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 Table of Contents  
Year : 2021  |  Volume : 16  |  Issue : 5  |  Page : 20-28

Spectrum of interstitial lung disease in rheumatic diseases

1 Department of Rheumatology, Southend University Hospital, Westcliff on Sea, UK
2 Department of Rheumatology, James Paget Hospital NHS Trust, Norfolk, UK
3 Department of Rheumatology, Leicester University Hospital NHS Trust UK, Leicester, UK
4 Department of Life Sciences, Leicester Medical School, University of Leicester, Leicester, UK

Date of Submission17-Sep-2021
Date of Acceptance17-Nov-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Gouri Koduri
Department of Rheumatology, Southend University Hospital NHS Trust, Prittlewell Chase, Westcliff on Sea
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.332975

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Among the diverse forms of lung involvement, interstitial lung disease (ILD) and pulmonary arterial hypertension are two important conditions in patients with rheumatic diseases that are associated with significant morbidity and mortality. The management of ILD is challenging and these challenges are associated with several mechanisms, particularly the inflammatory processes of immune cells and also fibrotic processes, which play a crucial role in disease progression, making immunosuppressive therapy less effective. However, recent advances in pharmacologic interventions have been shown to delay disease progression of these lung conditions and improve patient survival. Disease stratification and early identification of patients who are more likely to progress, and thus in need of more aggressive treatment, is important in the field of ILD. Early diagnosis, monitoring, and multidisciplinary team input are very important to improve overall outcomes. This review focuses on ILD in patients with various rheumatic diseases (rheumatoid arthritis, myositis, Sjogren' syndrome, and systemic sclerosis) and the challenges.

Keywords: Connective tissue disease, interstitial lung disease, myositis, scleroderma, vasculitis

How to cite this article:
Koduri G, Makkuni D, Jubber A, Moorthy A. Spectrum of interstitial lung disease in rheumatic diseases. Indian J Rheumatol 2021;16, Suppl S1:20-8

How to cite this URL:
Koduri G, Makkuni D, Jubber A, Moorthy A. Spectrum of interstitial lung disease in rheumatic diseases. Indian J Rheumatol [serial online] 2021 [cited 2023 Feb 2];16, Suppl S1:20-8. Available from:

  Introduction Top

Pulmonary involvement is a common feature of connective tissue diseases (CTD). There is a myriad of respiratory manifestations in CTD, which include pleuritis, pleural effusion, bronchiolitis obliterans, bronchiectasis, pulmonary hypertension (PH), and interstitial lung disease (ILD). Of the respiratory complications, ILD and PH carry significant morbidity and mortality. ILD are a group of diffuse parenchymal lung disorders that are classified according to specific clinical, radiological, and histopathological features. Rheumatoid arthritis-associated ILD (RA-ILD) is an underrecognized and serious manifestation of RA. Treatments and outcomes for RA have significantly improved in recent years; however, these benefits have not fully extended to rheumatoid lung disease. Although ILD is a well-established complication of RA with a substantial impact on prognosis, there are insufficient trials or registry data to inform evidence-based recommendations on screening and monitoring. The diagnosis of CTD-ILD is still one of the most pressing challenges. Usually, it is common for ILD to be diagnosed concurrently or after CTD, but rarely do patients present with ILD years before the diagnosis of the CTD. Although considerable progress has been made in understanding ILD, curing, and halting, it is still a distant goal. A clearer understanding of how the cells fail to adequately repair the lung and key pathogenetic pathways are much needed. Current clinical trials are studying agents that reduce the fibrotic signaling within the lung, reduce PH associated with ILD, and alleviate oxidative stress.

