Two sides of the same coin? A review of the similarities and differences between idiopathic pulmonary fibrosis and rheumatoid arthritis-associated interstitial lung disease

Scott Matson, Joyce Lee, Oliver Eickelberg
European Respiratory Journal 2021 57: 2002533; DOI: 10.1183/13993003.02533-2020

Abstract

Rheumatoid arthritis associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF) are distinct diseases; however, they share several clinical, radiographic and genetic features. For instance, usual interstitial pneumonia (UIP), which is an ILD pattern required for a diagnosis of IPF, is also the most common ILD pattern in RA-ILD. The presence of UIP in RA-ILD is a poor prognostic sign with outcomes similar to those seen in IPF. The recent finding of a shared genetic susceptibility between IPF and RA-ILD has sparked additional interest in this relationship. This review outlines these similarities and differences in clinical presentation, appearance and outcomes in RA-ILD and IPF.

In addition, this review highlights previous research in molecular biomarkers in both conditions, exploring areas of overlap and distinction. This focus on biomarkers in IPF and RA-ILD aims to highlight potential areas of discovery and clues to a potential shared pathobiology through investigation of novel molecular markers or the repurposing of biomarkers from one condition to the other.

The drive to better understand RA-ILD by leveraging our knowledge of IPF is underscored by our divergent treatment paradigms for these conditions and the concern for potential harm. As a result of advancing our understanding of the links between IPF and RA-ILD, current strategies for diagnosis, screening and treatment of ILD may fundamentally change in the coming years. Until then, clinicians face difficult clinical questions regarding the co-management of the articular disease and the ILD in RA.

Abstract

Idiopathic pulmonary fibrosis and rheumatoid arthritis-associated interstitial lung disease have common genetic risks, similar clinical courses and common radiographic features. This review explores the similarities and differences between these diseases. https://bit.ly/2UlaZqs

Introduction

Rheumatoid arthritis (RA) is a common disease, characterised by an erosive and inflammatory synovitis, which affects 1% of the general population [1]. Interstitial lung disease (ILD) is a frequent extra-articular manifestation of RA and causes significant morbidity and mortality [2]. While ILD in RA is common, our understanding of the pathogenesis of RA-ILD is limited [3]. There have been observations that certain subtypes of RA-ILD may be clinically similar to idiopathic pulmonary fibrosis (IPF) [4], a form of progressive ILD, histologically characterised by a usual interstitial pneumonia (UIP) pattern [5]. Recent work in the genetics of RA-ILD has uncovered shared genetic risk factors between RA-ILD and IPF [6–8], further supporting a possible connection between these two conditions.

The growing understanding of the overlap between RA-ILD and IPF has important pathobiological implications and, perhaps more importantly, has the potential to impact clinical care. To date, treatment paradigms for IPF and RA-ILD are divergent. Immunosuppression-based therapy with prednisone, N-acetyl cysteine and azathioprine is not recommended in patients with IPF [9]. This combination of therapy was not only found to be ineffective in slowing disease progression, but was associated with increased mortality in IPF [10]. In contrast, immunosuppression in RA is critical in order to achieve and maintain arthritis remission [11]. Furthermore, systemic immunosuppression for RA-ILD is the current standard of care, based primarily on data extrapolated from studies in scleroderma-associated ILD [12, 13]. However, the impact and efficacy of immunosuppression for ILD in RA is unknown. Other factors complicating RA-ILD treatment is the impact of RA disease activity [14] and its associated treatment (e.g. methotrexate) on risk for ILD development and progression [15–17].

Given the increasing data suggesting an overlap of these two diseases (table 1), and the differing treatment paradigms with potential clinical impact, this review compares and contrasts what is currently understood about RA-ILD and IPF (figure 1). In addition, we propose areas in need of additional investigation, including identification of targeted and novel biomarkers, as furthering our understanding of these two conditions may have diagnostic, treatment and research implications in the field of ILD.

