Korean Guidelines for Diagnosis and Management of Interstitial Lung Diseases: Connective Tissue Disease Associated Interstitial Lung Disease

1. RA-ILD

ILD represents the most prevalent pulmonary complication associated with RA, although its prevalence varies according to the study population and diagnostic criteria [11]. In prospective studies employing high-resolution computed tomography (HRCT), the prevalence of RA-ILD is observed to range between 19% and 60% [12-14]. This variation is attributed to differences in the definitions and diagnostic criteria used in each study. In cross-sectional studies where HRCT was conducted regardless of respiratory symptoms, ILD prevalence was reported as 19%, highlighting HRCT’s enhanced sensitivity in diagnosing ILD [15].

While RA is more prevalent in women, RA-ILD is more commonly observed in men [16,17]. Age and smoking stand as primary risk factors for RA-ILD, typically presenting in RA patients during their forties and fifties [18-20]. Rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) are also strongly linked to the development of ILD [21,22]. In surgical lung biopsies, usual interstitial pneumonia (UIP) emerges as the most common finding, accounting for 24% to 79% of cases, with nonspecific interstitial pneumonia (NSIP) as the second most frequent [20].

2. SSc-ILD

Pulmonary involvement is more prevalent in SSc than in RA [11]. NSIP is the most common finding both on HRCT and histopathologically in SSc-ILD [23,24]. The predominant autoantibody associated with pulmonary involvement in SSc is anti-topoisomerase I (anti-Scl-70) antibody [25]. Patients with diffuse SSc and a positive anti-Scl-70 antibody exhibit an elevated risk for developing ILD [26,27].

3. Sjögren’s syndrome-ILD

Pulmonary involvement affects 9% to 24% of patients with Sjögren’s syndrome, whereas asymptomatic patients often exhibit abnormal findings in pulmonary function tests, bronchoalveolar lavage, or HRCT [28-31]. ILD in Sjögren’s syndrome is frequently characterized by a predominance of fibrotic NSIP and radiological findings such as ground-glass opacities (GGO) and bronchiectasis, with numerous cases demonstrating overlapping UIP and NSIP patterns on HRCT [32]. Patients exhibiting any form of lung involvement in Sjögren’s syndrome have a fourfold increase in the 10-year mortality rate compared to those without lung involvement [28].

4. MCTD-ILD

MCTD is characterized by overlapping features of SLE, SSc, and polymyositis (PM), along with the presence of anti-U1 ribonucleoproteins (RNP) antibodies [33]. Pulmonary involvement is common, with HRCT frequently revealing NSIP patterns such as the GGO pattern [34,35]. Severe lung fibrosis occurs in approximately 19% of MCTD, with anti-Ro-52 antibodies serving as a biomarker for this condition [36,37].

5. IIM-ILD

IIM encompasses PM, dermatomyositis (DM), and clinically amyopathic DM [38,39]. ILD often presents as the first manifestation of IIM, with a prevalence ranging from 20% to 78% [40-42]. IIM-ILD has several subtypes, varying from an asymptomatic condition to a rapidly progressive form [38,39]. NSIP and UIP patterns are frequent pathological findings in IIM-ILD, with anti-synthetase syndrome being a notable subtype characterized by the presence of anti-Jo-1 antibody and associated ILD [43-46].

6. SLE-ILD

Although pulmonary involvement occurs in 33% to 50% of SLE patients, the incidence of ILD is relatively low, ranging from 1% to 15% [38,47]. Prolonged illness, Raynaud’s phenomenon, and specific autoantibodies such as anti-U1 RNP are risk factors for the development of ILD in SLE [48].

7. IPAF

IPAF is diagnosed in patients exhibiting characteristics suggestive of CTD who do not fulfill the complete criteria for a CTD diagnosis [3]. A diagnosis requires the presence of at least two of the following: clinical, serological, or morphological features indicative of autoimmunity [3]. IPAF serves as a framework for identifying autoimmune-related ILD, although it is not yet acknowledged as a distinct disease entity. Determining the incidence of IPAF is challenging due to the scarcity of reliable prevalence data. Nonetheless, it is increasingly recognized among patients with idiopathic interstitial pneumonia (IIP) who demonstrate subtle autoimmune features in the absence of a definitive CTD. Following the publication of the European Respiratory Society/American Thoracic Society (ERS/ATS) IPAF research statement, retrospective studies have identified cohorts of IPAF patients [3,49,50]. Oldham et al. [49] reported that 34% of 422 patients with either IIP or UCTD met the ERS/ATS IPAF criteria. Similarly, Ahmad et al. [50] found that 7.3% of 778 patients with IIP or CTD-ILD in a European cohort were identified as having IPAF based on the ERS/ATS criteria. These findings highlight the increasing recognition of IPAF and underscore the need for further research within ILD populations.

