Pulmonary Arterial Hypertension (PAH) Associated with Interferon β-1B Therapy R.Papani, A. G. Duarte Division of Pulmonary, Critical Care and Sleep Medicine University of Texas Medical Branch - Galveston, TX Clinical course Background Table 1. Right heart catheterization measurements at initial encounter and six month follow-up. IFN β - 1b was suspected as the cause of PAH and discontinued followed by replacement with dimethyl fumarate. Sildenafil and ambrisentan were prescribed with good compliance. Follow-up demonstrated improvement from functional class III to functional class II. Six minute walk distance improved from initial distance of 274 meters to 347 meters at 8 months. Follow-up right heart catheterization revealed an improved hemodynamic profile (Table 1). Interferon (IFN) is a cytokine with potent antiviral and immunomodulatory properties. Since 1981, IFN treatment has been evaluated for treatment of CML and its use has expanded to treat chronic infectious malignant conditions. Currently, IFN α therapy is approved for treatment of chronic hepatitis B and C, hairy cell leukemia, AIDS-related Kaposi sarcoma, follicular lymphoma, malignant melanoma and condyloma accuminata. IFN β therapy is approved for treatment of multiple sclerosis. However, the side effect profile may limit use of this therapy. Significant adverse effects related to IFN include acute influenza-like syndrome, bone marrow suppression, neuropsychiatric disorders, autoimmune conditions and ischemic events. Cardio-respiratory adverse reactions include peripheral edema, hypertension, palpitations, chest pain and influenza- like syndrome. IFN therapy has also been associated with development of pulmonary arterial hypertension (PAH).   RA (mmHg) RV (mmHg) PAP (mean) PCWP (mmHg) CO (L/min) PVR (WU) 10/1/2014 12 103/4 104/47 (73) 13 2.76 22 06/16/2015 68/7 65/26 (43) 15 3.73 8 Table 2. Clinical cases reporting Pulmonary Arterial Hypertension induced by interferon α or β therapy Author, year Number (Sex) Indication Onset of PAH PAH risk factors IFN β   Ledinek, 2009 1 (F) MS 3 years None Caravita, 2011 1 year Savale, 2014 5 (F) 4–10 years One atrial septal defect Prella, 2015 15 years McGovern, 2015 5 years Gibbons, 2015 Fok, 2015 2 (F) 7-9 years Baghizadeh, 2016 1.5 years IFN α Kramer, 1993 Renal cell carcinoma Fruehauf, 2001 1 (M) CML 6 months Jochmann, 2005 Melanoma 2.5 years Dhillon, 2010 4 (3 M & 1 F)  HCV 8–32 months Liver cirrhosis in 3 cases Anderson, 2014 12 months Advanced liver fibrosis Savale, 2014 48 (14 F & 34 M) 47 HCV 1 CML 6–88 months Portal hypertension and/or HIV infection in 47cases  Ko, 2015 After liver transplantation Discussion Interferons have been increasingly linked to the development of PAH. Several case reports and case series support the association with IFN exposure and development of PAH (Table 2). IFN associated with PAH has been more frequently linked with IFN α treatment. The largest number of cases was reported by the French Registry for PAH. (Savale et al. European Respiratory Journal, 2014). PAH was newly diagnosed or worsened after initiation of interferon therapy in 48 patients treated with interferon α and 5 patients treated with interferon β. In patients with multiple sclerosis, the development of PAH and interferon β treatment ranged from 59-117 months. Most cases of IFN associated PAH were diagnosed within three years of drug treatment. Treatment consisted of PAH-specific therapy and withdrawal of IFN Experimental studies reinforce the link between IFN and PAH. IFN can induce secretion of endothelin-1 from human pulmonary artery smooth muscle cells (Badiger R et al. PLOS One, 2012). Using in vitro and in vivo experimental techniques, IFN was associated with PAH in humans and linked to development of pulmonary hypertension in mice lacking functional IFNAR1 exposed to chronic hypoxia. (George et al, Circulation Research, 2014). Case presentation A 54 year old female with history of multiple sclerosis, presented with exertional dyspnea and progressive fatigue of 8 months duration. IFN β-1b had been administered for 5 years for treatment of multiple sclerosis. She denied chronic liver disease or HIV risk factors and was a 40 pack-year smoker. Assessment of dyspnea was initiated with pulmonary function tests that revealed moderate airflow obstruction with preserved gas exchange. Computerized tomography of the chest revealed emphysema and V/Q scan was low probability. Echocardiography revealed LVEF 55 %, mild mitral regurgitation, right ventricular dilatation and right ventricular systolic pressure of 50 mm of Hg. Serology for connective tissue disorders, hepatitis and HIV was negative. Right heart catheterization confirmed PAH (Table 1). Conclusion PAH associated with IFN β -1b therapy was identified and managed with discontinuation of IFN and initiation of combination PAH therapy that resulted in clinical and hemodynamic improvements.