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

Ju Hyun Oh; Jae Ha Lee; Sung Jun Chung; Young Seok Lee; Tae-Hyeong Kim; Tae-Jung Kim; Joo Hun Park

doi:10.4046/trd.2024.0148

Tuberc Respir Dis > Volume 88(2); 2025 > Article

Oh, Lee, Chung, Lee, Kim, Kim, Park, and on behalf of Korean Interstitial Lung Diseases Study Group: Korean Guidelines for Diagnosis and Management of Interstitial Lung Diseases: Connective Tissue Disease Associated Interstitial Lung Disease

Review

Interstitial Lung Disease

Tuberculosis and Respiratory Diseases 2025;88(2):247-263.

Published online: January 10, 2025

DOI: https://doi.org/10.4046/trd.2024.0148

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

Ju Hyun Oh, M.D.^1,^*

, Jae Ha Lee, M.D.², Sung Jun Chung, M.D.³, Young Seok Lee, M.D.⁴, Tae-Hyeong Kim, M.D.⁵, Tae-Jung Kim, M.D.⁶, Joo Hun Park, M.D.⁷

;on behalf of Korean Interstitial Lung Diseases Study Group

¹Department of Pulmonary and Critical Care Medicine, Inje University Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea

²Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea

³Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea

⁴Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea

⁵Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea

⁶Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

⁷Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Republic of Korea

Address for correspondence Joo Hun Park, M.D. Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, 164 World cup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea Phone 82-31-219-5116 Fax 82-31-219-5124 E-mail jhpamc@naver.com

^* Current affiliation: Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Republic of Korea

Received October 1, 2024 Revised December 5, 2024 Accepted January 6, 2025

It is identical to the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/).

Abstract

Connective tissue disease (CTD), comprising a range of autoimmune disorders, is often accompanied by lung involvement, which can lead to life-threatening complications. The primary types of CTDs that manifest as interstitial lung disease (ILD) include rheumatoid arthritis, systemic sclerosis, Sjögren’s syndrome, mixed CTD, idiopathic inflammatory myopathies, and systemic lupus erythematosus. CTD-ILD presents a significant challenge in clinical diagnosis and management due to its heterogeneous nature and variable prognosis. Early diagnosis through clinical, serological, and radiographic assessments is crucial for distinguishing CTD-ILD from idiopathic forms and for implementing appropriate therapeutic strategies. Hence, we have reviewed the multiple clinical manifestations and diagnostic approaches for each type of CTD-ILD, acknowledging the diversity and complexity of the disease. The importance of a multidisciplinary approach in optimizing the management of CTD-ILD is emphasized by recent therapeutic advancements, which include immunosuppressive agents, antifibrotic therapies, and newer biological agents targeting specific pathways involved in the pathogenesis. Therapeutic strategies should be customized according to the type of CTD, the extent of lung involvement, and the presence of extrapulmonary manifestations. Additionally, we aimed to provide clinical guidance, including therapeutic recommendations, for the effective management of CTD-ILD, based on patient, intervention, comparison, outcome (PICO) analysis.

Keywords: Connective Tissue Disease; Interstitial Lung Disease; Antifibrotic Therapy

Introduction

Connective tissue disease (CTD) encompasses a group of disorders characterized by circulating autoantibodies that can induce extensive organ damage in lung tissue. This damage frequently precipitates interstitial lung disease (ILD), which arises from immune-mediated lung inflammation and fibrosis [1,2]. A critical step in diagnosing ILD involves identifying underlying causes such as CTD. CTD-ILD is confirmed when ILD occurs in a CTD patient or when CTD is diagnosed in an ILD patient. Given that ILD may manifest initially as a symptom of CTD or be detected later, a comprehensive evaluation of clinical symptoms, autoantibody tests, and chest imaging is essential, even in ILD patients without a prior CTD diagnosis [2]. Patients exhibiting suggestive symptoms without a confirmed diagnosis of CTD-ILD are categorized as having interstitial pneumonia with autoimmune features (IPAF) [3].

Classification and Clinical Characteristics of Individual CTD-ILD

The incidence and clinical features of CTD-ILD differ depending on the specific type of CTD involved. The main forms of CTD that lead to ILD include rheumatoid arthritis (RA), systemic sclerosis (SSc), Sjögren’s syndrome, mixed connective tissue disease (MCTD), idiopathic inflammatory myopathies (IIM), and systemic lupus erythematosus (SLE) [2,4]. Recently, IPAF has been recognized as another contributing condition [3]. The diagnostic criteria for each type of CTD are summarized in Table 1 [5-10].

