• To evaluate the response to an in vivo immune challenge (KLH) in RA patients in responders versus non-responders to MTX therapy.• To evaluate the immune status of RA patients before and after the start of MTX therapy using an ex vivo immune…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Pharmacodynamic endpoints:
o In vivo immune challenge (KLH):
* Anti-KLH IgG and IgM in serum.
* Skin biopsy: IHC staining of immune cells and RNA sequencing.
* Skin blood perfusion with LSCI, erythema with multispectral imaging (Antera
3D) after intradermal KLH re-challenge.
o Ex vivo immunomonitoring:
* Production of cytokines after PHA stimulation, including but not limited to
IFNγ, IL1b, IL2, IL6, IL8, IL17.
* Inflammatory gene expression after PHA stimulation.
* KLH-specific T cell response.
o Flow cytometry
* Characterization of monocytes, and T and B cell subsets by flow cytometry
• Pharmacokinetic endpoints:
o MTX-PG concentrations in erythrocytes and PBMCs over time.
o Non-compartmental analysis of the PMBC and erythrocytes concentration-time
data: AUC0-8m, Cmax (dose-normalized), Tmax.
• Clinical endpoints:
o DAS44 <= 2.4 and/or ΔDAS44 >0.6 at 3 months
o DAS44 <= 2.4 at 6 months
o DAS44 <1.6 at 3 and 6 months
o Boolean remission 2.0 at 3 and 6 months (14)
o Individual components DAS44
o Evaluator global assessment of disease activity (VAS 0-100mm)
o Treatment response as assessed by the investigator.
o Adverse events (AEs)
o Concomitant medication
Baseline for PD measurements is defined as the last value prior to dosing on
Day 1.
Secondary outcome
N.a.
Background summary
Rheumatoid arthritis (RA) is a chronic and systemic autoinflammatory disease
that causes synovial inflammation and leads to joint damage. To prevent
irreversible joint damage and improve long term outcome, it*s important to
start effective treatment early after diagnosis. The first line of treatment
for RA is conventional disease-modifying antirheumatic drugs (DMARDs), of which
methotrexate (MTX) is the preferred drug to start, often combined with
short-term glucocorticoids. If symptoms are not effectively controlled within
3-6 months, treatment is escalated to other conventional DMARDs in mono- or
combination therapy (e.g. hydroxychloroquine, sulfasalazine or leflunomide),
biological DMARDs (e.g. TNF blockers) or more specific targeted synthetic
DMARDs (e.g. JAK inhibitors) (1).
While for most RA patients MTX is effective and results in a reduction of the
disease activity score (DAS), for more than one third of the RA patients MTX
therapy does not give the desired effect. Although several demographic,
clinical, biochemical and genetic predictors for MTX response have been studied
(2-5), identifying a reliable biomarker to predict treatment response that can
be used in clinical practice remains a challenge. While for other
immunomodulatory drugs the monitoring of plasma drug concentration is often
used, for MTX treatment this type of pharmacokinetic monitoring is less
informative. MTX has a relatively short half-life (~6 hours) and is
undetectable in serum after 18 hours, while patients are usually dosed once a
week to achieve clinical effect (6). However its main metabolites MTX 1-3
polyglutamates can be quantified in blood cells such as erythrocytes and
polymorphonuclear blood cells (PBMC*s) (7). It would be more informative to
monitor the effects of MTX on the immune system, rather than measuring
circulating drug concentrations alone. Monitoring the patient*s immune status
at the cellular level, and how it is affected by MTX treatment, could provide a
better understanding of the MTX response and may enhance the adequate use of
MTX in RA patients.
Since B and T cells play a critical role in the pathogenesis of RA (8) two
different immune challenges, ex vivo and in vivo, will be used to study the
immune-competence of B and T cells during MTX therapy.
For the in vivo immune challenge, the keyhole limpet hemocyanin (KLH) will be
used as a stimulus. KLH is a neo-antigen that has been safely used in many
clinical trials (9-12). When injected intramuscular, KLH elicits a T
cell-dependent immune response that can be studied by quantifying the
KLH-specific antibody response. Moreover, an extra adaptive immune response
will be evoked via a prime-boost regimen in which KLH is administered
intradermally, 2 to 4 weeks after the intramuscular (i.m.) KLH immunization.
This intradermal KLH challenge induces a delayed-type IV hypersensitivity (DTH)
reaction at the injection site. The immune response following this injection
can be quantified by monitoring the local skin response.
