Research Article

An International comparative Study on EuroQol-5-Dimension Questionnaire (EQ-5D) tariff scores between the UK and Japan

Tsuguo Iwatani*1, Shinichi Noto2, Koichiro Tsugawa1

  1. Department of Surgery, Division of Breast and Endocrine Surgery, St. Marianna University School of Medicine, Japan
  2. Department of Health Sciences, Niigata University of Health and Welfare, Japan

*Corresponding author: Tsuguo Iwatani, MD, PhD, Department of Surgery, Division of Breast and Endocrine Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, 216-8511, Japan,Tel: +81-44-977-8111; Fax: +81-44-975-1400; E-mail;


The purpose of this study is the evaluation of the difference in elicited EuroQol-5-Dimension Questionnaire (EQ-5D) health utility values across the range of different health states derived from the UK, Japanese tariffs. Hence, we conducted a comparative study on UK and Japanese Value Sets of EQ-5D-3L and 5L. Distributions of EQ-5D-3L tariffs were compared between the Japanese and UK versions. For the Japanese tariff, the mean value of Utility was 0.423 (mean)±0.217 (standard deviation: SD), and that for the UK tariff was 0.147±0.312; the median value for the Japanese tariff was 0.466, the minimum value -0.106, and for the UK tariff, the median was 0.122, the minimum value -0.594. Furthermore, distributions of EQ-5D-5L tariffs were compared between the Japanese and UK versions. The mean values of Utility for the Japanese and UK tariffs were 0.449±0.154 and 0.391±0.228, respectively; the median value for the Japanese tariff was 0.450, minimum value -0.0.25, and for the UK tariff, the median was 0.396, the minimum value -0.281. The correlation between the Japanese and UK tariffs for EQ-5D-3L was R2=0.739, RSME=0.160. For EQ-5D-5L, the correlation between the Japanese and UK tariffs was R2=0.907, RSME=0.069. We clarify Japanese and UK value sets was closer in EQ-5D-5L than in EQ-5D-3L. Moreover, the correlation was observed more prominently in EQ-5D-5L than in EQ-5D-3L as well. Therefore, it is recommended that in the future we should use EQ-5D-5L in Japan when conducting a clinical study to collect health state data using EQ-5D.

Key Words: EQ-5D, Health state values, Utility, Japan, UK


An increase in medical expenses has recently been a matter of concern to many countries [1]. One of the factors of this concern is the higher cost of novel medical technologies (new pharmaceutical products and medical devices) compared to that of pre-existing technologies [2]. Against this background, it has been a global issue to efficiently distribute the limited medical expenditures.

In 2016, new decision-making processes for the pricing of health technologies in medical fields based on economic evaluations were started in Japan [3]. In the field of oncology, the trial subjects included Trastuzubab-emtansine(Kadcyla, Roche) a therapeutic agent for HER2-positive metastatic breast cancer, and Nivolumab (Opdivo, Ono Pharmaceutical Co.Ltd) for Non-small cell lung cancer. As it is anticipated in cancer treatments that development of expensive pharmaceutical products such as molecular target drugs and immune checkpoint inhibitors will further progress, we will need to consider cost-utility in the clinical practice of oncology. Hence, it will be important for physicians including oncology specialists to understand health economics assessment in the future.

The Health Technology Assessment (HTA) system which has been provisionally used in Japan was established based on a UK’s method [3]. The guidelines for the economic evaluation of drugs/medical devices in Japan also follow methodology of National Institute for

Health and Care Excellence (NICE)[4], an HTA agency in the UK, and recommend using Quality Adjusted Life Years (QALYs), namely, life years adjusted with quality of life (QOL), as an outcome indicator of HTA and conducting cost-utility analysis (CUA) [5]. The quality adjustment of QALYs is performed with Utility and calculated using the Value Set of health state obtained from general population called tariff. The EuroQol-5-Dimension (EQ-5D) is a questionnaire, which is the most generally used for calculating Utility [6, 7]. The EQ-5D includes EQ-5D-3L [9, 10] which evaluates 5 items in 3 levels and EQ-5D-5L [11, 12] in 5 levels.