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.

Diagnosis of CTD-ILD

1. Assessment of CTD

1) Patients diagnosed with CTD

For patients diagnosed with CTD according to established criteria, the concurrent diagnosis of CTD-ILD can be established based on the identification of ILD. However, it is imperative to rule out other potential causes of ILD, such as those induced by medications or infections related to CTD treatment [31,51].

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].

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].

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].

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].

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.

Treatment of CTD-ILD

CTD is characterized by systemic inflammation due to circulating autoantibodies, potentially leading to multi-organ damage [53]. ILD presence in CTD is linked with poorer prognosis and elevated mortality rates [53]. However, current guidelines do not yet provide a standardized treatment protocol for CTD-ILD [61].

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].

2) Antifibrotic treatment

Antifibrotic agents, proven to mitigate FVC decline in IPF, remain underutilized in CTD-ILD. Recent investigations have explored the efficacy of antifibrotics in CTD-ILD patients experiencing disease progression despite treatment with corticosteroids and immunosuppressants [62-65]. Pirfenidone, the inaugural antifibrotic agent studied, demonstrated no significant effect on reducing FVC decline in patients with DM or SSc-ILD [84,85]. However, ongoing studies are currently evaluating the effects of pirfenidone on lung function and mortality in patients with RA-ILD, as well as its combined use with MMF in improving lung function in SSc-ILD. Nintedanib, another antifibrotic substance, has shown efficacy in CTD-ILD. In the INBUILD trial, encompassing 24.7% CTD-ILD participants, a significant reduction in annual FVC decline was observed [62]. According to the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) study, while nintedanib did not impact extrapulmonary manifestations, it reduced the annual FVC decline by roughly 44% in SSc-ILD [63].

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.

Acute Exacerbation of CTD-ILD

Acute exacerbation of CTD-ILD, characterized by widespread alveolar changes and a significant worsening of dyspnea, adopts the definition applicable to IPF, as shown in Table 5 [118,119]. The treatment of acute exacerbation in CTD-ILD relies on retrospective studies, which provide low-level evidence due to the absence of randomized controlled trials. Empirical treatment with corticosteroids, akin to that for IPF, is commonly attempted, despite the lack of specific guidelines regarding type, dose, and duration. For RA-ILD, CYC or rituximab may be considered, or a combination of immunosuppressants might be necessary, depending on the underlying CTD. Nonetheless, the impact of these treatments on prognosis remains uncertain and warrants further investigation [120,121]. For SSc-ILD, MMF is considered an option despite limited supporting evidence. Broad-spectrum antibiotics are often essential due to concurrent infections, thus making the judicious selection of antibiotics critical [119]. Mechanical ventilation or high-flow oxygen therapy might be necessary, with careful considerations to prevent ventilator-associated pneumonia and to facilitate timely intubation when required [122]. In cases unresponsive to treatment, lung transplantation should be considered, taking into account the patient’s age, overall health, and potential post-transplant prognosis.

The prognosis for acute exacerbation of CTD-ILD is notably poor, with in-hospital mortality rates ranging from 50% to 100% and exceeding 90% in patients requiring mechanical ventilation [123]. Following the onset of an acute exacerbation in CTD-ILD, respiratory symptoms intensify, quality of life declines, and long-term mortality escalates. Risk factors associated with a poor prognosis include rapidly progressing fibrosis, impaired baseline lung function, requirement for pre-hospital oxygen therapy, and extensive disease evident on chest computed tomography [57,123,124]. While the UIP pattern is recognized as a risk factor for exacerbation, its precise impact on prognosis remains undefined [125]. The gender-age-physiology model is also utilized to predict long-term outcomes [126].

Notes

Authors’ Contributions

Conceptualization: all authors. Formal analysis: all authors. Data curation: all authors. Writing - original draft preparation: all authors. Writing - review and editing: all authors. Approval of final manuscript: all authors.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Funding

No funding to declare.

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.

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.

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).

Table 1.

