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Jacobs Journal of Orthopedics and Rheumatology
Original Article

Biomarkers and Choice of Biologic Agent: A Comparison of the Efficacy of Tocilizumab and Etanercept in Rheumatoid Arthritis Patients Presenting with Leukocytosis or
Thrombocytosis
Kiyomitsu Miyachi 1,2, Belinda Sasse 1,3, So Nomoto 4
Department of Rheumatology, Keigu Clinic, 2-2 Ichibanishinaka-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0023, Japan

1

First Diagnostic Division, Health Sciences Research Institute, Yokohama, Kanagawa 240-0005, Japan2

Department of Rheumatology, Monash Health, 246 Clayton Rd, Clayton, Victoria 3168, Australia

3

Department of Orthopedic Surgery, Saiseikai Yokohama City Eastern Hospital, Yokohama, Kanagawa, 230-0012, Japan

4*Corresponding author: Dr. Kiyomitsu Miyachi,M.D. Keigu Clinic, 2-2 Ichibanishinaka-cho Tsurumi-ku Yokohama,
Kanagawa 230-0023, Japan, Tel: +81 45 501 5361; E-mail: mkiyomitsumd_8@hotmail.com
Received: 03-31-2015
Accepted: 09-05-2015
Published:
Copyright: © 2015 Kiyomitsu

Abstract
Objective: The aim of this study was to evaluate the relative efficacy of tocilizumab (TCZ) and etanercept (ETN) in patientswith rheumatoid arthritis (RA) presenting with upper normal limit or high white blood cell (WBC) and platelet counts, and therelative roles of inflammatory cytokines TNFα and IL-6 on the appearance of these hematological abnormalities, by comparing
laboratory results from RA patients pre and post administration of TCZ or ETN.
Methods: The influence of TCZ on white blood cell (WBC) and platelet (Plt) counts in 33 RA patients was compared to that of
ETN in 38 RA patients at Weeks 0, 12, and 24. The relationship between the presence or absence of WBC>9000 (high normal/
leukocytosis) or Plt>35x104 (high normal/thrombocytosis) before treatment, and the rate of clinical complete remission by DAS28 CRP at Week 24 in 33 patients treated with TCZ and 38 treated with ETN was investigated.

Results: In the 33 RA patients treated with TCZ, the pre-treatment mean WBC count (7708/μL) and plt count (29.4×104/μL)
were significantly decreased to 5970/μL (22.5%↓)and 20.8×104/μL (29.3%↓) respectively at Week 12. In the 38 RA patientstreated with ETN, initial WBC (7804/μL) and plt (31.7×104/μL) counts were also reduced to 6911/μL (11.4%↓)and 25.4×104/
μL (20.0%↓) respectively at Week 12. The decrease in mean plt count was significantly greater in RA patients treated with TCZ
than in those treated with ETN at Week 12 (p<0.05). Twelve of the 14 (85.7%) RA cases presenting WBC↑or Plt↑ treated with
TCZ achieved complete remission by Week 24, however, only 5 of the 20 (25.0%) cases treated with ETN achieved complete remission by this time. This difference was statistically significant with a X2 score of 6.6526 (P<0.01).
Conclusion: TCZ may be more suitable than ETN as a first-line therapeutic option for RA patients that have upper normal limit
platelet count, WBC, thrombocytosis and/or leukocytosis, parameters which may be influenced by IL-6.

Keywords: Tocilizumab; IL-6; Etanercept; TNFα; Rheumatoid Arthritis (RA); Cytokine; Biological Agents

Cite this article: Mi. Biomarkers and Choice of Biologic Agent: A Comparison of the Efficacy of Tocilizumab and Etanercept in Rheumatoid Arthritis Patients Presenting with Leukocytosis or Thrombocytosis. J J Ortho Rheum. 2015, 1(2): 007.

