Rheumatoid arthritis

Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214894 on 29 May 2019. Downloaded from http://ard.bmj.com/ on August 19, 2019 at East Carolina University. Protected by
Clinical science

Comparison of the effects of tocilizumab

monotherapy and adalimumab in combination with
methotrexate on bone erosion repair in
rheumatoid arthritis
Stephanie Finzel,1,2 Sebastian Kraus,1 Camille Pinto Figueiredo,1,3
Adrian Regensburger,1 Roland Kocijan,1 Juergen Rech,1 Georg Schett‍ ‍ 1

Handling editor Josef S Abstract

Smolen
►► Additional material is
published online only. To
view please visit the journal
online (http://​dx.d​ oi.​org/​10.​
1136annrheumdis-2​ 018-​
214894).
1
Department of Internal
Medicine 3, Friedrich Alexander
University Erlangen-Nurnberg
and Universitaetsklinikum
Erlangen, Erlangen, Germany
2
Department of Rheumatology,
University of Freiburg, Freiburg, using Clinical Disease Activity Index, Simple Disease
Germany
3
Division of Rheumatology,
Faculdade de Medicina da
Key messages
Objective  To compare the effects of interleukin-6
(IL-6) receptor and tumour necrosis factor inhibition on
What is already known about this subject?
inducing repair of existing bone erosions in patients with
►► Limited repair of bone erosions in rheumatoid
very early rheumatoid arthritis (RA).
arthritis is known from radiographic and other
Methods  Prospective non-randomised observational
imaging studies.
study in patients with active erosive RA with inadequate
►► Little is know about treatment strategies
response to methotrexate (MTX) receiving either
preferentially inducing repair of bone erosions
tocilizumab (TOC) monotherapy or adalimumab
in rheumatoid arthritis
(ADA) with MTX for 52 weeks. Erosion volumes were
assessed in metacarpal heads (MCH) and the radius by
What does this study add?
high-resolution peripheral quantitative CT at baseline
►► This study shows that inhibition of interleukin-6
and after 52 weeks. Clinical response was monitored
achieves more pronounced repair of bone
erosions than inhibition of tumour necrosis
Activity Index and Disease Activity Score 28-erythrocyte
factor alpha.
sedimentation rate (DAS28-ESR) scores every 12 weeks.
►► Repair of bone erosions upon inhibition of

