| Chapter 4

Rheumatoid arthritis
John A. Mackintosh 1, Anna Stainer2,3, Laurens J. De Sadeleer 4
,
Carmel Stock5,6, Wim A. Wuyts 4 and Elisabetta A. Renzoni5,6

RA may be complicated by pulmonary disease involving any compartment of the lung,

which can manifest before, synchronously or after the development of articular disease.
Genetic and environmental factors combine to increase the risk of certain pulmonary
manifestations, in particular ILD. Interestingly, RA-associated ILD (RA-ILD) and IPF share
many common features, in terms of both genotype and phenotype. For patients with RA
presenting with respiratory symptoms, a thorough evaluation is necessary, including full lung
function tests. CT is necessary to define the specific disease process. Management decisions
should be individualised, incorporating both pharmacological and nonpharmacological
strategies. The management of RA-ILD is made more challenging by the pulmonary
toxicities of commonly used disease-modifying therapies. Despite long-standing knowledge
of the associations between RA and ILD, clinical trial evidence is sorely lacking. Fortunately,
there are pioneering studies under way designed to fill this evidence gap.

Cite as: Mackintosh JA, Stainer A, De Sadeleer LJ, et al. Rheumatoid arthritis. In: Wuyts WA, Cottin V,
Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield,
European Respiratory Society, 2019; pp. 44–67 [https://doi.org/10.1183/2312508X.10014019].

@ERSpublications
Rhuematoid arthritis pulmonary manifestations are diverse and may involve any
pulmonary compartment. ILD represents a major diagnostic and management
challenge in patients with rhuematoid arthritis. http://bit.ly/2lDj2R7

T he chronic autoimmune inflammatory disorder RA is defined by its articular

manifestations. A diagnosis of RA requires the presence of clinical synovitis in
combination with other supportive features, such as a characteristic pattern of joint
involvement, joint erosion, rheumatoid serology (rheumatoid factor (RF) and
anti-citrullinated protein antibodies (ACPAs)) and raised inflammatory markers [1]. In
addition to the morbidity caused by chronic severe joint disease, RA morbidity and
mortality may be influenced by numerous extra-articular manifestations, at times predating
articular disease (figure 1). In RA, no other organ system manifests such diverse features as

1
Dept of Thoracic Medicine, The Prince Charles Hospital, Brisbane, Queensland, Australia. 2School of Medicine and Surgery, University
of Milano-Bicocca, Milan, Italy. 3Respiratory Unit, San Gerardo Hospital, ASST Monza, Monza, Italy. 4Unit for Interstitial Lung
Diseases, Dept of Respiratory Medicine, University Hospitals Leuven, Leuven, Belgium. 5Interstitial Lung Disease Unit, Royal Brompton
Hospital, London, UK. 6Imperial College London, London, UK.

Correspondence: John A. Mackintosh, Dept of Thoracic Medicine, The Prince Charles Hospital, Rode Road, Chermside, Brisbane,
Queensland 4032, Australia. E-mail: john.mackintosh@health.qld.gov.au

Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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a)

b)

Figure 1. Pulmonary disease identified prior to onset of RA. This 70-year-old man first presented with mild
exertional dyspnoea following a lower respiratory tract infection. At the time, he had no features of a CTD
and had negative serology. Lung function tests demonstrated an FVC of 105% predicted and a DLCO of 60%
pred. a) His initial CT showed minor subpleural reticular changes in the lower zones in addition to limited
bronchiectasis at the left lung base. b) 4 years later, following another lower respiratory tract infection, he
presented with worsening dyspnoea, inflammatory polyarthritis and positive anti-citrullinated protein
antibodies. There was a significant decline in his lung function tests to an FVC of 65% pred and a DLCO of
35% pred. His repeat CT demonstrated significant progression of his pulmonary fibrosis. The freestanding
bronchiectasis in the left lower lobe was unchanged.

the respiratory system. All compartments of the lung may be involved, including the
airways, interstitium, vasculature and pleura (table 1). The prevalence of the different
pulmonary manifestations varies across series and different classification criteria. The
impact of RA on the lung may result from the disease itself and/or from complications of
disease-modifying therapy. This chapter will detail the pulmonary manifestations observed
in RA. We will focus on RA-associated ILD (RA-ILD) to review its risk factors, presentation
and management, although other lung manifestations will also be mentioned briefly.

Pathobiology of RA pulmonary disease

Although the pathogenesis of RA is only partially understood, the origins of this disease are
probably set in motion many years before clinically apparent arthritis [3]. In an initial
“pre-clinical” phase, ACPAs can develop 3–5 years before the onset of arthritis [4].
Hereafter, the disease evolves into established RA with or without extra-articular
manifestations.

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Table 1. Pulmonary complications in RA

Interstitium Pleura
UIP Pleural effusion
NSIP Pneumothorax
LIP Nodules
Desquamative interstitial pneumonia Rheumatoid nodules
Acute interstitial pneumonia Caplan syndrome
OP Other
Airways Drug toxicity
Bronchiectasis Infection
Cricoarytenoid arthritis Malignancy
Follicular bronchiolitis Thoracic cage restriction
Obliterative bronchiolitis Thromboembolic disease
Vascular
Rheumatoid vasculitis
PH

Reproduced and modified from [2] with permission.