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2

Introduction

biological therapies, a subset of RA patients that presented
high normal platelet counts, high normal WBCs, leukocytosis, thrombocytosis, and/or severe anemia were noted at ourclinic. Most were in a very clinically active stage of establishedRA, although some had early RA. Of note, these patients had
no evidence of underlying infections or severe iron-deficiency
anemia, and it was hypothesized based on the biology of IL-6
action that this hematological disturbance was predominantly
due to IL-6 activity rather than TNFα, and as such IL-6 inhibitors may be more effective in this patient group.

Although the etiology of rheumatoid arthritis (RA) is notwell understood, both genetic and environmental factors are
considered to be involved. Patients with HLA-DRB1 sharedepitope alleles exhibit a poorer prognosis than patients withother haplotypes [1,2]. Environmental factors, including several bacterial, viral, and mycoplasma infections have also been
implicated in the etiology of the disease. These microbes arerecognized by Toll-like receptors (TLRs) expressed on the surface of a wide variety of cells including macrophages, and elicit
an innate immune response [3]. Since class II major histocompatibility complex (MHC) loci, such as HLA-DR, are known topromote TLR-triggered innate immunity [4], involvement ofinnate immunity and subsequent production of cytokine-mediated inflammatory responses are considered keys to thepathogenesis of RA.

Cytokines including tumor necrosis factor alpha (TNFα) andinterleukin 6 (IL-6) form the crux of the inflammatory processthat drives joint destruction in RA [5]. IL-6 is present in great
quantities in the serum and synovial fluid of RA patients, andlevels reflect disease activity well [6]. IL-6 is released by lymphocytes and monocytes that infiltrate the synovium, causing
inflammation and joint destruction by influencing multiple
other cell types (Refer Supplementary Figures (1 and 2)) [5].
This cytokine has been implicated in the development of anemia [6] and leukocytosis [7] in RA patients, and is also known
to affect megakaryocytopoiesis, with RA patients with thrombocytosis exhibiting higher IL-6 levels than patients with normal platelet counts [8]. Similarly, TNFα has a broad range ofaction on many cell types, including macrophages, activatedT-cells, B-cells, synovial lining cells and endothelial cells, withmyriad pro-inflammatory effects. Like IL-6, TNFα is a key mediator of joint destruction and inflammation in RA. [9].
TNFα inhibitor infliximab (IFX) [10] has been available for thetreatment of RA for approximately 11 years in Japan, and more
recently, etanercept (ETN) [11], adalimumab (ADA) [12], golimumab [13] and certolizumab pegol have become available.
These TNFα inhibitors were proven to be effective in clinical
trials of large cohorts in Japan, although their efficacy in combating leukocytosis and thrombocytosis has not yet been examined. Moreover, in Japan the IL-6 receptor inhibitor tocilizumab (TCZ) and the T-cell blocker abatacept [14] have beenused as second-line therapeutic options for RA over the last 7
years and the last 4 years, respectively. In addition, these twobiologic agents were approved as first line drugs in 2013. The
inflammatory cytokines TNFα and IL-6 both play very important roles in disease progression and outcomes of RA; however,the difference in disease response to these agents is not wellunderstood.
While treating RA patients with methotrexate (MTX) and/or

In this study, clinical and laboratory responses to TCZ or ETN,
including WBC count and platelet count, were compared in 71
RA patients randomized to each treatment group. It was hypothesized that IL-6 may play a greater role in the pathogenesis of thrombocytosis, leukocytosis, anemia, and/or the production of acute-phase reactants (CRP and serum amyloid A
protein) than TNF-α although IL-6 levels were not assessed inthis study. Results of this study suggest that TCZ used as a firstline biologic agent could be more effective for the treatment
of RA patients who present with increased WBC or platelet
counts than ETN.

