by Phyllis Hanlon, Contributing Writer 

WHO Group 1 PH (PAH, pulmonary arterial hypertension) is a progressive and chronic disease. There currently is no cure. In PAH, the arteries in the lungs become narrow, thickened or stiff, which causes high blood pressure in the lungs. The disease can present in several forms, one of which is PAH associated with connective tissue disease (CTD-PAH), such as scleroderma, CREST syndrome and lupus. Research has found that this particular form of PAH is difficult to treat and patients have worse outcomes compared to people with other types of PAH. Two groups of researchers looked at different approaches to treating CTD-PAH using PH-targeted medications.

Selexipag therapy

The European Respiratory Journal published the findings of one study on the use of selexipag (Uptravi®) in patients with CTD-PAH. ( Sean Gaine, M.D. — National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital in Dublin — led an international team of researchers to look at the effects of selexipag in CTD-PAH. To determine how patients with CTD-PAH might respond to selexipag, these researchers drew data from GRIPHON (, a large clinical trial that included 334 patients with CTD-PAH, including systemic sclerosis (SSc, “Scleroderma”) associated PAH (SSc-PAH) and systemic lupus erythematosus (SLE) associated PAH (SLE-PAH), and offered details on dosage, how well the drug worked and how well patients tolerated the drug. They reported that finding the most effective medication for patients with CTD-PAH is challenging since patients often have other medical conditions involving the musculoskeletal and gastrointestinal systems that affect their treatment response and outcomes.

In this study, the researchers reported that half the patients initially received 200 micrograms of selexipag and the other half received placebo (a “sugar pill”). The selexipag was increased by 200 micrograms on a weekly basis as long as patients could tolerate the higher dose; the maximum dose was 1,600 micrograms twice a day.

The authors were looking for any worsening of the disease or death.

The authors found selexipag to be beneficial for patients with CTD-PAH. While there were slight differences in response depending on whether the patient had CTD-PAH, SSc-PAH or SLE-PAH, the overall outcome was positive. One important effect the authors noted was that decreases in 6MWD were connected to worse outcomes; this is similar to other studies that have shown this, but not necessarily demonstrated a connection between 6MWD increases and better outcomes.

The authors concluded that selexipag, which patients in the study generally tolerated well and helped delay progression of disease, regardless of disease type, is beneficial for CTD-PAH. Furthermore, they suggested that their findings “…support the use of multiple PAH therapies when treating patients with PAH-CTD and that this treatment strategy can yield benefits in a population who had previously been considered difficult to treat.”

Combination ambrisentan and tadalafil

Another group of researchers from around the globe recently pursued the theory that combination therapy might benefit patients who have certain CTD-PAH subtypes. Gerry Coghlan, MD, FRCP, in the Cardiology Department, Royal Free Hospital in London, led the team as they analyzed data from AMBITION (, a clinical trial that included PAH patients and looked at combination therapy with two medications, compared to monotherapy with either of the medications by themselves. They published their findings in the Annals of the Rheumatic Diseases (ARD) ( last December. (

The data included in the primary AMBITION data analysis included 500 patients; 187 had CTD-PAH, 118 of whom had SSc-PAH. Similar to the selexipag study, this one looked for signs of deterioration, which included when the first hospitalization occurred, disease progression, failure to respond to medication or death.

After Dr. Coghlan and his colleagues looked at the data of the CTD-PAH patients, they reported that the group of patients taking combination ambrisentan (Letairis®) and tadalafil (Adcirca®) reduced their risk of experiencing a negative “event” compared with the patients taking either ambrisentan or tadalafil alone. Not only did patients with CTD-PAH reduce their risk of one of these negative clinical events, but those with SSc-PAH also did better than those patients taking just one drug or the other.

The 6MWD is typically one of the measures researchers use to determine the effectiveness of a drug. In this case, the use of both ambrisentan and tadalafil together caused a significant improvement in the 6MWD versus the use of just one of the drugs; the results were particularly impressive for patients with SSc-PAH.

Coghlan noted that another study led by the Johns Hopkins University PH program supports these findings. In that study (, daily use of this combination therapy for 36 weeks in patients with SSc-PAH dramatically improved a calculation called pulmonary vascular resistance, structure and function of the right side of the heart, as well as overall functional class.

The authors reported that, for the most part, the intervention was safe, although 47 percent of CTD-PAH patients in the combination group experienced swelling in their legs, 33 percent developed headaches and 29 percent had diarrhea. Thirty-four percent in the ambrisentan only group had edema, 32 percent got headaches and 32 percent reported diarrhea. For those in the tadalafil only group, 33 percent developed edema, 38 percent experienced headaches and 25 percent experienced diarrhea. These results were similar to the outcomes for patients in the other study who had idiopathic PAH (IPAH) and heritable PAH (HPAH).

After analyzing the CTD-PAH-related outcomes in this study, the authors suggested that some insights from the data could be useful in managing care for this patient population. Patients with SSc-PAH have not historically responded as well to monotherapy (just one drug) as patients with other types of PAH. The only other drug that seemed to have any significant effect on CTD-PAH was epoprostenol (Flolan®). The findings from this study indicate that combination therapy could also serve as a viable treatment option.

Based on the research findings from these two studies, patients with CTD-PAH, including those with SSc-PAH and SLE-PAH, could have safe and effective options with selexipag or combination therapy with ambrisentan and tadalafil.

Each PH patient is different. It is essential that you talk to your own doctor about what treatment options are best for you. For more information on finding a doctor or an accredited care center, visit


In pulmonary arterial hypertension (PAH), the arteries in the lungs become narrow, thickened or stiff, which causes the high blood pressure in the lungs.

One type of PAH is associated with connective tissue disease (CTD-PAH).

Researchers looked at different treatment approaches for people with CTD-PAH.

The authors of one study found selexipag to be beneficial to patients with CTD-PAH. Another study found the combination of ambrisentan and tadalafil to be beneficial to patients with CTD-PAH.

Treatment decisions should be made with a PH specialist. Patients should also work with a PH specialist to learn more about their unique health circumstances and properly diagnose the disease.