Health & Medical Lung Health

MEDLINE Abstracts: Sarcoidosis

MEDLINE Abstracts: Sarcoidosis
What's new concerning sarcoidosis? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pulmonary Medicine.

Sharma SK, Balamurugan A, Pandey RM, Saha PK, Mehra NK
Am J Respir Cell Mol Biol. 2003;29:225-231

Host genetic factors are known to contribute to disease susceptibility and course in sarcoidosis. They may also be important in defining the pattern of disease presentation and progression, as well as its overall prognosis. We have studied human leukocyte antigen (HLA) class I (n = 31) and class II alleles (n = 56) in a cohort of Indian patients with sarcoidosis and 275 healthy control subjects from north India. Although no specific HLA class I allele association was found among sarcoidosis, the functional classification of HLA-A, -B, and -Cw alleles into supertypes revealed an increased frequency of group 2 ligands (Cw2, Cw4, Cw5) for the Killer cell Ig-like receptors (KIR2DL1) in the patient group as compared with control subjects. Among class II alleles, positive association of DRB1*11, DRB1*14, DQA1*0101/4, and DQB1*0503 alleles with the disease was noticed. Clinical follow-up of the patient cohort up to a 5-year period showed a predominant occurrence of DRB1*14 and its linked DQ alleles in patients with insidious onset, advanced disease on chest radiographs, and chronic course with frequent relapses on tapering off the prednisolone treatment. Further, multivariate logistic regression analysis revealed that the presence of DRB1*11 (odds ratio [OR] 9) and DRB1*14 (OR 7), and absence of DRB1*07 (OR 63 and DQB1*0201(OR 3) alleles, were independent predictors of sarcoidosis. The present findings imply that HLA-associated genetic factors influence the risk for the development of sarcoidosis and disease progression.

Grutters JC, Fellrath JM, Mulder L, Janssen R, van den Bosch JM, van Velzen-Blad H
Chest. 2003;124:186-195

Objectives: To date, insufficient evidence is available to recommend serum soluble interleukin-2 receptor (sIL-2R) measurement as a routine test in the assessment of sarcoidosis. Therefore, we evaluated the clinical value of this test.
Design: Forty-seven patients with sarcoidosis, all presenting with active disease, were included in the study. Initial serum sIL-2R levels were determined by enzyme-linked immunosorbent assay, and clinical data at presentation and follow-up were collected retrospectively.
Results: The median follow-up period of all patients was 44 months (range, 6 to 100 months), and 38 patients had follow-up data present over at least 24 months. The median sIL-2R level was 1,068 U/mL (range, 248 to 4,410 U/mL; upper limit of normal, 710 U/mL). A positive correlation was found between serum sIL-2R levels and the number of CD4+ T lymphocytes in bronchoalveolar lavage (BAL) (rs = 0.53, P < .001). In accordance with this result, both sIL-2R level and the number of CD4+ T lymphocytes were elevated in stage I compared to stage III disease (P < .05). Patients with extrapulmonary disease (ED) [excluding Lofgren's syndrome] showed higher sIL-2R levels than those presenting with only pulmonary sarcoidosis (P = .001). No relation was found between sIL-2R level and response to treatment, and there was no association between sIL-2R levels and radiographic evolution and lung function outcome.
Conclusions: Our data suggest a role for serum sIL-2R as marker of pulmonary disease activity and ED in patients with sarcoidosis.

Utz JP, Limper AH, Kalra S, et al
Chest. 2003;124:177-185

Background: Tumor necrosis factor (TNF)-alpha is produced by macrophages and other cells, and is believed to participate in granulomatous inflammation. Targeted antagonism of TNF-alpha has been proposed as a novel treatment strategy for sarcoidosis. Etanercept is a dimeric fusion protein that binds specifically to TNF-alpha, rendering it biologically inactive.
Objective: To assess whether etanercept has potential efficacy in the treatment of progressive pulmonary sarcoidosis.
Design: Prospective, open-label, phase-2 treatment trial.
Setting: Mayo Clinic, Rochester, MN.
Patients: Stage II or III progressive pulmonary sarcoidosis.
Intervention: Etanercept, 25 mg subcutaneously twice weekly.
Measurements: Pulmonary function, chest radiographs, dyspnea, and TNF-alpha levels in serum and BAL fluid.
Results: The study was terminated after the enrollment of 17 patients due to an early-stop clause of the pretrial study design related to excessive treatment failures. Neither absolute levels of TNF-alpha nor TNF-alpha activity in the serum, BAL fluid, or alveolar macrophages were able to predict which patients would respond to etanercept.
Conclusions: In patients with progressive stage II or III pulmonary sarcoidosis, etanercept was frequently associated with early or late treatment failure. These data would not support the design of a large multicenter randomized trial comparing etanercept with conventional corticosteroid therapy.

