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Abstract
Objective
Evaluate effectiveness/safety of tacrolimus in patients in Korea with active rheumatoid arthritis (RA) and unsuccessful response to disease-modifying anti-rheumatic drugs (DMARDs).
Methods
Open-label, single-arm, non-comparative, 24-week, Phase-IV study in patients with active RA who had taken DMARDs for ＞6 months. Following a washout period, tacrolimus was initiated (baseline–12 weeks; dose 2 mg/day and 1.5 mg/day in patients aged ≤65 and ＞65 years, respectively). After 12 weeks, dose could be adjusted (remaining between 1∼3 mg); treatment continued to 24 weeks. Primary endpoint was American College of Rheumatology 20% improvement (ACR20) (baseline– Week 24). Secondary endpoints included ACR50/ACR70 response, disease-activity score in 28 joints (DAS28) erythrocyte sedimentation rate (ESR), number of tender/swollen joints, and bone mineral density (BMD) loss. Adverse events (AEs) were recorded.
Results
Overall, 121 patients were analysed. Mean ±standard deviation tacrolimus dose baseline– Week 24 was 1.81±0.47 mg/day. After 24 weeks, 64.5%, 39.7%, and 19.0% of patients were ACR20, ACR50, and ACR70 responders, respectively. DAS28-ESR score decreased from 5.5±0.8 (baseline) to 3.7±1.5 (Week 24; p＜0.0001); number of tender/swollen joints decreased. Between screening and Week 24, change in BMD-T score in lumbar and femur regions was −0.06±0.38 (p=0.1550) and −0.04±0.28 (p=0.0936), respectively, with no significant change in International Society for Clinical Densitometry classification. Fifty-six (46.3%) patients experienced 93 AEs; 75.3% were mild. No unexpected safety signals identified.
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Figure 2.
Proportion of ACR responders at Week 24 in the ITT and PP populations after 24 weeks of treatment with tacrolimus. ACR20, ≥20% improvement in the seven ACR response criteria. ACR50, ≥50% improvement in the seven ACR response criteria. ACR70, ≥70% improvement in the 7 ACR response criteria. ACR: American College of Rheumatology, ITT: intention-to-treat, PP: per-protocol, CI: confidence interval.
Table 1.
Patient demographics and baseline characteristics, overall and stratified by patient age (≤65 years vs. ＞65 years) (ITT population)
| Characteristics | Patients aged ≤65 years (n=106) | Patients aged ＞65 years (n=15) | All patients (n=121) |
|---|---|---|---|
| Female sex | 93 (87.7) | 14 (93.3) | 107 (88.4) |
| Age (yr) | 52.7±8.5 | 69.3±2.6 | 54.7±9.7 |
| Height (cm) | 157.3±6.6 | 152.7±6.4 | 156.7±6.7 |
| Weight (kg) | 57.4±9.4 | 54.3±7.9 | 57.0±9.3 |
| BMI (kg/m2) | 23.2±3.6 | 23.3±3.0 | 23.2±3.5 |
| Duration of RA (mo) ACR functional class | 87.0±73.8 | 136.1±108.5 | 93.1±80.0 |
| Class I | 4 (3.8) | 0 (0) | 4 (3.3) |
| Class II | 94 (88.7) | 10 (66.7) | 104 (86.0) |
| Class III | 6 (5.7) | 5 (33.3) | 11 (9.1) |
| Class IV | 2 (1.9) | 0 (0.0) | 2 (1.7) |
| DAS28-ESR score | – | – | 5.5±0.8 |
| BMD-T score* | |||
| Lumbar region | – | – | −1.43±1.34 |
| Femur region | – | – | −1.20±1.11† |
| ESR (mm/h) | – | – | 42.4±22.5 |
| CRP (mg/dL) | – | – | 1.30±1.28 |
| Bone turnover markers | |||
| Bone-specific alkaline phosphatase Normal | – | – | 81 (68.1) |
| Abnormal (non-significant) | – | – | 35 (29.4) |
