Rheumatology 2022;61:299–308

Rheumatology doi:10.1093/rheumatology/keab317
Advance Access publication 29 March 2021

Original article
Abatacept in monotherapy vs combined in interstitial
lung disease of rheumatoid arthritis—multicentre
study of 263 Caucasian patients
1,
Carlos Fernández-Dı́az *, Belén Atienza-Mateo1,*, Santos Castan~ eda2,*,
Rafael B. Melero-Gonzalez , Francisco Ortiz-SanJuan , Javier Loricera1,
3 4

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Ivette Casafont-Solé5, Sebastián Rodrı́guez-Garcı́a6, Clara Aguilera-Cros7,
Ignacio Villa-Blanco8, Enrique Raya-Alvarez9, Clara Ojeda-Garcı́a10,
Gema Bonilla11, Alejandra López-Robles12, Luis Arboleya13,
Javier Narváez 14, Evelin Cervantes15, Olga Maiz16, Marı́a N. Alvarez-Rivas17,
Iván Cabezas18, Eva Salgado19, Cristina Hidalgo-Calleja20,
Sabela Fernández21, Jesús C. Fernández22, Ivan Ferraz-Amaro23,
1,†
Miguel A. González-Gay and Ricardo Blanco 1,†; for the Spanish
Collaborative Group of Interstitial Lung Disease Associated with Rheumatoid
Arthritis

Abstract
Objective. To assess the efficacy and safety of abatacept (ABA) in monotherapy (ABAMONO) vs combined ABA
[ABA plus MTX (ABAMTX) or ABA plus non-MTX conventional synthetic DMARDs (csDMARDs) (ABANON-MTX)] in RA
patients with interstitial lung disease (ILD) (RA-ILD).
Methods. This was a restrospective multicentre study of RA-ILD Caucasian patients treated with ABA. We analysed in
the three groups (ABAMONO, ABAMTX, ABANON-MTX) the following outcome variables: (i) dyspnoea; (ii) forced vital capacity
(FVC) and diffusion capacity of the lung for the carbon monoxide (DLCO); (iii) chest high-resolution CT (HRCT); (iv)

CL IN IC A L
SC I E NC E
DAS28-ESR; (v) CS-sparing effect; and (vi) ABA retention and side-effects. Differences between basal and final follow-up
were evaluated. Multivariable linear regression was used to assess the differences between the three groups.
Results. We studied 263 RA-ILD patients (mean 6 S.D. age 64.6 6 10 years) [ABAMONO (n ¼ 111), ABAMTX (n ¼ 46) and
ABANON-MTX (n ¼ 106)]. At baseline, ABAMONO patients were older (67 6 10 years) and took higher prednisone dose [10
(interquartile range 5–15) mg/day]. At that time, there were no statistically significant differences in sex, seropositivity,
ILD patterns, FVC and DLCO, or disease duration. Following treatment, in all groups, most patients experienced stabil-
ization or improvement in FVC, DLCO, dyspnoea and chest HRCT as well as improvement in DAS28-ESR. A statistically
significant difference between basal and final follow-up was only found in CS-sparing effect in the group on combined
ABA (ABAMTX or ABANON-MTX). However, in the multivariable analysis, there were no differences in any outcome variables
between the three groups.

1
Rheumatology, HU Marqués de Valdecilla, IDIVAL, University of
Cantabria, Santander, 2Rheumatology, HU La Princesa, IIS-Princesa,
Cátedra UAM-Roche (EPID-Future), Madrid, UAM, 3Rheumatology,
C.H.U. de Vigo, Vigo, 4Rheumatology, H.U. La Fe, Valencia,
5
Rheumatology, H.U. Germans Trias i Pujol, Barcelona, Madrid,
6
Rheumatology, H.U. Clinic, Barcelona, 7Rheumatology, H.U. Virgen
del Rocı́o, Sevilla, 8Rheumatology, H. Torrelavega, Cantabria, Submitted 30 December 2020; accepted 25 March 2021
9
Rheumatology, H.U. San Cecilio, Granada, 10Rheumatology, H.U.
Virgen Macarena, Sevilla, 11Rheumatology, H.U. La Paz, Madrid, Correspondence to: Ricardo Blanco/Miguel A. González-Gay,
12
Rheumatology, H.U. León, León, 13Rheumatology, H.U. Central de Hospital Universitario Marqués de Valdecilla, Avda Valdecilla s/n, ES-
Asturias, Asturias, 14Rheumatology, H.U. Bellvitge, Barcelona, 39008, Santander, Spain.
15
Rheumatology, H.U. de Santiago, Santiago de Compostela, A E-mail:rblancovela@gmail.com//miguelaggay@hotmail.com
Corun~a, 16Rheumatology, H.U. Donostia, Donosti, 17Rheumatology,
H.U. Luca Augusti, Lugo, 18Rheumatology, H.U. Rı́o Hortega, *Carlos Fernández-Dı́az, Belén Atienza-Mateo and Santos Castan ~eda
Valladolid, 19Rheumatology, C.H.U. Ourense, Ourense, share first authorship.
20
Rheumatology, H.U. de Salamanca, Salamanca, 21Rheumatology,
H.U. Cabuen ~es, Asturias, 22Rheumatology, C.H.U. A Corun ~a and †
Ricardo Blanco and Miguel A. González-Gay share senior
23
Rheumatology, H.U. de Canarias, Tenerife, Spain authorship.

