78 research outputs found
Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis
No full textSarcoidosis is a heterogeneous disorder, both phenotypically and genetically. Two independent studies have recently shown that a functional polymorphism within butyrophilin-like 2 (BTNL2) gene predisposes to sarcoidosis independently of the
human leukocyte antigen (HLA)-DRB1 alleles. However, in both studies, data analysis was not stratified by Lo ̈ fgrens syndrome, a clinically and genetically distinct sarcoidosis subset. BTNL2, potentially encoding an immune coreceptor, is
adjacent and in linkage disequilibrium (LD) with HLA-DRB1. We investigated six BTNL2 variants, including the functional rs2076530 (G > A), as well as HLADRB1 alleles, by sequence-specific primers–polymerase chain reaction, in 288 patients and 446 controls from two European countries. In the patient group as a whole, the HLA-DRB1*14 [odds ratio (OR) 1⁄4 3.1, Pc 1⁄4 0.0003], DRB1*12 (OR 1⁄4 2.5, Pc 1⁄4 0.003), and BTNL2 rs2076530 A allele (OR 1⁄4 1.49, Pc 1⁄4 0.002) were all associated with disease susceptibility. However, after exclusion of patients presenting with Lo ̈ fgrens syndrome and after adjusting for HLA-DRB1 alleles, the association between BTNL2 rs2076530 A and disease disappeared (P 1⁄4 0.23). By contrast, both HLA-DRB1*14 and DRB1*12 remained strongly significant (OR 1⁄4 3.60, P < 0.0001 and OR 1⁄4 3.03, P 1⁄4 0.003, respectively). BTNL2 haplotype 4, tagged by the rs2076530 G allele, also remained associated with non-Lo ̈ fgren sarcoidosis after adjusting for HLA-DRB1 alleles (OR 0.37, P 1⁄4 0.016).
In summary, HLA-DRB1*14, DRB1*12, and BTNL2 haplotype 4 – but not rs2076530 A – are associated with non-Lo ̈ fgren sarcoidosis. However, the tight LD across the HLA complex makes it difficult to identify the precise location of the
susceptibility locus/i. Larger sample sets from different ethnic groups, finer mapping, and more robust LD analyses across the HLA region are needed
Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?
No full textIdiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF
C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis
No full textRationale: Genetic factors are likely to influence the clinical course and pattern of sarcoidosis, a granulomatous disease of unknown origin. Objectives: We tested this hypothesis for C-C chemokine receptor 5 (CCR5), a molecule involved in recruitment and activation of mononuclear cells. Methods: In addition to the known CCR5
Delta 32 insertion/deletion, we evaluated a further eight singlenucleotide polymorphisms in 106 British patients and 142 British unaffected subjects, and second-setted the results in 112 Dutch patients and 169 healthy Dutch control subjects. Measurements and Main results: In the British population, the frequency of one of the identified haplotypes (HHC) was strongly associated with the presence of parenchymal disease (radiographic stage II versus stages 0 and I) at presentation (odds ratio [OR], 5.2;95%confidence interval [CI], 1.96–13.7; corrected p 0.02), at 2 (OR, 6.6; 95% CI, 2.5–17.6; corrected p 0.006), and at 4 years follow-up (OR, 6.8;
95% CI, 2.5–18.0; corrected p 0.0045). In the Dutch population, the same association was seen at 2 (OR, 6.7; 95% CI, 2.8–16.4; corrected p 0.002), and 4 years follow-up (OR, 9.0; 95% CI, 3.5–23.1; corrected p 0.0009). Conclusions: No association between the CCR5 haplotype HHC and susceptibility to sarcoidosis was observed, indicating that this relevant gene only operates after disease induction. In summary, we report a strong association between
CCR5 haplotype HHC and persistent lung involvement in
sarcoidosis
Potential therapeutic targets to prevent organ damage in chronic pulmonary sarcoidosis
No full textIntroduction: Sarcoidosis is a granulomatous inflammatory disease with high chances of reduced quality of life, irreversible organ damage, and reduced life expectancy when vital organs are involved. Any organ system can be affected, and the lungs are most often affected. There is no preventive strategy as the exact etiology is unknown, and complex immunogenetic and environmental factors determine disease susceptibility and phenotype. Present-day treatment options originated from clinical practice and are effective in many patients. However, a substantial percentage of patients suffer from unacceptable side effects or still develop refractory, threatening pulmonary or extrapulmonary disease. Areas covered: As non-caseating granulomas, the pathological hallmark of disease, are assigned to divergent activation and regulation of the immune system, targets in relation to the possible triggers of granuloma formation and their sequelae were reviewed. Expert opinion: The immunopathogenesis underlying sarcoidosis has been a dynamic field of study. Several recent new insights give way to promising new therapeutic targets, such as certain antigenic triggers (e.g. from Aspergillus nidulans), mTOR, JAK-STAT and PPARγ pathways, the NRP2 receptor and MMP-12, which await further exploration. Clinical and trigger related phenotyping, and molecular endotyping will likely hold the key for precision medicine in the future
Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?