Universidade de São Paulo, São Results  TOC (N=33) and ADA/MTX (N=33) treatment
Paulo, Brazil groups were balanced for age, sex, body mass index,
comorbidities, disease and activity, functional state,
Correspondence to autoantibody status, baseline bone damage and baseline
Professor Georg Schett,
bone biomarkers. Both TOC (DAS28-ESR: baseline:
Department of Internal Medicine
6.2±0.5; 52 weeks: 2.3±1.0) and ADA/MTX (6.3±0.6;
3, Friedrich Alexander University
Erlangen-Nurnberg and 2.8±1.2) significantly reduced disease activity. Erosion
Universitaetsklinikum Erlangen, volumes significantly decreased in the MCH and radius
Erlangen 91054, Germany; of patients with RA treated with TOC (p<0.001) but
g​ eorg.​schett@​uk-​erlangen.d​ e
not in patients treated with ADA/MTX (p=0.77), where
Received 10 December 2018 they remained stable in size. Mean decrease in erosion
Revised 9 May 2019 volume in TOC-treated patients was −1.0±1.1 mm3
Accepted 10 May 2019 and −3.3±5.9 mm3 in the MCH and radius of TOC-
Published Online First treated patients, respectively, and −0.05±0.9 mm3 and
29 May 2019
−0.08±4.1 mm3 in patients treated with ADA/MTX.
Conclusions  The REBONE study shows that TOC
monotherapy achieves more pronounced repair of
existing bone erosions than ADA/MTX. Hence, IL-6 is a
central factor for the disturbed bone homeostasis in the
joints of patients with RA.
Introduction
Rheumatoid arthritis (RA) is characterised by the
resorption of juxta-articular bone leading to the
© Author(s) (or their
employer(s)) 2019. No formation of bone erosions.1 These lesions develop
commercial re-use. See rights on the basis of a local imbalance of osteoclast-medi-
and permissions. Published ated bone resorption and osteoblast-mediated bone
by BMJ. formation.2 Aside from autoantibodies,3 proinflam-
To cite: Finzel S, matory cytokines are the main triggers for bone
Kraus S, Figueiredo CP, erosions by inducing an imbalance of local bone
et al. Ann Rheum Dis metabolism.2 In RA, tumour necrosis factor alpha
2019;78:1186–1191. (TNFα) and interleukin-6 (IL-6) are the two major
1186   Finzel S, et al. Ann Rheum Dis 2019;78:1186–1191. doi:10.1136/annrheumdis-2018-214894
copyright.
interleukin-6 was associated with increased
markers of new bone formation.
How might this impact on clinical practice or
future developments?
►► Therapeutic strategies that inhibit IL-6 may
be preferentially used to achieve repair of
inflammatory bone damage.
►► Bone erosions in rheumatoid arthritis should
not be seen as irreversible lesions.
cytokines triggering synovitis and bone erosions.4
Thus, TNFα and IL-6 were shown to directly induce
the formation of bone resorbing osteoclasts through
binding to their respective surface receptors, as
well as indirectly by inducing receptor activator of
nuclear factor kappa-Β ligand (RANKL) expression
on stromal cells.5 6 In consequence, neutralisation
of TNFα and the IL-6 receptor retards or even
arrests the progression of bone erosions in RA—an
effect that is even found in the case anti-inflamma-
tory responses are not achieved.7 8
Traditionally, bone erosions are considered as
irreversible damage with little tendency to repair.
While disappearance of bone erosions is indeed an
uncommon phenomenon, limited repair can happen
and has been documented in radiographs, where
it is known as ‘sclerosis’.8–11 CT scans of patients
with RA provided conclusive evidence for limited
repair of erosions. Decrease in size of existing
bone erosions seems mechanistically feasible, given
that osteoblasts are present in the endosteal bone

