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

Anti IL6R Reduce Complement Serum Level in Rheumatoid Arthritis Patients: Facts and Implications: Monocentric Study in Belgian Center

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.

Study Overview

• Status: Unknown
• Conditions: Rheumatoid Polyarthritis
• Intervention / Treatment: Other: Data extraction from medical files

• Study Type: Observational
• Enrollment (Anticipated): 35

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • Recruiting
    • Brugmann University Hospital
    • Contact: Tracy Vandergraesen, MD; Email: Tracy.VANDERGRAESEN@chu-brugmann.be
    • Principal Investigator: Tracy Vandergraesen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients followed in the CHU Brugmann Hospital for a rhumatoid polyarthiritis and treated according to standard of care with tocilizumab / sarilumab or for which this treatment is about to be initiated, in intravenous or subcutaneous form

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tocilizumab intravenous; Patients followed in the CHU Brugmann Hospital for a rheumatoid polyarthritis and treated according to standard of care with tocilizumab, intravenous	Other: Data extraction from medical files; Data extraction from medical files
Tocilizumab subcutaneous; Patients followed in the CHU Brugmann Hospital for a rheumatoid polyarthritis and treated according to standard of care with tocilizumab, subcutaneous	Other: Data extraction from medical files; Data extraction from medical files
Sarilumab subcutaneous; Patients followed in the CHU Brugmann Hospital for a rheumatoid polyarthritis and treated according to standard of care with sarilumab, subcutaneous	Other: Data extraction from medical files; Data extraction from medical files

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Demographic data	Age, sex	5 minutes
Body Mass Index	Body Mass Index	5 minutes
Medical History (descriptive listing)	Medical History (descriptive listing)	5 minutes
Neoplasia	Active neoplasia, or neoplasia dated less than 5 years	5 minutes
Disease Activity Score Calculator for Rheumatoid Arthritis- DAS28VS	The DAS28 is a measure of disease activity in rheumatoid arthritis . DAS stands for 'disease activity score' and the number 28 refers to the 28 joints that are examined in this assessment. A DAS28 of greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.	5 minutes
Disease Activity Score Calculator for Rheumatoid Arthritis- DAS28CRP	The DAS28 is a measure of disease activity in rheumatoid arthritis . DAS stands for 'disease activity score' and the number 28 refers to the 28 joints that are examined in this assessment. A DAS28 of greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.	5 minutes
Health Assessment Questionnaire (HAQ)	The Health Assessment Questionnaire Disability Index (HAQ) is developed for the assessment of disability in patients with Rheumatoid Arthritis. It focuses on two dimensions of health status, physical disability (eight categories), and pain. The eight categories review a total of 20 specific functions and evaluate patient's difficulty with activities of daily living over the past week.	5 minutes
Concomitant medication (descriptive listing)	Concomitant medication (descriptive listing)	5 minutes
Adverse events linked to the medication (descriptive listing)	Adverse events linked to the medication (descriptive listing)	5 minutes
Hemogram: normal (yes/no)	A hemogram contains all of the pertinent information required for assessment of hematopoiesis as well as a visual assessment of plasma appearance and measurement of total solids (an estimate of total protein) in plasma.	5 minutes
Leukocyte count	Leukocyte count	5 minutes
Blood Ionogram: normal (yes/no)	The blood ionogram analyses the ionic composition of the blood	5 minutes
Renal function: normal (yes/no)	Renal function	5 minutes
Hepatic function: normal (yes/no)	Hepatic function	5 minutes
Parathyroid hormone count	Parathyroid hormone count	5 minutes
Vitamin D count	Vitamin D count	5 minutes
Lipid balance: normal (yes/no)	Lipid balance allows monitoring of cholesterol (LDL-cholesterol and HDL-cholesterol) and triglycerides	5 minutes
Glucose concentration in the blood	Glucose concentration in the blood	5 minutes
Rheumatoid factor concentration	Rheumatoid factor is an autoantibody that induces inflammation and damage to the joints.	5 minutes
AntiCCP antibodies count	The detection of anti-CCP antibodies is used to help diagnose and prognosticate rheumatoid arthritis and differentiate it from other types of arthritis	5 minutes
FAN count	FAN are autoantibodies against elements of the nucleus	5 minutes
Sedimentation rate	Sedimentation rate	5 minutes
CRP count	CRP count	5 minutes
Complement fraction C1q count	Complement fraction C1q count	5 minutes
Complement fraction C3 count	Complement fraction C3 count	5 minutes
Complement fraction C3d count	Complement fraction C3d count	5 minutes
Complement fraction C3a count	Complement fraction C3a count	5 minutes
Complement fraction C4 count	Complement fraction C4 count	5 minutes
Complement fraction C4a count	Complement fraction C4a count	5 minutes
Complement fraction CH50 count	Complement fraction CH50 count	5 minutes
Complement fraction FB count	Complement fraction FB count	5 minutes
Lectin count	Lectin count	5 minutes
Lectin complement pathway serine protease 2 (MASP-2) count	Lectin complement pathway serine protease 2 (MASP-2) count	5 minutes
Mannose Binding lectin (MBL) count	Mannose Binding lectin (MBL) count	5 minutes
Complement SC5b9 count	Complement SC5b9 count	5 minutes
Fibrinogen count	Fibrinogen count	5 minutes
Lymphocyte B count: memory cells	Lymphocyte B count: memory cells	5 minutes
Lymphocyte B count: transitional cells	Lymphocyte B count: transitional cells	5 minutes
Lymphocyte B count: plasmablast cells	Lymphocyte B count: plasmablast cells	5 minutes

Collaborators and Investigators

• Sponsor: BADOT, Valerie
• Investigators: Principal Investigator: Tracy Vandergraesen, MD, CHU Brugmann

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2020
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: August 6, 2020
• First Submitted That Met QC Criteria: August 7, 2020
• First Posted (Actual): August 10, 2020

Study Record Updates

• Last Update Posted (Actual): August 10, 2020
• Last Update Submitted That Met QC Criteria: August 7, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Arthritis
• Other Study ID Numbers: CHUB-IL6

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No