Diagnostic criteria of connective tissue disease

Disease	Diagnostic criteria
Rheumatoid arthritis [5]	At least one joint with clinically evident synovitis not explained by another disease. A total score of ≥6 is required, based on the following four components: (1) Joint involvement: scored 0-5 based on the number of affected joints; (2) serology: scored 0-3 based on RF and ACPA levels; (3) acute-phase reactants: scored 0-1 based on CRP and ESR abnormalities; (4) Duration of symptoms: scored 1 if symptoms persist for ≥6 weeks.
Systemic sclerosis [6]	A classification total score of ≥9 is based on the following components: (1) skin thickening of the fingers: scored 2-9 based on location and severity; (2) finger tip lesions: scored 2-3 for ulcers or pitting scars; (3) telangiectasia: scored 2 for presence; (4) abnormal nailfold capillaries: scored 2 based on capillaroscopy findings; (5) lung involvement: scored 2 for pulmonary hypertension or interstitial lung disease; (6) Raynaud’s phenomenon: scored 3 for presence; (7) SSc-specific autoantibodies: scored 3 for anti-centromere, anti-Scl-70, or anti-RNA polymerase III.
Sjögren’s syndrome [7]	A classification total score of ≥4 is based on the following components: (1) labial salivary gland biopsy: scored 3 for a lymphocytic focus score of ≥1 focus/4 mm²; (2) anti-SSA/Ro antibodies: scored 3 if positive; (3) ocular staining score: scored 1 if ≥5 (van Bijsterveld) or ≥4 (OSS); (4) Schirmer’s test: scored 1 if ≤5 mm/5 min; (5) unstimulated salivary flow rate: scored 1 if ≤0.1 mL/min.
MCTD [8]	Alarcón-Segovia criteria for MCTD: patients must meet the following criteria: (1) high titers of anti-U1 RNP antibodiesdetected in immunological testing (required); (2) of the following clinical manifestations, at least three are required: Raynaud’s phenomenon, Swollen hands, synovitis, myositis, and acrosclerosis with or without proximal systemic sclerosis.
IIM [9]	Probability-based scoring system: a total score ≥55% implies probable IIM, while ≥90% indicates definite IIM. The classification is based on the following components: (1) muscle weakness: scored based on proximal, distal, or neck flexor weakness; (2) skin involvement: scored for heliotrope rash or Gottron’s papules; (3) muscle enzymes: scored for elevated CK, LDH, or aldolase; (4) myositis-specific antibodies: scored for anti-Jo-1 or other specific autoantibodies; (5) muscle biopsy: scored for lymphocytic infiltrates or perifascicular atrophy; (6) EMG findings: scored for myopathic abnormalities.
SLE [10]	Positive ANA (≥1:80) serves as an entry criterion. A total score of ≥10 is essential for classification, based on the following components: (1) clinical domains: constitutional: fever (2 points), hematologic: cytopenias or hemolytic anemia (3-4 points), neuropsychiatric: headache, psychosis, or neuropathy (3-5 points), mucocutaneous: acute lupus rash, alopecia, or ulcers (2-6 points), serosal: pleuritis or pericarditis (5 points), musculoskeletal: arthritis (6 points), renal: proteinuria or glomerulonephritis (4-10 points); (2) immunological domains: anti-dsDNA, anti-Smith antibodies (6 points), complement levels (4 points).

RF: rheumatoid factor; ACPA: anti-citrullinated protein antibodies; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; SSc: systemic sclerosis; OSS: ocular staining score system; MCTD: mixed connective tissue disease; RNP: ribonucleoprotein; IIM: idiopathic inflammatory myopathy; CK: creatine kinase; LDH: lactate dehydrogenase; EMG: electromyography; SLE: systemic lupus erythematosus; ANA: antinuclear antibody; dsDNA: double-stranded deoxyribonucleic acid.

Table 2.

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

Organ	Manifestations to assess
Peripheral circulation	Raynaud’s phenomenon
Skin	Sclerodactyly, digital ulcerations or scars, telangiectasia, Gottron’s sign, heliotrope rash around the eyes, heliotrope rash on the neck, upper chest, and shoulders, photosensitivity, mechanic’s hands
Joint	Joint pain, joint swelling, morning stiffness (over 60 minutes)
Muscle	Muscle aches, muscle weakness
Mouth and eyes	Dry mouth, dry eyes (sicca syndrome)

Table 3.

