Anti-fibrotic medications work to reduce the formation and build-up of scar tissue in scleroderma patients. While these medications may slow or partially reverse organ damage caused by fibrosis, they cannot halt fibrosis and scar tissue build-up.

How anti-fibrotic medications work

Scleroderma is caused by an overactive immune system, leading to the accumulation of collagen in the skin and various other tissues and organs. When this is limited to the skin, the condition is called localized scleroderma. When it also involves internal organs, it is called systemic scleroderma.

Collagen is made by cells known as fibroblasts. In scleroderma, several chemicals present in the body promote fibroblasts that produce abnormally high amounts of collagen. Chemicals both related to the immune system and those that are not contribute to the fibrotic process in scleroderma. Anti-fibrotic therapies work by targeting the different molecules involved in stimulating fibroblast activation.

Therapies targeting non-immune system molecules

Anti-fibrotic medications target molecules known as transforming growth factor (TGF)-β, tyrosine kinases, and peroxisome proliferator-activated receptors (PPARs).

TGF-β plays a major role in activating fibroblasts. Esbriet (pirfenidone) is an anti-fibrotic medication that stops the action of TGF-β, reducing the amount of fibrosis. Initially developed to treat idiopathic pulmonary fibrosis (IPF), pirfenidone has been shown to be safe and effective in treating lung fibrosis in scleroderma patients.

Tyrosine kinases are a group of “molecular switches” that can trigger or suppress biological responses. Ofev (nintedanib) is an anti-fibrotic agent that blocks multiple tyrosine kinases, which are responsible for “switching on” the production of other molecules that promote fibrosis. Also initially developed for IPF, this medication is currently in a Phase 3 clinical trial (NCT02597933) evaluating its potential against placebo to treat interstitial lung disease in patients with systemic scleroderma.

PPARs are a family of receptors that act directly on DNA to suppress the gene encoding molecules that promote fibrosis. A proof-of-concept Phase 2b clinical trial (NCT02503644) is underway to test, against placebo, the ability of a medicine that works by stimulating PPARs —  lanifibranor (also known as IVA337) — to treat fibrosis in systemic scleroderma patients.

Therapies targeting immune system molecules

Some anti-fibrotic therapies target immune system molecules, such as interleukin-6 (IL-6) and interleukin-1 (IL-1) as well as immune system cells like B- and T-cells.

Interleukins are a large group of cell signaling molecules that can either promote or suppress inflammation. In scleroderma, IL-1 and IL-6 are two molecules that promote inflammation and are involved in the fibrotic process. Medications that block these molecules include Arcalyst (rilonacept), an IL-1 inhibitor, and Actemra (tocilizumab), an IL-6 inhibitor.

Unusual B- and T-cell activity also appears to promote fibrosis in scleroderma. Both rituximab, a B-cell inhibitor, and Orencia (abatacept), a T-cell inhibitor, have been shown to to treat fibrosis in scleroderma.

Fibroblast cell therapy

Fibroblast cell therapy involves collecting fibroblasts from a patient, modifying them to produce a protein that increases the breakdown of excess collagen, and returning the altered fibroblasts to the disease sites in the patient’s body.

The biotechnology company Fibrocell is currently developing FCX-103, which would use this gene therapy approach to potentially patients with linear scleroderma. An investigational new drug application for FCX-103 was approved by the U.S. Food and Drug Administration (FDA) in March 2018, a necessary step in testing the treatment in a clinical trial.

Other anti-fibrotic therapies

Sanofi is currently developing SAR100842, a molecule that blocks the action of lysophosphatidic acid, a molecule involved in systemic scleroderma-related fibrosis.

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