Materials and methods
Patients

In this study, 71 RA patients treated with biological therapies
were enrolled. They included 33 patients treated with TCZ at
the Keigu Clinic (Yokohama) and the Saiseikai Yokohama City
Eastern Hospital (Group 1), and 38 treated with ETN at the
Keigu Clinic (Group 2). Owing to different approaches in theenrollment of patients with established RA, the disease parameters of Group 1 and Group 2 differed as evidenced by thedifferences in disease duration, functional class, and other parameters (Table 1). In order to compare responses in patientswith similar disease status, we selected 17 patients with earlyRA (7 patients from Group 1 and 10 patients from Group 2).
76.8% of Group 1 patients and 71.1% of Group 2 patients wereconcurrently treated with MTX, respectively. Biologic monotherapy was only considered in cases of MTX intolerance or
toxicity. 48.5% of Group 1 and 65.7% of Group 2 patients received steroids.
All patients included in this study were provided with an explanation of the purpose of the study, and gave their written
and/or oral consent prior to enrollment. This study was approved by the Yokohama Society of Rheumatology.
RA diagnosis

Established RA patients were diagnosed by close adherence
to the 1987 American College of Rheumatology criteria [15].
However, early RA patients were more recently diagnosed according to the 2010 American College of Rheumatology/Eu-

Cite this article: Mi. Biomarkers and Choice of Biologic Agent: A Comparison of the Efficacy of Tocilizumab and Etanercept in Rheumatoid Arthritis Patients Presenting with Leukocytosis or Thrombocytosis. J J Ortho Rheum. 2015, 1(2): 007.

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ropean League against Rheumatism criteria [16]. If erosions
were not observed on bilateral X-rays of the hands and feet,a classification of early RA was allowed if 6 points or greater
were obtained.
Medical and biological drugs

MTX at a dose of 6 to 15 mg/wk was routinely administeredin early or established RA cases. MTX was not implemented
or was discontinued for some RA patients who complained ofpersistent nausea or dizziness or who had a history of interstitial pneumonia or hematological disturbances.

In Group 1, 8 mg/kg of TCZ every 4 weeks was used as a second-line biological agent for 17 patients with established RA.
Seven patients with early RA and 9 patients with establisheddisease were given 8 mg/kg of TCZ every 4 weeks as a first-line
biological agent, which was reduced to 4 mg/kg every 4 weeks
after 1 year.

In Group 2, ETN at a dose of 25 mg twice a week for 6 consecutive months was used in 28 patients with established RA. In
10 early RA patients who had favorable clinical responses, 25
mg of ETN twice a week were used for 1 or 2 months and thenreduced to 25 mg once a week.
Laboratory tests

In this study, white blood cell count (WBC count), platelet
count, and hemoglobin (Hb) were assessed at Weeks 0, 12,
and 24. In order to include patients with more subtle hematological disturbances, the slightly lower values WBC>9000 and
Plt>35x104 were used as cut-offs for leuko- and thrombocytosis instead of WBC>9100 and Plt>36.9x104. Changes in parameters in the 33 RA patients treated with TCZ (Group 1) werecompared at Weeks 0, 12, and 24 with changes in parametersin the 38 RA patients treated with ETN (Group 2). Anti-CCP
antibody was usually tested once at the initial visit, and in accordance with Japanese clinical practice guidelines was notretested thereafter.
Evaluation of efficacy

The clinical response to biologics was evaluated by using the
28-joint disease activity score DAS28-CRP [17] and the Boolean complete remission criteria [18]. Clinical complete remission was considered to be achieved in TCZ patients with a
DAS28-CRP score < 2.3, and in ETN patients with a score < 2.6.
A lower score was used in the TCZ group, as TCZ is known to
inhibit CRP, as has been done in previous studies [17]. Patientsachieving Boolean complete remission fulfilled all of the following criteria: tender joint count ≤1, swollen joint count ≤1,
CRP level of ≤1 mg/dL, and patient global assessment of ≤1 cm
on a 0 to 10 visual analogue scale (VAS).

Statistical Analysis
Patient baseline characteristics were summarized using mean(± standard deviation), median (interquartile range), or n (%).
The last observation carried forward (LOCF) method was usedin each analysis. Statistical significance was determined byStudent’s t-test (for continuous variables) and paired-samples
t-test. In addition, X2 test was used for the comparison of theefficacies of TCZ and ETN in patients with RA.