Some individuals with ILD may have minimal findings on assessment, or in some, it may reveal a phenotype consistent with certain rheumatic diseases. In the absence of a clear phenotype, the radiological pattern and serology can play a vital role in the diagnosis [Table 1].[1],[2],[3],[4],[5],[6],[7] The best current approach in the diagnosis of and management of ILD is the multidisciplinary team approach, which should consist of a pulmonologist, rheumatologist, and radiologist with a special interest in ILD. The correct diagnosis of ILD has important consequences for prognosis and treatment. This review aims to provide an overview of the spectrum of ILD in various rheumatic conditions.
Table 1: Rheumatic diseases, antibodies, and high-resolution computed tomography patterns associated with interstitial lung disease

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  Rheumatoid Arthritis-Associated Interstitial Lung Disease Top

Epidemiology and risk factors

There is variability in the estimated incidence and prevalence of RA-ILD because of different methods of case ascertainment. The lifetime risk of developing ILD in patients with RA is reported to be 6%–15%.[8] ILD may precede the articular manifestations or can be secondary to RA, but several disease-modifying antirheumatic drugs and biologics have also been associated with the development of ILD. A recent genome sequencing study has shown an association between the MUC5B gene variant, similar to findings in idiopathic pulmonary fibrosis.[9],[10] While the exact mechanism by which ILD occurs in patients with RA is still unclear, the most consistently reported risks factors in epidemiological studies are older age, male sex, smoking, and seropositivity, particularly rheumatoid factor and anti-cyclic citrullinated peptide antibodies[11],[12],[13] and RA disease activity in some studies.[8],[12]

Clinical features

Symptoms of ILD are indistinguishable from several more common lung diseases and include exertional dyspnea, cough, and fatigue. The variability of the clinical manifestations is most likely due to the heterogeneity of the disease. However, active arthritis may cause impaired physical activity and may disguise respiratory symptoms, and may lead to a delay in diagnosis. Although a large proportion (30%–76%) of patients with RA have signs of ILD on imaging, ILD is only deemed clinically significant in 5%–10%.[14],[15] It is still not clear whether treatment for subclinical RA-ILD should be initiated and whether it will alter the course of the disease.


Chest X-ray is an insensitive method to detect ILD; therefore, high-resolution computed tomography (HRCT) is a mandatory part of the diagnostic workup if ILD is suspected. The most common HRCT patterns in RA-ILD are usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), while organizing pneumonia (OP) and bronchiolitis are less common. Lung ultrasonography (LUS) has been a suggested modality to identify ILD by detection of sonographic B-lines. LUS has a high sensitivity (89%–97%) but varying specificity (50%–97%) compared to HRCT in patients with RA-ILD.[16],[17] However, the etiology of the B lines may be difficult to establish in clinical practice, and differentiation between inflammatory and fibrotic changes may not be possible using LUS.[18]

Screening and risk algorithms for interstitial lung disease

At present, there are no specific recommendations for screening ILD in RA patients. A simple probability score or risk calculator to identify high-risk patients, analogous to Q Risk for cardiovascular disease, would be invaluable. Paulin and colleagues[19] recently identified five variables comprising male gender, smoking, extra-articular manifestations, CDAI score, and ESR as risk factors for ILD. Kronzer et al.[20] identified obesity and poor functional status as additional predictors of RA-ILD in their model. Evaluation of lung involvement should be undertaken in all RA patients during routine clinical assessment because early intervention can improve quality of life. [Figure 1] depicts a schematic picture of screening and monitoring of RA-ILD.
Figure 1: A schematic picture on screening and monitoring Rheumatoid Arthritis interstitial lung disease. PFT: Pulmonary function test; HRCT: High-resolution computed tomography

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RA-ILD is the second most common cause of death in RA, and the mortality is greatest within the first 5–7 years after the diagnosis.[8],[21],[22] Male gender, smoking, anti-CCP antibodies, older age, lower lung diffusion capacity for oxygen (DLCO), and UIP subtype were reported to be significant predictors of mortality. In most patients, ILD is subclinical or mild and may not require treatment. Unlike other CTD-ILD, the most common histopathologic type is UIP, which shares many other analogies with IPF, in terms of clinical behavior, prognosis, and survival.[9],[23] In general, our practice should include close monitoring and initiation of treatment when clinical symptoms manifest, or when there is physiologic evidence of progression. Follow-up HRCT should be guided by symptoms and pulmonary function deterioration. The optimal follow-up interval is not known and may depend on disease course and treatment.