C The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
V
Carlos Fernández-Dı́az et al.

Conclusion. In Caucasian individuals with RA-ILD, ABA in monotherapy or combined with MTX or with other
conventional-DMARDs seems to be equally effective and safe. However, a CS-sparing effect is only observed with com-
bined ABA.
Key words: rheumatoid arthritis, interstitial lung disease, abatacept, methotrexate, conventional disease-
modifying antirheumatic drugs, high-resolution computed tomography, comorbidity

Rheumatology key messages

. Interstitial lung disease (ILD) is a serious manifestation of RA.

. Abatacept in monotherapy or combined may be equally effective and safe in RA-ILD patients.
. Abatacept plus conventional DMARDs may reduce the use of glucocorticoids in Caucasian patients with RA-ILD.

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Introduction
Interstitial lung disease (ILD) is a relatively common com-
plication of RA [1] ranging from 3% to 67% [2–5]. ILD is a
severe RA complication that significantly increases mortal-
ity [6] and, currently, represents the second most com-
mon cause of death, after cardiovascular disease [4, 5].
The treatment of RA-ILD remains controversial. On
one hand, the absence of specific randomized clinical
trials makes it difficult to establish solid therapeutic rec-
ommendations. On the other hand, many of the drugs
commonly used in the treatment of RA have been asso-
ciated with de novo and/or exacerbation of ILD.
Furthermore, neither the ACR nor the EULAR guidelines
[6, 7] provide specific treatment recommendations for
this group of patients. However, in some national guide-
lines [8, 9], abatacept (ABA) and rituximab are recom-
mended as biological therapies in RA-ILD.
Our study has focused on ABA therapy, due to the
good results obtained from experimental models [10,
11], clinical trials [12] and in clinical practice [13–18].
ABA therapy in RA is recommended combined with
MTX [6]. However, the role of MTX in the origin of de
novo or in the impairment of pre-established ILD remains
unclear [19–22]. Moreover, the concomitant use of MTX
with ABA has been questioned in one recent and large
Japanese study, which identified MTX as the main risk
factor for ILD deterioration when MTX is associated to
ABA according to a multivariate logistic regression ana-
lysis (odds ratio ¼ 12.75, 95% CI 1.09, 148.77) [17].
Taking all these considerations into account, our aim
in the present study was to assess the efficacy and
safety of ABA in monotherapy compared with ABA plus
MTX or ABA plus non-MTX conventional synthetic
DMARDs (csDMARDs) in a large series of RA-ILD
Caucasian patients evaluated in clinical practice.
Methods
Design, enrolment criteria and definitions
A retrospective national multicentre, unselected,
open-label study of all consecutive Caucasian
patients with RA-ILD treated with ABA was con-
ducted. A total of 263 patients with RA-ILD who had
received at least one dose of ABA between January
2010 and June 2019 were included. Fifty-three
Spanish Rheumatology Units participated in the re-
cruitment of patients for the study. The 263 RA-ILD
patients were distributed into three groups according
to their treatment modality: ABA in monotherapy
(ABAMONO group), ABA combined with MTX (ABAMTX
group) and ABA combined with a cDMARD different
from MTX (ABANON-MTX group).
Data were obtained from medical records and stored
in a computerized database. Variables were collected
between up to 4 weeks before ABA initiation and at the
end of the follow-up period (with a maximum of
60 months after ABA was initiated).
Data for these patients have been previously pub-
lished [23, 24].
All patients met the ACR 1987 classification criteria
[25] or the new 2010 classification criteria [26] for RA,
depending on the year of the diagnosis.
Seropositivity was considered if the disease was
associated with positive RF and/or CCP antibodies
(CCPAs) in at least two different determinations. RF was
determined by nephelometry, while CCPAs were
detected by standard commercial ELISAs. DAS28 was
calculated using the ESR (DAS28-ESR). ILD diagnosis
was confirmed by high-resolution CT (HRCT) scan in all
cases. The period between baseline chest HRCT scans
and ABA initiation ranged between 1 and 4 weeks. One
or two senior radiologists, depending on each centre,
assessed independently the chest HRCT scans, exclud-
ing other conditions such as hypersensitivity pneumonia,
pulmonary infections and heart failure. The findings were
classified into three general radiological patterns
according to the standardized criteria of the American
Thoracic Society/European Respiratory Society