View this table:
TABLE 1

Clinical features of rheumatoid arthritis associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF)

FIGURE 1
FIGURE 1

Schematic illustration highlighting the similarities and differences between idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). The yellow section identifies clinical features unique to IPF: the usual interstitial pneumonia (UIP) pattern is seen in all cases; treatment in IPF is anti-fibrotics and not immunosuppression; and IPF is a lung-limited condition. The blue section identifies clinical features unique to RA-ILD: UIP is the most common pattern of ILD in RA, but other patterns exist; the treatment strategy in RA-ILD is based on immune suppression; and RA is a multisystem disease where ILD is one of many possible manifestations of RA. The green section includes areas of overlap between IPF and RA-ILD: both are diseases of the ageing population; affect males more than females; risk factors include smoking and genetics; and are associated with poor survival and acute exacerbations.

Epidemiology

RA is an inflammatory arthritis that affects nearly 1% of the general population [1]. The presence of RA significantly increases the lifetime risk of the development of ILD by 10% compared with the general population risk of 0.9% [2]. While the risk of development of ILD increases with a diagnosis of RA, the incidence of ILD within RA cohorts has been variable, ranging from 1% to 58% [18–24]. Estimates of the overall incidence of RA-ILD is also probably under-reported, given the wide variance in diagnostic imaging techniques (e.g. chest radiography versus computed tomography (CT)) and studies of RA cohorts demonstrating rates of subclinical RA-ILD from 26% to 58% [24, 25]. As the treatment paradigm for RA advances and clinical outcomes in RA (such as mortality) are improving, it is hypothesised that the incidence of RA-ILD will increase [26].

In comparison, IPF has a lower annual incidence between 4.6 and 16.3 per 100 000 people [27, 28]. However, the incidence of IPF is increasing, due to higher detection and ageing of the general population [29], similar to that which has been observed in RA-ILD [30].

Natural history and clinical characteristics

RA-ILD has a significant impact on quality of life and survival [30, 31]. The presence of ILD increases mortality when compared to RA patients without ILD [2]. Median survival in RA-ILD varies, but has been reported to range from 2.6 years to 10.3 years, depending on the population studied [2, 31, 32].

The RA-ILD clinical course can also include the development of acute exacerbations, which are similar to what is observed in IPF [33–35]. Acute exacerbation in RA-ILD, characterised by acute hypoxaemic respiratory failure and increased ground-glass opacities on CT imaging, appears to be more common among RA patients with a UIP pattern when compared to those with a non-UIP pattern of ILD [33].

Among those with RA-ILD, patients with a UIP pattern of disease have a worse outcome with more rapidly progressive disease and increased mortality when compared to those with a non-UIP pattern of disease [36, 37]. In fact, the natural history of RA-ILD patients with a UIP pattern of disease appears to mimic that of IPF [38]; however, there are some conflicting data [39]. Furthermore, a prognostic model that was derived and validated in IPF (i.e. the GAP model, which relies on four variables: gender (G), age (A) and lung physiology (P) variables (forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO)) [40], has similar discrimination and calibration among a multinational cohort of RA-ILD patients [4].

One of the most significant clinical differences between RA-ILD and IPF, besides the articular disease, is the myriad pulmonary manifestations that can occur aside from ILD in patients with RA. While IPF is an isolated parenchymal disease, RA can affect all compartments of the lung, including the pleura (e.g. pleuritis, pleural effusion) [41] and airways (e.g. follicular bronchiolitis, constrictive bronchiolitis) [42], and is associated with other non-fibrotic parenchymal lung diseases (e.g. organising pneumonia [43], diffuse alveolar haemorrhage [44] or nodules [18]).