  Antineutrophil Cytoplasmic Antibodies Associated Interstitial Lung Disease Top

Pulmonary involvement is frequently observed in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients, and ILD is emerging as a possible phenotype. The prevalence of ILD is higher in microscopic polyangiitis (MPA) than in granulomatosis polyangiitis (GPA). ILD has been reported in about 23% of GPA patients and up to 45% of MPA patients.[24],[25],[26] Among AAV patients with ILD, the most frequent pattern is UIP.

ILD associated with ANCA is usually observed in older patients and can occur concurrently or antedates MPA in most affected individuals. The frequency of ILD in ANCA vasculitis seems to be higher in Japan than in western populations,[27],[28] with a higher prevalence of MPO-ANCA positivity and increased frequency of lung involvement and diffuse alveolar hemorrhage. There are several theories to the development of this complication in ANCA vasculitis. Frequent episodes of subclinical intra-alveolar hemorrhage and MPO-ANCA per se may play a direct role in the pathogenesis of lung fibrosis. In addition, damage induced by eosinophils and neutrophil extracellular traps could also play a role.[29] It seems plausible that repeated episodes of inflammatory alveolar-capillary injury result in a reactive fibrotic state. A recent meta-analysis of observational studies found a 2.9-fold increased risk of death in patients with AAV-ILD when compared with the control group.[30] Further research is needed to better characterize patterns of ILD, predict progression, and determine optimal therapeutic regimens.

  Myositis-related Interstitial Lung Disease Top

ILD is the most common and most serious complication of idiopathic inflammatory myositis (IIM). In patients with polymyositis (PM) and dermatomyositis (DM), any symptoms of shortness of breath should prompt further investigations to exclude ILD. Almost 40% of patients with myositis will have some form of lung involvement, the most common patterns being NSIP and OP, followed by UIP and AIP.[31],[32] The ILD symptoms can precede the development of myositis in 13%–38% of patients.[33],[34] Most ILD starts within 12 months of the onset of myositis. The availability of myositis-specific autoantibodies has changed the way clinicians assess these patients. Better clinical and serological phenotyping is now possible with the help of these tests, and there is growing evidence of genetic associations between the occurrence of ILD and myositis.

Pathogenesis and biomarkers

Myositis-specific antibody testing should be performed in all patients with negative conventional autoantibodies without any features of CTD. Various myositis-specific antibodies such as anti-Mi-2, anti-PM/Scl, anti-SRP, and anti-synthetase antibodies (ASAs) are detected in patients with PM or DM. Among these, ASAs have the highest association with ILD. Clinically amyopathic DM (CADM)-associated ILD (DM-ILD) is more refractory to corticosteroid therapy and carries a poorer prognosis than PM-associated ILD.[35]

Anti Jo-1 is the first and oldest ASA, or anti ARS (anti-aminoacyl-tRNA synthetase antibody). It is also the most studied, and is seen in up to 25%–40% of patients with myositis, and is often a marker of various anti-synthetase syndrome phenotypes with distinct clinical features and outcomes. Surfactant protein D is considered a predictor of mortality,[36] and KL-6, a glycoprotein, expressed on type 2 pneumocytes, is higher in PM/DM. High ferritin levels are also described as one of the markers of severity, especially in CADM.

The incidence of ILD rises to 75% among patients with anti-Jo-1 or anti-melanoma differentiation-associated protein (MDA)-5 antibodies. Compared to Caucasians, East Asians have a higher risk of rapidly progressive ILD when they have anti-MDA-5 antibody and amyopathic DM with poor outcomes.[37] Anti-PL12 antibody-positive patients tend to have a higher incidence of ILD, up to 35%, and a lower incidence of myositis. These patients also tend to have esophageal involvement and PH. Patients with anti-Ro52 autoantibodies also tend to have more severe ILD and an increased risk of cancer and poor survival. Anti-Ku antibodies could be associated with CTD such as SLE, Sjogren's syndrome (SS) and systemic sclerosis (SSc), and the ILD in these patients respond poorly to steroids.