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 ABAMONO vs combined in ILD of RA—multicentre study of 263 Caucasian patients
International Multidisciplinary Consensus Classification
of the Idiopathic Interstitial Pneumonias: (i) usual intersti-
tial pneumonia (UIP); (ii) non-specific interstitial pneumo-
nia (NSIP); and (iii) ‘other patterns’ (bronchiolitis
obliterans, organized pneumonia and mixed patterns)
[27, 28].
The study was approved by the Clinical Research
Ethics Committee of Santander, Cantabria, Spain.
Outcome variables
The primary outcomes variables were pulmonary effi-
cacy and safety, whereas the secondary outcomes
were CS-sparing dose effect and articular efficacy.
Pulmonary efficacy outcomes were evaluated according
to the modified Medical Research Council (mMRC)
scale for dyspnoea, lung function tests (LFTs) and chest
HRCT. With the mMRC scale (0–4 points), we consid-
ered improvement when there was a decrease <1
point, worsening when there was an increase 1 point
and no change when there were no changes in mMRC
values compared with the previous one before ABA
initiation.
Among the LFTs parameters, we recorded the differ-
ence in forced vital capacity (FVC) and/or diffusion cap-
acity of the lung for the carbon monoxide (DLCO) values
observed between the start of ABA and the end of the
follow-up. A 10% increase or decrease in FVC and/or
DLCO with respect to baseline values was considered
significant. Thus, ‘improvement’ was defined when there
was a 10% or higher increase over baseline values,
‘worsening’ when there was a 10% or higher decrease
and there was ‘no change’ when there was no change
or a change <10%.
Regarding chest HRCT scan, improvement, worsening
or no change was semi-quantitatively assessed by an
experienced radiologist at each participating centre,
comparing it with baseline HRCT, based primarily on the
extent and phenotype of ILD. In doubtful cases, the
images were evaluated separately and blindly through
HRCT by two independent radiologists, and sometimes
even by a third one. Efficacy outcomes of ABA in RA
activity parameters were estimated according to DAS28-
ESR. Furthermore, glucocorticoid dose (prednisone
equivalent, mg/day) was collected in every visit to as-
sess the final CS-dose sparing effect.
Statistical analysis
Demographic and clinical characteristics of each group
of patients, ABAMONO, ABAMTX and ABANON-MTX groups,
were described as mean (S.D.) or percentages for cat-
egorical variables. For non-normally distributed continu-
ous variables, data were expressed as a median and
interquartile range (IQR). Univariable differences be-
tween patients in the three treatments categories were
assessed through analysis of variance or Kruskall–Wallis
tests according to normal distribution or the number of
subjects. Differences between final follow-up and basal
visit were calculated as the average difference and 95%
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CI. Multivariable linear regression was used to study the
differences between ABAMTX and ABANON-MTX vs
ABAMONO group (reference category). Confounders were
selected from those variables with a P-value <0.20 in
the assessment of univariable differences between
groups. All analyses used a 5% two-sided significance
level and were performed using SPSS software, version
25 (IBM, Chicago, IL, USA). A P < 0.05 was considered
statistically significant.
Results
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General features at ABA initiation
The main demographic and disease related data within
the three groups of treatment (ABAMONO, ABAMTX and
ABANON-MTX) at baseline are shown in Table 1. Most of
the general features, clinical manifestations and previous
treatment were similar in all groups. However, patients
in the ABAMONO group were significantly older
(67 6 10 years) and were receiving a significantly higher
prednisone dose [10 (IQR 5–15) mg/day] compared with
the remaining groups.
There were no differences regarding sex, smoking
status or seropositivity. Similarly, we found no differ-
ences in RA or ILD duration. Also, ILD patterns in
chest HRCT scans and FVC and DLCO, expressed as
percentage of normal values, were similar. Additional
information concerning baseline data is shown in
Table 1.
Effect of different treatment categories on efficacy
The main indication of ABA in these patients was main-
tained active articular disease. After ABA initiation, the
median (IQR) time of follow-up was similar in the three
groups of treatment: 12 (6–36) months, 12 (6–36)
months and 18 (12–36) months (P ¼ 0.40) in ABAMONO,
ABAMTX and ABANON-MTX, respectively (Table 2).
At the end of follow-up, FVC and DLCO values were
stable compared with baseline in most patients in all
groups. When this analysis was performed using FVC
and DLCO as dichotomic variables (worsening vs im-
provement or stable), >80% of the patients in each
treatment category had a stable or improved FCV and
DLCO overtime. Moreover, the percentage of patients
that were stable or improved for FCV and DLCO at the
end of follow-up was not different between treatment
categories. In addition, mMRC and chest HRCT were
found to be unchanged or improved in >90% and
75% of the patients, respectively (Table 2).
DAS28-ESR significantly decreased when comparing
final follow-up and baseline values in the three groups.
In this sense, patients on ABAMONO, ABAMTX and
ABANON-MTX had, respectively, an average decrease in
DAS28-ESR (95% CI) of 1.5 (1.9, 1.0), 1.2 (1.8,
0.6) and 1.5 (1.8, 1.2). Similarly, prednisone dose
significantly declined in both ABAMTX [2.7 (4.6, 0.8)]
and ABANON-MTX [4.8 (6.3, 3.4)] groups, but not in
the ABAMONO group [3.8 (8.3, 0.8)].
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Carlos Fernández-Dı́az et al.

