Systemic Sclerosis Future Therapies and Outcome Measures Save
Nagaraja, Khanna and colleagues have published an overview of current and future therapies in patients with systemic sclerosis (SSc) and have reviewed the potential outcome measures for this difficult autoimmune disorder. Notably there have been several novel agents studied in recent years, yet despite their biologic plausibility, none have yielded consistent improvements in halting SSc manifestations, especially sclerodactyly/scleroderma and lung fibrosis.
The failure to prove efficacy of novel therapies has been possibly explained by not choosing the right, amenable, end points to study. Other concerns would include inclusion criteria and the focus on skin outcomes versus end organ (eg, ILD) outcomes. Thus, the authors focus on outcome measures and defining low disease activity in SSc.
First, they propose that disease modifying therapy in SSc should "positively impact the disease course by stabilizing and potentially improving organ function. This, in turn, improves HRQoL and reduces morbidity and mortality".
Potential therapies discusssed target well known SSc outcomes, including skin, Raynauds, digital ulcers, vasculopathy, pulmonary disease (ILD, NSIP, pulmonary hypertension), renal and cardiac outcomes. They list the following possibilities:
- Skin: despite several trials failing to show significant change in (modified Rodnan) skin scores, there are trials showing meaningful clinical change for mycophenolate, cyclophosphamide, abatacept, and possibly tocilizumab. The jury is still out on rituximab and nintedinib failed to improve skin scores.
- Raynauds and Digital Ulcers: success has been shown for sildenafil, bosentan, iloprost.
- Scleroderma Renal Crisis: proven benefits for ACE inhibitors.
- Pulmonary hypertension: several FDA approved therapies exist for PAH. These include: 1) endothelin antagonists, 2) nitric oxide (NO)/soluble guanylate cyclase (GC) agonists/stimulators, and 3) prostacyclin analogs. There is preliminary encouraging RCT results using rituximab and there is a trial of tocilizumab in PAH.
- Cardiac: there are no trials designed to assess cardiac endpoints.
- Stem Cell Therapy (HSCT): there are 3 prospective trials in progress, all aiming to improve skin thickness, lung function, quality of life and survival.
There have been challenges in defining optimal outcomes and low disease activity state in SSc, primarily because of the heterogeneity of the disease. Clearly the ideal outcome measure should be reversibly and not be weighed down by damage. They call for the need for further study and development with a particular focus on single targeted organ outcomes. Outcomes should be measured on and off drug intervention, show validity over time and favorably impact survival and/or HRQoL.