Clinical features

The clinical presentation can be very variable; common symptoms such as dry cough and shortness of breath occur in most patients with ILD. In some cases, conventional chest radiographic findings of ILD can be seen in relatively asymptomatic individuals. It is not uncommon to find patients presenting with respiratory failure or ARDS as the first presentation of the IIM-ILD. The anti-Jo-1 patients tend to have Raynaud's phenomenon, classical skin changes such as mechanic's hands (dry cracking or fissuring along the radial side of the fingers), arthritis, and ILD. The incidence of anti-Jo1 positivity ranges from 1.2 to 2.5 per million and the average age of diagnosis is 50 years. Many features of the anti-synthetase syndrome may evolve, making a clear diagnosis difficult at the outset.[36],[38] Nonlung parenchymal problems associated with myositis such as neuromuscular weakness, cardiac involvement, and aspiration pneumonia can also lead to respiratory symptoms.


Once ILD is suspected, patients need to be investigated with HRCT and PFTs as plain chest radiographs are less sensitive. The common HRCT pattern is NSIP, and less commonly OP; however, UIP or diffuse alveolar damage are more commonly seen in anti-synthetase syndrome. PFTs at baseline and annually will be able to identify early ILD and prompt the need for computed tomography imaging.

Predictors of prognosis

Older age, FVC < 60% in IIMs, CADM, and acute/subacute onset are generally considered the predictors of poor prognosis. FVC and DLCO have been shown to correlate with disease extent on HRCT (with major sensitivity for DLCO) and FVC also seems to predict the response to therapy. UIP pattern has poorer survival rates compared to other histologic patterns.

A prognosis model does not exist for this group of patients, and the ILD GAP index developed to predict mortality risks across all groups of chronic ILD is a poor prediction model for myositis-related ILD.[39] Antibody testing is useful to predict the clinical course and prognosis in inflammatory muscle disease-related ILD.[36] The presence of ILD in myositis patients carries high morbidity and mortality, and a multidisciplinary approach is essential to optimize the care of these patients.

  Sjogren's syndrome-related Interstitial Lung Disease Top

Sjogren's syndrome can occur as a primary condition (primary SS), or secondary to other autoimmune rheumatic diseases, for example, RA and systemic lupus erythematosus. Lung involvement in SS occurs in around 10%–20% of patients.[40] SS is characterized by lymphocytic infiltration of exocrine glands and can also affect the airways and lung parenchyma. There is a paucity of data on the association between autoantibody status and ILD severity, but one series of 30 patients found that anti-Ro-positive patients had a lower diffusing capacity than those who are anti-Ro negative.[4] Since SS overlaps with other autoimmune rheumatic diseases that can be associated with ILD, these conditions should also be considered and screened.

ILD types seen in SS include NSIP, UIP, OP, lymphoid interstitial pneumonia (LIP), follicular bronchiolitis, pulmonary nodular lymphoid hyperplasia, and pulmonary nodular amyloidosis. LIP is classically associated with SS and can also be a precursor to bronchus-associated lymphoid tissue lymphoma.[41] However, LIP is not the most common ILD type. NSIP and OP are the most common.[42] SS can also cause airway disease, affecting the exocrine glands in the tracheobronchial tree, leading to desiccation of the mucus and impaired clearance.[43] This may manifest as dry cough, dyspnea, and recurrent chest infections. Treatment of SS-ILD depends on the type, severity, and likelihood of progression. Some patients require glucocorticoid therapy, with or without glucocorticoid-sparing drugs such as azathioprine or mycophenolate. Other therapies often used include antifibrotics, for example, nintedanib,[44] inhaled steroids, and bronchodilators.