Inomata S, Shijubo N, Yamamoto-Miyajima S, et al
Nihon Kokyuki Gakkai Zasshi. 2003;41:356-360

A 30-year-old woman presented with multiple nodular shadows, which enclosed a cavity on a chest radiograph. Chest computed tomographic (CT) images showed mediastinal lymphadenopathy, and multiple nodular opacities enclosing a cavity. Histopathological findings of biopsy specimens from the lung and mediastinal lymph nodes revealed noncaseating epithelioid cell granulomas without any evidence of Mycobacterium or fungal growth. The lesion in the lung included granulomatous vasculitis. Even without corticosteroid or any other therapy, the lung lesions resolved and the cavity disappeared. We report a case of sarcoidosis with primary acute cavitation.

Sharma SK, Mohan A
Indian J Med Res. 2002;116:221-247

Sarcoidosis is now recognized as a member of a large family of granulomatous disorders and has been reported from all parts of the world. Current evidence points to genetic predisposition and exposure to yet unknown transmissible agent(s) and/or environmental factors as etiological agents. Depending on the organ systems involved, patients with sarcoidosis present themselves to various specialities; pulmonary involvement is by far the commonest and occurs in about 90% of the patients. The diagnosis is based on a compatible clinical and/or radiological picture, histopathological evidence of non-caseating granulomas in tissue biopsy specimens and exclusion of other diseases capable of producing similar clinical or histopathological appearances. Sarcoidosis is an underdiagnosed disease in India. However, owing to the increasing awareness, it is being diagnosed more frequently than a few decades ago. Most Indian patients with sarcoidosis are males and present in the fourth or fifth decade of life. The disease runs a benign course with spontaneous remission of the activity though some degree of residual pulmonary function abnormality persists. Only a minority of the patients develop complicated disease. Corticosteroids remain the mainstay of treatment. For asymptomatic patients with pulmonary sarcoidosis, no therapy is required. Corticosteroid treatment should be considered in symptomatic patients with evidence of radiological or pulmonary function deterioration. Treatment under close clinical monitoring should be tailored to suit the needs of the individual patient. Sometimes steroid-sparing alternative treatments may be beneficial. In this review, the current understanding of the global scenario and Indian perspective of sarcoidosis are critically reviewed.

Oltmanns U, Schmidt B, Hoernig S, Witt C, John M
Exp Lung Res. 2003;29:315-328

The study was designed to determine whether alveolar macrophages (AM) in acute pulmonary sarcoidosis release in vitro the anti-inflammatory cytokine interleukin (IL)-10. To learn more about the coherence between IL-10 and proinflammatory cytokines in active sarcoidosis, the release of interferon (IFN)-gamma, macrophage inhibitory protein (MIP)-1alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) was studied and additionally compared to normal controls and patients with pneumonia and interstitial lung fibrosis. AM were obtained by bronchoalveolar lavage from 13 patients with active sarcoidosis, 8 patients with interstitial lung fibrosis, 10 patients with bacterial pneumonia, and 14 normal controls. The spontaneous and stimulated (tumor necrosis factor [TNF]-alpha, IL-1beta) cytokine release was measured in the supernatant of cultured AM by enzyme-linked immunosorbent assay (ELISA). Unstimulated AM from sarcoidosis patients released more IL-10, IFN-gamma, MIP-1alpha, and GM-CSF than normal controls and patients with pneumonia and interstitial lung disease. Stimulation with TNF-alpha or IL-1beta increased the MIP-1alpha and GM-CSF release from AM of normal controls and patients with pneumonia and interstitial lung disease: however, no further enhancement of MIP-1alpha and GM-CSF production was observed in AM from sarcoidosis patients. Exogenous IL-10 reduced the spontaneous and stimulated MIP-1alpha and GM-CSF release in sarcoidosis to a lesser extent than in controls and patients with fibrosis and pneumonia. The up-regulated IL-10 in active pulmonary sarcoidosis may be a compensatory response to the enhanced expression of proinflammatory cytokines in order to down-regulate the inflammatory process. The results suggest an involvement of the anti-inflammatory cytokine IL-10 in the immunopathogenesis of sarcoidosis.