No full textIdiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF
New treatment strategies for pulmonary sarcoidosis: antimetabolites, biological drugs, and other treatment approaches
No full textAbout half of patients with sarcoidosis will need systemic therapy for their disease. Oral glucocorticoids are the standard first-line treatment for sarcoidosis. With time, patients might develop substantial morbidity from long-term use of high doses of these drugs. We propose a step-wise approach to the management of pulmonary disease in sarcoidosis and provide details about how and when to use alternatives to glucocorticoids. The antimetabolites, such as methotrexate, azathioprine, leflunomide, and mycophenolate, are often used as alternatives to steroids. For patients who cannot be treated with low-dose glucocorticoids and an antimetabolite, anti-tumour necrosis factor (TNF) monoclonal antibodies have been shown to control disease. Unfortunately, anti-TNF drugs are associated with substantial toxic effects and in some cases are ineffective. The next step in treatment includes new strategies such as rituximab. A new regimen combining four antibiotics (levofloxacin, ethambutol, azithromycin, and rifamycin) has shown some promise in preliminary studies; however, the mechanism of action is unknown. Non-inflammatory effects of sarcoidosis, such as pulmonary hypertension and bronchiectasis, might also contribute to an increase in pulmonary symptoms. In those cases, alternative treatment strategies have to be considered
C-C chemokine receptor 2 and sarcoidosis: association with Lofgren's syndrome
No full textSarcoidosis is thought to result from the interaction between an unknown environmental antigenic trigger and the host's genetic susceptibility. We hypothesized that sarcoidosis, or one of the disease subsets, could be associated with single nucleotide polymorphisms of C-C chemokine receptor 2 (CCR2) gene. Eight single-nucleotide polymorphisms in CCR2 were studied in a total of 304 Dutch individuals (90 non-Löfgren sarcoidosis, 47 Löfgren's syndrome, 167 control subjects). From the investigated CCR2 polymorphisms, nine haplotypes were deduced (haplotypes 1-9). In patients with Löfgren's syndrome, a strongly significant increase in the frequency of CCR2-haplotype 2, which includes four unique alleles (A at nucleotide position -6752, A at 3,000, T at 3,547, and T at 4,385), was observed compared with control subjects (74% vs. 38% respectively, p < 0.0001), whereas no difference was found between non-Löfgren sarcoidosis and control subjects (both 38%). The association between CCR2-haplotype 2 carriage frequency and Löfgren's syndrome (odds ratio, 4.4; p < 0.0001) remained significant after adjustment for human leukocyte antigen haplotype DRB1*0301-DQB1*0201 (odds ratio, 11.5; p < 0.0001) and female sex (odds ratio, 3.2; p = 0.003), two known risk factors for Löfgren's syndrome. In conclusion, this report describes a strong association between CCR2-haplotype 2 and Löfgren's syndrome. Further studies are needed to understand the molecular mechanisms underlying this association
Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups
No full textThe HLA class II (DRB1 and DQB1) associations with sarcoidosis have been studied by several groups but often without consistent results. In this paper, we consider the hypothesis that observed inconsistencies relate to distinct, genetically encoded disease phenotypes which differ in prevalence between centres. We therefore typed HLA-DRB1 and DQB1 in 340 UK, 139 Dutch and 163 Japanese sarcoidosis patients and, respectively, 354, 218 and 168 healthy controls from these populations. We applied consistent phenotyping and genotyping and investigated associations between HLA class II alleles and distinct disease phenotypes within and between ethnic groups. DRB1*01 and DQB1*0501 are protective against all manifestations of sarcoidosis. Lung-predominant sarcoidosis is associated with DRB1*12 and *14. Löfgren's syndrome is a common sarcoidosis phenotype in the Dutch and is strongly associated with the DRB1*0301 allele. This phenotype is not seen among the Japanese in whom DRB1*0301 is absent. The same allele is protective for UK uveitis. Sarcoid uveitis is common in Japan. The DRB1*04-DQB1*0301 haplotype is a risk factor for this disease manifestation in Japanese and UK subjects but protective for sarcoidosis overall. We show that distinct sarcoidosis phenotypes have similar genetic associations across ethnic groups. The disease case mix differs between centres and may be explained by different ethnic allelic frequencie
Whole lung lavage therapy of pulmonary alveolar proteinosis: a global survey of current practices and procedures
No full textChest Imaging
No full textChest imaging has a central role in the diagnosis and monitoring of sarcoidosis. For staging of pulmonary disease on chest radiograph, Scadding stages are still widely used. High-resolution CT (HRCT), however, is more accurate in visualizing the various manifestations of pulmonary sarcoidosis as well its complications. A generally accepted HRCT scoring system is lacking. Fluorodeoxyglucose F 18 positron emission tomography can visualize disease activity better than conventional makers in a significant proportion of patients. In patients with extensive changes on HRCT but no parenchymal fluorodeoxyglucose F 18 uptake, prudence with regard to initiation or intensification of immunosuppressive treatment is warranted
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