The lung as a cradle of autoimmunity in RA

Increasing evidence suggests that the lung, and more specifically its mucosa, may play a
crucial role from the very beginning of RA pathogenesis [3]. According to this hypothesis,
different processes, including smoking [5] and microbiome dysbiosis [6, 7], give rise to
post-translational protein modifications such as citrullination [8, 9]. In a specific genetic
context, including high-risk HLA-DR alleles that contain the “shared epitope” [10] and the
protein tyrosine phosphatase PTPN22 [11], autoreactivity against these citrullinated
proteins gives rise to local production of IgA and IgG ACPAs [12, 13]. Moreover,
antibodies against the Fc domains of self-Ig proteins are formed, called RFs [14]. Such
immunological activation gives rise to important structural changes in the lung visualised
on HRCT as the presence of small-airway involvement, including bronchial wall thickening,
bronchiectasis, bronchiolitis and air trapping (independent of smoking status) [15].

Analysis of induced sputum has revealed the presence of IgA and IgG RA-related
antibodies in at-risk patients (defined as having either a first-degree family member with
RA or serum ACPAs), even when serum ACPAs or RFs are absent [16, 17]. In a second
stage, due to loss of mucosal barrier integrity, these IgA and IgG antibodies spread
systemically, possibly mediated by the crosstalk between the microbiome and the local
immune system [3]. Moreover, there is limited evidence that the high proportion of
secretory component in RFs might facilitate the transport of IgA ACPAs over the mucosal
barrier [18]. Hence, the presence of serum ACPAs is a marker of unresolved mucosal
inflammation and loss of mucosal barrier function.

From pre-clinical to established RA

The evolution from this pre-clinical stage to established RA is preceded by epitope spreading,
defined as an increase in the diversity of epitopes against which ACPAs react [19].
Interestingly, rather than an increase in the avidity of ACPAs [20, 21], an expansion of the

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diversity of low-avidity ACPAs is observed [22–25]. Moreover, intensive glycosylation of

both the ACPA Fc domain and its Fab (antigen-binding fragment) [26, 27], supported by
autoreactive T-cells [28], lead to an increase in ACPA effector functions [29, 30]. In a
process of molecular mimicry, this wide variance of ACPA antibodies recognises
self-antigens in the synovium, leading to the onset of synovitis [31, 32]. Whereas the
development of the pre-clinical phase is believed to be mediated largely through
environmental factors, the evolution towards established RA may be determined more
genetically [5, 19], although specific environmental risk factors also play a role.
Smoking [33], particulate matter pollution [34, 35] and dust exposure, including silica [36],
textile dust [37], solvents and mineral oils [3], are known risk factors for established RA in
pre-clinical RA patients, again hinting at an underestimated role of the lung in the
development of established RA.

From RA to RA-ILD: risk factors

Established risk factors for the development of RA-ILD include older age, cigarette
smoking, male sex, and high titres of serum ACPAs and/or RFs [38]. Among the genetic
factors, the most frequently reported associated loci are in the HLA region. The full list of
RA-ILD genetic association studies is given in table 2. Controversy still exists as to whether
the shared epitope mentioned above, shared between RA-associated HLA-DR alleles, is also
associated with the development of RA-ILD. While FURUKAWA et al. [41] reported a
protective effect of the shared epitope against RA-ILD, others have found no association
[39, 40]. It has been suggested that smoking, the shared epitope and ACPA interact to
increase the risk of developing RA. The presence of ILD was found to be associated with
smoking only in the presence of the shared epitope, suggesting a gene–environment
interaction [42]. HLA-B40 [48], as well as a number of HLA-DRB1 and HLA-DQB1 alleles,
has been associated with the risk of developing RA-ILD [39–41, 43, 44], while other alleles
have been associated with protection against RA-ILD [41].

Recently, remarkable similarities between IPF and RA-ILD genetic risk factors have been
described [46, 47]. A common variant in the promoter region of the MUC5B gene
(rs35705950), strongly linked to the development of familial and sporadic forms of IIPs,
was also associated with RA-ILD [47]. Subgroup analysis revealed its association to be
restricted to RA-ILD with a possible or definite UIP pattern on CT [47]. Interestingly, the
same variant had no association with SSc-associated ILD (SSc-ILD), where the prevalent
pattern is NSIP [49]. More broadly, several of the genetic susceptibility loci for IIP
identified in recent large genome-wide association studies have also been associated with
RA-ILD, including TOLLIP rs5743890 and IVD rs2034650 [47], as well as telomere-related
genes [46]. These shared genetic risk factors suggest a similar pathophysiological
mechanism, although which of these pertain to a UIP pattern of disease, to progressive
fibrotic ILD or to RA-ILD overall remains to be fully established.

The factors that lead to the development of lung fibrosis in an RA patient remain largely
elusive. The above-mentioned associations point to a key role of autoimmunity/antigen
presentation, airway/alveolar epithelial cells and senescence, among others. Pathogenetic
pro-fibrotic pathways are likely to converge towards activation of mesenchymal cells with
extracellular matrix accumulation, insufficient resolution of the wound-healing response
and destruction of the lung architecture. Key factors in the pathogenesis of RA-ILD are
summarised in figure 2 [2].

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ERS MONOGRAPH | PULMONARY MANIFESTATIONS OF SYSTEMIC DISEASES

Table 2. Genetic associations in RA-associated lung disease

Gene/HLA region Serotype/polymorphism OR (95% CI) and p-value Population Cohort First author
size [ref.]