marrow space adjacent to bone erosions12 and such cell are able
to locally deposit new bone matrix at the erosion walls, which
later becomes mineralised and leads to reduction of erosion size.
Such processes, however, seem to be impaired by active syno-
vitis, which effectively downregulates osteoblast induced repair
of erosions through enhanced expression of antianabolic mole-
cules that interfere with bone morphogenetic protein-mediated
and Wnt-mediated pathways of new bone formation.13 14 This
concept is supported by the observation that osteoblast function
is compromised at sites of erosions and that resolution of inflam-
mation can restore their function.15 16
To date, it is unclear, which therapeutic approach is best
suited to achieve erosion repair. Direct stimulation of osteo-
blasts by parathyroid hormone has not led to significant erosion
repair suggesting that restoring the cytokine-induced imbalance
between bone resorption and formation may be essential for
erosion repair.17 On the other hand, an high-resolution periph-
eral quantitative CT (HR-pQCT) showed that the anti-RANKL
antibody denosumab induced repair of bone erosions.18 Blockade
of TNFα and IL-6 are the currently most feasible approaches to
achieve erosion repair as they are (1) approved for the treat-
ment of RA, (2) effectively control the signs and symptoms of the
disease and (3) target cytokines that influence local bone homeo-
stasis in the joint. To address the question whether inhibition of
TNFα or IL-6 provides better erosion repair in patients with
very early RA, we performed a prospective study comparing the
effect of these two cytokine blocking strategies on the change in
volume of bone erosions using HR-pQCT.
Methods
Study design and patients
REBONE (NCT02778789) is a prospective non-randomised
two-arm study that assessed the effect of tocilizumab (TOC)
monotherapy and adalimumab (ADA) in combination with
methotrexate (MTX) on erosion repair in RA. Inclusion criteria
for REBONE were (1) a diagnosis of RA according to Amer-
ican College of Rheumatology/European League Against Rheu-
matism 2010 criteria, (2) active disease with a Disease Activity
Score 28-erythrocyte sedimentation rate (DAS28-ESR) score of
more than 3.2, (3) failure or intolerance to at least 3 months
treatment with 20 mg/week MTX, (4) no more than 5 mg pred-
nisolone equivalent per day for the last 4 weeks and (5) the pres-
ence of bone erosions at the head of the metacarpophalangeal
joint 2 (metacarpal head 2 (MCH2)) and the head of the radius
(radius) in the HR-pQCT scan at baseline. Consecutive patients
fulfilling these requirements were offered either (1) a switch
from MTX to weekly subcutaneous administration of TOC or
(2) an addition of subcutaneous ADA to MTX at a standard dose
of 40 mg every other week. Patients were informed that both
strategies are effective for RA, are approved treatment strate-
gies for the disease and are in accordance with the guidelines
of treatment of RA of the German Society of Rheumatology,
which permit the initiation of biologic disease-modifying anti-
rheumatic drugs after failing MTX treatment in patients with RA
with risk factors (autoantibodies or erosions). Patients in both
groups were followed over 1 year before receiving the follow-up
HR-pQCT investigation. Written informed consent was taken
from all the patients.
Demographic and disease-specific characteristics
Age, sex and body mass index were assessed at baseline. In addi-
tion, disease duration, anticyclic citrullinated peptide 2 anti-
bodies, rheumatoid factor (RF) as well as comorbidities according
Finzel S, et al. Ann Rheum Dis 2019;78:1186–1191. doi:10.1136/annrheumdis-2018-214894
Rheumatoid arthritis
Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214894 on 29 May 2019. Downloaded from http://ard.bmj.com/ on August 19, 2019 at East Carolina University. Protected by
to Charlston Comorbidity Index and medication were recorded
at baseline. Swollen joint count-28, tender joint count-28, visual
analogue scale for patient and physician global disease activity
and visual analogue scale for pain were measured at baseline and
every 3 months thereafter up to 12 months. Erythrocyte sedi-
mentation rate (ESR) and C-reactive protein level were analysed
on a 3-monthly basis. Composite scores including DAS28-ESR,
Clinical Disease Activity Index (CDAI) and Simple Disease
Activity Index (SDAI) as well as Health Assessment Question-
naire Disability Index (HAQ-DI) were calculated at baseline and
every 3 months thereafter.
High-resolution peripheral quantitative computed
tomography
HR-pQCT scans of the dominantly affected hand were performed
at voxel size of 82×82×82 µm using an XtremeCT scanner
(SCANCO Medical AG, Bruettisellen, Switzerland) at baseline
and after 12 months. Scan times for the MCH2 were 8.2 min
and 5.6 min for the radius (three and two stacks, respectively).
To obtain optimal results, hands were positioned in a carbon
fibre brace. Based on the limited field of view of HR-pQCT,
volume of bone erosions was assessed at the known predilec-
tion sites including overall 322 2D slices for MCH2 and 211
slices for the radius.9 10 Erosions were defined as juxta-articular
breaks within the cortical shell visible in at least two consecutive
slices in two perpendicular planes. Physiological breaks (nutrient
vessels) were excluded based on their cylindrical form and local-
isation. Erosion volumes were calculated using a semiellipsoid
formula based on erosion length, width and depth.9 10 For eval-
uation of images, the open source DICOM viewer Osirix V3.2
copyright.
(Rosslyn, Virginia, USA) was used. All images were evaluated by
two independent readers (SK and AR), who were blinded to the
sequence of images as well as to the group assignment (treat-
ment) of the patients. Intraobserver reproducibility for erosion
volume (SK) was 0.99, interobserver reproducibility (SK and
AR) as determined by intraclass correlation was also very high
(0.94). Smallest detectable change was assessed according to
Bruynesteyn et al19 and was 0.1 mm3.
Bone formation and resorption markers
For assessment of bone resorption, C-terminal collagen cleavage
products (IDS), for assessment of bone formation, osteocalcin
levels (Thermo Fisher) were analysed at baseline and after 12
months.
Statistics
The primary parameter analysed in this study was the change
in erosion volume between baseline assessment and 12 months
follow-up assessment. Secondary parameters analysed are the
changes in composite disease activity instruments such as DAS28,
CDAI and SDAI between baseline and 12 months as well as the
change in HAQ-DI scores between baseline and 12 months. Data
were collected, organised and analysed through SPSS V.21.0 soft-
ware for statistics. If not stated otherwise, categorical variables
are presented as numbers and percentages, continuous variables
are provided as medians and IQR and means±SD. Assumptions
of normally distributed continuous variables were tested using
quantile-quantile plots as well as Kolmogorov-Smirnov and
Shapiro-Wilk’s test. Differences with respect to frequency distri-
butions of categorical variables were tested using Fisher’s exact
test. The above-mentioned parameters were compared between
TOC-treated and ADA-treated patients (Mann-Whitney U test)
and between baseline and follow-up assessment within the
1187
 Rheumatoid arthritis

Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214894 on 29 May 2019. Downloaded from http://ard.bmj.com/ on August 19, 2019 at East Carolina University. Protected by
Table 1  Patients characteristics
TOC (N=33) TNFi (N=33)
Mean±SD Mean±SD
(or N) Median (IQR) (or N) Median (IQR) P value
Demographic characteristics
 Age (years) 57.6±10.8 58 (51–63) 59.3±11.8 59 (51.5–69) 0.55
 Sex (N females) 22/33 – 23/33 – 0.99
 Body mass index 26.3±4.0 26 (25–28) 25.3±3.7 24.5 (22–28) 0.31
Disease-specific characteristics
 Disease duration (years) 0.76±0.49 1.0 (0.25–1.0) 0.83±0.57 0.75 (0.25–1.0) 0.24
 ACPA (N) 23/33 – 21/33 – 0.79
 RF (N) 19/33 – 14/33 – 0.32
 TJC (N) 10.3±3.4 10 (7.5–13) 10.3±3.3 10 (7–13) 0.97
 SJC (N) 8.1±2.5 8 (6–10) 8.3±2.8 8 (5.5–10.5) 0.78
 VAS-G (mm) 74.1±9.5 76 (66–80.5) 76.0±7.1 76 (70.5–80) 0.36
 VAS-P (mm) 72.4±8.6 72 (67.5–80) 70.2±10.5 68 (60.5–79) 0.35
 ESR (mm) 46.6±16.7 45 (32–63) 51.5±13.4 52 (42–61.5) 0.19
 CRP (mg/L) 13.6±6.2 13 (8.5–18.5) 13.8±5.2 14 (9.5–17) 0.84
 DAS28 (units) 6.2±0.5 6.3 (5.8–6.5) 6.3±0.6 6.4 (5.8–6.9) 0.25
 SDAI (units) 34.4±5.0 35 (31–37) 34.6±7.2 34 (27–40) 0.88
 CDAI (units) 32.9±4.7 33 (30–36) 33.2±7.1 35 (31–37) 0.84
 HAQ-DI (units) 1.03±0.23 1.0 (0.85–1.2) 1.01±0.23 1.0 (0.8–1.2) 0.75
Comorbidities
 Charlson Comorbidity Index 1.8±1.5 1.0 (0.6–2.5) 1.9±1.6 1.0 (1.0–3.0) 0.81
(units)
 Myocardial infarction (N) 2/33 – 2/33 – 1.00
 TIA/stroke (N) 1/33 – 2/33 – 0.99
 Diabetes mellitus (N) 6/33 – 4/33 – 0.73