1. Assessment of CTD

2) Patients not previously diagnosed with CTD

Occasionally, ILD may appear as the initial manifestation among the clinical features of CTD. This is particularly common in IIM, with a prevalence of about 10% to 30%, but it can also occur in RA and, less frequently, in SSc [52,53]. In patients with no significant medical history who present with acute onset of dyspnea, progressive respiratory failure and GGOs on HRCT, the diagnosis of CTD-ILD should be considered [53].

Elevated levels of muscle enzymes, such as creatinine phosphokinase and aldolase, may indicate underlying IIM. Consequently, even in cases of chronic ILD, a thorough investigation for CTD is warranted by examining clinical signs (Table 2 and Figure 1), serological markers, and radiological features indicative of CTD [54].

Table 2.

Key manifestations in interstitial lung disease patients for diagnosing underlying connective tissue disease

Fig. 1.

(A) Mechanic’s hand: cracking and fissuring along the sides of the digits and palm. (B) Gottron’s papules: red and scaly papules that erupt over the metacarpophalangeal joints. (C) Sclerodactyly: fixed fingers in a semi-flexed position with skin appearing tightened and wax-like. (D) Digital ulceration: ulceration at the tip of the finger in a patient with systemic lupus erythematosus. (E) Telangiectasias: multiple dilated small facial vessels. (F) Heliotrope rash: violaceous erythema on the upper eyelids.

2. Radiologic findings

Distinguishing between IIP and CTD-ILD based solely on radiological findings remains challenging. However, CTD-ILD frequently presents as NSIP, organizing pneumonia (OP), or, less commonly, lymphocytic interstitial pneumonia (Figure 2) [35]. Radiological patterns in CTD-ILD differ according to the specific type of CTD; while UIP prevails in 50%–60% of RA-ILD cases, NSIP is the dominant pattern in 80%–90% of SSc-ILD, even though UIP is present in 10%–20% of SSc-ILD cases [35]. In MCTD and PM/DM, NSIP is most common; however, OP, UIP, and diffuse alveolar damage may also occur [53].

Fig. 2.

(A) Radiologic pattern of nonspecific interstitial pneumonia in a patient with systemic sclerosis featuring high-resolution computed tomography (HRCT) images of bilateral basal predominant ground-glass opacity. (B) Radiologic pattern of organizing pneumonia in a patient with dermatomyositis showing HRCT images of multiple peripheral patchy consolidations. (C) The radiologic pattern of lymphocytic interstitial pneumonia in a patient with Sjögren’s syndrome is depicted in a HRCT image, which displays multifocal, variable-sized, thin-walled cystic lesions in both lungs.

3. Surgical lung biopsy

There is a controversy concerning the role of surgical lung biopsy in the diagnosis of CTD-ILD due to potential risks and complications. Pathological findings are critical in determining the therapeutic target for antifibrotics by distinguishing between ILD manifestations; however, surgical lung biopsy necessitates a thorough risk-benefit assessment[55,56]. In certain cases, bronchoalveolar lavage, which quantifies the number of inflammatory cells, can serve as an alternative to biopsy for excluding infections [53]. Given the high pathological prevalence of NSIP frequently observed in CTD-ILD, a comprehensive assessment for underlying CTD is imperative once NSIP is identified [55-57]. Pathologic features such as germinal centers, lymphoid hyperplasia, plasma cells, coupled with fewer fibroblastic foci and honeycombing, are indicative of CTD-ILD exhibiting a UIP pattern and aid in its differentiation from IIP with UIP pattern [1,58]. The presence of lymphocytic or follicular bronchiolitis also suggests CTD-ILD (Figure 3) [1,58].

Fig. 3.