HLA
HLA-DR Shared epitope 0.85 (0.51–1.43); p=0.54 Japanese 44/87# MIGITA [39]
Shared epitope 2.8 (1.45–5.63); p=0.001 UK 52/537¶ ENNIS [40]
Shared epitope 0.66; p=0.005 Japanese 129/321# FURUKAWA [41]
Smoking, in presence of 2.2 (1.1–4.5); North American 69/563# RESTREPO [42]
shared epitope no p-value given mixed ethnicities
Tryptophan at position 9 of 22.89 (1.2–432.56); p=0.037 Korean 7/8# SONG [43]
HLA-DRB1
HLA-DRB1*1502 3.81 (1.71–8.49); p=0.0006 Japanese 87/44# MIGITA [39]
HLA-DRB1*1502 Risk ratio 4.02; p=0.013 Japanese 24/332# MORI [44]
DRB1*07 2.7 (1.47–4.69); p=0.001 UK 129/321# ENNIS [40]
DRB1*04 0.57 (0.41–0.78); p=0.005 Japanese 129/321# FURUKAWA [41]
DR2 (DRB1*15 and 1.75 (1.22–2.51); p=0.002 Japanese 129/321# FURUKAWA [41]
DRB1*16)
DRB1*16 15.2 (1.82–127.01); p=0.037 Japanese 129/321# FURUKAWA [41]
HLA-DQB1 DQB1*04 0.57 (0.41–0.79); p=0.0036 Japanese 129/321# FURUKAWA [41]
https://doi.org/10.1183/2312508X.10014019

DQB1*06 1.57 (1.14–2.17); p=0.033 Japanese 129/321# FURUKAWA [41]

DR2 serological group 1.86 (1.23–2.81); p=0.0036 Japanese 107/773# OKA [45]
DR4 serological group 0.62 (0.41–0.93); p=0.025 Japanese 107/773# OKA [45]
DQB1*03:01 BAD: 1.99 (1.30–3.06); Japanese 116/773# OKA [45]
p=0.0021
DQB1*03:01 Emphysema: 2.43 (1.49–3.95); Japanese 83/773# OKA [45]
p=0.0007
DR5 Emphysema: 2.47 (1.39–4.37); Japanese 83/773# OKA [45]
p=0.0031
DR4 Emphysema: 0.61 (0.39–0.96); Japanese 83/773# OKA [45]
p=0.032
Continued

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Table 2. Continued

Gene/HLA region Serotype/polymorphism OR (95% CI) and p-value Population Cohort First author
size [ref.]

Non-HLA genes
TGFβ Codon 10 1.8 (0.82–3.94); p=0.142 Japanese 87/44# MIGITA [39]
IL4 −590 1.47 (0.44–4.91); p=0.536 Japanese 87/44# MIGITA [39]
Intron 3 1.11 (0.35–3.54); p⩾0.99 Japanese 87/44# MIGITA [39]
PADI4 padi4_92 Airway abnormalities: 2.22 Korean 92/22# SONG [43]
(1.05–4.49) p=0.034

RHEUMATOID ARTHRITIS | J.A. MACKINTOSH ET AL.

TERT, RTEL, Heterozygous mutations 3.17 (1.53–6.12); p=9.45×10−4 French 81/1010¶ JUGE [46]
PARN, SFTPC
MUC5B rs35705950 3.1 (1.89–5.4); p=7.4×10−5 French, Chinese, Greek, Japanese, 620/614# JUGE [47]
Mexican, Dutch, North American+
TOLLIP rs5743890 1.16 (1.06–2.48); p=0.03 French, Mexican, North American+ 272/242# JUGE [47]
IVD rs2034650 0.71 (0.54–0.95); p=0.02 French, Mexican, North American+ 272/242# JUGE [47]

All comparisons are for RA-associated ILD (RA-ILD) unless otherwise stated. BAD: bronchiectatic airway disease. #: number of RA-ILD/RA+no ILD;
¶
: number of RA-ILD/control; +: meta-analysis of the different populations listed.
49

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Environmental/
epigenetic factors

Epithelial damage

Genetic Inflammation Fibrosis

predisposition TNF-α, TNF-β, VEGF Fibroblast
Increased
PDGF, IL-1, IL-4, proliferation/
citrullination of
IL-5, IL-13, differentiation
proteins
chemokines

Proliferation
Autoimmunity

HLA-B54,
HLA-DQ1B*0601, Higher levels of Synthesis Degradation Antiprotease Protease
HLA-B40, ACPA antibodies
HLA-DR4
ECM MMP
Men (RA-ILD)

RA-ILD RA

Figure 2. The pathogenesis of RA-associated ILD (RA-ILD). Genetic and environmental factors contribute to
the development of protein citrullination, epithelial injury and autoimmunity. As a result, growth factors are
produced that mediate a pro-fibrotic response, which results in the development of ILD. TNF: tumor
necrosis factor; VEGF: vascular endothelial growth factor; PGDF: platelet-derived growth factor; ACPA:
anti-citrullinated protein antibody; ECM: extracellular matrix; MMP: matrix metalloproteinase. Reproduced
and modified from [2] with permission.

Natural history of RA-ILD

Wide differences in RA-ILD prevalence estimates exist, depending on the population studied
and case definition, with a key factor being whether subclinical ILD is included. Among
pulmonary manifestations, ILD is associated with the highest impact on mortality [2]. The
advent of symptomatic ILD in RA is associated with a 3-fold risk of mortality compared
with RA patients without ILD [50], with median survival between 3 and 10 years [51]. Two
recent systematic reviews focusing on factors predictive of mortality in RA-ILD identified
age, male sex, a UIP pattern on radiology, extent of fibrosis on CT and/or pulmonary
physiology as independent risk factors, although the reviewed studies were of variable
methodological quality [52, 53]. Interestingly, not all studies found a UIP pattern to be
independently predictive of mortality, after adjustment for severity of lung function
impairment [54] or treatment with methotrexate (MTX) [55]. Future prospective
standardised studies are needed to develop a clinical prediction algorithm for the
prognostication and management of patients with RA-ILD. Figure 3 provides a proposed
pathway for the investigation, staging and management of patients with RA-ILD.

