Neuroendocrine Modulation Induced by Selective Blockade of TNF‐α in Rheumatoid Arthritis

Abstract

Tumor necrosis factor-alpha (TNFalpha) is a main actor in the pathogenesis of rheumatoid arthritis (RA), interacting with other molecules in complex mechanisms. The neuroendocrine system is known to be involved and Chromogranin A (CHGA) serum levels are elevated in patients with RA. We evaluated the effect of the selective blockade of TNF-alpha, induced by treatment with anti-TNF-alpha monoclonal antibodies (mAbs), on the serum levels of CHGA and on its correlation with TNF-alpha and TNF-alpha receptors (TNFRs) serum levels. Seven patients with RA have been treated with the anti-TNF-alpha mAb, infliximab. We measured the serum levels of TNF-alpha, its receptors (tumor necrosis factor receptor-I [TNFR-I] and tumor necrosis factor receptor-II [TNFR-II]), and CHGA before and during the treatment. We also measured, as a control, the serum levels of CHGA, TNF-alpha, and soluble TNFRs in 14 patients who were being treated with infliximab, adalimumab, or etanercept and in 20 matching negative controls. The serum levels of TNFR-I and TNFR-II, which are a sensitive marker for the TNF-alpha pathway, correlated with those of CHGA before treatment (Pearson's coefficient, respectively, 0.59 and 0.53). Treatment with anti-TNF-alpha mAb provided a significant clinical response in all patients and the correlation between CHGA and TNFR-I and TNFR-II was no more evident during treatment (respectively, -0.09 and -0.07). TNF-alpha blockade allows a clinical effect in patients with RA and modifies the correlation between CHGA and TNFRs, suggesting that TNF-alpha and CHGA reciprocally interfere in the pathogenesis of RA, through intermediate adaptors, whose identification warrants further studies.

The endocrine role for chromogranin A: A prohormone for peptides with regulatory properties

“…TNF-a activation is a primary mechanism in the pathogenesis of RA. Interestingly, treatment of patients with anti-TNF antibodies was associated with significant clinical responses and loss of correlation between CgA and sTNFRs [84]. The tissue origin of circulating CgA in CHF and RA is unknown.…”

“…The good correlation between CgA and sTNFRs and the lack of correlation with neuroendocrine variables [63] suggest that circulating CgA reflects systemic inflammation much better than neuroendocrine activation in CHF. Rheumatoid arthritis (RA) is another inflammatory condition associated with increased levels of CgA [84]. Serum levels of CgA were particularly elevated in RA patients with severe extra-articular manifestations.…”

Chromogranins A and B and Secretogranin II as Prohormones for Regulatory Peptides from the Diffuse Neuroendocrine System

“…Plasma CgA is by now a commonly used diagnostic and prognostic marker for tumors of neuroendocrine origin, using antibodies raised to a range of epitopes along the CgA molecule (Stridsberg et al 2004;Greenwood et al 2006;Børglum et al 2007). Plasma CgA is also elevated in patients with a range of systemic diseases including renal and hepatic failure, cardiac arrest, and essential hypertension (Taupenot et al 2003) as well as in inflammatory conditions such as heart failure (Corti et al 2000;Ceconi et al 2002), acute coronary syndromes (Jansson et al 2009), rheumatoid arthritis (Di Comite et al 2006, 2009, systemic lupus erythematosis (Di Comite et al 2006) and acute systemic inflammatory response syndrome (Zhang et al 2009a). It seems well established that increased plasma CgA is predictive of shorter survival, not only in patients with metastatic neuroendocrine tumors (Arnold et al 2008;Nikou et al 2008), but also in chronic heart failure (Ceconi et al 2002) and in the critically ill, nonsurgical patients (Zhang et al 2008;2009a).…”

Utilizing a Novel Tandem Oral Dosing Strategy to Enhance Exposure of Low-Solubility Drug Candidates in a Preclinical Setting

“…23-28 TNF-a is believed to be responsible for stimulating the release of other inflammatory mediators that cause dilation of local microvasculature and permeabilization of capillaries and that in turn results in rheumatoid arthritis. 29,30 This compound was found to have an IC 50 value of less than 10 nM in an MK2 kinase assay. In vivo potency was evaluated by measuring the inhibition of TNF-a production in an acute lipopolysaccharide rat inflammation assay.…”