Petal A. Wijnen

Everyday Cognitive Failure in Sarcoidosis: The Prevalence and the Effect of Anti-TNF-α Treatment

Background: Cognitive symptoms, such as concentration problems, are frequently recorded by sarcoidosis patients. Objectives: The aim of this study was to assess the prevalence of perceived everyday cognitive failure in sarcoidosis patients and healthy controls. Furthermore, the effect of treatment on cognitive functioning was examined. Methods: The study included 343 sarcoidosis patients (44.6% females; age 49.3 ± 11.0 years). They completed the Cognitive Failure Questionnaire (CFQ) and Fatigue Assessment Scale (FAS) at baseline and the 6-month follow-up to evaluate the effect of treatment on cognitive functioning. The control group consisted of 343 age- and sex-matched healthy controls. Results: The mean CFQ score was significantly higher in sarcoidosis patients (37.3 ± 16.1) compared with the controls (31.3 ± 10.1; p < 0.0001).A high CFQ sore (≧43) was found in 35.0% of the patients and only 14.3% of the controls. No relation with disease severity and duration, or disease location was found. The proportion of patients receiving treatment did not differ among the groups with high and normal CFQ score. At the 6-month follow-up, only patients recently treated with anti-TNF-α therapy (n = 42) demonstrated a significant improvement in the CFQ score (Δ –7.07 ± 7.23) compared with the untreated patients (Δ –0.08 ± 9.35) and patients treated with prednisone with or without methotrexate (Δ 1.67 ± 9.22; p < 0.0001). After adjustment for the concomitant decrease in fatigue, the effect of anti-TNF-α therapy remained high and significant. Conclusions: Subjective cognitive failure is a substantial problem in sarcoidosis patients regardless of disease severity. Anti-TNF-α therapy had a positive effect on cognition, fatigue and other symptoms of sarcoidosis.

Inflammatory activity assessment by F18 FDG-PET/CT in persistent symptomatic sarcoidosis

BACKGROUND Establishing inflammatory activity in sarcoidosis patients with persistent disabling symptoms is important. Whole body F(18)-FDG PET/CT (PET) appeared to be a sensitive method to detect inflammatory activity in newly diagnosed symptomatic sarcoidosis. The aim was to assess the presence of inflammatory activity using PET in sarcoidosis patients with unexplained persistent disabling symptoms and the association between PET findings and serological inflammatory markers. METHODS Sarcoidosis patients who underwent a PET between June 2005 and June 2010 (n = 89), were retrospectively included. All PET scans were examined and positive findings were classified as thoracic and/or extrathoracic. As serological markers of inflammatory activity angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), and neopterin were considered. RESULTS In 65/89 (73%) of the studied patients PET was positive, 52 of them (80%) had serological signs of inflammatory activity. In 14/15 patients with a Chest X-ray stage IV PET was positive. In 80% of the PET positive patients extrathoracic inflammatory activity was found. Sensitivity of combined serological inflammatory markers for the presence of inflammatory activity as detected by PET was 80%, specificity 100%, positive predictive value 100%, negative predictive value 65%. CONCLUSIONS The majority of sarcoidosis patients with persistent disabling symptoms, even those with radiological stage IV, had PET positive findings with remarkably 80% extrathoracic lesions. In 20% PET was positive without signs of serological inflammatory activity. PET appeared to be of additional value to assess inflammatory activity in patients with persistent symptoms in the absence of signs of serological inflammatory activity and to detect extrathoracic lesions.

Review article: the prevalence and clinical relevance of cytochrome P450 polymorphisms

Background  Most drugs currently used in clinical practice are effective in only 25% to 60% of patients, while adverse drug reactions (ADRs) as a consequence of treatment are estimated to cost billions of US dollars and tens of thousands of deaths.

Association of the TNF-α G-308A polymorphism with TNF-inhibitor response in sarcoidosis

Responsiveness to tumour necrosis factor (TNF) inhibitors has been associated with the TNF-α G-308A polymorphism in rheumatoid arthritis. The aim of this study was to examine the association between the presence of this polymorphism and the response to TNF inhibitors in patients with refractory sarcoidosis. Patients (n=111) who started TNF-inhibitor treatment (76 infliximab, 35 adalimumab) were followed for at least 1 year. The main symptoms in these patients were fatigue (n=100, 90.1%), small fibre neuropathy (n=91, 82.0%), pulmonary involvement (n=69, 62.2%), and/or uveitis (n=31, 27.9%). Patients were additionally genotyped for the presence of the TNF-α G-308A polymorphism. Treatment response was assessed using clinical outcome measures and questionnaires. Three-quarters (n=83, 74.8%) of the patients responded well. Of the patients without the variant A-allele 93.6% (73 out of 78, p<0.001) improved, while 30.3% (10 out of 33) of variant A-allele carriers responded favourably to TNF inhibitors. For patients with the GG-genotype, the probability of improving compared with remaining stable or deteriorating was three times higher (risk ratio 3.09, 95% CI 1.84–5.20). Sarcoidosis patients without the TNF-α -308A variant allele (GG-genotype) had a three-fold higher response to TNF inhibitors (adalimumab or infliximab). Further research is needed to evaluate the value of genotyping for the TNF-α G-308A polymorphism in order to tailor TNF-inhibitor treatment. TNF-&agr; G-308A polymorphism predicts TNF-inhibitor response in refractory sarcoidosis: a step to personalised medicine? http://ow.ly/sQ7KO

Liver-test abnormalities in sarcoidosis.