TABLE 1 Main general and clinical features at ABA initiation in every treatment category of 263 patients with RA-ILD

Variable Overall ABAMONO ABAMTX ABANON-MTX P-value

N 5 263 N 5 111 N 5 46 N 5 106

Age, years 65 (10) 67 (10) 63 (9) 64 (11) 0.033

Women, n (%) 150 (57) 64 (57.7) 28 (60.9) 58 (54.7) 0.77
Smoker or ex-smoker 139 (53) 59 (53) 22 (49) 58 (54.7) 0.69
Duration of RA, median (IQR), months 88 (36–173) 88 (36–169) 98 (45–230) 84 (33–152) 0.13
Duration of ILD, median (IQR), months 12 (3–41) 12 (3–39) 9 (2–35) 15 (4–48) 0.26
Positive RF, n (%) 235 (89) 100 (90) 42 (91) 93 (88) 0.59
Positive CCP antibodies, n (%) 233 (89) 96 (86) 42 (91) 95 (90) 0.94
Positive RF and CCPA, n (%) 219 (82) 90 (81) 40 (87) 89 (84) 0.88

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DAS28-ESR mean (S.D.) 4.59 (1.49) 4.68 (1.42) 4.08 (1.51) 4.54 (1.51) 0.12
HRCT pattern of ILD, n (%)
Usual interstitial pneumonia 106 (40) 45 (41) 15 (33) 46 (43)
Non-specific interstitial pneumonia 84 (32) 41 (37) 16 (35) 27 (25) 0.27
Others 73 (28) 25 (23) 15 (33) 33 (31)
Basal FVC (% of the predicted), mean (S.D.) 86 (23) 83 (21) 90 (18) 87 (22)
Basal DLCO (% of the predicted), mean (S.D.) 66 (18) 63 (19) 67 (19) 67 (18) 0.35
Prednisone dose, median (IQR), mg/day 7.5 (5–10) 10 (5–15) 5 (5–7.5) 7.5 (5–10) 0.017
Previous conventional synthetic DMARDs, n (%)
MTX 212 (80.6) 84 (75.2) 46 (100) 82 (77.7) 0.28
LEF 108 (41.1) 48 (43.2) 19 (41.3) 41 (38.7) 0.92
Salazopyrin 33 (12.5) 14 (12.6) 5 (10.9) 14 (13.2) 0.79
HCQ 61 (23.2) 26 (23.4) 16 (34.8) 19 (27.9) 0.08
Others 21 (8) 12 (10.8) 5 (10.9) 4 (3.8) 0.12
Previous biological DMARD, n (%)
Etanercept 48 (18.3) 19 (17.1) 15 (32.6) 14 (13.2) 0.16
Infliximab 26 (9.9) 12 (10.4) 6 (13) 8 (7.5) 0.53
Adalimumab 39 (14.8) 17 (15.3) 6 (13) 16 (15.2) 0.93
Certolizumab 9 (3.4) 4 (3.6) 00 5 (4.7) 0.34
Golimumab 4 (1.5) 2 (1.8) 1 (2.2) 1 (0.9) 0.81
Rituximab 44 (16.7) 21 (18.9) 8 (17.4) 15 (14.2) 0.64
Tocilizumab 29 (11) 12 (10.8) 7 (15.2) 10 (9.4) 0.58

Data represent means (S.D.) or median (IQR) when data were not normally distributed. p-value: differences between the
three groups. ABAMONO: abatacept in monotherapy; ABAMTX: abatacept combinated with MTX; ABANON-MTX: abatacept
combinated with csDMARD different from MTX; DLCO: diffusing capacity of the lung for carbon monoxide; FVC: forced
vital capacity; HRCT: high-resolution CT; ILD: interstitial lung disease; IQR: interquartile range.