Histopathology of the lung in a patient with interstitial pneumonia with autoimmune features: (A) usual interstitial pneumonia featuring lymphoid follicles (hematoxylin eosin saffron [HES], ×10); (B) follicular bronchiolitis (HES, ×100); (C) lymphoplasmacytoid cell infiltrates (HES, ×200) (courtesy of Prof. Shim HS, Yonsei University).

4. Autoantibodies

Autoantibody testing is essential for diagnosing CTD-ILD (Table 3). Although clinical findings may not fully satisfy the criteria for a specific CTD, the presence of autoantibodies necessitates ongoing monitoring and consultation with a rheumatologist, given that clinical manifestations of CTD might appear subsequently [24,59].

Table 3.

Types and significance of autoantibodies in CTD-ILD

5. Multidisciplinary discussion

A recent prospective study at a specialized ILD center compared traditional multidisciplinary discussion (MDD) with MDD that included a rheumatologist for 60 patients with newly diagnosed ILD [60]. This study revealed that involvement of a rheumatologist led to the re-diagnosis of 21% of patients originally identified with idiopathic pulmonary fibrosis (IPF) in traditional MDD as having CTD-ILD, and identified a 77% increase in the rate of IPAF diagnosis [60]. This underscores the crucial role of rheumatologists in distinguishing CTD as a significant cause of ILD [60]. Moreover, effective management of CTD-ILD necessitates a collaborative approach between pulmonologists and rheumatologists.

1. Anti-inflammatory and antifibrotic treatment for CTD-ILD

There is currently limited evidence and no established therapeutic guideline for CTD-ILD, due to a lack of randomized controlled trials. The management of CTD-ILD predominantly involves corticosteroids and immunosuppressive agents, which provide anti-inflammatory effects and address the underlying CTD [61]. Antifibrotic medications have recently been explored in several trials for their potential benefits in treating fibrotic lesions in CTD-ILD [62-65].

1) Anti-inflammatory treatment

Immunosuppressive medications and corticosteroids comprise the mainstay of anti-inflammatory therapy for CTD-ILD (Table 4) [16,66-78]. Typically, corticosteroids are initiated at high doses (0.5 to 1 mg/kg/day) for a short period, and then are adjusted to maintenance doses (10 to 20 mg) based on clinical response [79]. Given the limited evidence supporting monotherapy, azathioprine (1 to 2 mg/kg/day), which is widely recognized as safer and more effective compared to other immunosuppressive agents, is often administered alongside corticosteroids [80]. Mycophenolate mofetil (MMF; 1.0 to 1.5 g) has demonstrated improvements in forced vital capacity (FVC) in patients with SSc-ILD, IIM-ILD, and RA-ILD [66,67], but not in mild SSc-ILD [81]. Prolonged use of cyclophosphamide (CYC) (2 mg/kg/day) is generally not recommended due to substantial adverse effects, despite evidence indicating FVC improvement in patients with SSc-ILD [72]. In patients with IIM-ILD, the combination of tacrolimus (1 to 3 mg/day) and corticosteroids enhances lung function and survival, although additional prospective studies are necessary [82]. Rituximab, a monoclonal antibody targeting CD20, is under investigation for severe ILD patients unresponsive to corticosteroids and immunosuppressants (1,000 mg intravenous on day 0 and day 14). However, a phase 2 trial in the United Kingdom demonstrated no significant benefit over CYC in terms of lung function and survival [83]. In a phase 3 trial, tocilizumab (TCZ), which targets the interleukin 6 (IL-6) receptor, was demonstrated to significantly reduce the decline in FVC over 48 weeks as compared to a placebo, indicating potential benefits for patients with SSc-ILD [68].

Table 4.

Immunosuppressants and biologic agents used in CTD-ILD

2. Treatment of RA-ILD

(1-1) Patient, intervention, comparison, outcome (PICO) for the treatment of patients with RA-ILD: Can antifibrotics decelerate the progression of RA-ILD?

