Table 14.5  Alarcón-Segovia and Villareal criteria for the classi cation of mixed connective tissue disease (MCTD) [75]

MCTD diagnosis: Positive serology plus at least three clinical criteria Reproduced table from [3] by permission

Pulmonary Manifestations

Pulmonary Hypertension

PH is frequently observed during the course of MCTD (Table 14.1) and can be classi ed into group 1, pulmonary arterial hypertension, or group 3, as a consequence of ILD according to the World Health Organization classi cation. Among CTDs, MCTD was found to be the most commonly associated with pulmonary arterial hypertension in a Japanese study [77]. In the national UK registry study, 8% of the pulmonary arterial hypertension-CTD patients presented MCTD compared to 74% presenting systemic scleroderma [78].

There are no speci c guidelines for the treatment of PH associated with MCTD, and the treatment options are derived from studies of pulmonary arterial hypertension-speci c therapies in idiopathic pulmonary arterial hypertension. In group 1 PH, endothelin receptor antagonists (bosentan, ambrisentan), phosphodiesterase 5 inhibitors (sildena l, tadala l), and prostanoids (intravenous epoprostenol, subcutaneous treprostinil, nebulized iloprost) could be discussed according to the prognostic risk calculation. Compared to idiopathic/heritable pulmonary arterial hypertension, patients with CTD respond poorly to treatment [79] and have a worse prognosis. Aggressive up-front combination therapy with ambrisentan and tadala l has been shown to reduce the risk of clinical failure compared to monotherapy [80] and could be the ideal option in CTD-PH patients.

Fig. 14.6  Fibrotic NSIP pattern in a patient with mixed connective tissue disease. Note the esophageal dilation

Interstitial Lung Disease

MCTD-associated ILD affects up to 60% of patients, is usually slowly progressive, and is associated with increased mortality (Figs. 14.6 and 14.7). No controlled data are available, but immunosuppressive treatments are commonly suggested, including corticosteroids and immunosuppressive therapies, such as azathioprine, mycophenolate mofetil, cyclosporine, and methotrexate. Intravenous cyclophosphamide should be considered in severe ILD [69, 81, 82].

Prognosis

The most common cause of death is PH followed by severe infections due to immunosuppressive therapies [83]. Data on the course and outcome of ILD in MCTD are limited. A study has calculated the 5-year survival rates for <5% ILD extent to be 94%, compared to 82% for >5%. Common risk factors for ILD progression in MCTD is male gender, high