Subclinical ILD in RA

The search for a precursor to fibrotic lung disease has led to the investigation of incidental
interstitial lung abnormalities (ILAs) in otherwise healthy populations. ILAs have been
identified in subjects not necessarily known to have RA but with positive RF or ACPA

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RA
(prior to onset of ILD)

Screen for respiratory symptoms at diagnosis

Higher degree of suspicion:
Examine for crackles
Seropositive
Baseline lung function (FEV1, FVC, DLCO)
Current or former smoker
Baseline chest radiography

Symptoms and/or No symptoms and

abnormal lung function normal lung function
Manage accordingly (synchronous joint and
lung disease at
diagnosis) Annual screening
Symptoms
FEV1, FVC, DLCO
Other pulmonary
manifestations of RA identified
(bronchiectasis, bronchiolitis, Symptoms/declining Exclude infective
nodules, pleural disease) lung function complication

Exclude drug toxicity,

Screen for RA-ILD with HRCT
malignancy
ILD
RA-ILD
(prior to onset of RA)

Pharmacological management Nonpharmacological management

MTX Define radiological subtype Smoking cessation Vaccinations

(Consider avoidance in those
not already on treatment, PJP prophylaxis Oxygen
particularly if poor respiratory
reserve. Continue MTX if stable Pulmonary rehabilitation Palliative care
on treatment for >6 months)
Lung transplant
Leflunomide Define disease extent
Stop/avoid CT >/<20% of total lung
FVC >/<70%
Anti-TNF agents
Stop/avoid

NSIP/OP/
UIP* DIP/LIP/
DAD

Limited/mild/ Extensive/moderate-to-
nonprogressive severe/progressive

Clinical trials Corticosteroids±

Observation
where available immunosuppressants

? Antifibrotics Regular evaluation

Progression

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Figure 3. Proposed algorithm for the approach to investigation and management of patients with RA and
RA-associated ILD (RA-ILD). The majority of patients will be diagnosed with RA prior to the onset of ILD,
although some cases of ILD will present synchronously or even prior to the onset of articular disease. All
patients with RA should be interrogated for the presence of pulmonary disease with a history for symptoms,
examined for signs, and have consideration given to a chest radiograph and baseline and surveillance PFTs.
HRCT is performed in those patients where pulmonary disease is suspected. When ILD is discovered, the
radiological phenotype and extent should be defined. Pharmacological management involves decisions
around which therapies are likely to be beneficial and avoidance of those that might be harmful.
Nonpharmacological therapies should be considered in parallel with pharmacological agents. MTX:
methotrexate; PJP: Pneumocystis jirovecii pneumonia; TNF: tumour necrosis factor; DIP: desquamative
interstitial pneumonia. *: The appropriate management of RA-ILD with a UIP phenotype is not clearly defined.
The response to immunomodulatory therapy may be less than that expected in other radiological phenotypes.
Pending the outcomes of recently completed clinical trials, enrolment in clinical trials should be considered
for this group of patients.

serology and a smoking history [56]. This finding raises further interest in the two
competing hypotheses on the joint or lung origins of RA.

Screening for RA-ILD is not performed routinely and therefore studies that identify
subclinical RA-ILD are confounded by the original indication for HRCT. In one study,
screening of asymptomatic (no cough or dyspnoea) individuals with RA demonstrated
subclinical ILD in 33%, most of whom had preserved baseline lung function [57]. The
presence of crackles was suggested as a simple, noninvasive and inexpensive means of
detecting ILD that could easily be adopted in clinical practice. DOYLE et al. [58] reported
that predictors of ILA included older age, higher antibody titres and greater RA joint
disease severity. As their cohort included patients who were symptomatic of cough and
dyspnoea, it may not be truly representative of subclinical RA-ILD. In contrast to the
previous study, those with an ILA had already lost lung function at the time of ILA
detection. This finding supports baseline and serial lung function (e.g. FVC, FEV1 and
DLCO) to screen for RA-ILD (figure 3). Baseline lung function tests and regular monitoring
with 6–12-monthly lung function tests are particularly indicated when new treatments (e.g.
biologics) are considered, with lung function decline prompting HRCT and pulmonology
referral (figure 3).

Radiological and histological patterns of RA-ILD

All the known histological IIP patterns can be observed in RA [59–63]. The presence of
multicompartment disease affecting various combinations of the interstitium, airways,
vasculature and/or pleura should raise suspicion for a CTD aetiology. In a recent large UK
cohort of RA-ILD patients, a CT UIP pattern was identified in the majority of cases (65%),
with NSIP in 24% [64]. In a separate cohort, JACOB et al. [65] identified features
inconsistent with UIP in 29% of RA-ILD patients, who also demonstrated the most
favourable prognosis. Lung biopsies are seldom performed in RA-ILD, given the support of
typical RA features to the diagnosis and the strength of HRCT in characterising the ILD.
However, it must be noted that radiologically indeterminate (figure 4) and NSIP patterns
may return UIP histologically [59]. These data do not support a role for biopsy in RA-ILD,
as a CT-defined UIP pattern provides prognostic separation, but emphasises the
predominance of UIP in this group of patients.

Both RA and RA-ILD have strong and well-defined associations with cigarette smoking and
therefore emphysema; however, emphysema also exists in RA never-smokers. Emphysema

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Figure 4. RA-ILD characterised by fibrosis and air trapping in a 64-year-old woman. The chest HRCT is
characterised by patchy ground-glass opacity, an extensive reticular pattern affecting all zones, with
traction bronchiectasis and architectural distortion, with the pattern indeterminate for UIP (e.g. some
features such as ground-glass opacity suggestive of an alternative pattern of fibrotic NSIP). There are a few
lobules of decreased attenuation (air trapping), indicating a degree of small-airways obstruction.

was identified in 27% of never-smoking RA-ILD patients. While less extensive than in
smokers with RA-ILD, emphysema was nevertheless associated with a worse prognosis [66].
The presence of emphysema in RA-ILD mirrors the same occurrence in other
CTD-associated ILDs, notably SSc [67, 68]. This observation supports the possible
contribution of autoinflammatory processes in the development of emphysema, as well as
the multicompartment model of lung disease in CTD.