Radiologic and histologic patterns

In RA-ILD, several radiologic patterns can be observed; however, the most common pattern in RA-ILD is the UIP pattern (figure 2), making RA-ILD unique among the connective tissue disease (CTD)-associated ILDs. In other CTD-ILDs, such as scleroderma-ILD or myositis-ILD, the most common ILD pattern is nonspecific interstitial pneumonia (NSIP) (figure 3). In RA-ILD, the UIP pattern on chest CT is seen in 40–62% of the cases [37], while the rest are made up of NSIP and organising pneumonia. Similar to IPF, the radiologic pattern of UIP in RA-ILD is highly specific for the UIP pattern on surgical lung biopsy (figure 4) [5, 45]. However, it is worth noting that the current diagnostic paradigm for RA-ILD, and all CTD-ILDs, does not include the determination of the underlying radiologic and/or histopathologic pattern.

FIGURE 2
FIGURE 2

Representative computed tomography image of the chest from a patient with rheumatoid arthritis associated interstitial lung disease. Radiologic usual interstitial pneumonia (UIP) pattern is defined as basilar, subpleural distribution of reticulation and traction bronchiectasis with honeycombing without features incompatible with UIP [105]. This radiologic pattern is highly specific for the UIP pattern on surgical lung biopsy [57].

FIGURE 3
FIGURE 3

Representative computed tomography image of nonspecific interstitial pneumonia (NSIP). Radiographic NSIP pattern is defined by bilateral and symmetrical ground-glass opacities. There can be fine peripheral reticulations and evidence of fibrosis by traction bronchiectasis. In this image there is also an example of subpleural sparing. Image courtesy of Tami Bang (University of Colorado, Denver, CO, USA).

FIGURE 4
FIGURE 4

a) Low-power and b) high-power view of a lung biopsy from a patient with rheumatoid arthritis associated interstitial lung disease. Usual interstitial pneumonia (UIP) on histopathology is characterised by subpleural fibrosis, spatial and temporal heterogeneity, fibroblast foci and microscopic honeycombing [106]. This biopsy has features of UIP, but also has an abundance of lymphoid aggregates. Scale bar=100 μm. Images courtesy of Carlyne Cool (University of Colorado, Denver, CO, USA).

IPF is defined by the presence of the UIP pattern in all cases, either radiographically or histologically [46], without an identifiable cause. The histologic findings of UIP in IPF are identical to UIP in RA-ILD, with the exception of findings that includes the presence of more extensive lymphoid aggregates, organising pneumonia and bronchiolitis.

Genetic susceptibility

Recent work in the genetics of RA-ILD suggests a common genetic susceptibility to the development of both IPF and RA-ILD. A whole-exome sequencing study, followed by a restricted analysis to familial pulmonary fibrosis-linked genes [47–54], found similar genetic mutations in TERT, RTEL1, PARN and SFTPC in a French RA-ILD cohort [8], although these findings were limited by the lack of comparison to RA subjects without ILD. Subsequently, the MUC5B gain of function single nucleotide polymorphism in rs35705950 was also found to be significantly associated with RA-ILD [7]. The MUC5B promoter variant has been shown to be a significant genetic risk factor for the development of IPF [6, 55–58] and this recent work finds that the promoter variant accounts for a similar risk for ILD in RA patients [59]. Furthermore, the MUC5B association with ILD in RA appears to be driven by those with a radiologic UIP or possible UIP pattern of disease [7]. This association between MUC5B and ILD in RA is more predictive than any other previously reported clinical risk factor or association, including smoking [7]. This relationship has not been observed in other CTD-ILDs (e.g. scleroderma, myositis) [60, 61], but has been observed in another ILD with a higher prevalence of the UIP pattern, fibrotic hypersensitivity pneumonitis [62]. Lastly, exploratory analyses have demonstrated similar associations between other common variants identified in IPF [63] in RA-ILD [59], although this study was not powered to confirm these common variants as genetic risk factors.