According to the Japanese guidelines, it is allowed to extrapolate foreign data in the CUA if there is no Utility data available for subject items investigated in Japan [5]. However, the correlation between the Value Set created in foreign countries and that created in Japan is not very clear, and it is unknown whether foreign data are extrapolatable or not.

Hence, we attempted to conduct an international comparative study on the UK, known as the leading country of HTA, and Japanese Value Sets of EQ-5D-3L and 5L.

Materials and Methods

A total of 70 outpatients with RA treated in Niigata University Hospital were evaluated in this study. Each patient satisfied the 1987 American Society of Rheumatology Criteria for RA [11]. Patients’ records were obtained from their medical records. None of these patients were treated with operation of gastrectomy. All 70 patients had not received MTX. Thirty-three cases were treated with DMARDs except for MTX and 37 cases were treated without DMARDs. DMARDs treatment was continued at least 4 months in all the patients. We estimated these patients’ disease activity to be stable and, therefore, were included in this study. Additionally, patients showing anemia (hemoglobin (Hb) <10.8 g/dl) were excluded from this study.
Laboratory procedure and vitamin B12, folic acid assay
Hb, MCV, serum creatinine, CRP, and RF were assessed by routine laboratory methods.  Erythrocyte sedimentation rate (ESR) was measured by Westergren method. Folic acid and vitamin B12 were each measured using folic acid and vitamin B12 assay kits with chemiluminescent Immunoassay (CLIA) technique (Beckman Coulter Corp, Tokyo, Japan). All of these samples were measured in duplicate.

Statistical analysis
Correlation between CRP and its possible modifiers (sex, age, MCV, Hb, folic acid, and vitamin B12) was assessed by Spearman rank-order correlation coefficients. Dose dependent association between CRP quintile rank and each possible modifier was tested by ordinal logistic regression model adjusted for all other possible modifiers. The statistical significance of these associations was expressed as P for trend. All statistical analyses were performed by using SPSS 13.0 for Windows (SPSS, Inc., Chicago, IL, USA), and P < 0.05 was considered statistically significant.
The study protocol was approved by the institutional review board of Niigata University Medical and Dental Hospital, and the subjects gave informed consent to participate in this study.


Clinical features
Seventy patients with RA treated without MTX were evaluated in this study. Twelve patients were male and 58 were female. Table 1 shows the clinical characteristics and laboratory findings of these patients at the time MCV measurement was assessed. The mean duration was about 10 years and many of these patients were treated with a few csDMARDs. Inflammatory measures such as ESR and CRP were elevated. Rheumatoid factor (RF) was also frequently elevated due to disease activity of RA. About 5% of these patients presented renal insufficiency, but their serum creatinine levels were minimally elevated. The abnormal elevation of MCV was detected only in one patient and the level of MCV was slightly elevated with upper limit. The incidence of anemia such as gastroduodenal ulcer was not detected Low level of serum folic acid was about 5% and low level of vitamin B12 deficiency was about 8%. However, both of their serum folic acid and vitamin B12 depression were not so severe.

Table 1. Patients characteristics.

Subjects Number or Mean SD Maximum Minimum
Age (years) 61 12.7 84 19
Sex (Male/Female) 12/58
Disease duration (years) 10.0 9.2 27 0.5
Cre (mg/dL) 0.8 0.5 2.9 0.4
CRP (mg/dL) 1.7 12.7 9.2 0.05
ESR (mm/h) 32.0 22.3 92.0 7.0
RF (IU/mL) 252.4 509.2 3.0 269.0
MCV (fL) 92.7 4.6 101.5 79.8
Hb (g/dL) 13.0 1.3 16.2 10.8
Folic acid (ng/mL) 5.4 2.8 14.1 1.6
Vitamin B12 (pg/mL) 516.0 502.0 3000.0 85.0
Number (%)
Elevation of Cre (>1.2 mg/dL) 4 (5.7)
Elevation of MCV (>100 fL) 1 (1.4)
Depression of Hb (<10.7 g/dL) 0 (0)
Depression of folic acid (<2.5 ng/mL) 4 (5.7)
Depression of vitamin B12 (<180 pg/mL) 6 (8.6)