Types and significance of autoantibodies in CTD-ILD

Test	Interpretation
ANA, anti-CCP, rheumatoid factor (RF)	Essential for suspected ILD
ENA antibodies (anti-Scl70, SSA/Ro, SSB/La, RNP, Sm autoantibodies), and myositis antibodies (anti-Jo1, PL-7, and PL-12)	Recommended for selective implementation
ANA	Nonspecific; high titers increase the likelihood of CTD
RF	Often elevated in RA but nonspecific in other CTDs
Anti-topoisomerase I antibodies (Scl-70)	Specific for SSc; associated with poor prognosis and a higher risk of ILD
Anti-centromere antibodies (ACA)	Associated with limited cutaneous SSc; absence increases the risk of SSc-associated ILD
RNP (serum autoantibodies to small nuclear ribonucleoproteins)	Associated with MCTD
Anti-Jo-1	Specific to myositis
Associated with various types of myositis
Antisynthetase antibodies	PL-7, PL-12, EJ, OJ; all associated with ILD
MDA-5	Associated with erosive Gottron's papules and severe ILD
PM-Scl	Observed in overlap syndromes, particularly with scleroderma and myositis
Ro-52	Associated with severe ILD
CPK, aldolase	Muscle enzymes; elevated levels indicate myositis but may be normal in clinically amyopathic dermatomyositis
Anti-SSA/Ro, anti-SSB/La	Associated with Sjögren’s syndrome
Anti-CCP	Highly specific for RA
ANCA	Rarely observed in pure ILD, although possible
Anti-dsDNA, anti-Sm	Highly specific for SLE

CTD: connective tissue disease; ILD: interstitial lung disease; ANA: antinuclear antibody; CCP: cyclic citrullinated peptide; ENA: extractable nuclear antigen; Scl: scleroderma; RNP: ribonucleoprotein; PL-7: threonyl-tRNA synthetase; PL-12: alanyl-tRNA synthetase; RF: rheumatoid factor; RA: rheumatoid arthritis; SSc: systemic sclerosis; MCTD: mixed connective tissue disease; EJ: glycyl-tRNA synthetase; OJ: components of multienzyme synthetase complex; MDA-5: melanoma differentiation-associated protein 5; PM: polymyositis; CPK: creatine phosphokinase; ANCA: anti-neutrophil cytoplasmic antibody; dsDNA: double-stranded deoxyribonucleic acid; SLE: systemic lupus erythematosus.

Table 4.

