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Abstract
Objective
The purpose of this study is to evaluate the clinical and hematological effects of tocilizumab in active rheumatoid arthritis (RA) patients.
Methods
Fourteen patients with active RA were enrolled in this study. The patients received tocilizumab 8 mg/kg intravenously every four weeks for 6 months. Disease activity, anemia-related factors including serum hepcidin-25, and hematological parameters were monitored at baseline and at 1, 3, and 6 months after the initiation of treatment.
Results
Significant reductions in tender joint count, swollen joint count, visual analogue scale, erythrocyte sedimentation rate (ESR), and C-reactive (CRP) protein plus reductions in a 28-joint disease activity score were observed within one month after the first tocilizumab treatment. These effects lasted throughout the six-month study period. In addition, significant improvements in anemia-related factors such as hepcidin-25, ferritin, iron, hemoglobin, red blood cell counts and mean corpuscular volume were observed during the treatment period. Hematological parameters were improved with reductions in counts for leukocytes, monocytes, neutrophils, and platelets. The lymphocyte counts and their subset numbers were unchanged. Changes in hepcidin levels showed significant correlation with changes in CRP, ESR, ferritin, hemoglobin and counts for red blood cells, leukocytes, and neutrophils during the treatment period.
Conclusion
This study demonstrates that tocilizumab significantly and meaningfully reduces disease burden in patients with active RA. In addition, tocilizumab diminishes the levels of inflammatory anemia by inhibiting hepcidin production. These clinical data provide evidence of a favorable outcome from tocilizumab in RA.
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Figure 1.
Clinical effects of tocilizumab in rheumatoid arthritis (RA) patients during six-month treatment period. Tocilizumab was administrated to 14 RA patients every four weeks. Disease activity was assessed at baseline and months 1, 3 and 6 during tocilizumab treatment. (A) Tender joint count (TJC). (B) Swollen joint count (SJC). (C) Visual analogue scale (VAS). (D) Erythrocyte sedimentation rate (ESR). (E) C-reactive protein (CRP). (F) 28-joint disease activity score (DAS28). Symbols represent individual subjects. p-values were determined using Wilcoxon's signed rank test. *p＜0.005, **p＜0.0005.
Figure 2.
Effects of tocilizumab on hepcidin-25 and anemia-related factors in rheumatoid arthritis (RA) patients during the six-month treatment period. Tocilizumab was administrated to 14 RA patients every four weeks. Hepcidin-25 and anemia-related factors were measured at baseline and months 1, 3 and 6 during tocilizumab treatment. (A) Serum hepcidin-25. (B) Serum ferritin.(C) Serum iron (Fe). (D) Hemoglobin (Hb). (E) Red blood cell counts (RBCs). (F) Mean corpuscular volume (MCV). (G) Erythropoietin (EPO). (H) Interleukin (IL)-6. Symbols represent individual subjects. p-values were determined using Wilcoxon's signed rank test.*p＜0.05, **p＜0.01, ***p＜0.005, † p＜0.001.
Figure 3.
Effects of tocilizumab on hematological parameters in rheumatoid arthritis (RA) patients during the six-month treatment period. Tocilizumab was administrated to 14 RA patients every four weeks. Hematologic parameters were measured at baseline and months 1, 3 and 6 during tocilizumab treatment. (A) Leukocyte count. (B) Monocyte counts. (C) Neutrophil counts. (D) Platelet counts. (E) Lymphocyte counts. (F) Eosinophil counts. (G) Basophil counts. Symbols represent individual subjects. p-values were determined using Wilcoxon's signed rank test. *p＜0.05, **p＜0.01, ***p＜0.005, †p＜0.0005.
Figure 4.