copyright.
 Chronic kidney failure (N) 1/33 – 0/33 – 0.99
 Chronic heart failure (N) 2/33 – 0/33 – 0.49
 Chronic obstructive 5/33 – 5/33 – 1.00
pulmonary disease (N)
 Smoking (N) 8/33 – 7/33 – 0.99
Erosion volume    
 Metacarpal head (mm3) 1.87±1.69 1.2 (0.7–2.6) 1.89±1.69 1.3 (0.8–2.6) 0.78
 Radius (mm3) 7.05±12.26 1.9 (0.9–8.4) 6.37±11.83 1.5 (0.4–6.4) 0.49
Bone metabolism
 Osteocalcin 24.0±4.7 23 (20.5–28.5) 24.4±3.8 25 (21–26) 0.30
 C-terminal telopeptide I 0.35±0.11 0.2 (0.3–0.4) 0.33±0.11 0.2 (0.3–0.4) 0.54
ACPA, anticitrullinated protein antibodies; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score 28; ESR, erythrocyte sedimentation rate;
HAQ-DI, Health Assessment Questionnaire Disability Index; RF, rheumatoid factor; SDAI, Simple Disease Activity Index; SJC, swollen joint count; TIA, transient ischaemic attack;
TJC, tender joint count; TNFi, tumour necrosis factor inhibitors; TOC, tocilizumab; VAS-G, Visual Analogue Scale for patient and physician global disease activity; VAS-P, VAS for
pain.

groups (Wilcoxon matched pairs signed rank test). A p value of status, functional status and comorbidity index were not signifi-
less than 0.05 was considered as statistical significant difference. cantly different among the two groups.

Results Effects on signs and symptoms of RA

Baseline characteristics
In total, 70 patients were screened and 66 patients recruited into
the study, 33 of them received TOC monotherapy, 33 the combi-
nation of MTX and ADA. Four patients had no bone erosions
and could not be included. In the TOC group, three patients
stopped treatment after 6 months due to lack of efficacy, in the
ADA arm two patients stopped treatment after 6 months and
each one patient after 3 and 9 months, all due to lack of effi-
cacy. All other patients completed the 12 months observation
on either TOC or MTX/ADA treatment. Baseline characteristics
are summarised in table 1. In brief, patients were balanced for
age, sex and body mass index and they were virtually identical
with respect to disease duration and activity. Also, autoantibody
1188
Clinical efficacy of TOC and MTX/ADA treatment was assessed
every 3 months. Tender and swollen joint counts decreased
rapidly with both treatments (figure 1A and B). Most of the
response occurred within the first 3 months (DAS28: TOC
−3.2±1.2; MTX/ADA −3.0±0.8). Also, patient global disease
activity and ESR decreased to a similar extent in the TOC and
MTX/ADA groups (figure 1C and D). Furthermore, DAS28,
SDAI and CDAI responses were highly similar in both groups
with virtually identical kinetics and no significant differences
(figure 1E–G). Twenty-two patients reached DAS28-ESR
remission in the TOC group, 19 in the MTX/ADA group,
while CDAI and SDAI remission criteria were fulfilled by 21
TOC-treated patients and 19 patients treated with MTX/
Finzel S, et al. Ann Rheum Dis 2019;78:1186–1191. doi:10.1136/annrheumdis-2018-214894
 Rheumatoid arthritis

Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214894 on 29 May 2019. Downloaded from http://ard.bmj.com/ on August 19, 2019 at East Carolina University. Protected by
Figure 1  Effects of TOC and ADA/MTX on signs and symptoms of RA REBONE study patients received treatment with either TOC monotherapy
(dashed line) or ADA in combination with MTX (solid line) for 12 months with assessment of disease activity every 3 months. (A) TJC based on 28
joints; (B) SJC based on 28 joints; (C) VAS-G; (D) ESR; (E) DAS28; (F) SDAI; (G) CDAI; (H) HAQ-DI. ADA, adalimumab; CDAI, Clinical Disease Activity
Index; DAS28, Disease Activity Score 28; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; MTX,
methotrexate; RA, rheumatoid arthritis; SDAI, Simplified Disease Activity Index; SJC, swollen joint count; TJC, tender joint count; TOC, tocilizumab;
VAS-G, Visual Analogue Scale of patient global disease activity.