Background Sarcoidosis is a multisystemic inflammatory granulomatous disease. The prevalence of hepatic involvement is not clear. Aim The aim of this study was to establish the presence and severity of the liver-test abnormalities in sarcoidosis. Methods Retrospectively, patients with confirmed sarcoidosis (n=837) presented with the liver-test abnormalities [alkaline phosphatase, &ggr;-glutamyl transaminase, alanine aminotransferase or aspartate aminotransferase >1.5 times the upper limit of normal (ULN)] who were classified according to severity into mild (zero liver tests ≥3×ULN), moderate (one or two liver tests ≥3×ULN) and severe (three or four liver tests ≥3×ULN) were evaluated. Moreover, the relationship between severity of liver tests and histology was examined. Results Liver-test abnormalities were found in 204 of 837 patients with chronic sarcoidosis (24.4%), among which 127 (15.2%) were suspected of having hepatic sarcoidosis (79 of 127 males, 111 Caucasian, eight African-American). In 22 of 127 patients (17.3%), a liver biopsy was obtained; 21 were compatible with hepatic sarcoidosis. In these 21 patients, severity of liver-test abnormalities was significantly associated with extensiveness of granulomatous inflammation (&rgr;=0.58, P=0.006) and degree of fibrosis (&rgr;=0.64, P=0.002). These results remained in the multiple regression analysis when controlled for treatment status, sex, genetics, ethnicity and age. Conclusion Liver-test abnormalities were present in 24% of the studied patients; in 15% highly because of hepatic involvement of sarcoidosis. Moderate and severe liver-test abnormalities seemed to be associated with more advanced histopathological disease. Therefore, in the management of sarcoidosis, for patients with moderate or severe liver-test abnormalities a liver biopsy is recommended.

Influence of different allelic variants of the CYP3A and ABCB1 genes on the tacrolimus pharmacokinetic profile of Chinese renal transplant recipients

Tacrolimus has a narrow therapeutic window and a wide interindividual variation in its pharmacokinetics. The cytochrome P450 3A (CYP3A) and the ATP-binding cassette B1 (ABCB1) genes play an important role in the tacrolimus disposition. Therefore, the aim of this study was to evaluate whether CYP3A and ABCB1 polymorphisms are associated with the area under the time concentration curve (AUC0-12) calculated using a two time point sample strategy. The CYP3A and ABCB1 genotypes were determined by real-time polymerase chain reaction (RT-PCR) fluorescence resonance energy transfer (FRET) assays in 103 Chinese renal transplant recipients and consequently related to their dose-normalized (dn)AUC0-12. A significant allele-dependent effect (Kruskal-Wallis; p < 0.001) was observed between the CYP3A5*3 polymorphism and the dnAUC0-12. Multiple regression analysis showed that the CYP3A5*3 polymorphism is the most significant independent variable and explained 35% of the dose requirement variability in relation to tacrolimus use. Regarding the ABCB1 G2677T/A and C3435T polymorphisms, a trend was observed between the different genotypes and the dnAUC0-12. In conclusion, the CYP3A5*3 polymorphism may be an important factor in determining the dose requirement for tacrolimus and genotyping can help determine the initial daily dose required by individual patients for adequate immunosuppression.

F-18 FDG PET/CT for Detecting Bone and Bone Marrow Involvement in Sarcoidosis Patients

Background: The prevalence of bone involvement in sarcoidosis has been estimated to be 3% to 5%, mostly affecting the phalanges. The aim of this study was to assess the prevalence and distribution pattern of bone and bone marrow involvement as detected by positron emission tomography/computed tomography (PET/CT) in sarcoidosis patients. Methods: Between June 2006 and September 2010, 122 patients suffering from severe sarcoidosis who underwent a PET/CT and met the inclusion criteria were studied. In 94 (77%) patients, the PET/CT demonstrated positive findings associated with sarcoidosis. The 94 PET/CTs were screened for the presence of bone/bone marrow localizations. Additionally, low-dose CT scans were screened for other causes of increased bone uptake. Relevant clinical data were gathered retrospectively. Results: Evidence for bone/bone marrow localizations was found in 34% of the 94 patients with PET/CT-positive findings. Of these patients, 60% showed obvious focal bone lesions at various localizations: axial skeleton (47%), pelvis (40%), extremities (34%), and skull (2%). In 40% of patients, diffuse increased uptake in both axial and peripheral bone marrow, without focal lesions, was found. Both diffuse and focal uptake were seen in 34%, whereas only focal lesions were observed in 25%. In all but 2 (6%) patients, no bone abnormalities on low-dose CT were found. Conclusions: More than one-third of PET/CT-positive sarcoidosis patients had osseous abnormalities on PET/CT. The majority of these lesions (94%) could not be detected on low-dose CT. No single localization of preference was found. These preliminary results stress the value of PET/CT imaging in the assessment of bone/bone marrow involvement in sarcoidosis patients.