Effects of tocilizumab on lymphocyte subsets in rheumatoid arthritis (RA) patients during the six-month treatment period. Tocilizumab was administrated to 14 RA patients every four weeks. Percentages of lymphocyte subsets were measured at baseline and 6 months after tocilizumab treatment. Freshly isolated peripheral blood mononuclear cells (PBMCs) from 14 RA patients were stained with appropriate monoclonal antibodies and then analyzed by flow cytometry. (A) CD3＋ T cells. (B) CD4＋ T cells. (C) CD8＋ T cells. (D) CD3− CD19＋ B cells. (E) Natural killer (NK; CD3− CD56＋) cells. (F) Mucosal associated invariant T (MAIT; CD3＋ TCRγδ− Vα7.2＋ CD161 high) cells. (G) Natural killer T (NKT; CD3＋6B11＋) cells. Symbols represent individual subjects. p-values were determined using Wilcoxon's signed rank test.
Table 1.
Baseline clinical characteristics of the 14 patients with RA
| Patient number | Age (yr)/sex | Disease duration (yr) | DAS28 | CRP (mg/dL) | ESR (mm/h) | Comorbidity | Previous medication* | Current medication |
|---|---|---|---|---|---|---|---|---|
| 1 | 61/F | 3 | 8.05 | 6.89 | 85 | None | IFX, MTX, PRD | MTX, PRD, TCZ |
| 2 | 73/F | 5 | 6.41 | 2.63 | 57 | None | MTX, RTX, PRD | MTX, PRD, TCZ |
| 3 | 37/F | 1 | 5.25 | 0.88 | 93 | None | ADA, MTX, PRD | MTX, PRD, TCZ |
| 4 | 60/F | 1 | 4.98 | 1.39 | 88 | DM, HTN | ADA, MTX, PRD | MTX, TCZ |
| 5 | 35/F | 8 | 3.63 | 0.59 | 49 | None | ETN, MTX, PRD | MTX, PRD, TCZ |
| 6 | 62/F | 16 | 4.58 | 1.42 | 70 | None | ADA, MTX | MTX, TCZ |
| 7 | 23/F | 3 | 5.36 | 3.53 | 80 | None | MTX, RTX | MTX, TCZ |
| 8 | 62/F | 10 | 5.76 | 3.60 | 104 | HTN | ETN, PRD, MTX | MTX, PRD, TCZ |
| 9 | 54/F | 8 | 5.34 | 3.50 | 41 | HTN | IFX, MTX, PRD | MTX, PRD, TCZ |
| 10 | 67/F | 15 | 5.35 | 0.23 | 46 | None | IFX, MTX, PRD | PRD, TCZ |
| 11 | 71/F | 11 | 4.72 | 2.01 | 106 | HTN | LEF, MTX, PRD | MTX, PRD, TCZ |
| 12 | 64/F | 21 | 4.85 | 1.12 | 49 | DM | ADA, MTX, PRD | MTX, PRD, TCZ |
| 13 | 39/F | 2 | 4.58 | 2.12 | 49 | None | MTX, SSZ, PRD | MTX, PRD, TCZ |
| 14 | 64/F | 8 | 4.87 | 1.49 | 65 | None | MTX, PRD, TAC | MTX, PRD, TCZ |
ADA: adalimumab, CRP: C-reactive protein, DAS28: 28-joint disease activity score, DM: diabetes mellitus, ESR: erythrocyte sedimentation rate, ETN: etanercept, F: female, HTN: hypertension, IFX: infliximab, LEF: leflunomide, MTX: methotrexate, PRD: prednisolone, RA: rheumatoid arthritis, RTX: rituximab, SSZ: sulfasalazine, TAC: tacrolimus, TCZ: tocilizumab.
Table 2.
Spearman's correlation coefficients for serum hep-cidin-25 with respect to clinical and laboratory parameters in 14 RA patients before tocilizumab therapy
Table 3.
Spearman's correlation coefficients for changes from baseline in serum hepcidin-25 with respect to changes from baseline in clinical and laboratory parameters in 14 RA patients treated with tocilizumab over 6-month treatment
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