Risk factors for development of ILD

Despite the female preponderance in RA, males are more commonly affected by RA-ILD. Similar to IPF, RA-ILD affects males nearly twice as often as females [3, 64, 65]. The other common associations with the development of ILD in RA are RA disease activity, age and smoking status, [14, 59, 65]. Most patients with RA-ILD are diagnosed with ILD in their fifth or sixth decades of life and age has repeatedly been shown to be an independent risk factor for development of ILD in RA populations [30]. Additionally, there is a clear preponderance for the development of IPF with ageing, for instance in one study the prevalence of IPF increased from four in 100 000 in persons aged 18–34 years to 227.2 per 100 000 in those aged >75 years [28]. Other risk factors specific for RA-ILD include the duration of RA and older age at RA onset [2, 66, 67]. In both IPF and RA-ILD the most common environmental risk factor is smoking. The odds ratio for development of ILD in RA for those who had smoked >25 years was 3.8 (95% CI 1.59–8.88) [68]. Similarly, the odds ratio for development of IPF in heavy smokers (21–40 pack-years) is 2.3 (95% CI 1.3–2.9) [69].

Other comorbidities and risk factors, such as gastro-oesophageal reflux disease (GORD) and obstructive sleep apnoea (OSA), have been described in IPF and may have implications for the development and/or progression of the disease [70–76]. However, the relationship of these comorbidities in RA-ILD is less clear. Further investigation into these associations would be clinically relevant, as both GORD and OSA have clinical interventions that are effective.

Nomenclature and diagnosis

The diagnosis of RA-ILD requires the presence of RA and radiologic findings compatible with ILD. Currently, the diagnostic paradigm does not require the identification of the underlying histopathologic pattern (e.g. UIP versus NSIP); however, it should include the exclusion of other causes of lung disease in an RA patient (e.g. drug toxicity, opportunistic infection), particularly if the imaging is not compatible [77]. In contrast, IPF is diagnosed by the presence of the UIP pattern on radiology and/or histopathology with the exclusion of other diseases that can lead to the UIP pattern, including RA and chronic hypersensitivity pneumonitis [46]. By virtue of this exclusion, a patient with RA cannot be diagnosed with IPF.

Given the clinical and genetic similarities that are being uncovered, some have questioned this construct. While there are risk factors specifically related to RA that appear to be risk factors for ILD in this population, as discussed earlier, there are other scenarios, albeit less common, that suggest this may not always be the case (e.g. concurrent presentation of RA and ILD and development of RA after the diagnosis of ILD) [5]. The majority of the data does not distinguish between these subphenotypes of clinical presentation and more work needs to be done to determine if UIP in RA is concurrent IPF or an extra-articular manifestation of RA.

Molecular markers of disease

Biomarkers may have diagnostic or prognostic functions in disease states. In addition, with ongoing development of therapeutic targets in ILD, biomarkers may also play a theragnostic role in quantifying or anticipating response to therapy. And, while an exhaustive discussion of biomarkers currently under study in both of these conditions is beyond the scope of this review, we highlight a few candidate biomarkers identified as a result of data from one or both conditions. See table 2 for a more exhaustive list of candidate molecular markers which have been shown to have diagnostic or prognostic ability in RA-ILD and/or IPF.

View this table:
TABLE 2

Molecular markers of disease in rheumatoid arthritis associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF)

Biomarkers associated with alveolar epithelial cell dysfunction: telomere length

Telomeres are a repetitive region of DNA-protein structure found at both ends of chromosomes and function to protect the chromosomes and genomic structures from nucleolytic degradation [78]. Disease states associated with short telomeres often are associated with mutations in the telomerase complex, which restores telomere length. Mutations in telomerase reverse transcriptase (TERT) and telomerase RNA lead to telomere shortening and are found in 8% of patients with familial pulmonary fibrosis [49]. In sporadic IPF, short telomeres are found in the circulating leukocytes of 23% of patients, even in the absence of a known telomerase mutation [79]. These data suggest that aberrant telomere repair and resultant cellular senescence may be involved in the development of IPF.

