Many systemic sclerosis (SSc) patients may develop interstitial lung disease (ILD) and, despite a growing consensus that all patients with SSc should be screened with high-resolution chest computed tomography (CT), screening varies among rheumatology practices.1,2
In March 2021, the U.S. Food & Drug Administration (FDA) approved tocilizumab to treat SSc-associated ILD. Tocilizumab, an anti-interleukin (IL) 6 agent, is the first biologic therapy to receive an indication for this condition. It also has indications for rheumatoid arthritis, giant cell arteritis, juvenile idiopathic arthritis and other rheumatologic conditions.
Tocilizumab Preserves Lung Function
The FDA approval of tocilizumab was based on data from two randomized controlled trials in patients with early SSc. The trials documented a large, clinically meaningful effect on forced vital capacity (FVC) and demonstrated tocilizumab preserved lung function in patients receiving therapy. This result stood in contrast to those of individuals in the placebo group, who experienced a large decline in lung function.3,4 However, the studies were limited because they did not describe radiographically evident, quantitative lung involvement.
Observational studies and clinical trials, such as the ones described above, have also shed light on the natural progression of SSc-associated ILD and the typical decline in FVC % associated with disease. In particular, the decline in the placebo group surprised experts because SSc-associated ILD is typically considered a slow progressive ILD. However, the trials documented a large and clinically meaningful average decline in FVC in the placebo group.
Focusing on Early SSC-Associated ILD
Recently, researchers reported the results of a post hoc analysis of patients from the focuSSced trial who were stratified by degree of lung involvement. The investigators used these data to analyze the effect of tocilizumab on lung function preservation in different subgroups and determine the relationship between degree of total lung involvement and fibrosis.
The researchers found patients with early SSc-associated ILD and progressive skin disease treated with tocilizumab demonstrated stabilized percent FVC at 48 weeks. The response described by David Roofeh, MD, a rheumatologist at the University of Michigan Health, Ann Arbor, Mich., and colleagues was independent of the extent of radiographically evident, quantitative ILD. The findings were published in the July issue of Arthritis & Rheumatology.4
The phase 3, multi-center, randomized, double-blind, placebo-controlled focuSSced trial, included patients with SSc who were at-risk for progressive ILD.5 All patients met the 2013 ACR/EULAR classification criteria and had disease onset of fewer than 60 months from the onset of their first non-Raynaud’s phenomenon sign or symptom, as well as a modified Rodnan skin score between 10 and 35. At baseline and week 48, the investigators performed baseline and serial spirometry along with high-resolution chest CT scans. Next, they used computer software to determine quantitative ILD and fibrosis scores. Using these baseline quantitative ILD scores, the researchers stratified patients into four groups: minimal (5% or less), mild (greater than 5–10%), moderate (greater than 10–20%) and severe (greater than 20%) lung involvement.
The Results
Of the 210 participants recruited for the study, only 30% had a history of ILD at baseline, whereas the investigators diagnosed 65% with ILD following uniform high-resolution chest CT scans. Most patients with ILD had moderate to severe lung involvement and approximately one-third of the patients in the trial had severe ILD.
The researchers documented an inverse relationship between baseline percentage of FVC and degree of quantitative ILD. The analysis revealed that early diffuse cutaneous SSc is associated with a high prevalence of ILD—77% of these patients had moderate to severe ILD. The patients’ characteristics surprised study author Dinesh Khanna, MBBS, MSc, a rheumatologist at University of Michigan, Ann Arbor, who expected a larger, mild ILD subset in the phase 3 trial.
The focuSSced study randomized patients to receive tocilizumab or placebo, and the investigators analyzed well-characterized data from the clinical trial using serial spirometry plus diffusing capacity for carbon monoxide corrected for hemoglobin to provide finer granularity for understanding the lung preservation effect of tocilizumab. They found higher quantitative ILD and quantitative lung fibrosis scores at baseline translated into higher quantitative ILD and quantitative lung fibrosis scores at 48 weeks. Patients in the tocilizumab arm had preserved percent FVC over 48 weeks with a difference of 6.2% (P<0.00001) between treatment group and placebo group. The least square mean change was 0.1% for tocilizumab and -6.3% for placebo.
The effect of tocilizimab was statistically significant and consistent across the spectrum of mild to severe ILD compared with placebo, which resulted in a consistent decline in FVC irrespective of the degree of ILD. The mean ± standard deviation changes in percent FVC in the tocilizumab arm at 48 weeks were −4.1 ± 2.5% (n=11) in mild ILD, 0.7 ± 1.9% (n=19) in moderate ILD and 2.1 ± 1.6% (n=26) in severe ILD. In the placebo group the changes were −10.0 ± 2.6% (n=11) in mild ILD, −5.7 ± 1.6% (n=26) in moderate ILD and −6.7 ± 2.0% (n=16) in severe ILD. Although the investigators documented treatment-related preservation findings that were independent of fibrosis severity, patients with severe lung involvement showed the largest improvement of any of the subsets.
“The decline in placebo group was surprising,” says Dr. Khanna, “especially in those with mild ILD or lung fibrosis.”
Dr. Khanna says a high-risk or at-risk phenotype for progressive decline in FVC exists in SSc-associated ILD. Patients at risk include those with early ILD, progressive skin disease and elevated acute phase reactants. He notes the current results underscore the fact that early SSc-associated ILD is not just mild SSc-associated ILD.
“SSc-associated ILD is an irreversible disease,” says Dr. Khanna. “This study highlights that there is a window of opportunity in which we can screen and treat early and preserve/conserve lung function.”
Although the authors noted in their paper that, because the analysis is post hoc, it’s primarily hypothesis generating, Dr. Khanna emphasizes some of the take-home messages for rheumatologists: “The post hoc analysis highlights, first, that patients with early ILD [don’t just have] mild ILD. Second, the effect of tocilizumab is consistent in those with mild to severe ILD. Third, the placebo group had a consistent decline, irrespective of the degree of ILD.”
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
References
- Deyton CP, Khanna D. Systemic sclerosis. Lancet. 2017 Oct 7;390(10103):1685–1699.
- Bernstein EJ, Khanna D, Lederer DJ. Screening high resolution computed tomography of the chest to detect interstitial lung disease in systemic sclerosis: A global survey of rheumatologists. Arthritis Rheumatol. 2018 Jun;70(6):971–972.
- Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): A phase 2, randomized, controlled trial. Lancet. 2016. 387:2630–2640.
- Khanna D, Lin CJ, Furst DE, et al. Tocilizumab in systemic sclerosis: A randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020. 8:963–974.
- Roofeh D, Lin CJF, Goldin J, et al. Tocilizumab prevents progression of early systemic sclerosis-associated interstitial lung disease. Arthritis Rheumatol. 2021 Jul. 73(7):1301–1310.