Hauber HP, Gholami D, Meyer A, Pforte A
Thorax. 2003;58:519-524

Background: Sarcoidosis is a systemic granulomatous disorder of unknown origin. Lymphocytic inflammation is dominated by expression of Th1 type cytokines such as tumour necrosis factor alpha (TNF alpha). Interleukin 13 (IL-13) is a Th2 cytokine that is expressed by CD4+ T cells and has been shown to suppress TNF alpha in human blood monocytes. The role of IL-13 as a possible anti-inflammatory cytokine in sarcoidosis was investigated.
Methods: mRNA expression of IL-13, IL-4, IL-10, and TNF alpha in bronchoalveolar lavage (BAL) fluid cells and peripheral mononuclear blood cells (PBM) of 18 patients with sarcoidosis and 9 healthy controls was assessed using RT-PCR. In addition, IL-13 protein levels in BAL cell culture supernatants from 12 patients and all controls were measured and immunocytochemistry of IL-13 protein was performed in BAL fluid cells of 8 patients. TNF alpha concentrations were measured with and without stimulation with recombinant human (rh) IL-13, rhIL-10, and lipopolysaccharide (LPS).
Results: IL-13 mRNA expression was significantly increased in BAL cells and PBM of patients compared with controls (P < .05). No significant difference was found in IL-4 mRNA or IL-10 mRNA expression in BAL fluid cells or PBM between the 2 groups. TNF alpha mRNA expression was significantly higher in BAL fluid cells of patients than controls (P < .05). IL-13 protein levels in BAL cell culture supernatants were slightly raised in half the patients investigated but in only 2 controls. Immunocytochemistry detected IL-13 protein in alveolar macrophages of patients. IL-13 led to decreased TNF alpha concentrations (P < .05).
Conclusions: IL-13 expression is increased in BAL cells and PBM in sarcoidosis and IL-13 is secreted from BAL cells. Alveolar macrophages may be the cellular source. These data suggest that IL-13 might have an anti-inflammatory effect by acting on TNF-alpha.

Gibejova A, Mrazek F, Subrtova D, et al
Am J Respir Crit Care Med. 2003;167:1695-1703

In this study, messenger RNA (mRNA) expression for novel T lymphocyte chemoattractants, leukotactin-1, macrophage inflammatory protein (MIP)-3 alpha, and MIP-3 beta was investigated in bronchoalveolar lavage fluid (BALF) cells from patients with sarcoidosis, a T cell-mediated disease with typical CD4+ lymphocyte alveolitis. Of these 3 chemokines, only MIP-3 beta mRNA was upregulated in sarcoidosis, and therefore, protein levels of this chemokine, its pharmacologic regulation, and association with disease clinical course were explored. MIP-3 beta protein concentrations were elevated in BALF from sarcoid patients compared with control subjects (P = .001) and in patients with chest X-ray stage II chemokine protein levels were increased compared with stage I (P = .003). MIP-3 beta protein was associated predominantly with alveolar macrophages and correlated with BALF lymphocytes and T cell subsets. mRNA expression for the MIP-3 beta receptor, CC chemokine receptor 7, was increased in sarcoidosis and correlated with MIP-3 beta protein levels. MIP-3 beta mRNA and protein expression in BALF cells was suppressed by dexamethasone and cyclosporine A in vitro. In conclusion, MIP-3 beta is implicated in T lymphocyte recruitment in sarcoidosis, is associated with disease progression, and is downregulated by drugs used for sarcoidosis treatment. This novel chemokine, therefore, represents a candidate for studies of sarcoidosis pathobiologic mechanisms.

Hauber HP, Beyer IS, Meyer A, Pforte A
Respir Med. 2003;97:521-527

Recently, increased expression of interleukin-18 (IL-18) has been shown in sarcoid airway epithelium. However, IL-18 expression has not been investigated extensively in bronchoalveolar lavage (BAL) cells in sarcoidosis yet. Expression of IL-18 and tumour necrosis factor-alpha (TNF alpha) mRNA in cells of the BAL of 23 patients with sarcoidosis and 9 healthy volunteers was determined using semiquantitative RT-PCR. IL-18 protein in BAL cells was investigated by immunocytochemistry (ICC). IL-18 protein levels in BAL cell culture supernatants from patients and controls with and without LPS stimulation were measured by enzyme-linked immunosorbent assay. BAL cells from patients were stimulated with either IL-10 or IL-13; and IL-18 protein levels were determined. IL-18 mRNA expression was significantly decreased in BAL cells of patients compared to control subjects (1.62 ± 0.27 vs. 4.29 ± 0.77, P < .05). TNF alpha mRNA expression was significantly increased in BAL cells of patients in comparison to control subjects (0.63 ± 0.09 vs. 0.11 ± 0.08, P < .05). ICC showed less positive alveolar macrophages in sarcoidosis patients than in control subjects (26% vs. 53%). IL-18 protein levels did not differ significantly between both groups. Stimulation with IL-10 significantly reduced IL-18 protein concentration in sarcoidosis patients. Our results suggest that BAL cells may not be the main source of IL-18 production in sarcoidosis in vivo. Since IL-18 production of BAL cells was not impaired in culture, anti-inflammatory cytokines might contribute to decreased IL-18 expression in vivo.

