Recent years have witnessed a remarkable transformation in the field of systemic sclerosis (SSc) therapeutics, marked by the emergence of novel targeted therapies, precision medicine approaches, and a growing emphasis on personalized patient care. 

SSc, also known as scleroderma, is a complex autoimmune disorder characterized by progressive fibrosis of the skin and multiple organs, accompanied by vascular abnormalities and immune dysregulation. This chronic and often debilitating condition poses significant challenges due to its heterogeneous clinical manifestations and unpredictable course.

Despite advances in understanding the underlying pathogenesis, therapeutic options for SSc have historically been limited, with no curative treatment available.1

However, new diverse therapeutic strategies are now under investigation and new directions that have emerged hold promise for improving patient outcomes. This article will highlight unique approaches to SSc research and detail some ongoing clinical trials that could provide new insights and breakthroughs that may revolutionize the treatment of SSc. 


FT011 is a novel, first-in-class, oral antifibrotic agent that has been shown to attenuate fibrosis in patients with experimental diabetic cardiomyopathy.2 It is thought to exert its antifibrotic effects by regulating the Smad and extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) pathways.2 The downstream effect of modulating these signaling cascades is inhibition of transforming growth factor β (TGF-β) and platelet derived growth factor BB (PDGF-BB).2,3

A recent phase 2, randomized, double blind, placebo-controlled, trial (NCT04647890) sponsored by Certa Therapeutics has produced what have been described as “groundbreaking” results.4,5 

After 12 weeks of treatment in the study, more than 60% of patients with scleroderma experienced clinically meaningful improvements. These improvements were observed across key indicators such as the Scleroderma HAQ-DI, Physician Global Assessment, and lung function, as measured by Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS). Importantly, the trial demonstrated that FT011 was safe and well tolerated in the patient cohort. Certa also said the outcomes observed in scleroderma patients provide exciting prospects for treating other diseases, including chronic kidney disease (CKD) and diabetic retinopathy.5

“These exceptional trial results demonstrate the potential of this novel treatment for patients with scleroderma,” Certa Therapeutics CEO Darren Kelly said. “The changes seen in CRISS score, lung function, and physician reported outcomes in addition to the patient reported outcomes within such a short treatment time frame of 12 weeks, is unprecedented and paves the way for a confirmatory global phase 3 study.”5

These results are very promising; however it’s worth mentioning that the data have not been peer-reviewed or published, and information has come directly from Certa.  

PLG Nanoparticles

Another group of researchers was able to do something quite unique using poly(lactic-co-glycolic) (PLG) acid nanoparticles to suppress fibrosis in mouse models. The idea for this preclinical study stemmed from the discovery of the role of a specific subset of monocytes and macrophages, distinguished by the expression of the scavenger receptor macrophage receptor with collagenous structure (MARCO).6

It has been documented that MARCO+ monocytes and macrophages accumulate in lesional skin and lung regions, in close proximity to activated myofibroblasts, in patients diagnosed with SSc and in mouse models of SSc induced by bleomycin. In the study, the researchers used an US Food and Drug Administration (FDA)-approved, biodegradable PLG nanoparticle polymer capable of modulating the activation and trafficking of MARCO+ inflammatory monocytes in bleomycin-induced SSc mouse models. This resulted in significant attenuation of skin and lung inflammation and fibrosis following short-term treatment.6 

Further mechanistic investigations employing isolated cells in culture unveiled that the PLG nanoparticles effectively hindered TGF-dependent fibrotic responses in vitro. Therefore, the findings of this study establish MARCO+ monocytes as potent effector cells driving skin and lung fibrosis and propose PLG nanoparticles as a potential therapeutic strategy for targeting these cells in the context of SSc.6 

This study also reported prophylactic treatment with PLG nanoparticles restricted the accumulation of activated immune cells in fibrotic tissue—namely, CD45+ leukocytes in the lungs, tissue-resident alveolar macrophages, peripheral monocyte-derived alveolar macrophages, inflammatory monocytes, noninflammatory monocytes, and conventional dendritic cells.6

Most importantly, targeted intervention has shown promise not only in mitigating fibrosis but also in reversing cutaneous and pulmonary pathology in the mouse model.6 By selectively curtailing the infiltration of pathogenic MACRO+ cells, the PLG nanoparticle strategy presents a potential avenue for addressing fibrotic disorders.6

A20 and DREAM

The A20 protein plays an important role in the development and progression of fibrosis. A20 is an enzyme encoded by the TNFAIP3 gene that acts as a ubiquitin-editing enzyme and has been associated with autoimmune and inflammatory diseases including SSc. Downstream regulatory element antagonist modulator (DREAM) is the negative transcriptional regulator of A20.7 