Recent data suggest that telomere length in in RA-ILD is shorter than that seen in other CTD-ILDs and that this group had poorer outcomes when compared to the other CTD-ILDs in terms of survival and pulmonary function, indicating a possible prognostic role for telomere length in RA-ILD [80]. Higher rates of mutations in genes encoding for telomere maintenance (e.g. TERT, RTEL1, PARN) have been found in RA-ILD when compared with controls. Those with the mutations had shorter leukocyte telomere lengths compared with controls [8]. Shortened telomeres have been thought to play a role in the increased age propensity for RA, where CD4 T-cells in RA exhibit ineffective upregulation of TERT, increasing apoptosis and limiting clonal expansion [81]. Immune senescence has long been a known feature of RA, and some investigators have hypothesised that this lack of telomere maintenance through TERT-mediated telomerase downregulation plays a role in the pathogenesis of immune dysregulation in RA [82].

Further understanding of telomere biology in RA-ILD may have therapeutic implications, and telomere length should be further explored as a prognostic and potentially theragnostic marker.

Biomarkers associated with extracellular matrix remodelling and fibroproliferation: matrix metalloproteases

Matrix metalloproteases (MMPs) play a role in extracellular matrix (ECM) turnover regulation. MMPs are endopeptidases whose primary role is to degrade ECM proteins [83]. MMP-1 and MMP-7 levels (in plasma and bronchoalveolar lavage fluid) were significantly higher in IPF than controls, which included subjects with acute and chronic hypersensitivity pneumonitis, and other fibrotic lung conditions such as sarcoidosis [84]. Aside from distinguishing IPF from chronic ILDs, MMP may also be a prognostic biomarker. MMP-7 levels in IPF have been shown to be negatively correlated with diffusing capacity and positively correlated with the GAP scoring system [85]. In addition, MMP-7 values change over time in individuals with IPF and this change has been shown to correlate, within individuals, with worsening lung function [86].

In RA synovial disease, the underlying pathogenesis is also related to abnormal deposition of ECM proteins as well as cartilage destruction, which is mediated by these endopeptidases, among others [87]. Expression of several MMPs (1–13) have been shown to be elevated compared to control cohorts in RA patients, and inhibitors of these enzymes have been proposed as a potential therapeutic target for RA synovial disease [87]. In RA-ILD, MMP-7 levels are elevated when compared to those with RA without ILD [88]. Additionally, in US cohorts of RA-ILD, the value of MMP-7 has been shown to be negatively correlated with markers of pulmonary function (FVC and DLCO) and with worse dyspnoea scores [88].

Biomarkers associated with immune dysfunction: citrullinated proteins

Citrullination is the post-translational modification of a peptide that is catalysed by peptidyl arginine deiminase, which converts an arginine to a citrulline. This formational and structural alteration fundamentally changes the way the immune system interacts with the protein. Having been altered, the immune system now recognises the protein as foreign. As such, auto-antibodies are subsequently generated to the “citrullinated” protein, known as anti-citrullinated protein antibodies (ACPA). ACPAs are implicated directly in the pathogenesis of RA and antibodies detected in serum, such as anti-cyclic citrullinated protein (anti-CCP), are highly predictive of RA development and are useful diagnostic biomarkers [89].

In RA-ILD, an association between ILD and the presence of APCAs has been observed. Studies have shown significantly higher levels of ACPA in those patients with RA-ILD when compared to RA without lung disease, even after matching for disease severity and age [90–92]. In addition, levels of ACPA titre have been associated with the presence of restrictive physiology or diffusion capacity limitations in patients with RA and the likelihood of having ILD [90]. This association between RA-ILD and APCA titre raises the possibility that ACPA generation could be related to the pathogenesis of RA-ILD.