Staging of RA-ILD

The staging of RA-ILD involves pattern categorisation (e.g. UIP, NSIP), assessment of
radiological extent and functional impact (FVC and DLCO). Of note, the prognostic impact
of UIP extends beyond classical radiological appearances. JACOB et al. [65] recently reported
that the presence of honeycombing in RA-ILD, even when occurring in a nonclassical UIP
distribution and associated with air trapping (in view of the frequency of concomitant
small-airways disease in RA), was associated with a median survival akin to IPF. By
adopting and validating a staging system first developed in SSc-ILD [69], the authors found
that patients with more extensive/advanced disease (⩾20% extent radiologically or FVC
⩽70% predicted) had a poorer prognosis, regardless of ILD subtype. A combination of the
modified UIP on CT and the above staging system defined a progressive fibrosing
phenotype of RA-ILD, present in 23% of cases, with a similar prognosis to IPF [65].

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Treatment of RA-ILD

Therapeutic advances for RA-ILD have lagged behind those for IPF and SSc-ILD. Early
literature revolved around the use of corticosteroids, with expert opinion suggesting, not
surprisingly, that some patients respond, some remain stable and some progress in spite of
high doses [70].

Patients with RA with suspected ILD should be evaluated thoroughly (figure 3). In
asymptomatic RA-ILD with normal lung function indices, treatment is often necessary for
the articular manifestations of the disease, and decisions regarding disease-modifying
therapy should consider the presence of RA-ILD, even if limited or asymptomatic. No
biomarkers currently exist to definitively predict those who will progress. The consistent
association between RA-ILD and smoking strongly suggests that smoking cessation should
be addressed as a priority at the time of RA/RA-ILD diagnosis, whichever comes first. RA
patients should be monitored regularly for respiratory symptoms and annual lung function.
The development of respiratory symptoms and/or a decline in FVC and/or DLCO of >10%
should prompt re-assessment of the ILD component and referral to a pulmonologist with
ILD experience.

It is clear that those with symptomatic RA-ILD and/or significant lung function
impairment require ILD-targeted therapy, although strong evidence to guide therapeutic
decisions is lacking. Monitoring over time is also key, particularly when in doubt, as even
patients with a UIP pattern can occasionally remain stable over time (figure 5). Experience
would suggest avoidance of anti-tumour necrosis factor (anti-TNF) therapy in patients with
RA-ILD, particularly in extensive disease [71]. MTX should not necessarily be stopped in
those who have tolerated this therapy for an extended period of time, but consideration
should be given to avoiding its commencement in cases of poor pulmonary reserve
(hypoxia, or low FVC or DLCO). Despite the historical concerns surrounding MTX-induced
ILD, ROJAS-SERRANO et al. [55] reported on a case series of 78 patients with RA-ILD, all
treated with immunosuppression (67% of patients with MTX). The authors found a
significantly better survival in MTX-treated patients, independent of baseline ILD severity
and age. Further recent evidence suggests that MTX may actually delay the onset of

Figure 5. Patient with RA-associated ILD with a classic UIP pattern. Surprisingly, over a period of 8 years,
this 68-year-old woman with a 20-year history of seropositive RA, maintained on low-dose prednisolone,
has not progressed significantly in any of the clinical, functional or radiological domains, despite a classic
UIP pattern on HRCT, usually associated with progressive disease.

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incident ILD in patients with RA [72]. While MTX can cause acute/subacute ILD, evidence
is growing to dispute its role as a long-term pro-fibrotic agent.

The evidence for other immunomodulatory strategies will be discussed in a later section. In
general, it must be remembered that patterns where inflammation plays a key role such as
NSIP/OP or LIP are likely to be more responsive to immunomodulation than UIP. Further
studies are required to assess the effect of immunosuppressive treatment in RA-ILD, in both
the UIP and non-UIP subgroups. The shared genetic loci with IPF [46, 47], in combination
with the results of the PANTHER-IPF (Prednisone, azathioprine and N-acetylcysteine for
pulmonary fibrosis) study [73, 74], suggest that future treatment approaches might be
stratified on the basis of imaging patterns, genetic factors and other biomarkers that may
come to light. Clinical trial enrolment should be strongly considered where available for
those who progress despite immunomodulation, particularly in the case of UIP (table 3).
Adjunctive therapies should be considered in all patients, such as vaccinations, Pneumocystis
jirovecii pneumonia (PJP) prophylaxis (where immunosuppression warrants), oxygen,
pulmonary rehabilitation, palliative care and lung transplantation [75, 76].

Mycophenolate

In 2008, SAKETKOO AND ESPINOZA [77] presented a small case series of four RA-ILD patients
who reportedly demonstrated dramatic responses to mycophenolate treatment. Treatment
with mycophenolate of 18 patients with RA-ILD was associated with a trend towards
stabilisation of previous FVC decline [78]. Although the efficacy of mycophenolate is well
established in SSc-ILD [79], trials of similar quality have not been performed in RA-ILD.
One barrier to the use of mycophenolate in RA-ILD is its limited effectiveness for articular
disease [80, 81]. Mycophenolate does, however, remain a potential option, particularly in
cases where ILD is the predominant RA disease manifestation.