Results
Comparison of treatment group demographics
The demographics of the study patients are shown in Table 1.
There were several differences between Group 1 (TCZ) andGroup 2 (ETN) with respect to patient background. First, the7.2 year observation period from diagnosis of RA to initiation of
biologic therapies in Group 1 was significantly shorter than the10.1 years in Group 2. Second, there was a higher percentage ofpatients with advanced RA (Steinbrocker functional class 3 or
4) in Group 2 (78.9%, 30/38) than in Group 1 (54.5%, 18/33).
Finally, the percentage of patients in Group 2 using ETN as thefirst-line biologic was higher (81.6%) than that of patients inGroup 1 (48.5%) using TCZ as a first-line therapeutic agent.
Table 1: Patient demographics

Table 1. Patient demographics.
Cases
Age (yr), mean (range)
Disease duration, yr
Steinbrocker radiographic stage(I:II:III:IV)
Steinbrocker functional class(1:2:3:4)
Steroid use, %Mean dose of steroid, mg
MTX use, %Mean dose of MTX, mg
Positive RF, %Biologic naïve
DAS28-CRP
peripheral blood examination

Group 1 TCZ (n=33)
64.0(39~81)
7.2(0.2~27.3)(4:5:16:8)

Group 2 ETN (n=38)
63.9(23~90)
10.2(0.2~40)(1:10:18:9)(1:14:18:0)(0:8:28:2)

48.5
2.2
76.8
6.9
76
48.5
4.64

65.7
3.3
71.1
7.5
81.2
81.6
5.04

（/μｌ）

7708

7804

Mean Platelet （/μｌ）

29.4

31.7

11.5

12.4

Mean WBC

Mean Hb（mg/ml）

These differences may be due to the different times at which
TCZ and ETN became available in Japan; as ETN was approved
four years prior to TCZ, it is more commonly used as a first line
agent. In addition, TCZ has only been available as a first line
agent since 2013.

Cite this article: Mi. Biomarkers and Choice of Biologic Agent: A Comparison of the Efficacy of Tocilizumab and Etanercept in Rheumatoid Arthritis Patients Presenting with Leukocytosis or Thrombocytosis. J J Ortho Rheum. 2015, 1(2): 007.

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Comparison of WBC counts in Group 1 and 2 at Weeks 0,
12, and 24
The mean WBC count of 7708±2767/μL before treatment with
TCZ was significantly decreased to 5970±2728/μL (↓22.5%) at
Week 12 and to 6258±2668/μL(↓18.8%) at Week 24 (p<0.05).
By comparison, the mean WBC count of 7804±1783/μL before
treatment with ETN was significantly reduced to 6911±2009/μL (↓11.4%) at Week 12 and to 6811±1739/μL (↓12.7%) at
Week 24 (p<0.05). Interestingly, the decrease in mean WBC
count at Week 12 appeared to be greater in the group treatedwith TCZ than in the group treated with ETN (Figure 1), however, this difference was not statistically significant because ofa wide standard deviation.

100

70.7

77.9

100

80.1

76.7

Figure 2: Serial platelet counts of 33 patients treated with TCZ and 38 patients treatedwith ETN—comparisons at Weeks 0, 12, and 24―

Baseline(mean) indicates 100

Comparison of hemoglobin levels in Group 1 and 2 atweeks 0, 12 and 24

100

77.5

81.2

100

88.6

87.3

Figure 1: Serial WBC counts of 33 patients treated with TCZ and 38 patients treated

The mean hemoglobin level was 11.5±1.4mg/ml before
treatment with TCZ, and was significantly increased to
12.1±1.5mg/ml (↑5.22%) at Week 12 and to 12.2±1.6 mg/ml(↑6.09%) at Week 24 (p<0.05). By comparison, the mean hemoglobin level of 12.4±1.7mg/ml before treatment with ETN
was only marginally increased to 12.7±1.6mg/ml (↑2.42%)
at Week 12 and to 12.6±1.6mg/ml (↑1.61%) at Week 24. The
difference in hemoglobin increase between the two groups
at Week 24 did not reach statistical significance (Figure 3).

with ETN—comparisons at Weeks 0, 12, and 24
Baseline(mean) indicates 100.