ADA. Finally, improvements of physical function, as assessed
by HAQ-DI scores, were comparable in the TOC and MTX/
ADA groups (figure 1H), although a tendency towards better
results was found for TOC (HAQ-DI change at 3 months: TOC
−0.76±0.29; MTX/ADA −0.61±0.21).
copyright.
radius (TOC vs ADA/MTX: p=0.0015)) (figure 2D). Probability
plots for the absolute and relative erosions volumes during TOC
and MTX/ADA treatments at the two anatomical sites as well as
the number of patients with regressing and progressing erosions
in the two groups are depicted in online supplementary figure 2.

Effects on erosion repair Effects on bone metabolism

Erosion repair was assessed by sequential volume measurement
of the largest erosion at the MCH2 and the radius in all patients.
Measurements were performed by HR-pQCT at baseline and
after 1 year. At the individual patients level, bone erosion
volumes significantly decreased in the MCH2 and radius in the
vast majority of patients with RA treated with TOC (both sites:
p<0.0001, figure 2A). In contrast, in the MTX/ADA group,
no significant regression of erosions was observed at both the
MCH2 and the radius. Most patients in the MTX/ADA group
showed an arrest of erosion size, while few slightly progressed
or regressed. Examples for erosions regression are depicted
in figure 2B. Furthermore, when analysing several different
erosions (N=10/patients) in single patients effects of TOC and
MTX/ADA remained consistent (online supplementary figure 1).
Similarly, at group level, absolute erosion volume decreased
in the TOC (baseline: 1.87±1.69 mm3; follow-up: 0.84±0.91
mm3; p=0.0006) but not the MTX/ADA group (baseline:
1.89±1.69 mm3; follow-up: 1.83±1.53 mm3) in the MCH2
(figure 2C). Similar results were obtained in the radius, with TOC
(7.0±12.2 mm3; 3.8±6.9 mm3; p=0.103) but not ADA/MTX
(6.3±11.8 mm3; 6.2±10.9 mm3) decreasing erosion volumes.
Also, the assessment of relative changes of erosion volumes
showed a significant decline in the TOC but not the MTX/ADA
group in the MCH2 (TOC vs ADA/MTX: p<0.0001) and the
Finzel S, et al. Ann Rheum Dis 2019;78:1186–1191. doi:10.1136/annrheumdis-2018-214894
To test whether the different effects of repair of erosion volumes
between TOC and MTX/ADA treatment are accompanied by
changes in bone metabolism, we analysed a standard marker
of bone formation (osteocalcin) and bone resorption (CTXI)
in all patients at baseline and after 1 year. While no signifi-
cant effect of TOC or MTX/ADA treatments on systemic bone
resorption were found, osteocalcin level significantly increased
in TOC-treated patients but not in patients treated with MTX/
ADA (online supplementary figure 3).
Discussion
The REBONE study shows that inhibition of the IL-6R by TOC
achieves better repair of bone erosions in patients with RA than
in combination with MTX. These data suggest that IL-6 exerts
a more fundamental effect on the generation of bone erosions
than TNFα. Previous data showing that baseline IL-6 serum level
is associated with the progression of bone erosions in RA.20 This
result is despite the fact that inhibition of IL-6R and TNFα show
virtually identical effects on the control of the signs and symp-
toms of RA, both reaching very similar remission rates.
Repair of erosions, though incomplete and usually not leading
to full disappearance of lesions, was consistently observed with
TOC. Erosion volumes decreased in the vast majority of patients
1189
 Rheumatoid arthritis

Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214894 on 29 May 2019. Downloaded from http://ard.bmj.com/ on August 19, 2019 at East Carolina University. Protected by
Figure 2  Effects of TOC and ADA/MTX on erosion repair. (A) Erosion volumes at baseline and 1 year follow-up in the MCH2 and radius in patients
receiving treatment with either TOC monotherapy or ADA in combination with MTX. (B) Exemplaric high resolution peripheral quantitative CT images
of the two patients receiving TOC monotherapy. Upper row shows BL images and lower row the FO images. The blue and orange squares mark the
localisation of the close-up image. (C) Mean±SD erosion volume at baseline and 1 year follow-up in the MCH2 and radius in patients receiving TOC
monotherapy or ADA/MTX. (D) Mean±SD change of erosion volume after 1 year in the MCH2 and radius in patients receiving TOC monotherapy or
ADA/MTX. ADA, adalimumab; BL, baseline; FO, follow-up; MCH2, metacarpal head 2; MTX, methotrexate; TOC, tocilizumab