(1-2) Summary of recommendations for the treatment: A thorough review of the literature identified two studies evaluating the potential of antifibrotic agents, nintedanib and pirfenidone, to decelerate disease progression in RA-ILD (1 nintedanib, 1 pirfenidone) [64,65]. Our meta-analysis demonstrated a significant mean difference in FVC % predicted change (2.20; 95% confidence interval [CI], 2.01 to 2.38). Despite limited evidence and practical challenges such as insurance constraints, antifibrotic treatment should be considered in patients with RA-ILD exhibiting a UIP pattern or those experiencing progression despite conventional therapies (evidence level: low, recommendation grade: conditional).

Antifibrotic therapy for RA-ILD in cases of progressive pulmonary fibrosis (PPF) has garnered interest for its potential merits, especially significant in cases exhibiting a UIP pattern. However, the impact of antifibrotics on joint symptoms remains uncertain, thus urging additional research to assess the effectiveness of integrating antifibrotic and immunosuppressive therapies [86].

A comprehensive study on PPF from various etiologies demonstrated the therapeutic efficacy of nintedanib, with post-hoc subgroup analysis revealing significant benefits in mitigating FVC decline across all diagnostic subgroups, including CTD-ILD [62]. Moreover, pirfenidone has been shown to reduce levels of IL-6 and tumor necrosis factor (TNF)-alpha, critical cytokines in RA pathogenesis, and to inhibit the transformation of fibroblasts into myofibroblasts in lung tissue of patients with RA-ILD [87,88]. Furthermore, the phase 2 randomized controlled RELIEF trial, which included 19 CTD-ILD patients out of a total of 127 non-IPF patients refractory to conventional treatment, reported that pirfenidone reduced FVC decline and mitigated ILD progression [89]. Therefore, pirfenidone therapy should be considered for RA-ILD, particularly in a UIP pattern.

However, no established guidelines exist for managing RA-ILD. High-dose corticosteroids are commonly employed when disease-modifying anti-rheumatic drugs (DMARDs) and TNF inhibitors are ineffective in treating RA-ILD exacerbations, despite the limited evidence supporting their efficacy and safety. Although various immunosuppressants and biologic agents are under investigation for RA-ILD treatment, the absence of prospective comparative studies complicates the assessment of their effectiveness. A retrospective study in Korea revealed that among RA patients with a UIP pattern, 50% of the 84 patients treated with corticosteroids alone or in combination with immunosuppressants experienced improvement or stability, though survival rates did not improve compared to the controls [90].

Another study involving 26 CTD-ILD patients, including 11 with RA-ILD, demonstrated that high-dose corticosteroids followed by a combination therapy of corticosteroids and tacrolimus over 1 year enhanced FVC, walking distance, and patient-reported outcomes [91]. However, findings from various studies on CYC and MMF have shown inconsistent outcomes [66,92].

For example, a study on 21 progressive RA-ILD patients, including 14 exhibiting a UIP pattern, observed that pulse CYC therapy significantly prolonged the mean survival time compared with controls (72 months vs. 43 months) [92]. Although MMF has shown efficacy in treating SSc-ILD, its effectiveness in RA-ILD has not yet been evaluated in prospective studies. A retrospective study involving 125 CTD-ILD patients, including 18 with RA-ILD, demonstrated that MMF improved lung function and decreased steroid requirements in patients not exhibiting a UIP pattern [66]. Due to limited evidence and the lack of international consensus, the administration of immunosuppressants in RA-ILD should be tailored to individual cases based on expert recommendations.

Therapeutic agents for RA, such as DMARDs and biologics, can induce lung toxicity, and their effectiveness in RA-ILD remains uncertain. Consequently, leflunomide is not advised for RA-UIP [93], and methotrexate (MTX) is not recommended for high-risk groups prone to drug-induced pneumonia [94]. However, recent research indicates that MTX may pose a lower risk of pulmonary toxicity than previously believed and could potentially slow the progression of RA-ILD [95]. TNF inhibitors exhibit both profibrotic and antifibrotic properties, potentially affecting the progression or stabilization [96] of ILD. Recent studies demonstrate that biologics, such as abatacept, rituximab, and TCZ, can diminish the progression and mortality of RA-ILD [97-99]. There is no definitive consensus on the initiation of these medications; however, in severe ILD cases, the combination of corticosteroids with MMF or rituximab should be considered, based on clinical judgment and expert recommendations.

3. Treatment of SSc-ILD

(1-1) PICO for the treatment of patients with SSc-ILD: Is MMF superior to CYC as an initial treatment for SSc-ILD?

