Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD) Treatment & Management

Updated: Aug 06, 2020
  • Author: Aniruddh Kapoor, MBBS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
  • Print

Approach Considerations

In patients with suspected connective tissue disease (CTD)-associated interstitial lung disease (ILD) (CTD-ILD), referral to a center with expertise in management of CTD-ILD is recommended. A multidisciplinary approach to help guide management includes collaboration with pulmonologists, rheumatologists, radiologists, and pathologists. Furthermore, referral to centers with expertise in pulmonary hypertension on lung transplantation may be required, depending on the individual clinical context.

The treatment of CTD-ILD requires immunosuppression with either steroid or steroid-sparing agents.

Lung transplantation may be an option for those with end-stage lung disease.

Issues to consider

Patients with CTD-ILD often present with poor quality of life; however, therapy is also associated with severe adverse effects. Thus, treatment is generally initiated when symptoms become clinically significant or progressive. The mainstay of therapy requires immunosuppression either through steroids or steroid-sparing agents.

Prolonged treatment with corticosteroids leads to a large number of comorbidities such as diabetes mellitus, hypertension, osteoporosis, and psychiatric disease. Therefore, all efforts should be made to decrease the steroid burden as soon as possible.

However, immunosuppressive agents are not without risk either. For example, cyclophosphamide, a cytotoxic immunosuppressant has been shown to cause hemorrhagic cystitis and is even associated with malignancy. Because the CTD-ILDs are a heterogeneous population, the addition of steroid-sparing medications should be considered, depending on the CTD being treated. Lastly, if a patient shows a progressive deterioration in lung function or shows no slowing in this decline, discontinuation of the immunosuppressive medications should be considered.

Most patients are treated in an outpatient setting. Chest radiography, the 6-minute walk test, arterial blood gas determinations (ie, arterial oxygen tension [PaO2]), and pulmonary function tests (PFTs)—especially forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO)—are monitored after therapy is started. Subspecialty consultations including pulmonologists and rheumatologist should be considered early in the management of these diseases. Transfer to a higher level of care is indicated if the diagnosis is in doubt or if treatment is ineffective.

Educate patients about the natural history, progression, and treatment of the disease. Before any immunosuppressive medication is started, the potential adverse effects, the duration of therapy, and the chances of success should be discussed with the patient.


Medical Care

As mentioned previously, immunosuppression is the cornerstone of the medical management of connective tissue disease (CTD)-associated interstitial lung disease (ILD) (CTD-ILD). These drugs include corticosteroids and corticosteroid-sparing medications, such as azathioprine, cyclosporine, cyclophosphamide, and methotrexate.


Glucocorticoids have often been tried as first-line therapy for a variety of CTD-ILDs, although the optimal dose or duration of prednisone is unknown. In systemic sclerosis (SSc), glucocorticoids have been tried as monotherapy and in combination with other immunosuppression. These combinations appear to show improvement in both pulmonary and nonpulmonary complications of SSc.

Corticosteroid-sparing agents

Cyclophosphamide,mycophenolate mofetil

Cyclophosphamide, an alkylating agent, can be used with or without steroids in the treatment of SSc. A scleroderma lung study that compared oral cyclophosphamide and placebo showed 1 year of cyclophosphamide was associated with a significant but modest improvement in dyspnea and lung function. [81] Common adverse effects of cyclophosphamide therapy in the study included hematuria, leukopenia, neutropenia, anemia, and pneumonia. In addition, a small prospective, multicenter, randomized control trial conducted in patients with granulomatosis with polyangiitis showed intravenous pulse cyclophosphamide may be not only as effective as oral cyclophosphamide but also may avoid some of the systemic toxicity. [82]

In an attempt to reduce the toxicity associated with cyclophosphamide, the Scleroderma II Trial compared it with mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase. [83] Mycophenolate mofetil exerts a cytostatic effect on B and T cell lymphocytes. In this trial, no significant difference was noted in forced vital capacity (FVC), the primary outcome. However, the investigators noted that although both study drugs showed an improvement in FVC (2.88% in the cyclophosphamide group and 2.19% in the mycophenolate mofetil group), those who received mycophenolate appeared have better drug tolerance as evidenced by a 43.8% withdrawal in the cyclophosphamide group and a 28.9% withdrawal in the mycophenolate group. [83] Nonetheless, mycophenolate mofetil is associated with several adverse effects, such as diarrhea (most common), bone marrow suppression, and progressive multifocal leukoencephalopathy.

