Prateek Deo MD, DM
Consultant and Head, Department of Clinical Immunology and Rheumatology, Bansal Hospital, Bhopal, India
Connective tissue diseases (CTDs) are a heterogeneous group of systemic autoimmune rheumatic diseases characterised by immune dysregulation and the production of disease-specific autoantibodies. CTDs frequently affect the cardiopulmonary system and substantially increase the risk for the development of pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH). It is a rare progressive condition that affects the pre-capillary vasculature. If left untreated, it ultimately leads to right heart failure and death. PAH is estimated to occur in 8‐12% of patients with SSc. Patients with limited cutaneous SSc (lcSSc) have a higher incidence of PAH than those with diffuse cutaneous SSc (dcSSc). Other CTDs like MCTD, SLE, and myositis have a variable prevalence of PAH.
Careful consideration of the patient’s hemodynamic profile, the presence or absence of Interstitial Lung Disease, and other comorbidities is required when developing a treatment plan for CTD‐PAH. There is usually an overlap in various PAH types.
In addition to PAH‐targeted therapies, the use of adjunctive supportive measures remains vital to the management of CTD‐PAH. Diuretics and salt/fluid restriction, Long-Term Oxygen Therapy, and iron supplementation are essential aspects of supportive care. The use of anticoagulants is not routinely recommended. Lung transplantation remains an important therapeutic option in patients with severe CTD‐PAH and an insufficient response to medical therapy. Patients should have continued reassessments and further optimisation of their CTD‐PAH while undergoing a transplant evaluation and while actively listed.
The current European Society of Cardiology/ European Respiratory Society (ESC/ERS) 2022 guidelines include CTD-PAH and idiopathic PAH(iPAH) under the same treatment umbrella protocol and use risk stratification to dictate the initial choice of drugs, with upfront dual therapy for patients in low and intermediate risk status, and upfront triple therapy for patients in high risk status. Escalation to triple drug therapy with a parenteral prostanoid is warranted in patients on dual therapy who either remain in the intermediate high-risk group or progress into the high-risk group at follow-up assessment. In patients who stratify as intermediate-low risk at follow-up, therapy augmentation with the addition of a non-parenteral prostanoid and/or a switch from phosphodiesterase type 5 inhibitors(PDE5i) to a Soluble guanylate cyclase (sGC) stimulator is recommended.
Most large RCTs of PAH-specific therapies include CTD-PAH patients (20%–30%), and the response to therapy appears broadly equivalent to that in patients with iPAH.
Upfront ambrisentan and tadalafil in SSc/PAH by Hassoun et al. demonstrated significant improvements in RV function, hemodynamics, 6 Minute Walk Distance, and B-type natriuretic peptide (BNP). The GRIPHON trial results show that the addition of selexipag to background treatment with one to two pulmonary vasodilators resulted in similar reductions in composite morbidity/mortality of 40% and 41% in the overall cohort and the CTD‐PAH subgroup, respectively.
Distinguishing between Group 3 PAH and Group 1 PAH can be particularly challenging in patients with CTD who can present with various severities of PAH and ILD, respectively. Features favouring Group 3 PAH include significant lung disease manifested by greater impairment of pulmonary function testing, extensive radiographic involvement, and milder hemodynamic impairment. Conversely, Group 1 PAH is suggested by milder underlying pulmonary disease and more severe hemodynamic impairment. Patients with mild ILD and significant PAH are often treated according to the Group 1 treatment algorithm. Patients with significant ILD present a bigger treatment challenge as they have historically been excluded from clinical trials. For patients with severe ILD and mild PAH, based on the INCREASE data, our current approach is to use inhaled treprostinil as first-line therapy.
The use of immunosuppressive therapy for the treatment of CTD‐PAH is limited, especially in SSc-PAH. No response has been demonstrated with corticosteroids or Cyclophosphamide, possibly suggesting more activation of fibrotic pathways. However, SLEMCTD-associated PAHs respond well to low to moderate doses of MMF, Rituximab, and Cyclophosphamide.
PAH complicates the natural history of CTDs, and prognosis can vary depending on the specific CTD. Developing an appropriate treatment plan for CTD‐PAH requires consideration of the specific CTD antibody involved, the patient’s hemodynamic parameters, and the presence of ILD. Despite CTD‐PAH being treated in a similar fashion to other causes of PAH, outcomes remain inferior.
