Disease Activity In Sarcoidosis Research Articles

Plasma level of interferon γ induced protein 10 is a marker of sarcoidosis disease activity

RationaleSarcoidosis is an idiopathic granulomatous disorder with heterogeneous clinical manifestations and variable prognosis. Monitoring disease activity is important to identify patients requiring treatment. Several cytokines have previously been shown to be elevated in the serum of patients with sarcoidosis and may be useful biomarkers of disease activity. ObjectivesTo identify novel biomarkers of sarcoidosis disease activity. To identify the relationship between plasma cytokines, disease severity and prognosis. MethodsThe study was approved by the institutional review board. Plasma concentration of 19 cytokines was measured in 112 subjects with chronic sarcoidosis and 52 matched controls, using the bead-based Milliplex xMAP multiplex technology. Plasma levels of individual cytokines were compared between the two groups, and between the groups with clinically active vs. inactive disease. Sensitivity, specificity and receiver operating characteristics curves were used to evaluate biomarker performance. Linear regression analyses were performed to identify associations between cytokine levels, pulmonary function tests and changes in pulmonary function. Measurements and main resultsSubjects with sarcoidosis had higher plasma levels of interferon gamma induced protein 10 (IP-10) and tumor necrosis factor α (TNFα). IP-10 had the highest sensitivity and specificity in identifying active disease. Higher levels of IP-10 and TNFα were associated with greater disease severity and better prognosis. ConclusionsIP-10 is a potentially useful biomarker of sarcoidosis and its severity.

Reliability and Convergent Validity of the Cutaneous Sarcoidosis Activity and Morphology Instrument for Assessing Cutaneous Sarcoidosis

A validated scoring system is essential to assess the effect of therapeutic interventions on a disease. The instrument introduced here captures sarcoidosis disease activity in a reliable, reproducible manner, which will help standardize clinical trial outcomes and allow comparative efficacy studies in the future and may help lead to more robust data regarding the effect of different treatments on cutaneous sarcoidosis. To assess the reliability and convergent validity of the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) and Sarcoidosis Activity and Severity Index (SASI) for evaluating cutaneous sarcoidosis outcomes. Cross-sectional study evaluating cutaneous sarcoidosis disease severity using CSAMI, SASI, and Physician's Global Assessment (PGA) as reference in the dedicated cutaneous sarcoidosis clinic of a teaching hospital. Eight dermatologists evaluating cutaneous sarcoidosis in 11 patients. Evaluation using the study instruments. Primary outcomes included interrater and intrarater reliability and convergent validity; secondary outcomes, correlation with quality-of-life measures and time required for completion. All instruments demonstrated good to excellent intrarater reliability. Interrater reliability was excellent for CSAMI Activity scores (intraclass correlation coefficient, 0.82 [95% CI, 0.66-0.94]) and fair to poor for CSAMI Damage scores (0.42 [0.21-0.72]), modified Facial SASI (0.40 [0.17-0.72]), and PGA scores (0.40 [0.18-0.70]). CSAMI Activity and Damage scores and modified Facial SASI all demonstrated convergent validity with statistically significant correlations with PGA scores. Trends for correlations were seen between CSAMI scores and specific Skindex-29 quality-of-life domains. Although CSAMI required longer time to complete than SASI, both were scored within adequate time for use in clinical trials. CSAMI appears to be a reliable and valid outcome instrument to measure cutaneous sarcoidosis and may capture a wide range of body surface and cutaneous morphologic types. This instrument can be adopted into clinical practice and clinical trials to allow physicians to assess the intensity of their patients' cutaneous sarcoidosis disease activity. Widespread use of one metric for disease severity assessment can help standardize the evaluation of the effect of various treatments on the disease. Future research is necessary to demonstrate its sensitivity to change and to confirm its correlation with quality-of-life measures.

