SSc autoantibodies can alter disease course, may affect clinical trials
Study ties changes seen in placebo group of Phase 3 trial to specific antibodies
The presence of different autoantibodies specific to systemic sclerosis (SSc) can determine how the disease is likely to progress in terms of how patients feel or function, which could affect findings in placebo groups in randomized clinical trials and determinations of benefit with an experimental therapy, a study indicates.
For the analysis, researchers drew on data from the Phase 3 focuSSced (NCT02453256) trial that tested the safety and efficacy of Genentech’s Actemra (tocilizumab) compared to a placebo in adults with SSc, also known as scleroderma. Study findings supported the therapy’s approval for interstitial lung disease associated with SSc.
Knowing how the disease is likely to progress should inform the design of clinical trials, where charting a more predictable course for patients on a placebo could improve the way experimental treatments are tested and compared, the researchers wrote.
The study, “Impact of Scleroderma-Associated Autoantibodies on Clinical Outcome Assessments: Post Hoc Analysis From a Randomised, Double-blind, Placebo-controlled, Phase 3 Trial of Tocilizumab in Scleroderma,” was published as a brief report in ACR Open Rheumatology.
Autoantibodies in scleroderma lead to excessive collagen, damaging tissue
Scleroderma is an autoimmune condition characterized by excessive thickening and hardening of the skin and internal organs. It occurs when the immune system mistakenly generates autoantibodies that target the body’s connective tissues, stimulating an overproduction of collagen protein. This surplus collagen leads to the formation of extensive scar tissue.
Not all patients produce the same autoantibodies, and while all are specific to SSc, they appear to cause the disease to manifest in different ways. For example, one group of these self-reactive antibodies are seen as more like to cause lung or kidney damage than others, while another study tied seven SSc-related autoantibodies to various organ damage, with some leading to a higher risk of death.
Three SSc autoantibodies are normally assessed — anti-centromere antibodies (ACAs), anti-topoisomerase 1 antibodies (ATAs), and anti-RNA polymerase 3 antibodies (RNAP3s) — as they are “linked to diverse clinical manifestations and outcomes,” the researchers wrote.
In a study sponsored by Genentech, a Roche subsidiary, the researchers drew on data from 99 patients, mostly female with a mean age of 48, who took part in the focuSSced study to see how their types of autoantibodies affected disease progression or response to treatment.
Patients were divided into four groups based on the presence of disease-causing autoantibodies: 49 patients tested positive for ATAs, 14 for RNAP3s, and nine for ACAs. Twenty-seven others were triple negative — that is, they had none of these autoantibodies.
Researchers then watched for differences in six clinical outcomes — skin thickness, lung function, disability, patient and doctor assessments, and a composite score that tells how likely it is that patients improve — among the four groups. The analysis was done separately for patients treated with Actemra in the trial and those randomized to a placebo.
In the placebo group, most clinical outcomes improved over 48 weeks (about 11 months), except in lung function, which was evaluated based on forced vital capacity (FVC%), a measure of the amount of air that can be forcibly and quickly exhaled after a deep breath.
Favorable skin changes seen in placebo patients with RNAP3 autoantibodies
Skin thickness, measured using the modified Rodnan skin score (mRSS), improved the most in the RNAP3 group (by 7.2 points) and the least in the ATA group (by 3.28 points) among placebo patients. The ATA group also showed the deepest decline in lung function, with an average decline of 7.34% in FVC% over a one-year time window.
“We observed an overall improvement in the COAs [assessed clinical outcomes] (except for FVC%) over the course of 48 weeks in the group who received [a placebo],” the researchers wrote, with these changes associated with the specific autoantibodies present in patients.
“Of the four SSc-Abs [SSc autoantibody] types, ATA showed the smallest improvement in the mRSS, [and] greatest decline in FVC%,” while “the RNA3P, triple negative, and ACA [autoantibody types] exhibited a large improvement in the mRSS, and small decline in the FVC%,” they added.
In Actemra-treated patients, improvements in skin thickness and the composite score were similar across groups. Lung function also was preserved among treated patients across all four autoantibody groups, supporting Actemra in helping to protect the lungs against damage regardless of disease-causing autoantibodies.
Findings suggest that autoantibodies influence both how patients respond to treatment and how their disease progresses, including among those given a placebo in a trial and serving as a comparative group.
This work “shows a differential effect of SSc-Abs on the trajectories of [clinical outcomes] over a 48-week [randomized clinical trial],” the researchers concluded. Its findings “highlight the importance of incorporating these data [on autoantibody types] in trial design, either as a stratification factor or limiting the SSc-Abs that are included in the trials.”
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