  Systemic Sclerosis Lung Disease Top

SSc is an autoimmune disease characterized by endothelial dysfunction, resulting in small-vessel vasculopathy, immune dysregulation, fibroblast dysfunction, and subsequent fibrosis. SSc is associated with increased mortality, primarily due to pulmonary complications; ILD accounts for 17% of deaths and pulmonary arterial hypertension (PAH) for 15% of deaths.[45],[46] In recent studies, respiratory failure due to ILD was reported to account for 43% of deaths.[47]

SSc may be diffuse or limited based on the extent of skin disease, and pulmonary involvement can occur in both subsets. It can affect all aspects of the respiratory tract, including the parenchyma, vasculature and musculature. Among all rheumatic diseases, ILD is most common in SSc, occurring in 50% or more patients. The most frequent pattern is NSIP, followed by UIP and other patterns.[48]

Patients with ILD may present with subacute dyspnea and cough. ILD tends to develop early and it occurs more frequently in the diffuse subset with anti-topoisomerase I antibody (ATA) positivity. In some patients, it can be the first clinical symptom,[49],[50] with most presenting within the first 5 years.[49] In EUSTAR (EULAR Scleroderma Trials and Research) study, ILD was more frequent (53%) in Diffuse Cutaneous SSc than in Limited Cutaneous SSc (35%).[51] In addition, males, Afro-Caribbean descent, older patients, and early decline in FVC and DLCO are more likely to develop progressive ILD.[52],[53],[54] Other lung manifestations in SSc include recurrent aspiration of gastric contents due to esophageal dysmotility, drug-induced pneumonitis, heart failure, respiratory muscle weakness, and an increased risk of lung cancer, especially in those with ILD.


Current concepts state that impaired repair of lung epithelial injury is an important driving process, with an aberrant expansion of mesenchymal cells and increased differentiation of resident fibroblasts to myofibroblasts.[55],[56] Transforming growth factor-β is also thought to play a central role in the development and progression of fibrosis in SSc-ILD[45],[55] as well as platelet-derived growth factor.[56],[57] Furthermore, patients with SSc-ILD can have increased levels of interleukin (IL)-8, IL-6, tumor necrosis factor-α, and macrophage inflammatory protein-1α.[58],[59],[60] A greater understanding of the underlying mechanisms may enable the identification of biomarkers that could be used to screen at-risk patients and facilitate the development of targeted and personalized therapy.

Early screening of Interstitial Lung Disease

There is a need for early systematic screening to identify ILD, which might improve outcomes. All patients should be screened with baseline PFTs, as well as echocardiography and HRCT. Baseline abnormal tests can increase the risk of progression and also be an indication for aggressive treatment. Nailfold videocapillaroscopy, lung ultrasound, and positron-emission tomography scan[61] have been suggested to be integrated with other approaches in the screening and identification of high-risk patients for ILD. Despite intense efforts and research, validated biomarkers that can serve as surrogate outcome measures in SSc are still lacking.

Clinical course and predictors of progression

Although highly variable, there are several consistent patterns for the clinical course of SSc-ILD. The progression is best predicted by the low baseline FVC or Goh criteria on HRCT,[47],[62],[63] and in a more recent study, an extensive disease was associated with a threefold increase in deterioration or death.[64] Although there are no validated predicted scores, biomarkers, or measures of disease progression, some risk factors have been reported. In some studies, African-American ethnicity, cardiac involvement, abnormal nailfold capillaroscopy, ATA positivity, and smoking have been reported.[52],[53] Serum KL-6 and surfactant protein D were found to be inversely correlated with DLCO and faster decline in FVC.[65],[66] A decline in FVC from baseline of >10% or diffusing capacity for carbon monoxide of >15% and radiographic progression within the first 2 years would indicate disease progression.


In a recent meta-analysis, the overall standardized mortality rate for SSc-ILD[50] was threefold, and the 5-year and 10-year survival of SSc patients from diagnosis were reported to be 74.9% and 62.5%, respectively. The mortality risk among SSc patients with ILD was 2.89 times compared to those without. Despite the established relationship between SSc-associated ILD and morbidity and mortality, there is still no consensus on screening for ILD, nor on monitoring for disease progression.

