Summary
Interleukin-6 is often understood as a pro-inflammatory cytokine, similar to TNFa and IL-1b.
This is not true, as IL-6 also triggers inflammation-limiting mechanisms, such as the expression of the tissue inhibitor of metalloproteinases (TIMP).
This effect underlies the dreaded intestinal perforation caused by tocilizumab (TCZ), because when IL-6 is blocked, TIMP is no longer expressed and catabolic enzymes such as collagenase and stromelysin can exert their effect uninhibited.
Conversely, IL-1 and TNF induce the initial processes of inflammation, for example the expression of chemokines, a property that IL-6 does not have.

The GUSTO study was the first and only study to selectively and comparatively investigate the effect of prednisone (PDN) and TCZ on proteins.
The protocol allowed the asservation of serum before the first administration of PDN, after 3 days of Solumedrol and then under TCZ monotherapy for 52 weeks.
We analyzed over 1400 proteins in serum using a proximity extension assay (PEA) on the Olink Explore 1536.
This approach allowed an unbiased search for proteins that are differentially regulated by PDN and TCZ.
It also enabled the identification of proteins that reflect subclinical disease activity and could in future replace the unreliable CRP in everyday clinical practice.

The data show the expected profound and rapid effect of PDN on proinflammatory molecules (but also, for example, an inducing effect on the catabolic MMP3).
After discontinuation of PDN, under TCZ, various chemokines such as CXCL9, CCL7 and CXCL10 return to baseline levels and slowly normalize over weeks, sometimes months.

In summary, the data support the statement made at the beginning, namely that IL-6 does not directly control certain primary inflammatory processes.
The data can explain early recurrences under TCZ monotherapy and argue in favor of PDN comedication for a few weeks.
Finally, they suggest that the chemokines mentioned may serve as follow-up parameters for monitoring subclinical inflammatory activity.
Taking into account the regulatory properties of TNF and IL-6 – together with the data mentioned – it can be assumed that in the case of critical ischemia (blindness), TNF inhibition with infliximab, for example, would be more promising than the administration of TCZ in addition to solumedrol pulses.

References
[1] Christ L, Gloor AD, Kollert F, Gaber T, Buttgereit F, Reichenbach S, Villiger PM.
Serum proteomics in giant cell arteritis in response to a three-day pulse of glucocorticoid followed by tocilizumab monotherapy (the GUSTO trial).
Front Immunol.
2023 May 23;14:1165758.
doi: 10.3389/fimmu.2023.1165758.
eCollection 2023.
PMID: 37287970

Written by
Prof. Dr. med. Peter M. Villiger
Monbijou Medical Center
Monbijoustrasse 10, 3011 Berne
August 2023