The relationships were further studied using ABAMONO
as the reference category (compared with ABAMTX and
ABANON-MTX). They were adjusted for age, disease dur-
ation up to ABA initiation, DAS28-ESR and prednisone
dose at baseline (Table 2). With this multivariable linear
regression analysis, no differences were found in the
changes of DAS28-ESR, prednisone dose, FVC and
DLCO, or in the frequency of mMRC and chest HRCT
scans stability or improvement.
A visit-to-visit analysis is shown in Fig. 1. No differen-
ces in LFTs evolution were observed in any visit during
the study, except for a marginally significant difference
at month 36 for FVC.
ABA retention rate and side effects
The retention rate was 77.5% (86 patients), 73.9% (34
patients) and 76.4% (81 patients) in ABAMONO, ABAMTX
and ABANON-MTX, respectively. It was similar in the three
groups (P ¼ 0.23) at the end of the follow-up. The main
reasons for ABA withdrawal were adverse events and
articular inefficacy (lack of improvement or worsening of
DAS28-ESR), while discontinuation by ILD impairment
was only reported in three cases (two patients in the
ABAMONO group and one patient in ABANON-MTX). The
causes of ABA discontinuation were similar in the three
groups (Table 3).
The main serious adverse events were also compar-
able in the three groups, with serious infection being the
most common cause (P ¼ 0.74) (Table 3).
Discussion
In this large national multicentre study of 263 RA-ILD
patients from the real-world clinical setting treated with
ABA, we compared three therapeutic groups: ABAMONO,
ABAMTX or ABANON-MTX. In all groups, most patients
showed a stabilization of FVC, DLCO, mMRC and

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 TABLE 2 Effect in FVC, DLCO, dyspnoea (mMRC) and HRCT pulmonary scan after abatacept treatment in the three groups

Variable ABAMONO ABAMTX ABANON-MTX ABAMTX ABANON-MTX

vs ABAMONO vs ABAMONO

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N 5 111 P-value N 5 46 P-value N 5 106 P-value P-valuea Unadjusted Adjustedb Unadjusted Adjustedb

Follow-up, median (IQR), 12 (6–36) 12 (6–36) 18 (12–36) 0.40 0.67 0.17

months
FVC, %, Differences between basal 0.5 (2.5, 1.5) 0.64 1.2 (0.6, 3.1) 0.17 1.2 (2.9, 0.5) 0.17 0.33 0.30 0.39 0.59 0.90
and final follow-up
Worsening 11 (16) 00 9 (13) 0.12 0.99 0.76
Stable or improving 56 (84) 23 (100) 63 (87)
DLCO %, Differences between basal 1.8 (0.7, 4.34) 0.16 0.5 (3.8, 4.8) 0.82 1.5 (4.1, 1.1) 0.26 0.20 0.58 0.80 0.07 0.32
and final follow-up
Worsening 7 (13) 2 (8) 3 (5) 0.34 0.64 0.11
Stable or improving 48 (87) 22 (92) 57 (95)
mMRC, n (%)
Worsening 5 (5) 3 (8) 5 (5) 0.83 0.47 0.99
Stable or improving 93 (95) 36 (92) 87 (95)
HRCT pulmonary
scan, n (%)
Worsening 13 (28) 2 (11) 15 (25) 0.24 0.10 0.78
Stable or improving 34 (72) 19 (89) 44 (75)
DAS28-ESR 1.5 (1.9, 1.0) <0.001 1.2 (1.8, 0.6) <0.001 1.5 (1.8, 1.2) <0.001 0.74 0.58 0.92
Prednisone, mg/day 3.8 (8.3, 0.8) 0.10 2.7 (4.6, 0.8) 0.006 4.8 (6.3, 3.4) <0.001 0.69 0.67 0.65

mMRC improvement is considered when there was a decrease <1 point, worsening an increase 1 point and stable when there were no changes in mMRC values compared
with the previous to abatacept initiation. Improvement, worsening, or no change in HRCT was defined comparing with the baseline scan. Differences in DAS28-ESR, prednisone,
FVC and DLCO are expressed as mean difference (95% CI) comparing final follow-up minus basal values. DLCO and FVC worsening is considered when there was a decrease
in 10% or higher at final follow-up compared with baseline values. Stable or improvement is considered if worsening was not present. aDifferences between the three groups.
b
Differences between abatacept þ MTX vs abatacept monotherapy, and between abatacept þ non-MTX vs abatacept monotherapy are adjusted for age, disease duration until
abatacept treatment and DAS28 and prednisone dose at baseline. The bold values obtained statistically significant differences with p<0.05 DLCO: carbon monoxide diffusing
capacity; HRCT: high-resolution CT; FVC: forced vital capacity; mMRC: modified Medical Research Council scale.
ABAMONO vs combined in ILD of RA—multicentre study of 263 Caucasian patients

303
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Carlos Fernández-Dı́az et al.