SD: standard deviation; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; RF: rheumatoid factor; Cre: serum creatinine. MCV: mean corpuscular volume = hematocrit (%) / red blood cell count (104/mm3) × 10.

csDMARDs treatment of these patients
All 70 patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) and 33 patients were treated with csDMARDs without MTX. The details of csDMARDs are shown in Table 2. SASP and bucillamine (BCL) were frequently used in these patients. About half of these patients were not treated with csDMARDs. Oral prednisolone therapy was given to 27 patients and their dose was 3.2 ± 5.0mg daily. MTX therapy is well known to act by inhibiting the metabolism of folic acid and the effect of MCV was easy to be thought of. Thus we excluded patients treated with MTX in this study.
Correlation between CRP and other variants
The correlation between CRP and other variants were tested by Spearman rank- order correlation coefficient. The results were shown in Table 3. Significant negative correlations were present between CRP and age, MCV, and Hb. However, serum levels of folic acid and vitamin B12 were not significantly correlated respectively.

Table 2. Details of DMARDs treated with RA patients.

csDMARDs Number of patients
DPC + AZ 1
AF 2
PSL 27
ND 31

csDMARDs: Conventional synthetic disease modifying anti-rheumatic drugs; SSZ: sulfasalazine; AZ: azthopurine; CY: cyclophosphamide; DPC:D-penicillamine; GST: gold sodium thiomalate; AF: auranofin; ACT: actarit; BCL:bucillamine; PSL: prednisolone; ND: No csDMARDs

Table 3. Spearman rank-order correlation coefficient (ρ) between CRP and each of the possible modifiers.

Variants ρ P-value
Sex (Female 1, Male 0 ) -0.03 0.822
Age -0.24 0.046
MCV -0.35 0.003
Hb -0.30 0.011
Folic acid -0.12 0.332
Vitamin B12 0.06 0.648

Correlation between CRP quintile and other variants
The correlation between CRP quintile and other variants were tested by Spearman rank-order correlation coefficient. All variants were adjusted to each other in the table. The results were presented in Table 4. Significant inverse correlations were present between CRP and MCV. As for MCV, the fluctuation was within normal range, but the more the CRP was increasing, the more MCV was decreasing. In contrast, the other variants of sex, age, Hb, folic acid and vitamin B12 were not significant, respectively.

Table 4. Adjusted dose dependent association between CRP quintile and each of the possible modifiers.

quintile 1st (n=17) 2nd (n=15) 3rd (n=12) 4th (n=13) 5th (n=13)
[range of CRP] [0.05] [0.1-0.3] [0.4-0.7] [0.8-1.6] [1.8-9.2] P for trend*
Sex (% of female) 88.2% 80.0% 83.3% 69.2% 92.3% 0.271
Age 64.9 (10.9) 64.6 (14.3) 63.2 (8.8) 58.6 (10.9) 54.2 (15.8) 0.083
MCV 94.7 (3.7) 94.0 (3.3) 92.7 (3.6) 91.0 (6.1) 90.3 (4.7) 0.035
Hb 13.3 (1.1) 13.3 (1.2) 13.0 (1.1) 12.4 (1.4) 12.8 (1.5) 0.201
Folic acid 5.2 (2.9) 6.3 (3.0) 6.1 (2.6) 4.6 (2.4) 5.0 (2.7) 0.900
Vitamin B12 385.6 (214.0) 467.3 (212.9) 664.5 (805.2) 506.9 (374.9) 615.4 (735.0) 0.148

mean (SD), * Adjusted for all variables in the table each other using ordinal logistic regression model.