(1-2) Summary of recommendations for the treatment: A comprehensive literature review identified three studies that prospectively evaluated the efficacy of MMF versus CYC as initial treatments for SSc-ILD [67,100,101]. Our meta-analysis revealed no significant difference in their effect on FVC % predicted between MMF and CYC in both randomized (mean difference, –0.69; 95% CI, –3.00 to 1.62) and non-randomized studies (mean difference, –4.23; 95% CI, –10.00 to 1.54). Therefore, MMF and CYC exhibit comparable effects on pulmonary function in SSc-ILD patients. However, considering the adverse effects associated with CYC reported in previous studies, MMF is recommended as the initial treatment for SSc-ILD (evidence level: low; recommendation grade: conditional).

(2-1) PICO for treatment of patients with SSc-ILD: Can biologics serve as an initial treatment for patients with SSc-ILD?

(2-2) Summary of recommendations for the treatment: A comprehensive literature search yielded three studies that evaluated the efficacy of biologics, specifically TCZ, as initial treatments for SSc-ILD [69,102,103]. Including one non-randomized study and two randomized controlled trials, the meta-analysis demonstrated that TCZ significantly enhanced FVC % predicted compared to conventional therapy or placebo (mean difference, 5.6; 95% CI, 3.84 to 7.35). Thus, TCZ is recommended as a primary therapeutic option for SSc-ILD (evidence level: moderate; recommendation grade: conditional).

(3-1) PICO for treatment of patients with SSc-ILD: Can biologics be administered to refractory SSc-ILD patients?

(3-2) Summary of recommendations for the treatment: A comprehensive literature review identified six studies assessing the effectiveness of the biological agent rituximab in patients with moderate to severe SSc-ILD who were unresponsive to initial therapies [70,104-108]. These studies comprised two randomized controlled trials and four non-randomized studies. Our meta-analysis revealed a significant enhancement in FVC % predicted, with a mean difference of 3.66 (95% CI, 0.51 to 6.19). Consequently, rituximab should be considered as a therapeutic alternative for moderate to severe SSc-ILD patients unresponsive to initial therapy (evidence level: low; recommendation grade: conditional).

4. Treatment of CTD-ILD including IIM, SLE, Sjögren’s syndrome, and MCTD

Due to the absence of large-scale randomized controlled trials, standardized treatments for CTD-ILD, encompassing IIM, SLE, Sjögren’s syndrome, and MCTD, are not established. Corticosteroids remain the primary therapy for IIM-ILD, with clinical improvement noted at initial doses of 0.25 to 1 mg/kg [109]. In cases with rapid progression or to reduce reliance on corticosteroids, a combination therapy comprising immunosuppressants such as azathioprine, CYC, and MMF is advisable. Studies have demonstrated that this combination therapy enhances FVC and reduces the dosage of corticosteroids [110]. Additionally, tacrolimus used alongside corticosteroids has been shown to improve short-term survival rates compared to monotherapy with corticosteroids [111]. Other therapies such as intravenous immunoglobulin or plasmapheresis are employed in refractory cases, although further studies are required for confirmation [112,113].

Corticosteroids are typically employed as initial therapy for other CTD-ILDs such as SLE, Sjögren’s syndrome, and MCTD, with immunosuppressants introduced as necessary. Azathioprine and MMF have demonstrated efficacy in enhancing lung function and reducing the required dosage of corticosteroids [66,114]. The RECITAL study, which evaluated rituximab against CYC in severe CTD-ILD, reported that rituximab was equally effective and associated with fewer adverse events [83].

It is crucial to engage in MDD, including non-pharmacological treatments such as respiratory rehabilitation, to enhance lung function and quality of life [115]. Home oxygen therapy is essential for persistent hypoxemia or significant dyspnea [116]. Lung transplantation remains an option for progressive ILD, with outcomes for CTD-ILD comparable to those for IPF, although IIM-ILD may demonstrate lower survival rates [117].

Current research on the treatment of CTD-ILD is investigating various pharmacological options, including immunosuppressants, antifibrotic agents, and biologic therapies, as well as non-pharmacological strategies. It is pivotal to focus not only on preserving lung function but also on managing extrapulmonary symptoms and mitigating pharmaceutical side effects.