In addition, ex vivo cytokine production will be measured after 24 h of
phytohemagglutinin (PHA) stimulation in whole blood, to study the
immunosuppressive effect of MTX. PHA is a lectin known for its membrane
glycoproteins binding, including the T cell receptor (TCR), which leads to the
activation of T cells (13). Unravelling the relationship between T cell
functionality and MTX dose, and MTX polyglutamate concentration in whole blood
and in the target cell, may enable a pharmacodynamic (PD), rather than a
pharmacokinetic (PK)-based approach for future therapeutic drug monitoring of
MTX.
In this study, we will investigate the KLH response in RA patients in
responders compared to non-responders to MTX therapy, aiming to make the
translation from the in healthy volunteers used KLH model to a RA patient
population on MTX therapy. Furthermore, the immune status of treatment-naïve RA
patients, before and after the start of MTX therapy, will be evaluated aiming
to provide a better understanding of the interpatient variability of MTX
efficacy and identify biomarkers that can potentially explain the difference
between responders and non-responders to MTX therapy. Concomitantly the
exposure to MTX will be quantified by measuring MTX polyglutamates in
erythrocytes and PBMC*s.
Study objective
• To evaluate the response to an in vivo immune challenge (KLH) in RA patients
in responders versus non-responders to MTX therapy.
• To evaluate the immune status of RA patients before and after the start of
MTX therapy using an ex vivo immune challenge (PHA stimulation).
• To characterize circulating immune cell subsets in RA patients before and
after the start of MTX therapy.
• To monitor MTX pharmacokinetics in RA patients during MTX therapy, by
measuring MTX polyglutamates (MTX-PG).
• To explore the relationship between the response to ex vivo and in vivo
immune challenges, and the clinical outcome of RA patients on MTX therapy.
• To explore the relationship between the response to ex vivo and in vivo
immune challenges and pharmacokinetics (MTX-PG).
• To explore the relationship between pharmacokinetics (MTX-PG), and the
clinical outcome of RA patients on MTX therapy.
• To explore the relationship between MTX polyglutamates (MTX-PG) in
erythrocytes and PBMCs.
Study design
This is an observational study in 20 treatment-naïve rheumatoid arthritis
patients that are starting with weekly MTX and short-term treatment of
glucocorticoids as standard of care. After 3 and 6 months, treatment response
will be evaluated.
Intervention
Weekly MTX and short-term treatment of glucocorticoids as standard of care.
KLH
Study burden and risks
All rheumatoid arthritis patients will be on methotrexate treatment, which is
their standard pharmacological therapy. The dose and regimen of these drugs
will not be adjusted for their participation to this study. The main
intervention that the study participants will undergo are blood withdrawal for
PD measures, KLH immunization and challenge including imaging of the skin and
one skin punch biopsy.
Immunization with KLH is not expected to yield any benefit for the
participating subjects. In terms of risks, all drugs that are used in the
present study are widely used in the Netherlands, and, apart from temporary
side effects associated with the administration of the drugs, it is unlikely to
expect that the subjects will be at risk of unforeseen events.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure;
2. Recently diagnosed treatment naïve rheumatoid arthritis patient (male or
female) fulfilling to the ACR2010 criteria that are starting methotrexate
therapy (with or without corticosteroids).
3. Patient must be between 18 and 75 (inclusive) years old at screening.
4. Has the ability to communicate well with the investigator and willing to
comply with the study restrictions.
Exclusion criteria
1. Contra-indication(s) to start methotrexate (e.g. ALT/AST >3x ULN, child
wish).
2. The use of any immunosuppressive or immunomodulatory medication other than
the patient*s prescribed RA treatment within less than 5 half-lives prior to
study participation, if the investigator judges that it may interfere with the
study objectives;
3. Any known factor, condition, or disease that might interfere with study
conduct or interpretation of the results, in the opinion of the investigator.
4. Unwillingness or inability to comply with the study protocol for any other
reason.
5. Participants with known previous exposure to KLH.
6. History of Schistosomiasis (infection with Schistosoma parasite);
7. Have any current and / or recurrent clinically significant skin condition at
the treatment area (i.e. atopic dermatitis); including tattoos.
8. Clinically significant bleeding disorders known to interfere with hemostasis
after skin biopsy and/or i.m. injection.
9. Disorders in wound healing (peripheral vascular disorders or neuropathy,
history of forming keloid scars).
10. Any known significant allergic reactions (urticaria or anaphylaxis) against
shellfish.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL87435.058.24 |