General Approach to screening and monitoring lung involvement in rheumatic diseases

[Table 2][67],[68],[69],[70],[71] shows when and how to screen and monitor patients with rheumatic disease-associated lung involvement. A thorough history and physical examination are mandatory given the impact of ILD on prognosis. There is no clear consensus on when and how to screen and monitor them because of the considerable heterogeneities in onset, severity, and prognosis. Noninvasive PFTs are often recommended at diagnosis, although many physicians perform chest HRCT, usually upon new onset or worsening of respiratory symptoms. Monitoring is done using PFTs, with or without chest radiography, at a frequency depending on the severity and progression rate of lung diseases. An annual follow-up would be sufficient for asymptomatic mild cases, while more frequent follow-up is required for rapidly progressive cases. In cases of PAH, since symptoms are nonspecific and physical examination/imaging studies are not helpful, early detection is often difficult. PAH should be screened using echocardiography, PFTs, and NT-proBNP in particular situations in even asymptomatic cases of SSc and SSc spectrum disorders.
Table 2: Investigations for screening and at follow-up for specific rheumatic conditions

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Treatment strategies

In patients with RA-ILD, the goals should be remission of articular disease and to halt the progression of ILD, but in practice, this decision is often difficult. As with any rare disease, there is a paucity of well-designed RCTs to guide optimal therapy. The difficulty is treatment options for RA-ILD are complicated by the implication of almost all drugs used for RA in ILD. Second, immunosuppressive drugs employed in CTD or antifibrotic drugs are not effective for arthritis, and histopathologic subtypes make it difficult to speculate therapies. The current treatment is based on retrospective studies and case series, which generally includes corticosteroids, azathioprine, mycophenolate mofetil, rituximab and cyclophosphamide. There is increasing interest in abatacept in RA-ILD and few studies have shown improvement or stabilization of RA-ILD.[72],[73] The INBUILD trial recently assessed the efficacy and safety of nintedanib in patients with RA-ILD.[74] Other adjunctive management should include physiotherapy, psychological support, smoking cessation, and supplemental oxygen. Patients should be routinely advised on vaccinations for influenza and pneumococcal pneumonia. Comorbidities such as PH, emphysema, gastro-esophageal reflux, and sleep apnea should also be treated. Suitable patients with progressive disease should be considered for a lung transplant and studies have evaluated posttransplant outcomes in RA-ILD patients.[75]

Standard therapy for AAV is considered a possible treatment also in patients with ILD and includes mainly systemic glucocorticoids, cyclophosphamide, rituximab, mycophenolate mofetil, methotrexate, and azathioprine. Many medications have been efficacious for the treatment of IIM-associated ILD, including calcineurin inhibitors, mycophenolate, azathioprine, cyclophosphamide, and rituximab. Cyclophosphamide is widely used in patients with significant ILD as the induction therapy and MMF for maintenance therapy seems to be the most widely used combination.

Treatment of SSc-ILD is determined by disease extent, severity, and likelihood of progression. EULAR and EUSTAR recommend cyclophosphamide and hematopoietic stem cell transplant in selected patients.[76] In the recent SENSCIS trial, patients treated with nintedanib had a lower rate of annual FVC decline.[77] Scleroderma Lung Studies advocate MMF as the first-line drug and cyclophosphamide or rituximab as the second-line drug.[78]

  Conclusion Top

We suggest a systematic approach to screening and monitoring through risk factors, serology, and emerging biomarker data that may help identify those patients with known rheumatic disease who are at the highest risk for the development of lung complications. Although ILD is a well-established complication of rheumatic disease, with a substantial impact on prognosis, several aspects including screening, monitoring, and appropriate management are still not studied adequately. The development and validation of a clinically predictive measure of disease progression would therefore be of great benefit. Researchers in this field are advancing our understanding of ILD, but many knowledge gaps remain. Finally, the collaboration between respiratory physicians and rheumatologists may seem logical for further well-designed studies on this topic, and a multidisciplinary approach involving radiologists, pathologists, pulmonologists, and rheumatologist is vital to improve outcomes in these patients.

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Conflicts of interest

There are no conflicts of interest.

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