Rituximab

A role for rituximab in RA-ILD has been proposed on the basis of the presence of follicular
B-cell hyperplasia and plasma-cell infiltrates in histological specimens of RA-ILD [82]. An
open-label study of rituximab (1000 mg on days 1 and 15, and again at weeks 24 and 26) in
progressive RA-ILD demonstrated improvement in one (UIP) and stabilisation in five (two
with UIP and three with NSIP) of seven patients [83]. Of three withdrawn patients, one
suffered an infusion reaction and another died of pneumonia/acute lung injury. A larger UK
study reporting experience with rituximab over 10 years in RA and RA-ILD has recently been
published [84]. In terms of ILD response, the pre-rituximab and post-rituximab median
relative FVC change was −2.4% (interquartile range (IQR) −7.1 to +0.8) and +1.2% (IQR −6
to +8.6), respectively. The overall lung response following treatment was improvement in
16%, stability in 52% and progression in 32%. Those with more severe, progressive or UIP
disease at the time of treatment were more likely to progress. Not to be overlooked was a 7.7
out of 100 patient-years incidence of serious infection. As opposed to mycophenolate,
rituximab is efficacious in articular disease and is recommended along with abatacept as
possible first-line biologic agents in RA-ILD by the British Society of Rheumatology [85–88].

Abatacept

The CTLA4 monoclonal antibody abatacept (10 mg·kg−1 for 4 weeks intravenously or
125 mg·week−1 subcutaneously) was recently studied in a small cohort of RA-ILD

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ERS MONOGRAPH | PULMONARY MANIFESTATIONS OF SYSTEMIC DISEASES

Table 3. Current RA-associated ILD (RA-ILD) clinical trials

Name (ClinicalTrials. Drug Design Inclusions Exclusions Primary outcome Status

gov identifier)

APRIL (NCT03084419) Abatacept Open label RA-ILD (n=30) FEV1/vital capacity <70% Change in FVC at Recruiting
(fortnightly for that has not 24 weeks
1 month, then responded or
monthly for progressed
20 weeks) despite
conventional
therapy
TRAIL1 (NCT02808871) Phase II trial of Randomised, RA-ILD (n=270), FEV1/vital capacity <70% Progression-free Recruiting
pirfenidone double blinded, FVC 40–100%, survival over 52
placebo DLCO 30–100% weeks (FVC decline
controlled ⩾10% or death)
INBUILD (NCT02999178) Nintedanib Randomised, Progressive Unstable CTD Annual rate of Recruitment
double blinded, fibrosing ILD Treatment with decline in FVC completed
placebo (n=663); requires azathioprine, cyclosporine,
https://doi.org/10.1183/2312508X.10014019

controlled evidence of mycophenolate, tacrolimus,

disease corticosteroids
progression >20 mg·day−1,
cyclophosphamide (within
8 weeks), rituximab (within
6 months)

APRIL: Abatacept in rheumatoid arthritis-ILD; TRAIL1: Phase II study of pirfenidone in patients with RA-ILD; INBUILD: Efficacy and safety of
nintedanib in patients with progressive fibrosing interstitial lung disease.

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participants [89]. The study demonstrated lung function and dyspnoea stability at 12 months
in the majority of subjects (approximately two-thirds). However, the study lacked both a
comparator arm and an analysis of pre-treatment versus post-treatment trajectory. The APRIL
(Abatacept in rheumatoid arthritis-ILD) study (ClinicalTrials.gov identifier NCT03084419),
which is also open label, is currently recruiting subjects with progressive RA-ILD (table 3).

Cyclophosphamide

Experience around the use of cyclophosphamide in very advanced RA-ILD is based on

anecdotal experience or information that has been extrapolated from SSc-ILD and
idiopathic inflammatory myopathies associated with ILD. Cyclophosphamide treatment is
usually considered as salvage therapy and/or in rapidly progressive disease, where there is
thought to be an inflammatory component (OP/NSIP or DAD/OP)

Antifibrotic agents

The fact that most patients in the cohort of progressive fibrosing RA-ILD in the study by JACOB
et al. [65] were likely to have received immunomodulation suggests that in a subset of RA-ILD
patients, progressive fibrosis occurs either despite, or as a result of, immunomodulation. The
similarities between RA-ILD and IPF, as well as evidence against immunomodulation in IPF,
support consideration of antifibrotic strategies to slow progression in this group of patients.
Data from a mouse model of RA-ILD demonstrated promising biological data to support a
role for nintedanib [90]. The results of the TRAIL1 (Phase II study of pirfenidone in patients
with RA-ILD) study (ClinicalTrials.gov identifier NCT02808871) are eagerly awaited (table 3).
The INBUILD (Efficacy and safety of nintedanib in patients with progressive fibrosing
interstitial lung disease) study (ClinicalTrials.gov identifier NCT02999178) may also provide
some data regarding antifibrotic agents in RA-ILD, although the study has fairly rigid criteria
with regard to CTD (table 3). Patients with symptomatic/severe/progressive RA-ILD clearly
require treatment, but indications on the strategy (immunomodulation, antifibrotics or both)
and how it relates to the individual patterns/patients remain to be defined.

RA-ILD acute exacerbations

Like IPF, the course of RA-ILD may be complicated by acute exacerbation events [91–97]. In
IPF, an acute exacerbation is defined as an acute, clinically significant respiratory
deterioration typically <1 month in duration, characterised by evidence of new, widespread
alveolar abnormalities not explained by fluid overload or cardiac failure [98]. While this
definition was created for IPF purposes, the occurrence of such events in RA-ILD supports
adoption of these criteria outside IPF. In RA-ILD, the widespread use of immunomodulation
necessitates a thorough evaluation for an infectious or drug-induced aetiology before an
exacerbation is deemed idiopathic. The yearly incidence of acute exacerbations in RA-ILD is
between 2.58% and 11.1%, and events are not necessarily reflective of the clinical activity of
the CTD outside the chest [91, 92]. Risk factors include a UIP pattern, advanced age and
surgical lung biopsy, which is fortunately rarely necessary in RA-ILD [91, 92, 95]. Mortality
due to acute exacerbations of CTD-ILD, which are most frequent in RA-ILD, is estimated to
be 65%, similar to that of IPF acute exacerbations [91]. In cases where infection (e.g. PJP) is
the major precipitant, there may be a greater chance of response. Drug-induced cases are
managed by cessation of the possible offending agent(s) and corticosteroids. In addition to

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supportive strategies, truly idiopathic events are typically treated with intensification of
immunosuppression, but further studies are urgently required [97, 99].

