Juan Mañá

Clinical Factors Predicting Persistence of Activity in Sarcoidosis: A Multivariate Analysis of 193 Cases

The prognosis of sarcoidosis is difficult to establish and it depends mainly on the persistence of activity over time and the degree of functional impairment of the involved organs. The aim of this study was to identify factors predicting persistence of disease activity at diagnosis. In a 14-year period (1974-1987), 209 patients were diagnosed with sarcoidosis at Bellvitge Hospital, a 1,000-bed teaching institution in Barcelona, Spain. One hundred ninety-three patients were followed up and included in the study. Clinical and radiological data were collected at diagnosis and a definition of disease activity was established. A Cox proportional-hazards regression model identified the following variables as independently influencing the persistence of activity: absence of erythema nodosum (risk ratio, RR = 2.37; 95% confidence interval, CI: 1.54-3.66), pulmonary infiltrates in chest x-ray (RR = 1.89, 95% CI: 1.28-2.8), splenomegaly (RR = 3.67, 95% CI: 1.46-9.23), age > or = 40 years (RR = 1.01, 95% CI: 1.006-1.03), and absence of lymphadenopathy in chest x-ray (RR = 2.26, 95% CI: 1.08-4.77). We suggest that the identification of factors predicting persistence of sarcoidosis activity at diagnosis may help to establish the prognosis of the disease and therefore improve the therapeutic approach.

Are the Pulmonary Function Tests and the Markers of Activity Helpful to Establish the Prognosis of Sarcoidosis

The prognosis of sarcoidosis is difficult to establish. It depends mainly on the persistence of activity over time and the degree of functional impairment of the involved organs. The aim of this study was to analyze whether the pulmonary function tests and the more commonly used markers of activity, such as serum angiotensin-converting enzyme (SACE) and gallium-67 scan, are helpful to evaluate the prognosis of sarcoidosis, besides the clinical data. Over a 14-year period (1974-1987), 209 patients were diagnosed as having sarcoidosis at the Bellvitge Hospital, a 1,000-bed teaching hospital in Barcelona, Spain. Clinical, radiological, pulmonary function tests, and activity markers (SACE and gallium-67 scan) data at diagnosis were collected and classified as variables, and a definition of disease activity was established. One hundred sixteen patients were on follow-up, had all the variables available and were included in the statistical analysis. A Cox proportional-hazard regression model identified the following variables as independently influencing the persistence of activity over time: absence of erythema nodosum [risk ratio (RR) = 2.78; 95% confidence interval (CI): 1.48-5.18], age > or = 40 years (RR = 1.67; 95% CI: 1.008-1.04), SACE level > or = mean + 2 SD U/ml (RR = 1.45; CI: 0.99-1.07), hyperglobulinemia (RR = 2.47; CI: 0.98-6.24), forced vital capacity < 80% predicted (RR = 2.17; CI: 0.97-4.85), and male sex (RR = 1.8; CI: 0.95-3.45). We conclude that the pulmonary function tests and the SACE level but not the gallium scan are helpful to identify the factors predicting persistence of activity in sarcoidosis. Therefore, we recommend to add these tests to the initial clinical evaluation of patients with sarcoidosis in order to establish the prognosis and improve the therapeutic approach.

Influence of serum amyloid A on the decrease of high density lipoprotein-cholesterol in active sarcoidosis

OBJECTIVE We have previously observed low levels of high density lipoprotein (HDL) cholesterol in active sarcoidosis. The aim of this study was to analyze the role of serum amyloid A (SAA) on this lipid disorder. METHODS Eighty five untreated sarcoid patients, 40 with active disease and 45 with inactive disease, were recruited. Sarcoidosis activity was evaluated by means of clinical, chest X-ray, gallium-67 scan, serum angiotensin converting enzyme (peptidyl-dipeptidase A) values, and pulmonary function tests. Analysis of lipoprotein metabolism included: serum cholesterol, low density lipoprotein (LDL)-cholesterol, HDL-cholesterol, HDL(2)-cholesterol, HDL(3)-cholesterol, apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), and triglyceride concentrations. Serum amyloid A protein and lecithin-cholesterol acyltransferase (LCAT) activity were measured. RESULTS In active sarcoidosis we found significantly reduced levels of HDL-cholesterol (1.17+/-0.36 vs. 1. 44+/-0.39 mmol/l, P=0.002), HDL(3)-cholesterol (0.78+/-0.23 vs. 1. 02+/-0.21 mmol/l, P<0.0001), and apo A-I (1.36+/-0.29 vs. 1.61+/-0. 27 g/l, P<0.0001) and significantly increased levels of triglyceride (1.51+/-0.64 vs. 1.03+/-0.46 mmol/l, P<0.0001), and apo B (1.14+/-0. 25 vs. 0.99+/-0.27 g/l, P=0.012) versus inactive sarcoidosis. Serum amyloid A concentrations were significantly increased in the patients with active disease (155.45+/-154.01 mg/ml) compared to the inactive sarcoid patients (89.70+/-65.36 mg/ml) (P=0.011). There were no significant differences in cholesterol, LDL-cholesterol, HDL(2)-cholesterol or LCAT values between groups. Multivariate logistic regression analysis showed that HDL-cholesterol (regression coefficient b=-1.96; S.E.=0.87; P=0.02) and SAA (regression coefficient b=0.01; S.E.=0.004; P=0.01) were the two variables independently associated with disease activity. Moreover, a significant negative correlation was observed between SAA levels and both HDL-cholesterol (r=-0.39; P=0.01) and apo A-I (r=-0.35; P=0.03) levels, in the active sarcoid group. Conversely, no correlation was found in the inactive sarcoid group. CONCLUSION The low HDL-cholesterol and apo A-I concentrations seen in active sarcoid patients are associated with a significant increase of SAA levels. We suggest that the displacement of apo A-I by SAA on HDL accounts for the lower level of HDL-cholesterol seen in active sarcoidosis.