Comparison of platelet counts in Group 1 and 2 at weeks
0, 12 and 24
The mean platelet count of 29.4±9.5×104/μL before treatment with TCZ was significantly reduced to 20.8±6.3×104/
μL (↓29.3%) at Week 12 and to 22.9±9.9×104/μL (↓22.1%)
at Week 24 (p<0.05). Similarly, the mean platelet count of
31.7±9.6×104/μL before treatment with ETN was significantly reduced to 25.4±6.85×104/μL (↓20.0%) at Week 12 and to
24.3±6.07 ×104/μL (↓23.3%) at Week 24 (p<0.05). Interestingly, the decrease in mean platelet count at Week 12 was statistically significantly greater in the group treated with TCZ than in
the group treated with ETN (p<0.05) (Figure 2).

100

105.2

106.2

100

102.4

101.6

Figure 3: Serial hemoglobin levels of 33 RA patients treated with TCZ and 38 RA
patients treated with ETN―comparison at Weeks 0, 12 and 24－

Baseline (mean) indicates 100

Comparison of achievement of Boolean’s complete remission in Group 1 and 2
Of 33 RA patients treated with TCZ, 5 (15.1%) achieved Boolean’s complete remission within 3 months, two of whom had
early RA. Eleven of 33 (33%) patients in this group achieved

Cite this article: Mi. Biomarkers and Choice of Biologic Agent: A Comparison of the Efficacy of Tocilizumab and Etanercept in Rheumatoid Arthritis Patients Presenting with Leukocytosis or Thrombocytosis. J J Ortho Rheum. 2015, 1(2): 007.

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remission within 1 year. All patients with early RA in thisgroup obtained Boolean’s complete remission within 2 years,
except 2 patients who failed to achieve a patient global assessment VAS score of less than 1cm. Of the 38 RA patients treated with ETN, 7 (18.4%) achieved complete remission within
3 months, five of whom had early stage RA. Ten of 38 (26.3%)
achieved remission within 1 year. Patients with an inadequate
response to TCZ and ETN, as determined by a CRP> 1mg/ml,
were changed to other biologic agents. (Table 2). Eight cases
were lost to follow up in Group 1 and two cases in Group 2.
Table 2: 2.
Comparisonof achievement
Boolean’s complete ofremissionin RA patientstreated with remisTable
Comparisonof ofachievement
Boolean’scomplete
TCZ andsion
inETN
RA patients treated with TCZ and ETN.
Biologics

No of Pts

Months to Achieve

No

DroppedOut

TCZ(33)

ETN(38)WBC↑ orDAS28-CRP

Plt↑

<2.3

Yes

Yes

12

Yes

No

2

No

Yes

10

No

Remission

WBC↑

rate

or

%

Plt↑

Total

No

9

12/14(87.5%)

10/19(52.6%)

TCZ

33 (7)

5(2)

3＜ ≦6
4(2)

6＜ ≦122(1)12＜ ≦24
2(2)

12

8

TCZ ( ): Tocilizumab (total patients), ETN (ETN

38 (11)

7(5)

2(1)

1(1)

2(1)

24

(2)

WBC ↑: >9000/µl, Plt ↑: >35x104/µl

Type

≦3

Achievement

TCZ: Tocilizumab, ETN: Etanercept(

Table 3: Relationshipbetween thebetween
presence or absenceof leukocytosis
thrombocytosis
Table
3. Relationshipthe presenceororabsence
ofbeforeleukocytotreatment
and the rate of clinical complete
by DAS-28
CRP atWeek
24 in ofGroup
1 and 2 comsis
or thrombocytosis
beforeremission
treatment
and
the
rate
clinicalplete remission by DAS-28 CRP at Week 24 in Group 1 and 2.