S96 A combination score of raised sACE, lymphopenia and hypergammaglobulinaemia correlates with active disease on thoracic CT scan of patients with pulmonary sarcoidosis

IntroductionClinical decisions about treatment in pulmonary sarcoidosis, and phenotyping research studies are hampered by inability to objectively measure disease activity. We reviewed 120 consecutive patients from our Sarcoidosis Clinic and...

Central skeletal sarcoidosis: a case report with sustained remission only on methotrexate, and a literature review on the imaging approach, treatment, and assessment of disease activity

We report a case of multifocal involvement of the central skeleton in a patient with long-term stage I pulmonary sarcoidosis who experienced sustained clinical remission of musculoskeletal symptoms while on methotrexate (MTX) alone. Concomitant normalization of laboratory tests [inflammatory markers and angiotensin-converting enzyme (ACE) levels] was observed, and improvements were seen in follow-up magnetic resonance imaging (MRI) of the lumbar spine and bone scintigraphy. To date, there are no specific tools for the assessment of skeletal disease activity in sarcoidosis. Our case suggests that inflammatory markers and ACE levels, when initially elevated, bone scintigraphy, and-in the case of vertebral involvement-MRI could serve as such tools. A literature review on the imaging approach, treatment, and disease activity monitoring of skeletal sarcoidosis is also provided.

Quantiferon test for tuberculosis screening in sarcoidosis patients

Tumour necrosis factor-alpha (TNF-α) inhibitors have been introduced in the treatment of refractory sarcoidosis. These biologics may reactivate latent tuberculosis infection (LTBI). Despite its known limitations, the tuberculin skin test (TST) is currently used for the diagnosis of LTBI in Danish sarcoidosis patients. We report the results of a screening using the interferon-gamma release assay (IGRA) QuantiFERON TB Gold (QFN) for the diagnosis of LTBI. We aimed to assess whether the QFN is reliable for diagnosing LTBI among sarcoidosis patients and if results are influenced by disease activity or immunosuppressive treatment. A prospective study was performed from 2005 to 2007 among sarcoidosis patients who were candidates for TNF-α inhibitor treatment. Information on immunosuppressive treatment was obtained from the medical records. Disease activity was assessed by biochemistry, chest roentgenograms and pulmonary function tests. The predictive value of QFN results was evaluated by follow-up in the Danish National Tuberculosis Registry. A total of 44 sarcoidosis patients (22 men) with a median age of 39 y (range 25-59 y) were enrolled; 93% had a negative QFN test result and 7% had an indeterminate result. Forty-three percent had disease activity and 57% (n = 25) received immunosuppressive treatment. There was no significant difference in QFN interferon-γ response between subjects with or without disease activity (p > 0.4) and between treated vs non-treated patients (p > 0.5). At follow-up using the Danish tuberculosis registry, there was no occurrence of tuberculosis among study participants. The predictive value of the QFN seems good among Danish sarcoidosis patients and the results appear to be unaffected by sarcoidosis disease activity and immunosuppressive treatment.

Serum soluble IL-2 receptor level in patients with sarcoidosis

Serum levels of soluble IL-2 receptors (sIL-2R) by an ELISA method in 28 patients with sarcoidosis and 16 healthy controls were studied, and the source of sIL-2R was further examined. sIL-2R in serum was significantly higher in sarcoidosis than in controls. In sarcoidosis sIL-2R in serum significantly correlated with serum ACE level, and was significantly higher in stage II or III patients than in stage O patients. sIL-2R in supernatants of cultured monocytes (Mo) and alveolar macrophages (AM) was significantly higher in sarcoidosis than in controls. sIL-2R in supernatants of cultured T lymphocytes obtained from peripheral blood or BALF was barely detectable in sarcoidosis, while it was undetectable in controls. Furthermore, sIL-2R in serum was significantly correlated with sIL-2R in supernatants of cultured Mo and AM. These results indicate that sIL-2R in serum is an useful index of the disease activity of sarcoidosis, and may be mainly derived from IL-2R on Mo and AM.