TABLE 3 Adverse events and discontinuation in every treatment category of 263 patients with RA-ILD

Overall ABAMONO ABAMTX ABANON-MTX P-value

N 5 263 N 5 111 N 5 46 N 5 106

Adverse events, n (%)

Serious infections 30 (11.4) 11 (9.9) 5 (10.9) 14 (13.2) 0.74
Cardiovascular events 3 (1.14) 1 (0.9) 1 (2.2) 1 (0.9) 0.97
Neoplasia 3 (1.14) 0 0 1 (0.9) 0.51
Others 1 (0.38) 1 (0.9) 0 3 (2.8) 0.28
Discontinuation, n (%)
Adverse event 30 (11.4) 10 (9.0) 6 (13) 14 (13.2) 0.58
RA flare 27 (10.26) 12 (10.8) 6 (13) 9 (8.5) 0.68

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ILD worsening 3 (1.14) 2 (1.8) 0 1 (0.9) 0.55
Others 2 (2.28) 1 (0.9) 0 1 (0.9) 0.98

p-value: differences between the three groups. ILD: interstitial lung disease.

FIG. 1 FVC, DLCO, DAS28-ESR and prednisone mg/day dose

FVC, DLCO, DAS28-ESR and prednisone mg/day dose are shown during follow-up. DAS28-ESR, prednisone, FVC
and DLCO are expressed as mean (95% CI) and compared between the three groups; *P < 0.05. DLCO: carbon
monoxide diffusing capacity; FVC: forced vital capacity; Aba: abatacept.

