We included 187 consecutive sarcoidosis subjects with histological evidence of noncaseating granulomas and a clinical presentation consistent with sarcoidosis (Table 1). The majority of the subjects were white (70.6%) or African American (17.1%). The mean age at diagnosis was 45.8 ± 12.4 years, with no significant difference between males (44.7 ± 12.5 years) and females (47.1 ± 12.1 years), and whites (47.1 ± 12.6 years) and blacks (43.3 ± 10.9 years). More than half of the subjects were males (55.1%). The mean body mass index (BMI) was 31.2 ± 7.1 kg/m2, with no significant difference between males (31.4 ± 6.4 kg/m2) and females (31.0 ± 7.8 kg/m2), and Whites (31.6 ± 6.8 kg/m2) and Blacks (29.6 ± 6.4 kg/m2). The use of anti-inflammatory medications for at least one month for sarcoidosis was present in 71.1% of subjects. The mean age at diagnosis for the treated group (44.2 ± 12.0 years) who received immunosuppression for ≥ 1 month was lower compared to cases (50.0 ± 12.4 years) that were never treated or treated < 1 month. The treated group also had a higher mean BMI (32.0 ± 7.5 kg/m2 vs 29.4 ± 5.7 kg/m2, p = 0.01). Only a minority of the subjects (9%) reported a family history of sarcoidosis. Thirty eight percent of subjects were former cigarette smokers, and 8% were current smokers.
Organ involvement was assessed using the WASOG sarcoidosis organ assessment instrument . Thoracic involvement was detected in 184 (98.4%) subjects by histology or imaging studies with chest x-ray (CXR) and/or CT scan, with the majority of the cases (85.9%) having histological evidence of noncaseating granulomas (Table 2). Extra-thoracic involvement was observed in 128 (68.4%) subjects, 59 (31.6%) subjects had thoracic involvement only, and 3 (1.6%) subjects had extra-thoracic involvement only. Bone and joint involvement were more frequent for whites (8.2 % vs 0 % for blacks, p = 0.04). Otherwise, there was no statistically significant association between each of the organ involvement and sex, race, or treatment group.
Other organs that were commonly involved included extra-thoracic lymph nodes (34.2%), eye (20.9%), and spleen (20.9%). Extra-thoracic adenopathy was detected by imaging in at least two sites, including cervical, supraclavicular, axillary, paraoesophageal, mesenteric, retroperitoneal, portocaval, hepatogastric, paraaortic, porta hepatis, inguinal, or iliac chain node stations; 28.1% of those with adenopathy underwent biopsy that provided evidence of granulomatous lymphadenitis. Among those with ocular disease, uveitis (61.5%) and lacrimal gland enlargement (18.0%) were the primary manifestations. In cases with splenic involvement, splenomegaly was present in 12 (30.8%), and splenic lesions were detected in 28 (71.8%) by imaging studies. In five subjects, splenomegaly was secondary to portal hypertension from non-alcoholic steatohepatitis (NASH), and these cases were not considered to have sarcoidosis splenic involvement as there was an alternative explanation for the splenomegaly. The majority of subjects (67.9%) had more than one organ involved (Table 3). Multiorgan involvement (at least five different organs involved) was identified in 13.4% of subjects. The mean number of organs involved was higher in treated vs. untreated cases in our cohort (2.7 vs 2.1, p = 0.004). Otherwise, there was no significant difference in the mean number of organs involved across gender and racial groups.
High-risk sarcoidosis with cardiac or neurologic involvement was observed in 20 (10.7%) and 14 (7.5%) subjects, respectively. Among subjects with cardiac involvement, three had endomyocardial biopsies demonstrating granulomatous inflammation; eight had a history of ventricular tachycardia and/or high-degree atrioventricular (AV) block such as Morbitz type II or complete heart block found in five subjects; ten had left ventricular ejection fraction below 50%. Nine patients received automatic implantable cardioverter defibrillators and two cases had pacemaker implantation. Advanced cardiac imaging was abnormal with suggestion of myocardial involvement in 16 cases. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) performed with a cardiac protocol demonstrated abnormal uptake in 13 subjects, while late gadolinium enhancement (LGE) on cardiac MRI was detected in 9 subjects . One subject underwent heart transplant. For nervous system involvement, three subjects had small fiber neuropathy, followed by three pituitary, two meninges, two spinal cord, 1 cranial nerve, 1 white matter, 1 sensory hearing loss, and 1 cranio-facial with peripheral neuropathy. Two subjects had both cardiac and neurological involvement.
Pulmonary function test and Scadding stage
Pulmonary function tests were available for 185 subjects. Normal pulmonary function tests were observed in 109 (58.9%) subjects, a restrictive pattern in 40 subjects (21.6%), an obstructive pattern in 32 subjects (17.3%), and mixed pattern in 4 (2.2%) subjects. For forced vital capacity (FVC), the median and 25th percentile were 88 percent predicted and 72 percent predicted, respectively. For forced expiratory volume in 1 second (FEV1), they were 84 percent predicted and 67 percent predicted, and for diffusing capacity of the lungs for carbon monoxide (DLCO), they were 93 percent predicted and 75 percent predicted, respectively. Lung volumes were available for 129 subjects, and the median and 25th percentile of total lung capacity (TLC) were 95 percent predicted and 82 percent predicted, respectively. Twenty-nine (22.5%) cases had decreased TLC (below 80 percent predicted), and 22 (17.1%) had restriction on spirometry and decreased TLC. Decreased TLC with normal spirometry was seen in only 4 (3.1%) cases. Fifty-five (30.4%) subjects had reduced DLCO, while 12 (6.6%) had reduced DLCO with normal spirometry. Eighteen (14.0%) subjects had abnormal DLCO with normal TLC, and 4 (2.2%) had an isolated decrease in DLCO with normal spirometry and lung volumes. Black subjects had lower mean FVC, FEV1, and DCLO than white subjects (p < 0.001) (Figure 1, panel A, B, D). Likewise, subjects treated with anti-inflammatory medications for at least ≥ 1 month had lower mean FVC, FEV1, and DLCO (p < 0.001), and lower FEV1/FVC ratio (p = 0.006) compared to untreated subjects (Figure 1, panel E, F, G, H).