Iannuzzi MC, Maliarik MJ, Poisson LM, Rybicki BA
Am J Respir Crit Care Med. 2003;167:1225-1231

Sarcoidosis, in the United States, more commonly and severely affects African Americans. HLA associations with sarcoidosis have been reported, but most studies used case-control designs, which may produce biased results because of population stratification. We examined transmission of HLA-DQB1 alleles in 225 African-American families with at least one offspring with sarcoidosis. Of 5 low-resolution HLA-DQB1 alleles, *02 and *06 showed significant deviation in transmission patterns to affected offspring. High-resolution typing of these allelic subsets revealed that HLA-DQB1*0201 was transmitted to affected offspring half as often as expected (P = .001), whereas DQB1*0602 was transmitted to affected offspring about 20% more often than expected (P = .029). Examining interactions between *0201 and *0602 alleles and environmental exposures showed that *0602 varied little with respect to exposure, but sarcoidosis risk associated with *0201 often depended on exposure status. Alternatively, the *0602 allele in affected probands was associated with radiographic disease progression, but the *0201 allele showed no significant correlation with phenotype. Major differences in the amino acid sequences encoded by *0201 and *0602 alleles exist, which may explain the differential effects these alleles have on sarcoidosis susceptibility and progression in African Americans.

Lopez Garcia-Gallo C, Ussetti P, Diaz B, Pablo Ad A, Laporta R
Arch Bronconeumol. 2003;39:187-189

Pulmonary sarcoidosis is an idiopathic granulomatosis with a clinical picture involving dyspnea, coughing, chest pain, and characteristic radiologic changes. A review of English and Spanish language publications (PubMed 1990 through 2002) suggests that our report of a case of pulmonary sarcoidosis associated with primary antiphospholipid syndrome is the first one in the literature for this period. The patient was a 35-year-old man with venous thrombosis who later developed pulmonary sarcoidosis. The clinical course was not favorable in spite of good prognostic factors. We conclude that the association of these two clinical conditions is rare and that the presence of antiphospholipid syndrome may lead to greater morbidity and mortality.

Huang WJ, Li WF, Xu H, Fang Y, Li ZB
Di Yi Jun Yi Da Xue Xue Bao. 2003;23:430-434

Objective: To facilitate the diagnosis and treatment of pulmonary sarcoidosis.
Method: The clinical data of 15 cases of pulmonary sarcoidosis were retrospectively analyzed.
Results: Among these patients, 7 were identified with respiratory symptoms as the initial clinical representations, and 6 patients initially presented extrapulmonary symptoms, with 2 patients having no discomfort. Chest X-ray and lung computed tomography (CT) scan results of 13 cases showed symmetrical lymph node enlargement in the bilateral lung hilus and mediastinum. Twelve patients had increased serum angiotensin-converting enzyme levels, and 10 had increased erythrocyte sedimentation rate, with only 1 case showing positive result in purified protein derivative skin test.
Conclusion: Pulmonary sarcoidosis has atypical clinical symptoms, and the diagnosis should be reached by a careful evaluation of the clinical representations in conjunction with X-ray, CT, and laboratory test results.