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 ABAMONO vs combined in ILD of RA—multicentre study of 263 Caucasian patients
chest HRCT, and an improvement in RA activity
(DAS28-ESR). However, a CS-sparing effect was only
found with combined ABA (ABAMTX or ABANON-MTX) but
not with monotherapy. Nevertheless, in the multivariate
linear regression analysis (unadjusted and adjusted), no
differences were found between the three groups.
Several predisposing factors for ILD-RA such as male
sex, age, smoking, HLA, seropositivity (RF and/or
CCPA), uncontrolled disease activity or genetics factors
have been described [29–31]. These factors were previ-
ously discussed in the whole series [24]. Male sex was
more frequent in the three groups compared with the
general RA population, and 90% had RF and/or CCPA
positivity. The only statistically significant different group
at ABA initiation was the one that included patients in
the ABAMONO group, who were older (67 6 10 years).
Different radiological patterns have been associated
with RA, such as UIP, NSIP, bronchiolitis obliterans and
organized pneumonia [26]. Classically, the UIP pattern is
the most frequently related to RA-ILD and has been
associated with worse prognosis than the other radio-
logical patterns [32]. In our series, the different radio-
logical patterns were similar in the three groups
(Table 1); the most frequent pattern in all patients was
UIP followed by NSIP (72% between both groups). In
the ‘other patterns’ subgroup (28% in total), most of the
patients presented mixed patterns with ground glass
opacities that, due to their characteristics, did not meet
all the requirements to be classified as UIP or NSIP in
the baseline HRCT. However, some of these patients
progressed to fibrotic UIP or NSIP throughout the clinic-
al course.
Glucocorticoids are considered the first-line treatment
for RA-ILD patients. The mean CS dose in our series
was relatively low. This was probably because most
patients had previously been treated with different
cDMARDs and in some cases with biologic DMARDs
(bDMARDs) [24]. In this regard, patients without
concomitant cDMARDs (ABAMONO group) required a sig-
nificantly higher dose of prednisone. Different immuno-
suppressive drugs not usually used in RA, such as AZA,
MMF or CYC, have been used in ILD associated with
CTDs with controversial results [33, 34]. However, these
drugs were exceptionally used in our series [24].
Several bDMARDs, especially anti-TNF-a, have been
related with de novo or with the impairment of pre-
established ILD [14, 20, 35–38]. However, ABA seems to
be a relative safe bDMARD in RA-ILD [12–17].
Mochizuki et al. [17] studied 131 Japanese patients with
RA-ILD who were treated with ABA for >1 year and
showed a worsening of ILD in only 11 patients (8.4%).
They assessed potential risk factors of ILD deterioration
and identified MTX as the main risk factor for ILD deteri-
oration according to a multivariate logistic regression
analysis (odds ratio ¼ 12.75, 95% CI 1.09, 148.77). We
believe that the genetic differences between our patients
and those reported by Mochizuki et al. may explain the
different toxicity related to MTX, and it motivated us to
only include Caucasian patients. In keeping with our
https://academic.oup.com/rheumatology
findings, Cassone et al. [39] carried out a retrospective
study including 44 Italian RA-ILD patients treated with
ABA. At the end of follow-up, only 13.9% showed wor-
sening of FVC. As observed in our series, they found no
differences in relation to the combined therapy with
MTX.
Certainly, although it is a rare complication, pneumon-
itis secondary to MTX has been described. It can occur
mainly in the first year of treatment and is an acute
pathology that usually requires drug withdrawal and
treatment with glucocorticoids [40–42]. Interestingly,
Sparks et al. performed a pre-specified analysis of pul-
monary adverse events (EAs) in the Cardiovascular
Downloaded from https://academic.oup.com/rheumatology/article/61/1/299/6199428 by guest on 17 March 2023
Inflammation Reduction Trial. They included 2391 sub-
jects randomized to receive low-dose MTX and 2395 to
receive placebo alone. Pneumonitis and possible pneu-
monitis were rare events; there were 13 severe pulmon-
ary adverse events (0.5%) and 7 cases of possible
pneumonitis (0.3%) in the low-dose MTX group, com-
pared with 8 (0.3%) and 1 (<0.1%), respectively, in the
placebo group but they were more likely to occur in
those randomized to receive low-dose MTX. The main
risk factors associated with an increased risk of pulmon-
ary adverse events in those who received low-dose
MTX were White race, older age, male gender and insu-
lin use [43].
However, in recent years several studies have high-
lighted the absence of an increased risk of developing
ILD in patients with MTX, as well as its beneficial role
[2, 22].
In our study, ABAMTX was similar in efficacy and
safety compared with ABAMONO and ABANON-MTX, thus
supporting these studies and highlighting a possible CS-
sparing effect in ABA combination therapy groups.
In our study, ABA retention rate was similar in the
three groups, around 75%. This was in keeping with a
previous report on ABA monotherapy vs ABA combined
with a cDMARD in RA patients [44]. In that study, the
authors found a similar ABA retention rate when it was
initiated either as a monotherapy or in combination with
cDMARDs (75 vs 76%, respectively). The low immuno-
genicity of ABA may partly explain the comparable
results in drug retention, with a similar drug survival
both in monotherapy and in combination with
cDMARDs. Most reasons leading to discontinuation of