Clinical aspects of sarcoidosis with autoantibodies

Among 64 sarcoidosis cases, 6 cases with autoantibodies or autoimmune disorders are described. All 6 cases were females over 40 years old, and made up 24% of the original 25 patients over 40 years old. Rheumatoid factor was observed in 2 cases, anti-DNA antibody in 4 cases and anti-microsomal antibody in 2 cases. Four cases of sarcoidosis were associated with ITP or Hashimoto's disease or rheumatoid arthritis. The presence of these autoantibodies or autoimmune diseases seemed to correlate with continued disease activity of sarcoidosis. The analysis of the clinical features of sarcoidosis with coexistent autoimmune diseases may clarify immunologic processes involved in the pathogenesis of both disorders and also provide clues to understanding the relatively poor clinical outcome of longstanding sarcoidosis.

Increased Expression of CD16, CD69, and Very Late Antigen-1 on Blood Monocytes in Active Sarcoidosis

Different types of immune cells are involved in the formation of granulomas, a hallmark of pulmonary sarcoidosis. Proinflammatory monocytes are activated circulating monocytes thought to be related to the initial events of granuloma formation. We tested the hypothesis that peripheral blood monocytes in patients with active pulmonary sarcoidosis have an activated phenotype and, secondly, that measuring this activation status can provide a new tool for monitoring disease activity. Blood was collected of 23 steroid-naive patients presenting with pulmonary sarcoidosis and 10 healthy control subjects. Expression of CD16 (Fc-gamma type III receptor), CD69 (a general activation marker of cells of the hematopoietic lineage), and the integrin very late antigen (VLA)-1 (on interaction with extracellular matrix compounds mediates cell adhesion) was measured by flow cytometry. Percentages of monocytes expressing CD16, CD69, and VLA-1 in patients vs control subjects were 56.2 +/- 4.1% vs 12.2 +/- 2.4% (p < 0.0001), 87.3 +/- 2.1% vs 8.6 +/- 3.3% (p < 0.0001), and 66.5 +/- 3.6% vs 11.2 +/- 2.3% (p < 0.0001), respectively. Moreover, the CD69+VLA-1+ monocyte subset, abundantly present at disease presentation, was found to decrease to normal levels during follow-up with disease remission. Peripheral blood monocytes from patients with pulmonary sarcoidosis show a highly activated phenotype. Phenotyping circulating monocytes might be a promising tool for monitoring sarcoidosis disease activity but needs further investigation.

Chitotriosidase as a marker of disease activity in sarcoidosis

Sarcoidosis is a chronic granulomatous inflammation. The clinical spectrum in childhood is heterogeneous. Angiotensin converting enzyme (ACE) activity is used as a marker for disease activity. Human chitotriosidase is produced in macrophages. In this study serum chitotriosidase levels were significantly higher in active sarcoidosis, than in inactive disease or healthy controls. Serum chitotriosidase concentrations may be a useful marker for monitoring disease activity in sarcoidosis.

Elevated α‐defensin levels in plasma of patients with pulmonary sarcoidosis

Pathogens such as mycobacteria and proprionibacterium have been implicated in the pathogenesis of sarcoidosis. alpha-Defensins (DF) are naturally occurring antimicrobial peptides. The aim of the present study was to assess whether DF are increased in the airway and/or systemic circulation in patients with pulmonary sarcoidosis and whether DF levels are related to sarcoidosis disease activity. DF levels in plasma and BAL fluid (BALF) were measured in 30 patients with pulmonary sarcoidosis and in 10 controls. Plasma and BALF DF levels were compared according to disease activity. Molecular forms were analysed using reverse-phase (RP) HPLC to confirm plasma and BALF DF kinetics in pulmonary sarcoidosis. DF concentrations in plasma and BALF were higher in patients with pulmonary sarcoidosis than in the controls. Plasma DF levels correlated with lysozyme but not with angiotensin-converting enzyme. These levels were high in patients in whom more organs were involved, whereas BALF DF levels were higher in patients at stage II or III than with those at sarcoidosis I. RP-HPLC showed high plasma levels of pro-defensins, DF precursors from the bone marrow, in sarcoidosis, although DF in peripheral neutrophils and BALF were the mature type. High plasma DF concentrations resulted from bone marrow stimulation and seemed to be associated with disease activity, whereas BALF DF were released from accumulated neutrophils in the lungs and may contribute to parenchymal involvement in sarcoidosis.