Shigehara K, Shijubo N, Ohmichi M, et al
Clin Exp Immunol. 2003;132:152-157

In sarcoidosis, a T helper 1 (Th1) response is an essential event and the up-regulation of interleukin-12 (IL-12) has been detected in affected disease sites. In order to investigate the clinical usefulness of circulating IL-12, we measured the serum concentrations of IL-12 by ELISA and performed immunohistochemistry using specific MoAbs for IL-12 in the lungs and scalene lymph nodes of patients with sarcoidosis. The serum concentration of IL-12 p40 was detectable in all 45 patients with pulmonary sarcoidosis and 18 normal controls, whereas that of IL-12 p70 was undetectable. The serum concentrations of IL-12 p40 in pulmonary sarcoidosis were significantly higher than those of the normal controls, especially in cases with abnormal intrathoracic findings detected by chest roentogenogram. The serum concentrations of interferon-gamma (IFN-gamma) also increased compared with those of normal controls and there was a significant positive correlation between the serum concentrations of IL-12 p40 and IFN-gamma. Furthermore, serum angiotensin-converting enzyme (ACE) and lysozyme, which are known to be useful markers for disease activity in sarcoidosis, correlated well with the serum concentrations of IL-12 p40. The positive 67Ga scan group (for lung field) had significantly elevated serum IL-12 p40 levels compared with those of the negative group. No bioactivity of IL-12 p70 was detected in 3 sarcoid cases' sera by using the IL-12 responsive cell line. Finally, the immunohistochemical approach revealed that IL-12 p40 was expressed in the epithelioid cells and macrophages of sarcoid lungs and lymph nodes. We concluded that the production of IL-12 p40 was far greater in the sera and we have demonstrated this to be a useful clinical marker for disease activity and the Th1 response in pulmonary sarcoidosis.

Mixides G, Guy E
Can Respir J. 2003;10:114-116

A rare case of sarcoidosis is presented. A 32-year-old white woman initially diagnosed with asthma was to undergo thyroidectomy to eliminate what was thought to be the real source of her symptoms. Instead, the cause was found to be sarcoidosis involving only the major airways, without intrathoracic adenopathy, atelectasis, pulmonary parenchymal infiltrates, or evidence of extra-pulmonary disease. She rapidly responded to systemic glucocorticoids, which later was supplemented successfully by inhaled glucocorticoids for persistent cough.

Ziegenhagen MW, Rothe ME, Schlaak M, Muller-Quernheim J
Eur Respir J. 2003;21:407-413

The aim of the present study was to determine which bronchoalveolar lavage fluid (BALF) and serological parameters reflect the severity of newly diagnosed pulmonary sarcoidosis. Seventy-four previously untreated sarcoid patients were categorised into 3 groups: 10 patients with Lofgren's syndrome, 51 patients with stable disease, and 13 patients with progressing disease requiring systemic steroid treatment. Total BALF cell count, percentage of alveolar lymphocytes, and lymphocyte CD4/ CD8 ratio were not associated with severity of disease. Interestingly, a significant increase in percentages of BALF neutrophils (5.2 ± 1.1%) and eosinophils (1.7 ± 0.6%) was observed in sarcoid patients with progressing disease. Elevated percentages of these 2 cell types were the only BALF parameters associated with a more frequent necessity for systemic steroid therapy. This association between an elevated percentage of BALF neutrophils and the necessity for steroid treatment was observed in advanced as well as early sarcoidosis (radiological types I and II). Serum levels of soluble interleukin-2 receptor and neopterin were significantly elevated in progressing disease compared to stable disease or Lofgren's syndrome. The present results demonstrate that increased percentages of neutrophils (> 3.0%) and eosinophils (> 1%) in bronchoalveolar lavage fluid from newly diagnosed pulmonary sarcoidosis is associated with a significantly higher risk of necessity for steroid therapy and may be helpful markers of progressive disease. Furthermore, of the serological parameters investigated, only serum levels of soluble interleukin-2 receptor and neopterin were associated with disease severity.

Miao JZ, Du DJ, Zeng P
Zhonghua Jie He He Hu Xi Za Zhi. 2003;26:14-17

Objective: To evaluate the effects of corticosteroids on the prognosis of sarcoidosis.
Methods: There was analysis and comparison of the prognosis of natural course and corticosteroids therapy of 133 patients with sarcoidosis diagnosed by biopsy pathologic histology follow-up over 4 years.
Results: Six of the 7 patients with ocular sarcoidosis were cured by oral prednisone (PRED), and 1 patient receiving intraocular dexamethasone lost his sight. In patients with extra-pulmonary sarcoidosis who were not treated, 33 of the 38 cases underwent spontaneous remission, but another 5 cases progressed. Twenty-two of the 26 patients with stage I pulmonary disease underwent spontaneous remission, 3 progressed, with only 1 case cured by PRED therapy. In the 55 patients with stage II pulmonary sarcoidosis who received PRED therapy, the chest roentgenogram and lung function were back to normal in 45 cases, but 10 cases failed. One patient with stage II pulmonary disease without treatment progressed to stage IV. Three patients with stage III pulmonary sarcoidosis were cured by PRED therapy, but 3 patients with stage IV sarcoidosis failed to respond to PRED therapy.
Conclusions: Systematic therapy with oral corticosteroids for ocular and stage II approximately III pulmonary sarcoidosis is a curative intervention. Corticosteroids can relieve symptoms, reduce inflammation, and improve the prognosis of ocular and pulmonary sarcoidosis.

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