Minimal (clinically) important differences for the Fatigue Assessment Scale in sarcoidosis

OBJECTIVE The usefulness of any questionnaire in clinical management and research trials depends on its ability to indicate a likelihood of treatment success during follow-up. The Minimal Clinically Important Difference (MCID) reflects a clinically relevant change score. The aim of this study was to estimate the MCID for the Fatigue Assessment Scale (FAS) in patients with sarcoidosis. METHODS Outpatients (n = 321) of the ild care team of the Department of Respiratory Medicine of the Maastricht University Medical Centre, The Netherlands, participated in this prospective follow-up study. Anchor-based and distribution-based methods were used to estimate the MCID. Based on the anchor Physical Quality of Life, a Receiver Operating Characteristic (ROC) was obtained. The distribution-based methods consisted of the Effect Size and Standard Error Measurement (SEM). RESULTS The anchor-based MCID found with ROC was 3.5. The distribution-based methods showed that the corresponding change scores in the FAS for a small effect was 4.2. The SEM criterion was 3.6 points change in the FAS. CONCLUSIONS Based on the anchor-based and distribution-based methods, the MCID is a 4-point difference on the FAS. This MCID can be used in the follow-up of fatigue (FAS) in clinical trials and in the management of individual sarcoidosis cases.

The role of tumor necrosis factor alpha G-308A polymorphisms in the course of pulmonary sarcoidosis

This study was designed to evaluate the relationship between the presence of tumor necrosis factor (TNF) polymorphisms, human leukocyte antigen (HLA)-DRB1*03 linkage and the prognosis of sarcoidosis. In a retrospective case-control study, TNF-alpha G-308A, TNF-alpha G-238A, lymphotoxin-alpha (LTA) and HLA-DRB1*03 were genotyped in 625 sarcoidosis patients. These patients were classified into 298 patients with persistent disease and 327 patients with non-persistent disease using chest X-ray (CXR) appearances and lung function parameters after at least 2 years of follow-up. The TNF-alpha-308A variant allele was observed in 25.5% of patients with persistent disease compared with 44.0% of patients with non-persistent disease. The corresponding odds ratio (OR) was 0.43 with a 95% confidence interval (CI) of 0.30-0.61. A strong linkage was found between TNF-alpha G-308A and HLA-DRB1*03 (OR = 0.03, 95% CI: 0.02-0.05). For TNF-alpha G-238A and LTA NcoI A252G, there were no statistically significant differences in the distribution of genotypes between the groups with and without persistent disease. The data indicate that presence of a TNF-alpha-308A variant allele and HLA-DRB1*03 were associated with a favorable prognosis. Because of the strong linkage between TNF-alpha G-308A and HLA-DRB1*03, genotyping of one simple and less expensive TNF-alpha single nucleotide polymorphism can be used to predict the prognosis of pulmonary sarcoidosis in clinical practice.

Butyrophilin-like 2 in pulmonary sarcoidosis: a factor for susceptibility and progression?

The aims of this study were to assess the association of BTNL2G16071A with the course of pulmonary sarcoidosis and to verify the association with disease predisposition. In addition, the linkage between BTNL2G16071A and certain human leukocyte antigen (HLA)-DRB1/DQB1 types was investigated. In a retrospective case-control study BTNL2G16071A, HLA-DQB1, and HLA-DRB1 were typed in 632 sarcoidosis patients. These patients were classified into 304 patients with persistent sarcoidosis and 328 patients with nonpersistent sarcoidosis. The BTNL2 16071A variant allele was present significantly more often in patients with persistent disease (92.4%; 281/304) compared with patients demonstrating a nonpersistent course (86.6%; 284/328; odds ratio (OR) = 1.89 with 95% confidence interval (95% CI) 1.11-3.22). Furthermore, BTNL2 16071A variant allele carriers have an increased risk (OR = 1.85, 95% CI 1.19-2.88) of developing sarcoidosis. Moreover, the strong linkage between variant allele and HLA-DRB1*15 presence (OR = 8.43, 95% CI 3.02-23.5) was confirmed. The presence of a BTNL2G16071A variant allele almost doubles the risk of progressing to persistent pulmonary sarcoidosis in addition to increasing the risk of developing sarcoidosis. Presumably, these increased risks are caused by the strong linkage between BTNL2G16071A and DRB1*15. The choice between determining BTNL2G16071A SNP or the HLA-DRB1 type depends on the ability and/or availability to perform either test.