Chitotriosidase as a marker of disease activity in sarcoidosis

Sarcoidosis is a chronic granulomatous inflammation. The clinical spectrum in childhood is heterogeneous. Angiotensin converting enzyme activity is used as a marker for disease activity. Human chitotriosidase is produced in macrophages. In this study, serum chitotriosidase levels were significantly higher in active sarcoidosis than in inactive disease or healthy controls. Serum chitotriosidase concentrations may be a useful marker for monitoring disease activity in sarcoidosis.

Serum levels of chitotriosidase as a marker of disease activity and clinical stage in sarcoidosis

Grosso S, Margollicci MA, Bargagli E, Buccoliero R, Perrone A, Galimberti D, Morgese G, Balestri P, Rottoli P. Serum levels of chitotriosidase as a marker of disease activity and clinical stage in sarcoidosis. 2004; 64: 57-62.Background: Sarcoidosis is a systemic granulomatous disease characterized by T-lymphocyte activation and lymphocyte migration into involved organs, usually the lungs. The amounts of a number of biochemical markers, such as angiotensin converting enzyme (ACE) activity, increase in the serum of patients with sarcoidosis. Chitotriosidase is an enzyme secreted by activated macrophages able to catalyze the hydrolysis of both chitin and chitin-like substrates. Chitotriosidase is involved in defense against, and in degradation of chitin-containing pathogens such as fungi, nematodes, and insects. Methods: Forty-three patients affected by chronic sarcoidosis, in active (23 patients) or inactive (20 patients) phase, were studied. Serum levels of chitotriosidase and ACE activity were evaluated and compared with those of 32 healthy subjects. Serum chitotriosidase concentration and ACE activity were also correlated with radiographic stage of disease. Results: Individuals with chronic sarcoidosis have higher serum chitotriosidase concentrations and ACE activity than those of normal subjects. Sarcoidosis patients in the active phase of the disease had significantly higher chitotriosidase and ACE levels than those in the inactive phase. In contrast to serum ACE activity, a significant relationship between serum levels of chitotriosidase and the four radiographic stages of the disease was observed. Conclusion: Although the data need to be validated by further investigation, the observations made in this study seem to indicate that serum chitotriosidase concentrations may be a useful marker for monitoring sarcoidosis disease activity and prognosis.

Circulating soluble intercellular adhesion molecule-1 (sICAM-1) in patients with sarcoidosis.

sICAM-1 has been elevated in sera of specific inflammatory diseases, and circulating sICAM-1 concentrations reflect disease activity in these diseases. We measured circulating sICAM-1 concentrations and serum angiotensin-converting enzyme (SACE) activity in patients with sarcoidosis. Patients with sarcoidosis had significantly increased circulating sICAM-1 concentrations (62.8 +/- 33.5 U/ml) and SACE activity (23.7 +/- 7.4 U/l) compared with controls (circulating sICAM-1 50.9 +/- 12.1 U/ml, and SACE 13.5 +/- 3.8 U/l). Successive measurements showed that circulating sICAM-1 values changed in parallel with disease activity in sarcoidosis. In the progressive disease group (progressed or without change for 2 years or more), circulating sICAM-1 values (102.2 +/- 35.3 U/ml) at the time of diagnosis were significantly increased compared with those in the regressive disease group (disappeared or regressed within 2 years) 46.4 +/- 12.6 U/ml). However, there was no significant difference in SACE activity of the regressive and progressive disease groups. Fifteen patients with a high value of circulating sICAM-1 (> 75 U/ml, mean of controls + 2 s.d.) all had progressive disease, while only 15 of 44 patients with a high value of SACE had progressive disease. Circulating sICAM-1 will be a useful blood marker to predict outcome and to monitor disease activity in sarcoidosis.