| Abnormal (clinically significant) | – | – | 3 (2.5) |
| N (missing) | – | – | 119 (2) |
| Osteocalcin | |||
| Normal | – | – | 94 (79.0) |
| Abnormal (non-significant) | – | – | 25 (21.0) |
| Abnormal (clinically significant) | – | – | 0 (0.0) |
| N (missing) | – | – | 119 (2) |
| C-telopeptide | |||
| Normal | – | – | 117 (98.3) |
| Abnormal (non-significant) | – | – | 2 (1.7) |
| Abnormal (clinically significant) | – | – | 0 (0.0) |
| N (missing) | – | – | 119 (2) |
| Receptor activator of NF-B | |||
| Normal | – | – | 4 (100.0) |
| Abnormal (non-significant) | – | – | 0 (0.0) |
| Abnormal (clinically significant) | – | – | 0 (0.0) |
| N (missing) | – | – | 4 (117) |
| Osteoprotegerin | |||
| Normal | – | – | 4 (100.0) |
| Abnormal (non-significant) | – | – | 0 (0.0) |
| Abnormal (clinically significant) | – | – | 0 (0.0) |
| N (missing) | – | – | 4 (117) |
| Prior DMARDs/biological agents DMARDs | 106 (100.0) | 15 (100.0) | 121 (100.0) |
| Methotrexate | 97 (91.5) | 14 (93.3) | 111 (91.7) |
| Hydroxychloroquine | 46 (43.3) | 5 (33.3) | 51 (42.1) |
| Sulfasalazine | 41 (38.7) | 5 (33.3) | 46 (38.0) |
| Leflunomide | 6 (5.7) | 1 (6.7) | 7 (5.8) |
| Others | 12 (11.3) | 3 (20.0) | 15 (12.4) |
| Biological agents | 3 (2.8) | 1 (6.7) | 4 (3.3) |
| Infliximab | 2 (1.9) | 0 (0.0) | 2 (1.7) |
| Etanercept | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Adalimub | 1 (0.9) | 1 (6.7) | 2 (1.7) |
| Rituximab | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| RA medications other than DMARDs/biological agents | 101 (95.3) | 14 (93.3) | 115 (95.0) |
Values are presented as number (%) or mean±standard deviation unless otherwise stated. ITT: intention-to-treat, BMI: body mass index, RA: rheumatoid arthritis, ACR: American College of Rheumatology, DAS28: disease activity score in 28 joints, ESR: erythrocyte sedimentation rate, BMD: bone mineral density, CRP: C-reactive protein, NF- B: nuclear factor B, DMARD: disease-modifying anti-rheumatic drugs.
Table 2.
DAS28-ESR response by EULAR classifications at Week 24, in the ITT and PP populations
Table 3.
Summary of BMD-T score at screening versus Week 24, and BMD-T score classification by ISCD guideline, for the ITT and PP populations
| BMD-T score | ITT population | PP population |
|---|---|---|
| Lumbar vertebra region (n) | 121 | 97 |
| Screening | −1.43±1.34 | −1.35±1.31 |
| Week 24 | −1.50±1.35 | −1.42±1.34 |
| Difference from screening to Week 24 | −0.06±0.38 | −0.06±0.33 |
| p-value* | 0.1550 | 0.1138 |
| Transitioned from normal/osteopenia to osteoporosis (screening– Week 24) | 2 (1.7) | 1 (1.0) |
| Transitioned from osteoporosis to normal/osteopenia (screening– Week 24) | 4 (3.3) | 3 (3.1) |
| p-value† | 0.6875 | 0.6250 |
| Femur region (n) | 120 | 96 |
| Screening | −1.20±1.11 | −1.10±1.10 |
| Week 24 | −1.24±1.08 | −1.16±1.08 |
| Difference from baseline to Week 24 | −0.04±0.28 | −0.06±0.26 |
| p-value* | 0.0936 | 0.0483 |
| Transitioned from normal/osteopenia to osteoporosis (screening– Week 24) | 2 (1.7) | 1 (1.0) |
| Transitioned from osteoporosis to normal/osteopenia (screening– Week 24) | 2 (1.7) | 1 (1.0) |
| p-value† | 1.000 | 1.000 |
Table 4.
Incidence of AEs experienced by ≥1% of patients in the SAF, by system organ class and preferred term
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