Drug-induced toxicity in RA-ILD

Drug-induced toxicity can range from mild to life-threatening. It can occur in a patient not
previously known to have lung disease or can complicate a known ILD pattern. In a
proportion of cases, lung toxicity is reversible following cessation of the drug with or
without the addition of corticosteroids and/or immunosuppression. However, permanent or
progressive pulmonary damage can be observed, particularly if the causative drug is not
withdrawn early [100]. A diagnosis of drug-induced lung disease requires an appropriate
temporal relationship, exclusion of potential alternative causes including opportunistic
infections and knowledge of the pulmonary toxicity associations with the putative drug,
through websites such as www.pneumotox.com, a regularly updated database curated by
Philippe Camus. Although cytohistological analysis can help exclude opportunistic
infections, radiological and histological patterns are nonspecific and each drug can be
associated with more than one pattern [100, 101]. Often only a probable or possible
diagnosis of drug-induced ILD, rather than a definite conclusion, is reached. Clearly, the
more acute the presentation and the closer it is to the initiation of the drug, the easier it is
to make the potential connection [102, 103].

Patterns of ILD for commonly used drugs in RA are summarised in table 4. Nonbiologic
therapies such as MTX (figure 6), sulfasalazine and leflunomide are well-known causes of
lung toxicity [105]. Of the biologic therapies, anti-TNF agents appear to be associated with
the highest incidence of drug-induced ILD. Reports of rapidly progressive DAD in patients
with pre-existing ILD suggest caution with the use of anti-TNF agents in patients with
known RA-ILD. Rituximab and tocilizumab have also been reported as causative agents
[102, 103, 105, 110, 111], although lung toxicity appears to be less frequent than for
anti-TNF agents. Interestingly, a recent meta-analysis of RCTs has not revealed an increase
in the risk of noninfectious respiratory adverse events for tocilizumab [119]. Abatacept lung
toxicity has been described in only a few case reports [114, 115, 120], such that, in
comparison with anti-TNF agents, abatacept may represent a safer option, and together
with rituximab may be considered as a first-line biologic in patients with RA-ILD [88],
although more data are needed [120]. Other molecules, such as janus kinase (JK) inhibitors
(baricitinib and tofacitinib) and anakinra, have so far shown safe profiles [116–118].

In summary, the diagnosis of drug-induced ILD remains challenging and one of exclusion.
Further evidence is required to clearly define the risks of specific RA therapies and
drug-induced ILD in those with RA with and without prevalent ILD. Clinicians should
remain vigilant around the potential for various agents to induce ILD and approach each
case individually.

PH in RA

In contrast to other CTDs, the prevalence of PAH in RA appears to be no higher than that
in the general population [121]. However, given the association between diastolic dysfunction
and RA, there is a higher prevalence of post-capillary PH [122]. Interestingly, a possible
association between leflunomide and the development of PAH has been reported [123].
Conflicting evidence exists on the benefits of immunosuppression on PH in RA [124, 125],

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Table 4. Reported patterns of drug-induced toxicity for commonly used drugs in

RA-associated ILD

Drug Reported drug-induced ILD patterns First author [ref.]

Methotrexate Acute/subacute cellular interstitial AKIYAMA [104], ROUBILLE [105]

pneumonitis (also termed drug-induced
hypersensitivity pneumonitis)
Chronic pneumonitis with fibrosis
Leflunomide DAD RAJ [106], ROUBILLE [105]
Eosinophilic pneumonia
OP
HP
Progression of pre-existing ILD
Pulmonary alveolar proteinosis
Sulfasalazine Eosinophilic pneumonia PARRY [107], MOHYUDDIN [108]
HP
Interstitial pneumonitis
Others: bronchiolitis obliterans, bronchiolitis
obliterans OP, desquamative interstitial
pneumonia, sarcoid-like reaction
Hydroxychloroquine Single case report of eosinophilic pneumonia ISHIGURO [109]
Anti-TNF DAD ROUBILLE [105]
OP
Alveolar haemorrhage
Progression of pre-existing ILD
Tocilizumab OP IKEGAWA [103], WENDLING
DAD [110], KAWASHIRI [111]
Progression of pre-existing ILD
Rituximab Acute/subacute OP ROUBILLE [105], HADJINICOLAOU
Interstitial pneumonitis [112], NAQIBULLAH [113]
DAD
Hypersensitivity pneumonitis
Abatacept DAD WADA [114], DOĞU [115]
JAK inhibitors Ruxolitinib: single case of DAD in MCCARTY [116], HARIGAI [117]
myelofibrosis
Tofacitinib: no reports
Baricitinib: no reports
Peficitinib: no reports
Anakinra No reports RAMÍREZ [118]

The patterns most frequently reported with a particular drug are highlighted in bold. TNF:
tumour necrosis factor; JAK: janus kinase. Information from www.pneumotox.com

while the approach to assessment and treatment follows that for other CTDs, noting the
possible higher risk of post-capillary disease [126].