DAS28-CRP<2.6

Remission
Total

rate
%

Yes

Yes

5

Yes

No

15

No

Yes

12

No

No

6

5/20 (25%)

12/18 (66.7%)): Etanercept (total patients)

DAS: Disease Activity Score)：No of early RA

Relationship between the presence or absence of highWBC and/or plt count before treatment and the rate ofclinical complete remission by DAS-28 CRP at Week 24 inGroup 1 and 2
TCZ and ETN were used in 14 and 20 RA patients presenting
with WBC >9000/µl (upper normal/leukocytosis) or platelet
count plt>35x104/µl (upper normal/thrombocytosis), respectively. In both groups, high normal WBC /leukocytosis andhigh normal platelets/thrombocytosis were evident before
commencing the biologic agents. Surprisingly, 12 of the 14(85.7%) RA cases treated with TCZ achieved complete remission by DAS 28- CRP: 2.3 at Week 24, however, only 5 of the 20(25%) cases treated with ETN achieved complete remission by
DAS28–CRP: 2.6 at Week 24. This difference was statisticallysignificant with a X2 score of 6.6526 (P<0.01).
In contrast, TCZ and ETN were used in 19 and 18 RA patients
not presenting with high normal WBC/leukocytosis or highnormal platelet count/thrombocytosis, respectively. Twelve of
the 18 (66.7%) cases of RA treated with ETN reached complete
remission by Week 24, however, only 10 of the 19 (52.6%) cases of RA treated with TCZ achieved complete remission. Furthermore, of the 33 cases of RA treated with TCZ, the proportion of patients achieving remission was higher in the groupthat presented with high normal WBC/leukocytosis or highnormal platelets/thrombocytosis (87.5%, 12/14) than in patients without these abnormalities (52.6%, 10/19). However,this difference was not statistically significant (Table 3).

Limitations
This trial was conducted on a relatively small patient cohort,
all of whom were ethnically Japanese. These results therefore
may not be generalizable beyond this population, and further
studies should be considered to confirm this. In addition, whilein early RA it is easier to attribute leuko- and/or thrombocytosis to the disease, patients with established RA may havemultiple other possible causes for these abnormalities such as
infection or steroid use. This may reduce the reliability of using
WBC or platelet count as a biomarker for selection of an appropriate biologic agent.

Discussion

Interleukin 6 (IL-6)/B cell stimulating factor 2 (BSF-2) was
first discovered and cloned in 1986 [19]. IL-6 was found to
stimulate the proliferation of myeloma cells [20] and to promote platelet production in mice [21], and is known to contribute to anemia, leukocytosis and thrombocytosis in RA patients(6,7,8). TCZ is a humanized antibody targeting the IL-6R thatwas first produced in Japan for the treatment of RA, and is distinct from TNFα inhibitors. In previous studies of patients with
Castleman disease and systemic juvenile idiopathic arthritis,
diseases in which overproduction of IL-6 is a key feature [22],IL-6R inhibitors have been shown to markedly reduce WBC
and plt count within one month [23,24].

The differing efficacies of the wide range of available biologic agents have been the subject of many studies. The efficacy
of TCZ and ADA monotherapy were compared in a large, randomized, double-blind controlled trial (the ADACTA study);
TCZ monotherapy was found to be more effective [25]. TCZ
was also shown to be more effective than MTX in another trial;

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49.2% of patients given TCZ monotherapy achieved an ACR50
response and 29.5% achieved ACR70 at 24 weeks, in contrast
with MTX monotherapy where only 10.9% achieved an ACR50
response and 6.3% achieved ACR70 [26]. DAS28-ESR scores of<2.6 were attained by 47.2% of RA patients treated with TCZ
monotherapy and by 2.8% treated with MTX. These results indicate that efficacy of TCZ monotherapy in RA is superior totherapy with MTX alone. In addition, another study showed
the mean modified total Sharp score (mTSS) of 2.3 obtainedin RA patients treated with TCZ monotherapy at 52 weeks was
significantly lower than the mTSS of 6.1 in RA patients treated with MTX (6–8 mg/wk) alone over the same period [27].
TCZ plus MTX versus TCZ alone has also been examined in one
study, in which patients who did not tolerate MTX + TCZ were
given TCZ monotherapy; TCZ alone was found to be equally effective [28].