In IPF, a disease not currently thought to have any significant component of autoimmunity, higher rates of ACPAs are detectable in explanted lung tissue than those of controls (46% versus 20%) [67]. Rates of citrullinated proteins in explanted IPF lung tissue were as high as those found in patients with RA-ILD [67]. Furthermore, in a cohort of patients with IPF, rates of serum anti-CCP (IgA isotype) were 21% compared to 6% in the control cohort [93]. While both IPF and RA-ILD have ACPAs in their serum, ACPA has been clearly linked to the pathogenesis of synovial RA. While in IPF and RA-ILD, the association with ACPA and presence of pulmonary fibrosis is seen, it remains to be understood how these serum and lung ACPAs are generated and what, if any, role they may play in the pathogenesis of the condition.

Future directions in understanding pathogenesis of RA-ILD and IPF

The biomarkers described here are obvious candidate biomarkers based on our current understanding of RA, RA-ILD and IPF. These biomarkers may help us better understand the pathophysiology of RA-ILD and its seeming overlap with IPF. However, other approaches could also identify novel biomarkers for either or both of these disease states that could be equally, if not more, informative.

The advancing field of omics holds the promise of identifying a “molecular endotype”, which may provide new insights into the link between these two conditions. Additionally, given that IPF and RA-ILD are heterogeneous disorders that can funnel into a common histopathologic pathway of UIP, the application of an omics approach may shed light on common or disparate biological pathways and processes that lead to the fibrotic phenotype of UIP in these conditions.

Furthermore, comparisons across fibrotic diseases affecting different organs (e.g. liver, skin, kidney) is another strategy that could be employed to elucidate common fibrotic pathways which may not be conserved to IPF. For example, in an analysis of the lung and skin tissue of scleroderma patients with ILD, a deep proteomics profiling strategy identified a shared high prevalence of MZB1-positive plasma B-cells in both the lung and skin [94]. The presence of an antibody-producing plasma cell signature in fibrotic models of disease further lends credence to the theory of antibody mediated-fibrotic mechanisms, which could be another mechanistic trait connecting IPF and RA-ILD.

Summary

While the presence of an underlying autoimmune disease such as RA has impacted the diagnostic approach and approach to treatment in ILD, it may be that we can learn important lessons from IPF. This review outlines the similarities and differences in clinical presentation, appearance and outcomes in RA-ILD and IPF. The recent finding of a shared genetic susceptibility between IPF and RA-ILD has sparked additional interest in this relationship. Further investigation of candidate and novel biomarkers that are similar or dissimilar in RA-ILD and IPF will better elucidate common biological mechanisms between these two conditions. The drive to better understand RA-ILD in the context of what we know in IPF is underscored by our divergent treatment paradigms for these conditions and the concern for potential harm. As a result of advancing our understanding of the links between IPF and RA-ILD, current strategies for diagnosis, screening, and treatment of ILD may fundamentally change in the coming years. Until then, clinicians face difficult clinical questions regarding the comanagement of the articular disease and the ILD in RA and treatment decisions should be made in a multidisciplinary format with collaboration between pulmonologists and rheumatologists.

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Footnotes

  • Conflict of interest: S. Matson has nothing to disclose.

  • Conflict of interest: J. Lee reports grants from NIH, grants and personal fees for advisory board work from Boehringer Ingelheim, personal fees for advisory board work from Galapagos and Celgene, personal fees for consultancy from Eleven P15, outside the submitted work.

  • Conflict of interest: O. Eickelberg reports grants from NHLBI (R01 1R01HL146519), during the conduct of the study; personal fees from Blade Therapeutics, Pieris, Boehringer Ingelheim and Novartis, outside the submitted work.

  • Received June 27, 2020.
  • Accepted November 8, 2020.

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Two sides of the same coin? A review of the similarities and differences between idiopathic pulmonary fibrosis and rheumatoid arthritis-associated interstitial lung disease
Scott Matson, Joyce Lee, Oliver Eickelberg
European Respiratory Journal May 2021, 57 (5) 2002533; DOI: 10.1183/13993003.02533-2020
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