Tacrolimus, sirolimus

Tacrolimus and sirolimus are calcineurin inhibitors, drugs that inhibit the action of calcineurin and thus impair T cell lymphocytes by impairing the transcription of cytokines such as interleukin 2. These agents have been used in the maintenance of immunosuppression for several years. More recently, multiple retrospective studies have evaluated their use in either steroid-resistant ILD associated with the inflammatory myopathies or as adjunctive immunosuppression with steroids in these conditions. [43] Calcineurin inhibitors are associated with several adverse effects, including nephrotoxicity, hypertension, neurotoxicity including posterior reversible encephalopathy syndrome, increased risk for infections, and malignancy.


Azathioprine, a generally well-tolerated immunosuppressant, exerts its effect by halting DNA replication by incorporating itself into DNA metabolism. Azathioprine has been extensively used to maintain remission in antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis. In fact, in this cohort, azathioprine is considered first line after induction therapy with cyclophosphamide. [84, 85] Although data are limited, retrospective studies seem to suggest azathioprine is associated with the stabilization of pulmonary function in patients with CTD-ILD. [43]


Rituximab, a monoclonal antibody that targets the CD20 antigen, is used in the treatment of several autoimmune diseases. In ANCA vasculitis, a French prospective, randomized, controlled study that compared rituximab to the first-line therapy (azathioprine) found rituximab was superior to azathioprine in maintaining remission. [86] Another prospective, randomized, controlled trial showed rituximab to be as effective as cyclophosphamide in the induction of remission in ANCA vasculitis. [87] In fact, in the cohort of patients with relapsing disease, rituximab may be more effective than cyclophosphamide. Similarly, rituximab may be an option in refractory CTD-ILD. An ongoing study comparing cyclophosphamide and rituximab for the treatment of CTD-ILD is expected to be completed in 2021. [88]

Other medications have been tried in the treatment of RA-related ILD, including methotrexate, [89] leflunomide, and biologic inhibitors (eg, tumor necrosis factor–α [TNF-α] inhibitors). Hagiwara et al described a case in which an acute exacerbation of preexisting ILD occurred after the administration of etanercept for RA. [90]

Pirfenidone, nintedanib

Pirfenidone and nintedanib are antifibrotic drugs used in the management of idiopathic pulmonary fibrosis (IPF).

In September 2019, nintedanib received FDA approval in the treatment of ILD associated with SSc after being shown to slow the rate of decline in pulmonary function. [91, 92] Nintedanib is a tyrosine kinase inhibitor (TKI) that targets growth factors (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR] 1-3, colony-stimulating factor 1 receptor [CSFIR]) that are implicated in the pathogenesis of ILDs.

Nintedanib gained approval for chronic fibrosing ILDs with a progressive phenotype in March 2020. Unclassifiable ILDs, autoimmune ILDs, chronic hypersensitivity pneumonitis, sarcoidosis, myositis, Sjögren syndrome, coal worker pneumoconiosis, and idiopathic forms of interstitial pneumonias (eg, idiopathic nonspecific interstitial pneumonia) are among the diseases that may develop a progressive form of chronic fibrosing ILD.

Approval of nintedanib for chronic fibrosing ILDs was based on the INBUILD phase 3 clinical trial (N = 663). INBUILD was the first clinical trial of ILDs to group patients based on the clinical behavior of their disease rather than the primary clinical diagnosis. Results showed nintedanib slowed pulmonary function loss by 57% (107 mL/year) across a range of patients compared with placebo (P < 0.001). In patients with usual interstitial pneumonia (UIP)-like fibrotic pattern shown by high-resolution computed tomography (CT) scanning, nintedanib slowed the loss of pulmonary function by 61% (128.2 mL/year) compared with placebo (P < 0.001). [93]

Secondary pulmonary hypertension in patients with CVD is usually resistant to treatment and is associated with poor prognosis. Current guidelines recommend using the same classes of pulmonary hypertension drugs and treatment algorithm as in idiopathic pulmonary arterial hypertension (PAH). [94] Patients should be referred a pulmonary hypertension center.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) has emerged as a novel approach to the management of advanced SSc. [43] HSCT aims to reduce the activity of aberrant T cells and B cells through aggressive immunosuppression followed by transplantation of a renewed and more tolerant immune system. [95] Although three randomized controlled trials have shown survival benefit, improvement in FVC, skin thickening, and health quality of life, the phase 3 trial comparing cyclophosphamide and HSCT is pending.


Surgical Care

Lung transplantation is the only available treatment for refractory connective tissue disease (CTD)-associated interstitial lung disease (ILD) (CTD-ILD) related with progressive fibrosis. Despite this, many centers are reluctant to perform lung transplantations in patients with CTD because of the concern for extrapulmonary disease. However, a retrospective study from South Korea showed similar survival rates for CTD-ILD relative to idiopathic pulmonary fibrosis (IPF). [96] In patients with disease refractory to treatment or who have extensive fibrosis, it is recommended that patients are referred to a transplant center for evaluation.