treated with TOC; the decrease was observed at two different assessed in this study, affects joint function as well24 and may

anatomical sites and was characterised by the formation of new
cortical bone. While in most patients treated with ADA/MTX an
arrest of erosion volume was observed, repair of existing lesions
occurred only rarely. Erosion repair with TOC was accompa-
nied by a more robust increase of serum osteocalcin level sugges-
tive for increased bone formation. Of note, previous data from
clinical studies of TOC (in combination with MTX) in RA have
shown an increase in markers of bone formation in patients
treated with TOC.21 22
Limitation of this study is the small sample size. Nonetheless,
the high sensitivity and reproducibility of HR-pQCT measure-
ment of erosion size allowed detecting significant differences in
erosion repair between treatment groups even in a rather limited
patient number. Another limitation is that the REBONE study
is not randomised. Hence, channelling bias cannot be ruled
out. However, detailed analysis of the baseline characteristics of
the two treatment groups showed no differences. Importantly,
demographic and disease-specific parameters that influence not
only bone erosions but also baseline erosive damage and comor-
bidities were well balanced between the groups. In support of
these findings, also the effect of the two treatment strategies on
the signs and symptoms of RA were identical. Finally, co-treat-
ment with MTX may have blunted osteoblast responses in the
ADA treatment arm.23 Importantly, however, positive effects
on osteoblasts have previously been observed also in patients
receiving TOC+MTX combination treatment.21 22
In summary, these data provide first evidence for a path-
way-specific induction of erosion repair in patients with RA.
Inhibition of IL-6R appears to be an effective strategy to induce
damage repair in RA. It remains to be determined whether
erosion repair turns into better functional outcomes. HAQ-DI
showed only a tendency towards a better functional outcome in
the TOC group. Notably, cartilage damage, which has not been
copyright.
potentially blunt the relation between erosion repair and func-
tion. On the other hand, more sensitive instruments to assess
hand function may be needed to demonstrate the functional
impact of erosion repair.
Contributors  SF recruited the patients and performed the CT scans. SK and AR
read the images. RK and CF collected the data and performed the statistical analysis.
JR and GS wrote the manuscript.
Funding  REBONE study is an investigator-initiated study that was in part supported
by a grant from Chugai.
Competing interests  None declared.
Patient consent for publication  Parental/guardian consent obtained
Ethics approval  The study was approved by the institutional review board of the
University Clinic of Erlangen (324_16B and 334_18B).
Provenance and peer review  Not commissioned; externally peer reviewed.
Data availability statement  Data are available upon reasonable request. All
data relevant to the study are included in the article or uploaded as supplementary
information.
References
1 McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med
2011;365:2205–19.
2 Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis
and treatment. Nat Rev Rheumatol 2012;8:656–64.
3 Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone
loss by human autoantibodies against citrullinated vimentin. J Clin Invest
2012;122:1791–802.
4 Schett G, Elewaut D, McInnes IB, et al. How cytokine networks fuel inflammation:
toward a cytokine-based disease taxonomy. Nat Med 2013;19:822–4.
5 Lam J, Takeshita S, Barker JE, et al. TNF-alpha induces osteoclastogenesis by direct
stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest
2000;106:1481–8.
6 Axmann R, Böhm C, Krönke G, et al. Inhibition of interleukin-6 receptor directly blocks
osteoclast formation in vitro and in vivo. Arthritis Rheum 2009;60:2747–56.
7 Smolen JS, Han C, Bala M, et al. Evidence of radiographic benefit of treatment with
infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical

1190 Finzel S, et al. Ann Rheum Dis 2019;78:1186–1191. doi:10.1136/annrheumdis-2018-214894


improvement: a detailed subanalysis of data from the anti-tumor necrosis Factor
Trial in rheumatoid arthritis with Concomitant Therapy Study. Arthritis Rheum
2005;52:1020–30.
8 Smolen JS, Avila JCM, Aletaha D. Tocilizumab inhibits progression of joint damage in
rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the
link between inflammation and destruction. Ann Rheum Dis 2012;71:687–93.
9 Finzel S, Rech J, Schmidt S, et al. Interleukin-6 receptor blockade induces limited
repair of bone erosions in rheumatoid arthritis: a micro CT study. Ann Rheum Dis
2013;72:396–400.
10 Finzel S, Rech J, Schmidt S, et al. Repair of bone erosions in rheumatoid arthritis
treated with tumour necrosis factor inhibitors is based on bone apposition at the base
of the erosion. Ann Rheum Dis 2011;70:1587–93.
11 Rau R, Herborn G. Healing phenomena of erosive changes in rheumatoid arthritis
patients undergoing disease-modifying antirheumatic drug therapy. Arthritis Rheum
1996;39:162–8.
12 Jimenez-Boj E, Redlich K, Türk B, et al. Interaction between synovial inflammatory
tissue and bone marrow in rheumatoid arthritis. J Immunol 2005;175:2579–88.
13 Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint
remodeling. Nat Med 2007;13:156–63.
14 Lories RJU, Daans M, Derese I, et al. Noggin haploinsufficiency differentially
affects tissue responses in destructive and remodeling arthritis. Arthritis Rheum
2006;54:1736–46.
15 Walsh NC, Reinwald S, Manning CA, et al. Osteoblast function is compromised
at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res
2009;24:1572–85.
16 Matzelle MM, Gallant MA, Condon KW, et al. Resolution of inflammation induces
osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum
2012;64:1540–50.
Finzel S, et al. Ann Rheum Dis 2019;78:1186–1191. doi:10.1136/annrheumdis-2018-214894
Rheumatoid arthritis
Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214894 on 29 May 2019. Downloaded from http://ard.bmj.com/ on August 19, 2019 at East Carolina University. Protected by
17 Solomon DH, Kay J, Duryea J, et al. Effects of teriparatide on joint erosions
in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol
2017;69:1741–50.
18 Yue J, Griffith JF, Xiao F, et al. Repair of bone erosion in rheumatoid arthritis by
denosumab: a high-resolution peripheral quantitative computed tomography study.
Arthritis Care Res 2017;69:1156–63.
19 Bruynesteyn K, Boers M, Kostense P, et al. Deciding on progression of joint damage
in paired films of individual patients: smallest detectable difference or change. Ann
Rheum Dis 2005;64:179–82.
20 Kondo Y, Kaneko Y, Sugiura H, et al. Pre-treatment interleukin-6 levels strongly affect
bone erosion progression and repair detected by magnetic resonance imaging in
rheumatoid arthritis patients. Rheumatology 2017;56:1089–94.
21 Bay-Jensen AC, Platt A, Byrjalsen I, et al. Effect of tocilizumab combined with
methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE
study. Semin Arthritis Rheum 2014;43:470–8.
22 Garnero P, Thompson E, Woodworth T, et al. Rapid and sustained improvement in
bone and cartilage turnover markers with the anti–interleukin-6 receptor inhibitor
tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate
response to methotrexate: results from a substudy of the multicenter double-blind,
placebo-controlled trial of tocilizumab in inadequate responders to methotrexate
alone. Arthritis Rheum 2010;62:33–43.
23 Scheven BAA, van der Veen MJ, Damen CA, et al. Effects of methotrexate on human
osteoblasts in vitro: modulation by 1,25-dihydroxyvitamin D3. J Bone Miner Res
1995;10:874–80.
24 Smolen JS, van der Heijde DM, Keystone EC, et al. Association of joint space
narrowing with impairment of physical function and work ability in patients with
early rheumatoid arthritis: protection beyond disease control by adalimumab plus
methotrexate. Ann Rheum Dis 2013;72:1156–62.
copyright.
1191