Relevance of adrenomedullin in Sjögren’s and non-Sjögren’s sicca

[N_Dina]

Hi everyone!

I am a little bit in a crash currently and not a professional, so please take my summary with a grain of salt. But I came across a British study by Benjamin A Fisher comparing Sjögren’s syndrome (SjS) and non-Sjögren’s sicca cohorts with the same substantial burden of symptoms and found the results (about the relevance of adrenomedullin) quite interesting.

Spoiler: Brief AI summary of the OASIS initiative:

The Optimising Assessment in Sjögren’s Syndrome (OASIS) initiative, led by Professor Benjamin Fisher at the University of Birmingham, is a prospective clinical cohort study designed to identify multi-omic biomarkers from blood, saliva, and tissue to better differentiate disease subsets and guide targeted clinical trial design for Sjögren’s and related sicca syndromes.

This research was largely prompted by the disappointing results of rituximab trials in Sjögren’s, where B-cell depletion showed virtually no benefit for patient-reported symptoms like fatigue and dryness:

Despite the belief that B cells play an important role in SjS pathogenesis,3 these negative findings include phase 3 trials of rituximab.4 5Similarly, a recent large phase 2b study of a novel B cell depleting agent failed to show a reduction in ESSPRI compared with placebo, despite showing a dose response in the primary outcome of systemic disease activity.6 One possible explanation for these discrepancies may be that the initiation but not the persistence of some SjS associated symptoms, particularly fatigue and pain, is immunologically driven.7 This would be compatible with observations in persistent interferon-induced fatigue and chronic fatigue syndrome.8–10 In addition, chronic fatigue syndrome has been associated with a metabolic signature.11 12

Researchers analyzed serum proteomics using Olink inflammation and cardiovascular panels in 53 patients with primary Sjögren’s syndrome and 60 patients with non-Sjögren’s sicca to identify biological drivers of symptom burden (ESSPRI). While both groups experienced an equivalent, high burden of fatigue, pain, and dryness, classic inflammatory cytokines uncoupled from symptom severity in the Sjögren’s group. Conversely, in non-Sjögren’s sicca, a panel of 20 serum proteins significantly correlated with symptoms, with a triad of adrenomedullin (ADM), soluble CD40, and spondin-2 explaining 51% of symptom variance. Adrenomedullin emerged as the strongest independent predictor of symptom severity in sicca (r = 0.62, p < 0.0001), even after adjusting for BMI, age, and mood scores.

• Correlations between body mass index and symptoms were found in sicca and to a lesser extent in SjS patients.
• Adrenomedullin strongly correlates with symptoms in sicca patients.
• Proteomic analysis reveals cluster stratification with symptom associations in SjS and sicca patients.
• SjS and sicca clusters associated with highest symptom burden are less distinct proteomically.

Little bit more about adrenomedullin from the study:

ADM is a vasoactive peptide belonging to the calcitonin gene related peptide family that is released during inflammation. It has additional immune regulatory and neurological functions including pain signalling.27 ADM has been implicated in central and peripheral pain sensitisation induced by inflammation and bone metastases.27 28 Intrathecal injection of an ADM receptor antagonist markedly reduced the hyperalgesia following complete Freund’s adjuvant induced inflammation in rats.29 In addition, ADM has been associated with renal function30 which can explain the inverse correlation with GFR we have observed.

Link to the study:

Spoiler: Link to the study:

Pucino V, Turner JD, Nayar S, Kollert F, Rauz S, Richards A, Higham J, Poveda-Gallego A, Bowman SJ, Barone F, Fisher BA. Sjögren's and non-Sjögren's sicca share a similar symptom burden but with a distinct symptom-associated proteomic signature. RMD Open. 2022 May;8(1):e002119. doi: 10.1136/rmdopen-2021-002119. PMID: 35589331; PMCID: PMC9121491.

 

[Jonathan Edwards]

This research was largely prompted by the disappointing results of rituximab trials in Sjögren’s, where B-cell depletion showed virtually no benefit for patient-reported symptoms like fatigue and dryness:

I don't think improvement should have been expected from rituximab in Ro-positive disease at least because Ro antibodies do not go down much with rituximab. The quoted argument looks misplaced to me.