HLA-DRB1 alleles associate with hypercalcemia in sarcoidosis

Abstract

Background:The mechanisms behind and which patients are at risk of developing sarcoidosis associated hypercalcemia (SAHC) have not been addressed. Different human leukocyte antigen (HLA) alleles associate with disease phenotypes in sarcoidosis. Insights into associations between HLA alleles, clinical phenotype and calcium levels may provide clues to mechanisms behind SAHC and help monitoring patients at risk for SAHC. Aims and objectives: To identify any HLA-association with SAHC, and to phenotypically characterize this patient group. Methods: 66 patients with SAHC (s-Ca 2+ >1.33 mmol/L) and 150 normocalcemic patients as controls were identified in a cohort of sarcoidosis patients. Data on HLA-DRB1 alleles, sex, angiotensin-converting enzyme (ACE), creatinine, extrapulmonary manifestations (EPM), age at sarcoidosis diagnosis, and how long after diagnosis SAHC emerged, were retrieved. Results: HLA-DRB1*04 was more common in patients with SAHC and the proportion of patients with HLA-DRB1*04 increased the more pronounced hypercalcemia. In patients with s-Ca 2+ >1.4 mmol/L, 20 out of 30 carried the HLA-DRB1*04 allele (67%, p < 0.01). Patients with SAHC more often disclosed renal insufficiency, elevated ACE, EPM, and a non-resolving disease than controls. The mean duration between sarcoidosis diagnosis and detection of SAHC was 1.39 years. Conclusions: SAHC is associated with a more severe disease phenotype, particularly patients carrying the HLA-DRB1*04 allele are at higher risk for SAHC. HLA-assessment in the clinic can be a way to identify these patients. The results provide a basis for future studies on the connection between HLA-DRB1*04 and SAHC mechanisms.

Extrapulmonary Sarcoidosis With Multi-Organ Involvement Presenting Primarily as Hypercalcemia

“…It results due to an excess conversion of 25(OH) vitamin D to 1,25(OH) vitamin D by macrophage 1-a-hydroxylase within granulomas. Hypercalcemia itself has been shown to be associated with more severe disease phenotypes, and if hypercalciuria occurs, it predisposes to nephrolithiasis as well [6,8]. In light of this, it is imperative to remember that this mechanism of hypercalcemia is not specific to sarcoidosis, and so it is imperative that other etiologies be first considered.…”

“…Sarcoidosis can also present with renal involvement, presenting as granulomatous interstitial nephritis and hypercalcemia [6,8]. Other extrapulmonary findings include ocular manifestations, most commonly uveitis.…”

Increased susceptibility to organic dust exposure-induced inflammatory lung disease with enhanced rheumatoid arthritis-associated autoantigen expression in HLA-DR4 transgenic mice

“…Extensive genetic studies have demonstrated that the HLA-DRB1 shared epitope contributes to risk across different populations, particularly in ACPA-positive RA patients [ 49 , 51 ]. The importance of these risk alleles is not limited to RA, as these HLA haplotypes are strongly associated with sarcoidosis (including Löfgren’s syndrome), obliterative bronchiolitis, and idiopathic bronchiectasis [ 11 – 15 , 52 ]. Moreover, HLA-DRB1 alleles are linked to more severe forms of sarcoidosis, including a higher burden of lung granulomas as well as extrapulmonary manifestations such as hypercalcemia and ocular disease [ 52 ].…”

“…The importance of these risk alleles is not limited to RA, as these HLA haplotypes are strongly associated with sarcoidosis (including Löfgren’s syndrome), obliterative bronchiolitis, and idiopathic bronchiectasis [ 11 – 15 , 52 ]. Moreover, HLA-DRB1 alleles are linked to more severe forms of sarcoidosis, including a higher burden of lung granulomas as well as extrapulmonary manifestations such as hypercalcemia and ocular disease [ 52 ]. Our findings demonstrating significant gene (DR4) by environment (ODE) outcomes, strongly suggest that this unique MHC determinant markedly skews the host response to air pollutants towards a more robust lung inflammatory phenotype, with features shared by RA-associated lung disease as well as other primary inflammatory lung diseases.…”

Follow-up of patients with sarcoidosis in an internal medicine unit from a hospital in Asturias, Spain. Analysis of extrapulmonary manifestations

“…Studies have reported an increased risk for patients of White European ancestry, male sex and over 40 years of age. The average duration between sarcoidosis diagnosis and detection of hypercalcemia was 1.39 years, when it occurs it´s considered a progressive form of the disease [10].…”