ABA in our study were serious infections or articular in-
efficacy. However, the frequency of adverse events was
similar in the three groups.
The major strength of our study is the large number of
patients and their stratification into three relatively
homogeneous groups. Two of the main limitations of our
study are the retrospective design and the absence of a
control group, although these aspects were outside the
scope of our study, since ours was designed to com-
pare the efficacy of ABA in monotherapy or in combin-
ation with cDMARDs in a real-life setting. In addition,
the follow-up of the patients was carried out according
to the clinical practice of each centre, which led to the
existence of some missing data in LFTs and HRCT. This
305
Carlos Fernández-Dı́az et al.
is a common problem in observational studies like this
one, and it could have influenced our perception of the
apparent beneficial effect of ABA in our series. Another
potential limitation of our work is due to the inclusion of
a possible confounding bias by indication in the ABAMTX
group, when selecting those patients with milder dis-
ease, which could limit the evaluation of the drug to pre-
vent progression of the disease. Finally, another
restriction to our work is the absence of data on the
evolution of ILD in patients before the initiation of ABA
in order to more precisely identify the possible beneficial
role of ABA in the evolution of ILD.
In conclusion, in a large series of Caucasian patients
with RA-ILD from clinical practice, ABA in monotherapy
or combined with MTX and non-MTX csDMARDs seems
to be equally effective and safe in RA-ILD with mild af-
fection. A CS-sparing effect was observed only with
combined ABA. Therefore, ABA may be prescribed
combined, especially with MTX.
Acknowledgements
We thank all the members and patients of all participat-
ing hospitals. This study was presented in part at the
ACR/ARHP Annual Meeting of Rheumatology held in
Atlanta, USA, in November 2019.
Members of the Spanish collaborative group of intersti-
tial lung disease associated to RA: Alejandro Olivé,
Samantha Rodrı́guez-Muguruza (H.U. Germans Trias i
Pujol, Barcelona), Raquel Almodóvar-González (H.U.
Fundación Alcorcón, Madrid), Carmen Carrasco-Cubero
(C.H.U. Infanta Cristina, Badajoz), Antonio Juan-Mas (H.
Son Llàtzer, Palma de Mallorca), Raúl Castellanos-
Moreira (H.U. Clinic. Barcelona), In ~ igo Hernández
Rodrı́guez (C.H.U. de Vigo, Vigo), Neus Quillis-Marti (H.
Vinalopo Elche), José A. Bernal-Vidal (H. Marina Baixa,
Villajoyosa), Angel Garcı́a-Aparicio (H. Virgen de la
salud, Toledo) Sonia Castro-Oreiro (H.U. Joan XXIII,
Tarragona), Julia Fernández-Melón (H. Son Espases,
Palma de Mallorca), Paloma Vela Casasempere (H. U.
Alicante, Alicante), Marı́a C. Fito, Carmen González-
Montagut (C.U. Navarra, Navarra,), Manuel Rodrı́guez-
Gómez (C.H.U. Ourense, Ourense), Trinidad Pérez-
Sandoval, Miriam Retuerto-Guerrero (H.U. León)
Deseada Palma-Sánchez (H. Rafael Mendez, Lorca),
José L. Andreu (H. U. Puerta del Hierro), Patricia
Carreira-Delgado (H. 12 de Octubre, Madrid), Lorena
Expósito-Pérez (H.U. de Canarias, Tenerife), Juan RD
Jiménez-de Aberásturi (H.U. Txagorritxu, Araba), Ana
Urruticoechea-Arana (H. Can Misses, Ibiza), Rosa
Expósito-Molinero (H. Laredo, Laredo), Rubén López
Sánchez (H. Negrı́n Las Palmas), Manuel J. Moreno-
Ramos (H. Virgen de la Arrixaca, Murcia), Isabel
Serrano-Garcı́a (H. Puerta del Mar Cadiz), Blanca
Garcı́a-Magallón (H. San Jorge Huesca) José Marı́a
Andreu Ubero (H. Virgen de las Nieves Granada), Natalia
Mena-Vázquez (H.R.U Málaga), Iván Castellvi-Barranco
(H.U. De la Santa Creu i Sant Pau, Barcelona), Carmen
González-Montagut (H.U. Valladolid, Valladolid), Juan
Blanco-Madrigal (H. Basurto, Bilbao), Pilar Morales-
306
Garrido (H.U. San Cecilio, Granada) Cilia Peralta-Ginés
(H. Lozano Blesa, Zaragoza), Mireia López-Corbeto
(H.U. Vall d’Hebron, Barcelona), Sergio Ordón~ez-Palau,
H. Lleida, Lleida), Ana Ruibal-Escribano (H. Txagorritxu
HUA Vitoria), Andrea Garcı́a-Valle (H.U. Palencia) and
Susana Romero-Yuste (H.U. Pontevedra, Pontevedra).
Funding: B.A.-M. is recipient of a ‘López Albo’ Post-
Residency Programme funded by Servicio Cántabro de
Salud (Cantabria), Spain. This work was partially sup-
ported by RETICS Program (RD16/0012/0009) (Instituto
de Salud Carlos III, co-funded by the European Regional
Development Fund) from ‘Instituto de Salud Carlos III’
Downloaded from https://academic.oup.com/rheumatology/article/61/1/299/6199428 by guest on 17 March 2023
(ISCIII) (Spain).
Disclosure statement: Disclosures that may be inter-
preted as constituting of possible conflict(s) of interest
for the study: C.F.-D. has received fees in company-
sponsored speaker’s bureau from BMS and Roche. S.C.
is Assistant Professor of the cátedra UAM-ROCHE,
EPID-Future, UAM, Madrid, Spain. M.A.G.-G. has
received grants/research supports from Abbvie, MSD,
Jansen and Roche, and had consultation fees/participa-
tion in company-sponsored speaker’s bureau from
Abbvie, Roche, Sanofi, Lilly, Celgene, Sobi and MSD.
R.B. received grants/research supports from Abbvie,
MSD and Roche, and had consultation fees/participation
in company-sponsored speaker’s bureau from Abbvie,
Lilly, Pfizer, Roche, BMS, Janssen and MSD.
Data availability statement
Data are available upon reasonable request by any
qualified researchers who engage in rigorous, independ-
ent scientific research, and will be provided following re-
view and approval of a research proposal and Statistical
Analysis Plan (SAP) and execution of a Data Sharing
Agreement (DSA). All data relevant to the study are
included in the article.
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