However, ETN or ADA combined with MTX has been shown
to be more effective than ETN or ADA monotherapy [29,30],
and monotherapy with ETN or ADA is not as effective as MTX
monotherapy [30].

TCZ has been shown as an appropriate choice for inadequate
responders to MTX. In a randomized placebo-controlled trialof TCZ in MTX inadequate responders, the rate of accomplishment of DAS28-ESR<2.6 in the TCZ 8 mg/kg group (47.2%)
was much higher than that of the placebo group (7.9%). TCZ
was also found to have an adequate safety profile [31]. Likewise, in RA patients with disease refractory to TNF blockers,
TCZ 8mg/kg proved safe and effective in another randomized
placebo-controlled trial [32].
Administration of TCZ is associated with neutropenia in RA patients; however, it remains unclear why leukocyte recruitment
from bone marrow to the peripheral circulation is affected bytreatment with TCZ. WBC counts have been shown to be markedly reduced on the first day of treatment [33], and although
WBC counts return to the normal range over time, they do notrecover to initial levels for two to three months. As IL-6 enhances platelet release from megakaryocytes directly, the phenomenon of decreased platelet count following TCZ therapy
is more easily understood. In the present study, the decreasein levels of leukocytes and platelets was significantly greaterin patients on TCZ therapy than in those on ETN therapy, suggesting that TCZ has a more direct effect on bone marrow thanETN.
In addition, although not statistically significant, recovery fromanemia was quicker in patients receiving TCZ treatment thanin those on ETN. This may be related to the effect of TCZ on theblockade of hepcidin production, and on aberrant regulationof absorption of iron in the intestine and release of iron fromthe spleen [34].
It is known that both TNF-α and IL-6 are involved in the patho-

genesis of RA, however, while undoubtedly some pathways areshared, it is likely that both cytokines also have independent
pathogenic effects. While TNFα has been reported to be theprimary cytokine responsible for the pathogenesis of RA [35],and that IL-6 is dependent upon TNFα, this may not be thecase. In the RISING study, a randomized double-blind trial, patients treated with infliximab (IFX) were found to be divisible
into two groups. The first group (80% of patients) maintained
therapeutic IFX concentrations (>1µg/ml), and IL-6 was suppressed to less than 10pg/ml. These patients achieved good
disease control. The second group (20%) also maintained
therapeutic IFX concentrations, but IL-6 was not suppressed(>10pg/ml). These patients did not achieve good disease control [36]. This suggests that TNFα suppression does not always
result in IL-6 suppression; as such, in these patients IL-6 isable to act independently. Should this be the case, identifying
which cytokine plays a greater role in the disease process ofeach patient may assist with choosing a more effective biologic
agent. This study’s demonstration of the benefit of TCZ overETN for RA patients with high normal WBC/leukocytosis andhigh normal platelets/thrombocytosis may suggest that different patients with RA may be more affected by overactivity of
one cytokine than another (IL-6 dominant or TNFα dominantdisease). As IL-6 is more directly involved in megakaryocytopoiesis and is known to increase circulating platelet count(8), and can also contribute to increased WBC (7), it may bethat patients with “IL-6 dominant” RA are more likely to present with thrombo- or leukocytosis, and consequently are also
more likely to respond to TCZ.

TCZ has been shown in many studies to be an effective, safe
treatment for patients with RA. The results of this study suggest that in patients who present with high normal WBC/leukocytosis or high normal platelets/thrombocytosis, TCZ may
be more effective than the TNFα inhibitor ETN. This may be
due to relatively high IL-6 activity in these patients causing
hematological disturbances. Accordingly, TCZ is likely a more
effective choice of first-line agent in early or established RA patients presenting with high normal platelets/thrombocytosis[37], high normal WBC/leukocytosis, or severe anemia.

Acknowledgements

We thank Mr. Steven Smoley for editing this manuscript.

Conflict of interest
None declared

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