In scleroderma, the immune system mistakenly targets healthy connective tissue, which is an integral part of many organs, including the lungs.  This causes both inflammation, leading to damage and swelling, and fibrosis, or scarring, due to the overproduction of collagen.

Scleroderma that damages the lungs in this way can result in a patient developing pulmonary arterial hypertension (PAH) as an associated condition. 

PAH is marked by abnormally high pressure in the blood vessels supplying the lungs, lowering oxygen levels and putting a strain on the heart.  

Neither scleroderma nor PAH have treatments that might stop or alter disease progression, but certain therapies — like IP receptor agonists — can help to manage PAH symptoms.

How IP receptor agonists work

Scleroderma-associated PAH is caused by a build-up of scar tissue blocking small arteries of the lung, or by stimulating vasoconstriction, the process in which the smooth muscle walls of the arteries contract. This is triggered by signaling pathways that are part of the damage response to immune system attacks. 

The body naturally produces a protein called prostacyclin, which binds to and activates the IP receptor in the lungs. When the IP receptor is activated, it triggers the relaxation of the arteries.

IP receptor agonists act by binding to and activating the IP receptor, even if prostacyclin is not present. Again, such receptor activation results in vasodilation, causing the arteries to become wider, and reducing the resistance to blood flow. Ultimately, this reduces the strain on the heart as blood flows more easily, and increases the supply of oxygen throughout the body. 

Types of IP receptor agonists 

Uptravi (selexipag), marketed by Actelion, is the only approved IP receptor agonist currently available. It is highly selective to the IP receptor, which helps to lessen potential side effects on other systems. 

The treatment’s safety and efficacy  have been investigated in several clinical trials. One of these, a Phase 3 randomized, double-blind, and controlled clinical trial called GRIPHON (NCT01106014) included people with scleroderma-associated PAH. The results, published in the European Respiratory Journal, suggested that Uptravi was well-tolerated and had a clinical benefit, especially when used in combination with other PAH therapies. 

Other IP receptor agonist therapies that are currently under development. Arena Pharmaceuticals is investigating ralinepag (APD811) as a potential PAH therapy, which has completed a Phase 2 clinical trial (NCT02279160) in about 60 PAH patients, with a long-term extension study (NCT02279745) still ongoing. 

Other information 

IP receptor agonists may be used in combination with other PAH treatments that target different pathways, such as PDE-5 inhibitors. 

Common side effects of Uptravi include diarrhea, headache, jaw pain, joint pain or swelling, nausea, anemia, decreased appetite, and muscle pain. 

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