TOLERA: Tolerance Enhancement in RA
- Registration Number
- NCT04120831
- Lead Sponsor
- University of Erlangen-Nürnberg Medical School
- Brief Summary
Although anti-citrullinated protein antibodies (ACPA) including anti-CCP2 antibodies are known to promote inflammation and joint destruction in patients suffering from ACPA-positive rheumatoid arthritis, there are currently no therapies available to efficiently eliminate autoantibody production and to re-induce immune tolerance in these patients. However, both a B cell-targeting therapy (Rituximab) and a T cell targeting therapy (Abatacept) were described to lower anti-CCP2 antibody levels and occasionally trigger disappearance of these autoantibodies (sero conversion). By sequentially combining Rituximab and Abatacept, we thus aim to enhance the tolerogenic potential of these drugs and seek to eliminate autoantibody production and significantly lower ACPA titers. This would for the first time correspond to a "deep" immunological remission and a re-induction of immune tolerance.
- Detailed Description
Based on fact that both a B cell-targeting therapy with Rituximab and a T cell-targeting therapy with Abatacept affect ACPA levels and can occasionally induce seroconversion and an immunological remission as well immune tolerance in ACPA-positive RA patients, we conclude that T/B cell-mediated autoimmunity can be in principle reversed in RA patients suffering from active disease. We hypothesize that we can increase the tolerance-inducing potency of Rituximab and Abatacept by combining these two approaches and delivering a sequential B cell/T cell therapy with Rituximab and Abatacept. Such a combined approach might increase the rate of seroconversions in RA patients and thus re-induce tolerance in a significant number of patients which would pave the way for a long-lasting "deep immunological" and drug-free remission.
In the proposed project, we thus plan to perform a sequential treatment with initial B cell depletion with Rituximab followed by blockade of the immunological synapse by Abatacept. Such an approach aims to deplete autoreactive B cells and plasmablasts, which constitute the major source for ACPA (3) and thus reboot part of the immune system, before blocking the immunological synapse in order to enable reconstitution of self-tolerance.
Based on their recently discovered pathogenic properties and to determine a potential immunological remission in the participating RA patients, we primarily plan to evaluate the effect of a sequential Rituximab/Abatacept treatment on changes in the levels of anti CCP2 antibodies between Baseline and Week 52 and will determine the rate of seroconversions.
Secondary, we plan to perform an additional quantitative and qualitative analysis of the ACPA response. Glycosylation of ACPA was shown to modulate their inflammatory activity and is thus considered to control the onset of arthritis in ACPA-positive individuals (9). We will therefore measure glycosylation (galactosylation, fucosylation and sialylation) of ACPA and total IgG. Moreover, we plan to determine changes in total IgG, IgA and IgM subclasses, numbers of total B cells and plasmablasts as well as of CCP2-specific B cells and plasmablasts in the peripheral blood of the participating patients. The clinical outcome will be measured at week 52 described by disease activity parameters and patient questionnaires.
The longitudinal setup of this proof of concept mode of action study is to evaluate the efficacy of a subsequent Abatacept therapy post B cell depletion in regard to ACPA seroconversion, ACPA titers and B cell phenotype changes.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 20
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Rituximab + Abatacept + MTX Abatacept Injection all participants receive Rituximab. Study subjects will be randomized into one of two treatment arms (Abatacept+MTX vs MTX) following a 1:1 randomization at Visit 3, at the day of the 2nd Rituximab Infusion. Rituximab + MTX (standard of care) Abatacept Injection all participants receive Rituximab. Study subjects will be randomized into one of two treatment arms (Abatacept+MTX vs MTX) following a 1:1 randomization at Visit 3, at the day of the 2nd Rituximab Infusion.
- Primary Outcome Measures
Name Time Method Primary endpoint week 52 Proportion of anti CCP2 antibody seroconversions in anti-CCP2-positive
- Secondary Outcome Measures
Name Time Method secondary endpoints week 52 Explorative serological biomarkers:
* Change in anti CCP2 antibody levels (RE/ml)
* Change in anti CCP2 antibodies in HLA-defined subgroups
* Change in levels of total IgG, IgG subclasses, IgA and IgM
* Glycosylation profile of total IgG, and of ACPA
* Change in B cell numbers
* Change in CCP2-specific B-cell numbers
Clinical outcome:
* Number of patients in DAS28, SDAI and ACR-EULAR Boolean remission at week 52
* DAS28 , SDAI, CDAI, CRP and ESR change over 52 weeks
* Response: ACR20, 50, 70 response at week 52
Trial Locations
- Locations (1)
Universitiy Hospital Erlangen
🇩🇪Erlangen, Bavaria, Germany