Unsupervised Clustering Reveals Sarcoidosis Phenotypes Marked by a Reduction in Lymphocytes Relate to Increased Inflammatory Activity on 18FDG-PET/CT

Abstract

Introduction: Sarcoidosis is a T-helper cell mediated disease characterized by granulomatous inflammation. We posited that unsupervised clustering of various features in sarcoidosis would establish phenotypes associated with inflammatory activity measured by 18FDG-PET/CT. Our goal was to identify unique features capable of distinguishing clusters and subsequently examine the relationship with FDG avidity to substantiate their potential use as markers for sarcoidosis inflammation.Methods: We performed a retrospective study of a diverse, but primarily African American, cohort of 58 subjects with biopsy proven sarcoidosis followed at the University of Illinois Bernie Mac Sarcoidosis Center and Center for Lung Health who underwent 18FDG-PET/CT scan. Demographic, therapeutic, radiographic, and laboratory data were utilized in unsupervised cluster analysis to identify sarcoidosis phenotypes. The association between clusters, their defining features, and quantitative measurements on 18FDG-PET/CT was determined. The relevance of these features as markers of 18FDG-PET/CT inflammatory activity was also investigated.Results: Clustering determined three distinct phenotypes: (1) a predominantly African American cluster with chronic, quiescent disease, (2) a predominantly African American cluster with elevated conventional inflammatory markers, advanced pulmonary disease and extrathoracic involvement, and (3) a predominantly Caucasian cluster characterized by reduced lymphocyte counts and acute disease. In contrast to the chronic quiescent cluster, Clusters 2 and 3 were defined by significantly greater FDG avidity on 18FDG-PET/CT. Despite similarly increased inflammatory activity on 18FDG-PET/CT, Clusters 2, and 3 differed with regards to extrathoracic FDG avidity and circulating lymphocyte profiles, specifically CD4+ T-cells. Notably, absolute lymphocyte counts and CD4+ T-cell counts were found to predict 18FDG-PET/CT inflammatory activity by receiver operating curve analysis with a 69.2 and 73.42% area under the curve, respectively.Conclusions: Utilizing cluster analysis, three distinct phenotypes of sarcoidosis were identified with significant variation in race, disease chronicity, and serologic markers of inflammation. These phenotypes displayed varying levels of circulating inflammatory cells. Additionally, reduction in lymphocytes, specifically CD4+ T-cells, was significantly related to activity on 18FDG-PET/CT. Though future studies are warranted, these findings suggest that peripheral lymphocyte counts may be considered a determinant of sarcoidosis phenotypes and an indicator of active inflammation on 18FDG-PET/CT.

Trimer IgG and neutralising antibody response to COVID-19 mRNA vaccination in individuals with sarcoidosis

“…Despite these defects, vaccine induced development and persistence of neutralization antibodies in sarcoidosis subjects is a particularly important and reassuring finding. However, it is worth noting the median peripheral absolute lymphocyte count (1.8 x 10 9 cells/liter) in our cohort is greater than previously described thresholds of significant sarcoidosis-related lymphopenia [34]. This suggests lymphopenia is unlikely to be a significant disease manifestation in this cohort and therefore may explain the preserved nAb activity.…”

“…Sarcoidosis is a T cell mediated disease characterized by local CD4+ T lymphocyte inflammation and peripheral lymphocyte depletion in severe or active disease, as well as anergy and exhaustion in progressive disease [4,5,33,34]. Defects within humoral immunity have also been described and include evidence of B cell hyperactivation, autoantibody production, decreased circulating memory B cells, as well as previously mentioned impaired serologic responses to Tetanus and Hepatitis vaccines [10,11,20,[35][36][37][38].…”

The role of PET in the management of sarcoidosis

“…A prospective study, which enrolled 30 patients with untreated sarcoidosis measured various biomarkers including soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), ACE, and urine calcium in addition to splenic FDG uptake on PET and found that there was a significant linear correlation between sIL-2R and SUVmax on PET [ 32 ]. It has also been shown that a reduction in absolute peripheral CD4+ T-lymphocyte count is associated with increased PET activity and possibly serves as a proxy for inflammatory activity [ 33 ▪ ]. A less commonly known laboratory marker, serum chitotriosidase, was found to be significantly correlated with PET activity whereas no correlation was found with ACE [ 34 ].…”

Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis

“…The interactions between lymphocytes, macrophages, and immune mediators, such as tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-g), lead to an exaggerated and polarized CD4+ T-helper (Th) 1 and Th17 cell response against an unknown antigenic stimulus at sites of granuloma formation (2). While local CD4+ T-cell accumulation, proliferation, and activation are invariably observed within affected tissues, 10-50% of those with sarcoidosis paradoxically exhibit peripheral lymphopenia coupled with anergy or exhaustion (3)(4)(5)(6)(7)(8). When present, lymphopenia specifically related to low CD4+ T-cell counts, has been linked with greater inflammatory activity in sarcoidosis (7).…”

“…While local CD4+ T-cell accumulation, proliferation, and activation are invariably observed within affected tissues, 10-50% of those with sarcoidosis paradoxically exhibit peripheral lymphopenia coupled with anergy or exhaustion (3)(4)(5)(6)(7)(8). When present, lymphopenia specifically related to low CD4+ T-cell counts, has been linked with greater inflammatory activity in sarcoidosis (7).…”