Elevated level of soluble HLA class I antigens in serum and bronchoalveolar lavage fluid in patients with sarcoidosis.

Soluble HLA class I antigens (sHLAs) in human serum have been reported to be associated with allografts and autoimmune disease and could modify immunological reactions induced by membrane type HLAs. To investigate the clinical significance of sHLAs in sarcoidosis, we assessed concentrations of sHLAs in both serum and bronchoalveolar lavage fluid (BALF) and also examined their production by peripheral blood mononuclear cells (PBMCs) and BALF cells. Concentrations of sHLAs were determined by enzyme-linked immunosorbent assay, using a monoclonal antibody against HLA class I (W6/32) and an enzyme-labeled polyclonal antibody to human beta2-microglobulin. PBMCs and BALF cells were cultured in the presence or absence of either LPS or PHA. Serum levels of sHLAs were assessed in 96 patients with sarcoidosis and in 32 healthy control subjects. sHLAs concentrations in BALF were also investigated in 17 active sarcoidosis patients and in 13 control subjects. sHLAs levels in both serum and BALF were higher in sarcoidosis cases than in control subjects (p<0.05, in both). In the patients, values were significantly higher in active than in inactive stages (p<0.001) and significantly correlated with angiotensin-converting enzyme (ACE) levels. Both PBMCs and BALF cells produced enhanced amounts of sHLAs in patients with active sarcoidosis compared with those in control subjects. These results demonstrated that the level of sHLAs in serum is a useful index of disease activity of sarcoidosis, partly reflecting production by PBMCs and BALF cells.

Increased levels of interleukin-18 in patients with pulmonary sarcoidosis.

Interleukin-18 (IL-18) has recently been identified as an interferon-gamma (IFN-gamma)-inducing factor, and it plays an important role in T helper 1 (Th1) response. We measured the serum levels of IL-18 and IFN- gamma in 37 patients with pulmonary sarcoidosis and 25 healthy control subjects. We also measured the levels of IL-18 and IFN-gamma in 10-fold concentrated bronchoalveolar lavage (BAL) fluids of 19 patients with pulmonary sarcoidosis and 9 healthy control subjects (all lifelong nonsmokers). The levels of serum IL-18 and IFN-gamma were significantly increased in patients with sarcoidosis. The levels of BAL fluid IL-18 were significantly elevated in patients with sarcoidosis, however, the IFN-gamma levels of the patients and control subjects were all below sensitivity. Serum IL-18 levels significantly correlated with serum IFN-gamma levels and lysozyme activity. The patients positive for gallium-67 ((67)Ga) scan had significantly elevated serum IL-18 levels as compared with those of the negative patients. BAL fluid IL-18 levels significantly correlated with serum IL-18 levels in patients with sarcoidosis, and there was a significant correlation between IL-18 levels and lymphocyte proportions in sarcoid BAL fluids. In patients with sarcoidosis, IL-18 seems to induce IFN-gamma production and IL-18 levels in sera may reflect disease activity of sarcoidosis.

Serum lysozyme levels and clinical features of sarcoidosis.