Pulmonary infections and malignancy in RA

RA patients are subject to increased risk of infections due to the disease itself and to the
use of immunosuppressive drugs [127]. Increased infection rates have been associated with
MTX and leflunomide but not with sulfasalazine or hydroxychloroquine [127, 128].
Biologic therapies have been associated with a higher infection risk compared with

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Figure 6. A case of methotrexate (MTX)-induced ILD. This 49-year-old woman with RA treated with MTX for
12 months developed respiratory symptoms and lung function decline. On stopping MTX, there was a
significant improvement in lung function. MTX-induced ILD is typically characterised by a cellular interstitial
pneumonitis.

nonbiologic therapies [127, 129]. Anti-TNF agents increase the risk of severe infections [127],
including re-activation of latent tuberculosis [130]. Screening for active and latent
tuberculosis should be performed before starting anti-TNF agents and, where positive, local
guidelines should be followed regarding tuberculosis management, with an appropriate
delay in anti-TNF initiation [131]. As the risk of PJP in RA is reported to be less than that
observed in other autoimmune diseases [132, 133], prophylaxis against PJP in RA/RA-ILD
should be considered on a case-by-case basis, dependent on the type and degree of
immunosuppression.

The risk of malignancy in patients with RA appears to be only modestly increased

compared with the general age-matched population. A recent meta-analysis reported an
increased risk of lung cancer and lymphoma in RA [134]. MTX has been associated with
an increased incidence of lymphoproliferative disorders [135]. Evidence on anti-TNF agents
is inconclusive, with some studies suggesting an increased incidence of nonmelanomatous
skin cancer [136].

Other pulmonary manifestations of RA

Airways involvement

Radiological bronchiectasis is observed in up to 30% of patients with RA [137] but is

symptomatic in up to 3% only [138]. Symptomatic bronchiectasis may complicate decisions
around immunomodulatory treatment in RA. Furthermore, the prognosis of bronchiectasis
complicating RA is poorer than that for idiopathic bronchiectasis [139].

Small-airways involvement (bronchiolitis) is found on HRCT in almost two-thirds of RA

patients [140]. Histologically, follicular bronchiolitis and obliterative (or constrictive)
bronchiolitis are the most frequently observed patterns, and can overlap in the same patient.
While follicular bronchiolitis is characterised by lymphocytic inflammation of the small
airways and is corticosteroid responsive [141], obliterative bronchiolitis is characterised by
narrowing and obliteration of the small airways, visualised on HRCT as a mosaic
attenuation pattern with air trapping (figure 7). Although this type of bronchiolitis responds

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Figure 7. A case of obliterative bronchiolitis in a young woman with RA.

poorly to immunosuppression, and can rapidly progress towards a fatal outcome [142],
a recent case series has reported long-term stability in a substantial proportion of RA
patients [143]. As an extension from lung transplant literature, macrolide therapy may be
useful in this disease entity and has been reported in small series [143, 144]. However,
randomised controlled trial evidence is lacking.

Upper-airway involvement is also possible in RA [145]. A potentially severe complication is

cricoarytenoid arthritis. This complication should be suspected in any patient with RA who
develops dysphonia, stridor or other upper-airway symptoms. Other upper-airway
complications include secondary amyloidosis of the larynx, laryngeal rheumatoid nodules
and vocal cord paralysis.

Pleural disease

Pleural disease, including pleural effusions, pleural thickening/nodules and pneumothorax, may
affect 50–70% of RA patients [146]. Effusions are the most common pleural manifestation.
They are usually unilateral, and are associated with male sex, longer disease duration and
rheumatoid nodules [146]. Only 5–10% of pleural effusions are symptomatic [146].
RA-associated pleural effusions are exudative and classically have a low pH (<7.3), low glucose
(<50% of serum glucose level) and elevated lactate dehydrogenase (>700 IU·L−1) [146].
Lymphocytosis may be observed in chronic rheumatoid effusions. RA effusions may therefore
be confused with an infectious effusion, including tuberculosis. RF may be found in the pleural
fluid but provides little additional information above serum RA serology [146–149].
Symptomatic effusions require drainage and often optimisation of immunomodulatory
therapy. Chronic effusions may lead to long-term pleural complications.

Pulmonary nodules

In ∼20% of RA patients, pulmonary nodules are found, ranging from 1 to 50 mm [60, 150, 151].
Nodules may be multiple and can cavitate. Most often, these nodules are found
peripherally, in the upper and middle lung regions. Most pulmonary nodules are
asymptomatic; however, some may cause pneumothorax, hydropneumothorax and

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haemoptysis. Histologically, these nodules are composed of a central fibrinoid necrosis,

surrounded by granulomatous inflammation [152–154].

Conclusion

The pulmonary manifestations of RA are diverse in terms of both their pulmonary

compartment and their severity. Disease manifestations may range from incidental,
asymptomatic pulmonary nodules to severe and life-limiting RA-ILD. The most significant
pulmonary complication of RA, RA-ILD, has lacked clinical trials to guide treatment
decisions. As a result, treatment strategies have been guided largely by extrapolation from
other ILDs and reports of drug-induced toxicity rather than from controlled data to
support drug efficacy. Fortunately, current clinical trials are likely to provide robust
evidence to guide clinical management. In light of the diverse range of disease patterns and
longitudinal behaviours, clinicians should approach each patient with a pulmonary
manifestation of RA individually and holistically.

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Disclosures: J.A. Mackintosh reports receiving a speaker honorarium from Roche, outside the submitted
work. J. De Sadeleer reports receiving a travel grant from Roche, outside the submitted work. W.A. Wuyts
reports receiving the following, outside the submitted work: a grant from Roche paid to his university; a grant
from Boehringer Ingelheim; and consultancy fees from Galapagos paid to his university. E.A. Renzoni reports
receiving lecture and advisory board fees from Boeringher Ingelheim and Roche, outside the submitted work.

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