Anemia is often present in patients with RA. Many types of anemia are associated with RA [12,13]. Vitamin B12 and folic acid deficiency are reported to be more prevalent among patients with RA than controls [14,15]. The current treatment paradigm of RA entails the early use of csDMARDs [16]. The various csDMARDs available include MTX, SASP, BCL, actarit (ACT), leflunomide, azathioprine, chloroquine, cyclosporine, gold and D-penicillamine (D-PC). MTX is the most popular drug due to its proven clinical efficacy and low discontinuation rates demonstrated in several long-term observational studies [17]. Hematological toxicity of MTX is well known, because of its pharmacological action [18]. However, in clinical practice, there are many patients who cannot use MTX, because of interstitial lung disease, chronic kidney disease, and infections. Thus we examined our RA patients treated with DMARDs but not with MTX. SASP has been demonstrated to inhibit both folate transport across intestine and various folate-metabolizing enzymes [19]. The effect of SASP on folate-dependent enzymes is particularly similar to the anti-rheumatoid action of MTX. A low level of folate is often seen in patients with RA and it might be expected that treatment with SASP may cause folate deficiency. However, no major effect on serum and red cell folate levels was seen in SASP treated patients [20]. Among our patients, one patient treated with SASP presented a depression of folic acid under 2.5 pg/ml and two additional patients treated with SASP revealed a relatively low level of folic acid below 3.0 pg/ml. In Japan, BCL was frequently used for the treatment of RA. BCL has 2 sulfhydryl moieties and its chemical structure is similar to D-PC. And BCL was shown to possess similar pharmacokinetic actions to D-PC [21]. However, the hematological effect of BCL remains to be validated. None of our patients showed low levels of folic acid below 3 pg/ml. Renal insufficiency was a consequence of anemia due to a lack of erythropoietin. The presence of anemia detected by a lack of erythropoietin was usually shown in normocytic and normochromic anemia [22] and usually did not affect MCV.
Vitamin B12 is associated with enlargement of MCV in patients with anemia. Pernicious anemia is a condition in which the body cannot make enough healthy red blood cells because it does not have enough vitamin B12 [23]. Vitamin B12 is a nutrient found in certain foods. Patients who have pernicious anemia cannot absorb enough vitamin B12 from foods due to a lack of intrinsic factors [24]. This leads to vitamin B12 deficiency. It is also well known that a deficiency of vitamin B12 or folic acid results in megaloblastic anemia in post-gastrectomized patients. Our patients had no history of gastrectomy. The number of patients with depression of vitamin B12 was 6/70 (8.6%). In these patients, their average MCV was 97.2±2.0. The level of MCV in these six patients was relatively high compared to the rest of our patients. A vitamin B12 deficiency may have contributed to MCV enlargement in our RA patients. Anemia of chronic disease is a form of anemia seen in chronic illnesses, chronic infection, chronic immune activation or malignancy. Anemia of chronic disease is often a mild normocytic anemia, but can sometimes be more severe, or can sometimes be microcytic anemia [25-30]. In our study, multivariate analysis revealed that the CRP level and MCV were inversely correlated. Our patients were not correlated with Hb level in Table 4. The degree of MCV depression was depended on the level of the inflammation of RA and the level of Hb was not correlated with the level of CRP.


Our data suggested that change of MCV was depend on the inflammation and was not related to the level of folic acid and vitamin B12. Moreover, chronic inflammation may be contributing factor. The doses of csDMARDs, such as SASP, prescribed for RA in Japan are less than those prescribe abroad. Additional studies are warranted in which RA patients are carefully monitored for several years after the onset of the disease to determine changes in MCV and CRP.


This work was supported by a grant for JSPS KAKENHI Grant Number17K09973, and a grant from the Amyloidosis Research Committee of the Ministry of Health,

Conflict of Interest Statement
None of the authors has a conflict of interest to declare.


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Received:  July 02, 2018;
Accepted: July 25, 2018;
Published: July 27, 2018

To cite this article:

Kuroda T, Tanabe N, Sato H. Association between Elevated Mean Corpuscular Volume and C-reactive protein in Patients with Rheumatoid Arthritis. Japan Journal of Medicine. 2018: 1:5.

©Kuroda T, et al. 2018.