Immunosuppressants and biologic agents used in CTD-ILD

Drug types	Mechanism of action	Key studies	Administration and dosage	Precautions
Azathioprine (AZA)	Purine analogue, inhibits purine synthesis and DNA replication in lymphocytes	(1) SSc-ILD (FAST trial, RCT) [71], (n=45) IV CYC+steroid, followed by AZA vs. placebo. Trend towards improved FVC	(1) AZA 2.5 mg/kg/day	Bone marrow suppression, nausea, LFT abnormalities
Azathioprine (AZA)			(1) AZA 2.5 mg/kg/day	Monitoring: CBC weekly for the first 4 weeks, then every 3 months; LFTs, U&Es
Cyclophosphamide (CYC)	Alkylating agent, exerts multiple effects on T-cells	(1) SSc-ILD (FAST trial, RCT) [71], (n=45) IV CYC+steroid, followed by AZA vs. placebo. Trend towards improved FVC	(1) IV CYC 600 mg/m²+oral prednisolone 20 mg (alternate days)	Bone marrow suppression, increased risk of infection and malignancy, and hematuria
		(2) SSc-ILD (SLS-I) [72], (n=158) oral CYC vs. placebo. Improvement in FVC, dyspnea, and QoL	(2) Oral CYC 2 mg/kg/day	Monitoring: CBC, U&Es, urinalysis every 2-4 weeks
		(3) SSc-ILD (SLS-II, RCT) [67], (n=126) oral CYC vs. oral MMF. Both improved lung function, but MMF was better tolerated and exhibited less toxicity.	(3) Oral CYC 2 mg/kg/day	Monitoring: CBC, U&Es, urinalysis every 2-4 weeks
Mycophenolate mofetil (MMF)	Reduces T-cell and B-cell proliferation	(1) SSc-ILD (SLS-II, RCT) [67], (n=126) oral CYC vs. oral MMF. Both improved lung function, MMF was better tolerated with less toxicity.	(1) MMF 1,500 mg bid	Constipation, nausea, vomiting, headache, diarrhea, stomach upset, insomnia, CMV disease, UTI, leukopenia
Mycophenolate mofetil (MMF)	Reduces T-cell and B-cell proliferation	(2) CTD-ILD (retrospective) [66], (n=125) stable or improved pulmonary function	(2) MMF 3,000 mg/day (65% patients)	Monitoring: CBC weekly for the first 4 weeks, then bimonthly for 2 months, and monthly thereafter for a year
Tacrolimus cyclosporine	Calcineurin inhibitor	(1) IIM-ILD (retrospective) [73], (n=13) showed improvement in myositis, FVC, and DLco	(1) Tacrolimus 0.075 mg/kg bid	Abdominal pain, agitation, chills, confusion, seizures, diarrhea, dizziness, and more
Tacrolimus cyclosporine	Calcineurin inhibitor	(2) Antisynthetase syndrome-ILD (retrospective) [16], (n=17) notable improvement in FVC and DLco	(2) Cyclosporin 3 mg/kg/day	Monitoring: U&E, LFTs, glucose
Rituximab (RTX)	Anti-CD20 B-cell depleting monoclonal antibody	(1) CTD-ILD (retrospective) [74], (n=33) approximately 85% of patients responded	(1) RTX 1,000 mg on day 0 and day 14	Abdominal pain, back, tarry stools, bloating or swelling of the face, arms, hands, lower legs, or feet, blurred vision, body aches, etc.
		(2) SSc-ILD (open label) [70], (n=51) RTX vs. conventional treatment (MMF, AZA, or MTX), demonstrated stable FVC and a lower proportion with FVC decline >10%	(2) RTX 375 mg/m² weekly for 1 month, then every 6 months
		(3) Diffuse cutaneous SSc (RCT) [75], (n=16) RTX vs. placebo showed a trend toward improved FVC and HRCT extent	(3) RTX 1,000 mg on day 0 and day 14, followed by 1,000 mg at 6 months
Tocilizumab (TCZ)	Anti-IL-6 receptor monoclonal antibody	(1) In the diffuse SSc (RCT) [76], (n=87) TCZ vs. placebo, reduced incidence of FVC decline	(1) TCZ 162 mg SC weekly	Infusion-related reactions, hypersensitivity reactions, GI perforation, hepatotoxicity, alterations in platelets, lipids, liver enzymes, HBV reactivation, and secondary infections
		(2) In the SSc-ILD (RCT) [69], (n=136) TCZ vs. placebo, preserved FVC	(2) TCZ 162 mg SC weekly
		(3) In the SSc-ILD (RCT) [68], (n=210) TCZ vs. placebo, preserved FVC	(3) TCZ 162 mg SC weekly
Abatacept (ABA)	CTLA-4-Ig fusion protein	(1) RA-ILD [77], (n=44) associated with either stability or improvement in RA-ILD (88.6%)	(1) ABA 125 mg administered SC weekly	Headaches, upper respiratory tract infections, nasopharyngitis, nausea
Abatacept (ABA)	CTLA-4-Ig fusion protein	(2) RA-ILD (open label) [78], (n=263) exhibiting stable or improved FVC and DLco	(2) ABA 125 mg administered SC weekly or 10 mg/kg IV monthly

CTD: connective tissue disease; ILD: interstitial lung disease; SSc: systemic sclerosis; FAST: The Fibrosing Alveolitis in Scleroderma Trial; RCT: randomized controlled trial; IV: intravenous; FVC: forced vital capacity; LFT: liver function test; CBC: complete blood cell count; U&E: urea and electrolytes; SLS: scleroderma lung studies; QoL: quality of life; CMV: cytomegalovirus; UTI: urinary tract infection; IIM: idiopathic inflammatory myopathy; DLco: diffusing capacity of the lung for carbon monoxide; HRCT: high-resolution computed tomography; IL-6: interleukin-6; SC: subcutaneous; GI: gastrointestinal; HBV: hepatitis B virus; CTLA-4: cytotoxic T lymphocyte-associated antigen-4; Ig: immunoglobulin; RA: rheumatoid arthritis.

Table 5.

Definition of acute exacerbation in CTD-ILD

Criterion	Description
Target patients	Patients diagnosed with, or suspected of having, CTD-ILD
Symptoms	Acute worsening or new onset of dyspnea within 1 month
Radiological findings	New bilateral ground-glass opacities (±consolidation) on CT, alongside pre-existing ILD lesions
Aggravating factors	Infection, gastroesophageal reflux disease, micro-aspiration, surgery, bronchoscopy, or fine dust exposure
Exclusion criteria	Heart failure and fluid overload subsequent to the administration of rheumatoid medications

CTD: connective tissue disease; ILD: interstitial lung disease; CT: computed tomography

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Ju Hyun Oh
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Joo Hun Park
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