Kahlenberg, J Michelle

Objective Antiphospholipid syndrome (APS) is a thromboinflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody (aPL)–positive patients using whole‐blood transcriptomics. Methods Whole‐blood RNA sequencing was performed on 174 aPL‐positive patients, including those with primary APS (n = 102), secondary APS (n = 29), and aPL positivity without classifiable APS (n = 43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes. Results Four transcriptionally distinct clusters were identified. At one end of the spectrum, cluster 1 showed up‐regulation of ribosomal and metabolic pathways and down‐regulation of mechanistic target of rapamycin (mTOR), NETosis, and Hippo/interleukin‐6 (IL‐6) signaling. In contrast, cluster 4 exhibited the opposite pattern, with strong up‐regulation of mTOR, NETosis, and Hippo/IL‐6 signaling. Cluster 2 demonstrated modest enrichment in messenger RNA processing and amino acid metabolism, and cluster 3 showed biosynthetic suppression with mild Hippo/IL‐6 activation. Clinically, cluster 4 stood out with higher IgG anticardiolipin and anti–β 2 ‐glycoprotein I positivity, elevated neutrophil counts, and increased urine protein‐to‐creatinine ratios. Immune deconvolution revealed distinct cell type profiles: cluster 1 was lymphoid predominant; cluster 2 had a balanced composition; cluster 3 was enriched in Treg cells, natural killer cells, macrophages, mast cells, and memory B cells; and cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features, including white matter lesions, seizures, and cardiac valve disease. Conclusion This study reveals four endotypes of aPL‐positive patients, a step toward personalized medicine for APS through pathway‐informed stratification and therapy.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1β as a key mediator, orchestrating an NF-κB–mediated IL-1β–CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1β. With the central role of IL-1β underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1β antagonists in PRP.

ObjectiveWhile thrombosis and pregnancy loss are the best‐known clinical features of antiphospholipid syndrome (APS), many patients also exhibit “extra‐criteria” manifestations, such as thrombocytopenia. The mechanisms that drive APS thrombocytopenia are not completely understood, and no clinical biomarkers are available for predicting antiphospholipid antibody (aPL)–mediated thrombocytopenia. Calprotectin is a heterodimer of S100A8 and S100A9 that is abundant in the neutrophil cytoplasm and released upon proinflammatory neutrophil activation. Here, we sought to evaluate the presence, clinical associations, and potential mechanistic roles of circulating calprotectin in a cohort of primary APS and aPL‐positive patients.MethodsLevels of circulating calprotectin were determined in plasma by the QUANTA Flash chemiluminescent assay. A viability dye‐based platelet assay was used to assess the potential impact of calprotectin on aPL‐mediated thrombocytopenia.ResultsCirculating calprotectin was measured in 112 patients with primary APS and 30 aPL‐positive (without APS criteria manifestations or lupus) patients as compared to patients with lupus (without APS), patients with unprovoked venous thrombosis (without aPL), and healthy controls. Levels of calprotectin were higher in patients with primary APS and aPL‐positive patients compared to healthy controls. After adjustment for age and sex, calprotectin level correlated positively with absolute neutrophil count (r = 0.41, P < 0.001), positively with C‐reactive protein level (r = 0.34, P = 0.002), and negatively with platelet count (r = −0.24, P = 0.004). Mechanistically, we found that calprotectin provoked aPL‐mediated thrombocytopenia by engaging platelet surface toll‐like receptor 4 and activating the NLRP3‐inflammasome, thereby reducing platelet viability in a caspase‐1‐dependent manner.ConclusionThese data suggest that calprotectin has the potential to be a functional biomarker and a new therapeutic target for APS thrombocytopenia.image