Treating Systemic Sclerosis Interstitial Lung Disease: Evidence on Best Uses of Newly Approved Drugs

Kimberly Showalter, MD, MS; Jessica K. Gordon, MD, MS


March 22, 2022

Editorial Collaboration

Medscape &

Kimberly Showalter, MD, MS

Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) as well as a leading cause of death in this population. Nintedanib (Ofev) and tocilizumab (Actemra) are both recently approved treatments for SSc-ILD; these novel therapies are the focus of this article. Nintedanib is also approved for progressive fibrosing ILD.

Jessica K. Gordon, MD, MS

Clear treatment guidelines, including when to initiate immunosuppressive therapy for SSc-ILD, have not yet been delineated. Scleroderma Lung Study (SLS)-Iestablished that cyclophosphamide is modestly superior to placebo in the treatment of SSc-ILD over 12 months. However, the benefit was not clearly durable when studied without maintenance treatment. SLS-II established that mycophenolate mofetil (MMF) has efficacy similar to cyclophosphamide but with a favorable side-effect profile. At this point, MMF is frequently considered as an initial treatment for ILD in individuals with SSc; cyclophosphamide is considered in some cases. Azathioprine is considered when these medications are contraindicated or not tolerated. Pirfenidone (Esbriet) is an antifibrotic medication that is currently under investigation in SLS-III. Emerging data have also shown a possible benefit of rituximab for SSc-ILD, including a systematic review and meta-analysis and recent randomized, controlled trial. Further data are needed to inform optimal antifibrotic and immunomodulatory strategies for patients with connective tissue disease–associated ILD.


Nintedanib is a multitargeted tyrosine kinase inhibitor that impairs the activation, proliferation, and migration of fibroblasts. Nintedanib is currently approved for idiopathic pulmonary fibrosis, chronic fibrosing ILD with progression, and SSc-ILD.

The SENSCIS trial is the largest-to-date phase 3 trial in SSc-ILD and includes 580 adults with SSc with a disease duration of less than 7 years, ILD on high-resolution CT involving at least 10% of the lungs, and on stable background medications. Compared with placebo, nintedanib was associated with slower rate of decline in forced vital capacity (FVC) (difference 41 mL/y [95% CI, 2.9-79], P = .04). The most common adverse event was diarrhea, observed in 76% of those who received nintedanib (vs 32% in placebo). Most gastrointestinal side effects were mild to moderate and occurred during the first 3 months of treatment. There was no increased risk for infection.

The INBUILD trial included a wider range of individuals with progressive fibrosing ILD (including rheumatoid arthritis [RA], SSc, mixed connective tissue disease, "other autoimmune ILDs," idiopathic nonspecific interstitial pneumonia, and others) and reported a slower rate of ILD progression among those receiving nintedanib compared with placebo (FVC decline, -80.8 mL/y vs -187.8 mL/y, P < .001). A subgroup analysis was performed for individuals with autoimmune disease–related ILD who also demonstrated lower rate of FVC decline with nintedanib compared with placebo (FVC decline, -75.9 mL/y vs -178.6 mL/y, nominal P = .012).

When prescribing nintedanib, physicians should reduce the dose in the setting of mild hepatic impairment and use caution in patients with high cardiovascular risk as well as in those with recent abdominal surgery or history of diverticulitis because of concern for possible gastrointestinal perforation. Liver function tests should be monitored, and pregnancy should be avoided during and 3 months after nintedanib use. Patients should be encouraged to stop smoking because smoking has been associated with decreased nintedanib exposure. There are notable drug interactions with CYP3A4 inhibitors (eg, ketoconazole, erythromycin), which increases nintedanib blood levels and CYP3A4 inducers (eg, St John's wort, carbamazepine), which decreases nintedanib blood levels. Caution is advised in patients taking anticoagulants because of the possible risk for bleeding. Additional prescribing information is available here.

Combination Therapy

The safety and efficacy of combination therapy with MMF and nintedanib was explored in a prespecified subanalysis from the SENSCIS trial. Nintedanib benefited those using and not using MMF, and the least FVC decline was observed among individuals on combination therapy with both MMF and nintedanib. With combination therapy, there was no increase in adverse events (including gastrointestinal symptoms). However, it is important to note that the MMF dose for participants was stable and tolerated prior to the study start date.


Tocilizumab is a biologic medication that blocks interleukin (IL)-6 receptor. In addition to its indications in the treatment of RA, giant cell arteritis, and juvenile idiopathic arthritis, tocilizumab was approved in March 2021 for slowing the rate of decline in pulmonary function in SSc-ILD and is the first and only biologic currently approved for that indication.

In the focuSSced trial, tocilizumab (162 mg/w subcutaneously) was compared with placebo in 210 patients with SSc of less than 5 years duration (including 136 individuals with SSc-ILD). Individuals in the study had signs of systemic inflammation (elevated C-reactive protein, erythrocyte sedimentation rate, and/or elevated platelets), and active SSc (disease duration ≤ 18 months, increasing modified Rodnan skin score [mRSS] in the preceding 6 months, or involvement of two new body areas; and at least one tendon friction rub). The primary study endpoint was not met (change in skin thickness measured by the mRSS). However, a difference was noted in rate of FVC decline in treatment groups compared with placebo groups (difference in least square means, 4.2; 95% CI, 2.0-6.4; nominal P = .0002).

Side effects of tocilizumab include infection (including serious infections), injection site reactions, headaches, intestinal perforation (caution if there is a history of diverticulitis), elevated blood pressure, increased cholesterol (check 4-8 weeks after treatment), neutropenia, thrombopenia, and others. Tocilizumab can be transported across the placenta during the third trimester; patients may join a registry assessing outcomes for those taking tocilizumab during pregnancy. Patients should not breastfeed while taking tocilizumab. Additional prescribing information is available here.


As treatment options for progressive connective tissue disease–associated ILD are expanding, patients will benefit from evidence-based guidelines regarding ILD treatment, including use of combination therapy. The need for guidelines has been recognized by professional groups and planning for this work is underway. Further study comparing therapies as well as further definition of patient subtypes is needed.

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