Serum amyloid A and high‐density lipoprotein cholesterol: serum markers of inflammation in sarcoidosis and other systemic disorders

Hypocholesterolemia has been observed in several inflammatory diseases such as rheumatoid arthritis, myeloproliferative disorders, systemic lupus erythematosus and sarcoidosis. Serum amyloid A is an acute‐phase reactant that is related to the high‐density lipoprotein cholesterol. This review discusses the relationship between the activation of the cells of the monocyte‐macrophage system, determined by the serum amyloid A levels, and the lipid metabolism, measured as alterations in plasma lipoprotein concentrations. The mechanisms of this association during acute inflammation are also discussed in this review.

Combined portal and pulmonary hypertension in sarcoidosis.

A case is reported of a 48-year-old man previously diagnosed as having mitral valvular disease, who was admitted for evaluation of chronic cor pulmonale. Seven years before admission, an intraoperative liver biopsy had shown multiple noncaseating granulomas. The further course was characterized by progressive chronic intrahepatic cholestasis and portal hypertension. Right heart catheterization revealed a mean pulmonary artery pressure of 43 mm Hg and a normal wedge pressure (5 mm Hg). A perfusion lung scan was normal. Open lung biopsy demonstrated noncaseating granulomas and extensive pulmonary fibrosis. To our knowledge, only one case of sarcoidosis with combined portal and pulmonary hypertension has previously been described.

Molecular imaging in sarcoidosis.

Purpose of review In recent years molecular imaging techniques have made important advances as regards the study of sarcoidosis. This paper reviews new developments in these techniques as well as their present role and limitations in the assessment of patients with sarcoidosis. Recent findings PET with 18F-fluorodeoxyglucose (18F-FDG PET) has proved to be more sensitive than 67gallium (67Ga) scan for assessing the inflammatory activity of sarcoidosis. Integrated 18F-FDG PET/computed tomography (CT) scanners have improved diagnostic accuracy, and an emerging role for 18F-FDG PET/CT in monitoring therapy has been described. The use of MRI is well established in neurosarcoidosis and musculoskeletal sarcoidosis. MRI is also the test of choice in suspected cardiac sarcoidosis. It provides anatomical information and quantification of ventricular function, and reveals very early changes in the signal of the myocardium in delayed enhancement. Summary 18F-FDG PET/CT is useful in the detection of occult granuloma sites and residual activity in patients with fibrotic pulmonary sarcoidosis. It has an emerging role in the therapeutic management of patients with multisystemic sarcoidosis. MRI is indicated when neurosarcoidosis or cardiac or musculoskeletal involvement is suspected. Although most lesions detected are nonspecific in appearance, some patterns may be present in the early stages.

High expression of p21Waf1 in sarcoid granulomas: a putative role for long‐lasting inflammation

In sarcoid granulomas, apoptotic events are reduced, which explains their characteristic long‐lasting inflammation. We have described that interferon‐γ (IFN‐γ) inhibits apoptosis in macrophages through the expression of p21Waf1. Here, we explore the molecular mechanisms involved in the inhibition of apoptosis in sarcoid granulomas. We analyzed skin biopsies from 19 sarcoidosis patients and 16 controls. Total RNA was subjected to semiquantitative reverse transcriptase‐polymerase chain reaction analysis. There was no difference found in the expression of proapoptotic (Bax and Bcl‐Xs) or antiapoptotic (Bcl‐2 and Bcl‐XL) genes nor in the expression of the tumor suppressor gene p53. Furthermore, the expression of IFN‐γ and the cdk inhibitors p21Waf1 and p27Kip1 were analyzed. IFN‐γ was detected in 37% of the sarcoidosis patients, and controls were negative (P<0.02). In addition, a higher proportion of patients expressing p21Waf1 (58%) versus controls (12%) was found (P<0.005). There was a significant correlation between the expression of IFN‐γ and p21Waf1 (r=0.69) and between p21Waf1 and fibronectin (r=0.65). Finally, using immunohistochemistry, high p21Waf1 reactivity was observed inside the granuloma. We conclude that the high levels of p21Waf1 in sarcoidosis may explain the absence of apoptosis in the granuloma and the persistence of inflammation.