Ninety-two (49.2%) cases had parenchymal lung involvement with Scadding stage II or III disease. Seventy cases (37.4%) had Scadding stage 0 disease, and 2.1% had primarily fibrotic stage IV (Table 4). Difference in the mean FVC, FEV1, FEV1/FVC and DLCO were observed based on Scadding stage (p < 0.001, Figure 2). The mean FVC was 92 ± 19% for stage 0, 95 ± 17 % for stage I, 80 ± 20 for stage II, 79 ± 21 for stage III, and 48 ± 18 for stage IV. The mean FVC was lower in stage 4 disease compared to other Scadding stages, suggesting a restrictive pattern in these cases. Cases with parenchymal involvement (stage II or III) had lower mean FVC than those without parenchymal disease (stage 0 or I). The mean DLCO was 97 ± 23% for stage 0, 99 ± 28 % for stage I, 86 ± 21% for stage II, 81 ± 26% for stage III, and 39 ± 19% for stage IV. Similar to FVC, the mean DLCO was lower for the Scadding stage 4 cases compared to those of other Scadding stages, and although in normal range, the mean DLCO of stage II and II combined was lower than cases with no parenchymal lung disease. The mean FEV1 was 90 ± 20 for stage 0, 94 ± 13 for stage I, 69 ± 21 for stage II, 74 ± 22 for stage III, and 31 ± 10 for stage IV. Of the 32 cases with obstructive disease, the mean FEV1 was 69 ± 10 for stage 0 (n = 5), 53 ±18 for stage II (n = 15), 55 ± 14 for stage III (n = 10), and 27 ± 6 for stage IV (n = 2). No subject with obstructive pattern had stage I disease.
The majority (71.1%) of subjects reported treatment for at least 1 month for sarcoidosis. Systemic anti-inflammatory agents for greater than three months were needed in 123 (65.8%) cases, and only 22 (11.8%) were off therapy at one-year anniversary of start treatment (Table 5). Prednisone was the first agent for majority (70.1%) of the cases, and methotrexate and Imuran were used in 59 (31.6%) and 9 (4.8%) cases respectively. Fourteen cases received infliximab with a preferred dose of 5 mg/kg for induction (0, 2 and 4 weeks) and a maintenance dose given every 4 weeks. Solumedrol 1 gm once a month was used in cases with cardiac disease and when there were adverse effects or intolerance of conventional oral or biologic agents. 31.0% of subjects were treated with only one anti-inflammatory agent, while 23.5% were treated with two and 10.7% with three anti-inflammatory agents (Table 6) for management of sarcoidosis over the duration of illness.
Clinical phenotypes per GRADS
Clinical phenotypes were determined using the GRADS study criteria. Cases with remitting disease, i.e., subjects who were never treated or were off treatment for greater than 12 months, were the largest group (n = 45 [24.1%]) in this cohort (Table 7). Of those classified into Group 8, five subjects had multiorgan involvement while four subjects had cardiac involvement. We then evaluated the proportion of cases with parenchymal disease based on GRADS phenotyping. Forty-four (23.5%) subjects were classified into Group 3, Stage II-III treated, with 23 (12.3%) subjects classified into Group 4 Stage II-III untreated. Meanwhile, only 1.1% and 0.5% of subjects were classified into Group 5 Stage IV treated and Group 6 Stage IV untreated, respectively. A substantial number of cases were not classifiable based on GRADS phenotyping (n = 37 [19.8%]), including 4.3% with Stage I who were treated, 14.4% with Stage 0 treated, and 1.1% with Stage 0 untreated. Some of the cases who met criteria for Group 1 (multiorgan disease) or Group 9 (cardiac defining therapy) were not included for the respective groups if they met criteria for remitting disease. For instance, while 25 subjects had multiorgan involvement, only 16 of them were classified into Group 1 Multiorgan since six of them were classified into Group 8 Remitting and three of them were classified into Group 9 Cardiac defining therapy. Likewise, while 20 subjects had cardiac involvement, only seven of them who were treated for cardiac involvement and not remitting were classified into Group 9 Cardiac defining therapy.
The sarcoidosis relevant laboratory studies for this cohort are shown in Table 8. A higher WBC count (p = 0.003), and lower albumin (p = 0.04) was seen in cases who were treated. White cases had lower IgG (p = 0.01), higher albumin (p = 0.01), and lower total protein levels (p = 0.002) compared to blacks. No significant difference between treated and untreated groups, and between whites and blacks was found for ACE, percent lymphocytes, soluble IL2 receptor, CRP, total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, calcium, parathyroid hormone, 25-OH Vitamin D, and 1,25 Di OH Vitamin D.