Anti IL6R Reduce Complement Serum Level in Rheumatoid Arthritis Patients: Facts and Implications

Interleukin 6 is identified as a cytokine with pro and anti-inflammatory effects, depending on the context to which it is exposed, exerting a role in the expansion and activation of T lymphocytes, in the survival, expansion and the maturation of B lymphocytes and plasmablasts as well as in the regulation of the acute phase response. The IL-6 receptor complex is a dimer in which each monomer is composed of an 80 kD subunit, IL-6R or CD126, expressed in hepatocytes, leukocytes and in megakaryocytes, which binds IL- 6 and a 130 kD subunit, gp130 or CD130, which is expressed ubiquitously. Its effects are mediated mainly by the way of tyrosine kinases of the Jaks family, and transcription factors of the STATs family.

The complement system is made up of a set of plasma proteins, cascading through three activation pathways (classical, alternate and lectin pathway). This system is considered part of innate immunity. It is also part of the acute phase response.The complement has several functions: cell lysis by formation of the membrane attack complex; opsonization and activation of phagocytosis of foreign particles, elimination of circulating immune complexes, and regulation of the adaptive immunity response and inflammation via anaphylatoxins.

After reviewing the literature, the link between IL6 and the complement system can be summarized as an induction of factor C3 and factor B, but also probably CD55 (DAF or Decay acceleration factor) and CD59 (MAC-IP or MAC-Inhibitory Protein) by interleukin-6. The effects of IL-6 on the lectin pathway, on the other hand, seem contradictory: inhibition or induction of the synthesis of MASP1 / 3 and 2 depending on the experimental model.

It has become common knowledge that anti-IL6 receptor monoclonal antibodies, used in the treatment of patients with rheumatoid arthritis and other inflammatory conditions, reduce the serum levels of acute phase proteins and in particular the levels of CRP. But what about other acute phase proteins and in particular the complement ?

A recent study showed that the serum levels of the complement components C3 and C4 were also reduced after the use of tocilizumab and this as early as 4 weeks after the first administration. To the investigator's knowledge, this is the only study reporting a decrease in complement during treatment with anti-IL6R.

This study would allow the evaluation of complement parameters in the population of patients under treatment with antiIL6R (tocilizumab or sarilumab) within the CHU Brugmann Hospital in order to

* confirm or not this observation
* look for a possible secondary clinical consequence
* compare this decrease with the activity of the disease in order to see if it could be a marker of effectiveness
* put this decrease in parallel with the side effects / tolerance of the treatment in order to see if it could be a marker of toxicity / safety

This study will also investigate the subpopulations of B lymphocytes (memory B, transitional B, and plasmablasts) in order to assess whether the evolution of one of these lines would be predictive of a therapeutic response.

Secondly, this study would eventually allow

* to improve the understanding of the mechanisms of action of the treatment on inflammatory markers by evaluating the activity of the residual complement
* to raise the need to find new parameters for monitoring inflammatory activity in these patients, since CRP assays are not very helpful.


Eligibility Criteria:
Inclusion Criteria:

* Patient ≥ 18 years old
* Regular follow-up at CHU Brugmann Hospital for confirmed rheumatoid arthritis and meeting the ACR 2010 criteria
* On tocilizumab / sarilumab or for which this treatment is about to be initiated, in intravenous or subcutaneous form

Exclusion Criteria:

* Patients with a known complement deficiency before their rheumatic pathology
* Patient with hepatic impairment