Vertebral and Rib Sarcoidosis: Long-Term Clinical Remission with Methotrexate

Abstract: We describe a patient with bilateral hilar lymphadenopathy shown on a chest radiograph and supraclavicular lymphadenopathy. Biopsy of a supraclavicular lymph node showed non-caseating granulomas. A diagnosis of sarcoidosis was made and no treatment was given. One year later she complained of cervical and lumbar pain and decreasing strength of the right hand. Magnetic resonance imaging of the spine showed multiple lesions within the vertebral bodies of six vertebrae, and thoracic computed tomography showed partial destruction of the first right rib. A biopsy of the second lumbar vertebra demonstrated non-caseating granulomas. Corticosteroid treatment was unsuccessful and long-term remission of the symptoms was achieved with a weekly low dose of methotrexate.

Corticosteroid therapy increases HDL-cholesterol concentrations in patients with active sarcoidosis and hypoalphalipoproteinemia

BACKGROUND We have previously reported that the decrease in high-density lipoprotein (HDL)-cholesterol that is observed in patients with untreated sarcoidosis is limited to those with active disease. AIM To determine the effect of corticosteroids, used in the treatment of active sarcoidosis, on the reported lipoprotein metabolism abnormalities. METHODS We studied 62 patients with biopsy-proven sarcoidosis, all of them with active disease. Sarcoidosis activity was evaluated by means of clinical, chest X-ray, gallium-67 scan, serum angiotensin-converting enzyme (peptidyl-dipeptidase A) values, and pulmonary function tests. A total of 40 patients were not treated with prednisone and 22 patients were treated with prednisone. The mean daily prednisone dosage in the treated patients with sarcoidosis was 20 mg and the mean duration of prednisone therapy was 6 months. Analysis of lipoprotein metabolism included: serum cholesterol, low-density lipoprotein (LDL)-cholesterol, HDL-cholesterol, HDL(2)-cholesterol, HDL(3)-cholesterol, apolipoprotein (apo) A-I, apo B, and triglyceride concentrations. RESULTS When patients with active sarcoidosis not treated with prednisone were compared to those treated with prednisone, the former had significantly lower HDL-cholesterol (1.17+/-0.36 vs. 1.42+/-0.42 mmol/l; P=0.01) and HDL(2)-cholesterol (0.37+/-0.18 vs. 0.53+/-0.25 mmol/l; P=0.009) levels. Multiple regression analysis demonstrated that the HDL-cholesterol (P=0.004), HDL(2)-cholesterol (P=0.002), HDL(3)-cholesterol (P=0.02), and apo A-I (P=0.02) levels were the variables independently and significantly associated with steroid therapy. CONCLUSIONS Corticosteroid therapy, used in the treatment of active sarcoidosis, increased HDL-cholesterol levels to those seen in inactive disease. These changes are manifestations of reducing disease activity.

Low levels of high density lipoprotein cholesterol in patients with active sarcoidosis

OBJECTIVE To determine lipoprotein abnormalities in patients diagnosed with sarcoidosis and their relation to disease activity. METHODS We studied 90 patients with biopsy-proven sarcoidosis who had not been treated with corticosteroids (44 with active disease and 46 with inactive disease) and 147 control subjects. Sarcoidosis activity was evaluated by means of clinical, chest X-ray, gallium-67 scan, serum angiotensin converting enzyme (peptidyl-dipeptidase A) values, and pulmonary function tests. Analysis of lipoprotein metabolism included: serum cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, HDL2-cholesterol, HDL3-cholesterol, apolipoprotein A-I, apolipoprotein B, and triglyceride concentrations. RESULTS Patients with active sarcoidosis had significantly low HDL-cholesterol concentrations (1.15 +/- 0.27 mmol/l) as compared with inactive sarcoid patients (1.40 +/- 0.34 mmol/l) and with the healthy control subjects (1.49 +/- 0.34 mmol/l) (p = 0.00001). The decrease in the HDL-cholesterol concentrations seen in patients with active disease was due mainly to the cholesterol bound to HDL2 subfraction. Apolipoprotein A-I concentrations were significantly reduced in the patients with active disease (1.18 +/- 0.32 g/l) compared to the healthy controls (1.38 +/- 0.27 g/l) (p = 0.003). There were no significant differences in cholesterol, triglyceride, LDL-cholesterol or apolipoprotein B values among the three groups. Multivariate logistic regression analysis showed that HDL-cholesterol was the only variable independently associated with disease activity (Regression Coefficient b = -0.03; S.E. = 0.008; p = 0.0005). CONCLUSION The decrease in HDL-cholesterol that is observed in patients with sarcoidosis is limited to those with active disease.