abstract

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.     

Assessment of the validity of the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) as a disease activity index of rheumatoid arthritis in the efficacy evaluation of 24-week treatment with tocilizumab: subanalysis of the SATORI study

Abstract

As tocilizumab (TCZ) greatly inhibits inflammatory markers, methods of evaluating rheumatoid arthritis (RA) disease activity that include inflammatory markers may overestimate the effect of TCZ treatment. We have evaluated the impact of inflammatory markers on the efficacy of TCZ by comparing the efficacy indicated by the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) with that indicated by the clinical and simplified disease activity indexes (CDAI and SDAI, respectively) and the American College of Rheumatology (ACR) core set criteria in a double-blind study of TCZ—the SATORI study. The Spearman correlation coefficient between DAS28-ESR and CDAI was comparable between that at week 24 and that at baseline [correlation coefficient at baseline and week 24 was 0.823 (p < 0.0001) and 0.818 (p < 0.0001), respectively]. A large difference between the DAS28 remission rate and CDAI remission rate was observed at week 24. However, these results are comparable to those of a previous study conducted with non-TCZ-treated patients. Moreover, the same results were obtained in the comparison between the DAS28-ESR and SDAI, even though the SDAI includes an inflammatory parameter as a component. These results confirm that the DAS28-ESR has a validity comparable to that of other methods in terms of evaluating the RA treatment efficacy of TCZ, despite its strong inflammatory marker-inhibiting effects.     

LY2439821, a humanized anti–interleukin‐17 monoclonal antibody,in the treatment of patients with rheumatoid arthritis: A phase I randomized,double‐blind,placebo‐controlled,proof‐of‐concept study

Objective

We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti–interleukin‐17 (anti–IL‐17) monoclonal antibody, in a first in‐human trial in rheumatoid arthritis (RA) patients taking oral disease‐modifying antirheumatic drugs (DMARDs).

Methods

This randomized, double‐blind, placebo‐controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.

Results

Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all‐LY2439821–combined groups (−2.3, −2.4, and −2.3, respectively) than in the placebo group (−1.7) at week 10 (P ≤ 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821‐treated patients than in placebo‐treated patients at multiple time points. There was no apparent dose‐response relationship in treatment‐emergent adverse events.

Conclusion

LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL‐17 as a potential novel goal for the treatment of RA.

     

Impact of methotrexate dose on efficacy of adalimumab in Japanese patients with rheumatoid arthritis: Results from registered data analyses

Objective: Upper limit of methotrexate (MTX) for patients with rheumatoid arthritis (RA) was recently increased from 8 to 16?mg/week in Japan. We therefore examined the effect of concomitant MTX dose on the efficacy of adalimumab (ADA) in clinical practice.

Method: Sixty-one consecutive RA patients treated with ADA were followed for minimum 52 weeks and retrospectively compared by MTX dose; patients receiving concomitant MTX of 10?mg/week or more (MTX ≥10?mg group) and <10?mg/week (MTX <10?mg group). Disease activity and remission were evaluated by the disease activity score 28 (DAS28) criteria.

Results: The MTX ≥10?mg group consistently showed better improvement in DAS28 and resulted in more patients (52.8%) with DAS28-remission compared with the MTX <10?mg group (26.1%). Multivariate analysis showed that MTX ≥10?mg had a significant effect on DAS28 remission with odds ratio of 5.12. ADA retention rate was 72.2% in MTX ≥10?mg group compared with 52.0% in MTX <10?mg group. Discontinuation of ADA due to adverse events were comparable in the MTX ≥10?mg and MTX <10?mg groups (11.1% vs. 12.0%).

Conclusions: These findings support the critical role of concomitant MTX in the efficacy of ADA, and recommend use of MTX ≥10?mg in Japanese RA patients.     

A multi-biomarker disease activity score tracks clinical response consistently in patients with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study

Abstract

Objectives. To assess the ability of a multi-biomarker disease activity (MBDA) score to track clinical response in patients with rheumatoid arthritis (RA) treated with different TNF inhibitors.

Methods. The study included 147 patients who had received adalimumab, etanercept, or infliximab for a year or more, during routine clinical care at the University Hospital of Occupational and Environmental Health, Japan. MBDA scores and clinical measures of disease activity were evaluated at baseline and, after 24 weeks (N = 84) and 52 weeks of treatment. Relationships between the changes (?) in MBDA score and changes in clinical measures or EULAR response categories were evaluated.

Results. The median disease activity was 5.7 by DAS28-ESR and 64 by MBDA score at baseline, and decreased significantly with treatment. ?MBDA scores over 1 year correlated with ?DAS28-ESR (r = 0.48) and ?DAS28-CRP (r = 0.46). Linear relationships between ?MBDA scores and ?DAS28-ESR or ?DAS28-CRP were not significantly different between TNF inhibitors. The MBDA scores declined significantly more in good responders (median change: –29) than moderate (–21), and more in moderate than in non-responders (+ 2), by the EULAR criteria.

Conclusions. MBDA scores tracked disease activity and treatment response in patients with RA treated with three TNF inhibitors. The relationships between ?MBDA scores and ?DAS28-ESR or ?DAS28-CRP were consistent across the three TNF inhibitor groups.