Please refer to e-Appendix 1 for additional methodologic details. Adult patients (≥ 18 years old) were enrolled in the study after first obtaining written informed consent in compliance with The Ohio State University Biomedical Sciences Institutional Review Board (#2008H0006). In addition, the use of nicotine as an investigational new drug for sarcoidosis was approved by the US Food and Drug Administration. The diagnosis of sarcoidosis was based on established criteria, including biopsy confirmation and exclusion of other potential causes. 28 In this regard, all subjects were purifi ed protein derivative (PPD) skin test negative and had no evidence of infectious organisms by tissue acid-fast bacillus and Grocott methenamine silver staining. The study design was unblinded, randomized, and controlled, with specifi cally identified patient inclusion and exclusion criteria. All patients were diagnosed as having sarcoidosis; however, the nicotine treatment study was restricted to those patients with symptomatic (active) granulomatous lung disease (radiographic stage II or III), including chronic cough and/or dyspnea, 29 of at least 6 months' duration following diagnosis. Patients with any of the following characteristics: active smokers, those with previous splenectomy, prisoners, and those who required high-dose immunosuppression (ie, ≥ 0.2 mg/kg/d prednisone [or equivalent] or > 15 mg/wk methotrexate or required second-line cytolytic agents [eg, cyclophosphamide, azathioprine] or anti-tumor necrosis factor [TNF] treatments [eg, thalidomide, anti-TNF antibodies, and so forth]) to control disease activity were excluded. The study further excluded patients at high risk of complications relating to the use of nicotine, including patients with known intolerance of nicotine or those with active cardiac or CNS disease who were at higher risk of cardiac arrhythmias or seizures, respectively. Finally, patients with extensive pulmonary fibrosis (based on lung biopsy or highresolution CT scan) or those who were unable to provide informed consent were also excluded. Patients were then assigned to symptomatic (n = 13) and asymptomatic (n = 6) groups based on their reported symptoms at the time of enrollment. Although diagnosed with radiographic evidence of biopsy-proven pulmonary sarcoidosis, asymptomatic patients were symptom-free, were not receiving any form of sarcoidosis-directed therapy, and, thus, did not receive nicotine but served as a reference cohort according to the study design. Symptomatic patients who met exclusion criteria demonstrated signs of disease progression (eg, altered lung function [pulmonary function tests]) with developed symptoms of cough and dyspnea in accordance with study inclusion criteria and remained so despite receipt of conventional fi rst-line therapies. In addition, these are patients who would be considered candidates for escalation of corticosteroids and/or steroid-sparing agents (eg, methotrexate) 30 but elected instead to participate in the current study.