Despite extensive research on the expression, regulation, and mechanism of action of A20 in the context of inflammatory and autoimmune diseases associated with TNFAIP3 variants, understanding of A20’s involvement in SSc remains limited. Specifically, there is a paucity of knowledge regarding the regulation and function of A20 in tissue-resident stromal cells and its potential contribution to organ fibrosis in SSc.7 

Researchers sought to investigate the specific role of A20 and DREAM to gain insight into the pathogenesis of SSc. Utilizing SSc patient-derived skin and lung tissues along with isolated fibroblasts, they conducted a series of experiments involving engineered mice with specific deletions of A20 or DREAM to elucidate their roles in SSc. The experiments uncovered a significant reduction in A20 expression accompanied by a marked elevation in DREAM expression in SSc cells.7

Notably, the expression levels of A20 and DREAM exhibited an inverse correlation. It was observed that mice with either a global loss of A20 function across all tissues or selective deletion limited to fibroblasts had heightened inflammatory and fibrotic responses in the skin and lungs. In contrast, mice lacking DREAM displayed protective effects against fibrosis. Furthermore, fibroblasts lacking DREAM exhibited enhanced A20 induction, which was associated with nearly complete attenuation of inducible fibrotic responses.7

Interestingly, TGF-β, a cytokine involved in fibrosis, was found to induce the expression of A20 in DREAM-null fibroblasts compared to wild-type fibroblasts. This suggests that the absence of DREAM may enhance the expression of A20 in response to fibrotic stimuli, resulting in protection.7

Furthermore, the researchers tested the hypothesis that targeting A20 expression may be a novel therapeutic strategy for the treatment of SSc. To prove this, AdipoRon, an oral small molecule that increases A20 expression, was given to SSc mouse models. It acts by stimulating AdipoR1 and AdipoR2, receptors that stimulate the production of adiponectin, which in turn upregulates A20 production.

Chronic administration of AdipoRon demonstrated the ability to alleviate bleomycin-induced fibrosis in wild-type mice. Notably, the treatment of transiently transfected wild-type fibroblasts with AdipoRon resulted in a significant elevation in A20-luc promoter activity and A20 transcription. Furthermore, the 4-week administration of AdipoRon in wild-type mice led to the prevention and regression of bleomycin-induced fibrosis, concomitant with the upregulation of A20 expression in the affected skin.7

Overall, the research indicates that A20 and DREAM represent novel druggable targets for fibrosis therapy in SSc. Manipulating the expression or function of A20 and DREAM may help regulate fibroblast activation and inhibit the fibrotic process, providing potential avenues for the development of new treatments for SSc-related fibrosis.7

Propelling Advancements

These three unique potential avenues have opened the doors for exploration and drug development. The pathologic role of MARCO+ macrophages exposed through research with LPG nanoparticles has called attention to the possibility of developing targeted therapies to inhibit their negative effects. Insights into the role of A20 and its negative transcriptional regulator DREAM in the development of fibrosis are particularly interesting and may spark investigations in the development of targeted genetic therapies.

The trials with FT011 are the furthest along in clinical research and have revealed that fibrosis may be attenuated and even reversed through inhibition of signaling cascades that modulate TGF-β and PDGF-BB. 

All in all, the field of SSc therapeutics is undergoing a remarkable transformation, propelled by advancements in scientific understanding, innovative technologies, and a shift towards personalized medicine.


1. Adigun R, Goyal A, Hariz A. Systemic sclerosis. StatPearls. May 8, 2022. Accessed May 28, 2023. 

2. Zhang Y, Edgley AJ, Cox AJ, et al. FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy. Eur J Heart Fail. 2012;14(5):549-562. doi:10.1093/eurjhf/hfs011

3. Benfaremo D, Svegliati S, Paolini C, Agarbati S, Moroncini G. Systemic sclerosis: from pathophysiology to novel therapeutic approaches. Biomedicines. 2022;10(1):163. doi:10.3390/biomedicines10010163

4. Effects of FT011 in systemic sclerosis. December 1, 2020. Updated July 21, 2022. Accessed May 24, 2023. 

5. Ground-breaking results in phase 2 scleroderma study by Certa Therapeutics demonstrates improvement in more than 60% of patients. News release. Certa Therapeutics; February 6, 2023.

6. Xu D, Bhattacharyya S, Wang W, et al. PLG nanoparticles target fibroblasts and MARCO+ monocytes to reverse multiorgan fibrosis. JCI Insight. 7(5):e151037. doi:10.1172/jci.insight.151037

7. Wang W, Bale S, Wei J, et al. Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs. Nat Commun. 2022;13(1):6358. doi:10.1038/s41467-022-33767-y