Serum lysozyme is used as a marker of sarcoidosis disease activity. In this study we examined the association between lysozyme levels and the clinical features of sarcoidosis and thus the clinical usability of this parameter in a large population. One hundred ten sarcoidosis patients from central Japan were examined for clinical features and serum lysozyme level at the first visit to our hospital and on a regular basis thereafter. The sensitivity of lysozyme for predicting sarcoidosis was 79.1%, whereas that of serum angiotensin-converting enzyme (ACE) was 59.0%. Even in the cases without an elevated serum ACE level, a value of 72.1% was obtained. The serum lysozyme level demonstrated a significant tendency to increase with the number of organs involved (p < 0.01). There were significant differences among the four radiographic stages (p < 0. 05). The maximum serum lysozyme levels of patients without a disappearance of abnormal shadows on chest radiography within 5 years were significantly greater than those of individuals with a disappearance (p < 0.05). A positive correlation between serum lysozyme and serum ACE levels was observed. Because serum lysozyme is much less specific for sarcoidosis than serum ACE, its diagnostic value may be limited. However, the sensitivity was high even when serum ACE levels were within normal limits and correlated well with clinical features in sarcoidosis. Therefore, this parameter seems suitable for disease monitoring in proven cases.

Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis

BACKGROUNDSerum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE...

Ionized calcium and 1,25-dihydroxyvitamin D concentration in serum of patients with sarcoidosis.

The aim of this study was to evaluate alterations in calcium metabolism in sarcoidosis. The serum concentrations of calcium (sCa), ionized calcium (sCa2+), 1,25-dihydroxyvitamin D (s1,25(OH)2D3) and parathyroid hormone (sPTH), serum angiotensin-converting enzyme activity (sACE) and urinary excretion of calcium (uCa) were studied in 36 Japanese patients with pulmonary sarcoidosis, aged 48.1+/-15.3 yrs (mean+/-SD), 15 males and 21 females. During the study the patients were on a daily diet with 500 mg calcium and 1000 mg phosphorus for a total of 6 days. sCa2+ was above the normal range (>1.26 mmol x L(-1)) in 10 patients (27.8%), 12 patients (33.3%) were hypercalciuric, and 16 patients (44.4%) showed alteration in calcium metabolism, with an increase in values of sCa, sCa2+ or uCa. There was a significant correlation between sCa2+ and s1,25(OH)2D3 (p<0.001), as well as between sCa2+ and sACE (p<0.001). s1,25(OH)2D3 in patients with extrathoracic involvement (ETI) tended to be higher than in patients without ETI. sCa2+ was less than 1.23 mmol x L(-1) (p<0.05) in the majority of patients without ETI, and sCa2+ was less than 1.24 mmol x L(-1) in the majority of normocalciuric patients. In conclusion, a disease-related alteration in calcium metabolism was seen in about 40% of patients with sarcoidosis, and 1,25-dihydroxyvitamin D probably plays a crucial role in this abnormality. The serum concentration of ionized calcium was considered to be a useful index for the disease activity of sarcoidosis.

Polymorphism in the angiotensin-converting enzyme (ACE) gene and sarcoidosis.

It has recently been shown that an insertion (I)/deletion (D) polymorphism exists in the angiotensin-converting enzyme (ACE) gene, and that this polymorphism affects the serum ACE level. There are three genotypes: DD, DI, and II, with the ACE level highest in DD, intermediate in DI, and lowest in II. In the present investigation of the possible significance of the polymorphism for sarcoidosis, a total of 207 patients and 314 normal control subjects were examined. There were no significant differences in the I/D ratio and the genotype distribution between the two groups, and no significant variation in organ involvement (i.e., eye, skin, and heart) was noted among the three genotypes. To determine any prognostic influence of the polymorphism, we examined the disappearance ratio of abnormal shadow on chest radiography over 3 and 5 yr. No significant difference among the three genotypes was observed. New normal ranges of serum ACE level were determined for each genotype, and found to be 22% more sensitive overall than the conventional normal range and 39% more so for II type, suggesting an advantage for diagnosis and assessment of the disease activity of sarcoidosis.

Bacterial components of Propionibacterium acnes accumulated in the site of disease activity of sarcoidosis

Bacterial components of <i>Propionibacterium acnes</i> accumulated in the site of disease activity of sarcoidosis