The primary goal of this study is to identify immunological alterations in blood, lymphoid tissue, bone marrow and muscle in IIM patients. Furthermore, our objective is to specifically profile autoreactive B lineage cells from IIM patients isolated…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Muscle disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Identifying the cellular and molecular changes in immune system and functional
characterisation of B cells, T cells, stromal cells and their signalling
pathways in peripheral blood, lymph nodes and bone marrow as well as inflamed
muscle tissue in IIM patients.
Secondary outcome
Not applicable
Background summary
Idiopathic inflammatory myopathy (IIM) is an auto-immune disorder leading to
muscle weakness with considerable loss of function and quality of life. The
underlying pathogenesis and cellular and molecular alterations of the immune
system in this disease remain largely unknown. A better understanding of these
alterations in bone marrow, lymph nodes, muscle tissue and peripheral blood is
needed to gain insight in the mechanisms driving IIM and useful biomarker
information for diagnosis and prognosis and may help to identify potential new
treatment strategies. Both B and T cells have an important role in
immunopathology of myositis. The role of B cells in IIM is supported by the
presence of autoreactive B lineage cells in inflammatory lesions which produce
autoantibodies and beneficial effect of B cell depleting, anti CD20 therapy.
However, a considerable proportion of patients respond poorly to this
treatment. The Janus kinase (JAK)/signal transduction and activator of
transcription (STAT) pathway is a crucial downstream signaling pathway which is
important for many functions in B lineage cells, including proliferation,
differentiation, survival and antibody production. Our preliminary data showed
that that JAK/STAT signaling is crucial in B cell responses in IIM patients, as
a JAK/STAT inhibitor tofacitinib significantly reduced B cell proliferation and
plasmablast differentiation in peripheral blood cultures. Current
immunosuppressive treatments do not deplete certain plasmablasts and long-lived
plasmacells in lymph nodes, bone marrow and muscle tissue, where they can
survive and promote further disease activity by persistent autoantibody
production. Consequently, there is an unmet need in targeting autoantibody
producing plasmacells. This potential novel target for therapy has several
advantages over currently available treatments as targeting of intracellular
signaling pathways requires small molecules that are able to reach the lymph
nodes/bone marrow and usually have a short half-life, which makes it possible
to stop treatment directly in case of infections and cause less complications
than B cell depleting agents. Furthermore current treatments result in
long-term impairment of humoral immune response, which may increase the
susceptibility to infections.
We hypothesize that JAK/STAT signalling in (autoreactive) B lineage cells is
essential for proliferation, differentation into plasma cells and/or
maintenance of these cells in bone marrow niches, and autoantibody production
contributing to disease activity in IIM.
Study objective
The primary goal of this study is to identify immunological alterations in
blood, lymphoid tissue, bone marrow and muscle in IIM patients. Furthermore,
our objective is to specifically profile autoreactive B lineage cells from IIM
patients isolated from inflamed muscle tissues, lymph nodes, bone marrow and
peripheral blood and to investigate the immunological and downstream molecular
effects of targeting JAK/STAT and other signalling pathways in IIM B lineage
cells.
Study design
Observational study
Study burden and risks
Patients/healthy subjects will have a needle biopsy of a lymph node in the
groin, a bone marrow biopsy from the pelvis, additional blood collection and a
muscle biopsy. For patients, some of these procedures are part of the normal
diagnosis of myositis, such as a muscle biopsy and blood tests. During the
blood test we will take extra blood (97cc extra) for this research project and
during the muscle biopsy we will take a small amount of extra muscle tissue
from myositis patients for this research project. The muscle biopsy by needle
biopsy in healthy subjects is performed for this research and is not part of
regular care. For healthy subjects it is possible to give permission to undergo
only a lymph node biopsy and bone marrow biopsy without a muscle biopsy.
The research will increase the insight into the pathogenetic processes that
play a role in the onset and persistence of myositis. This insight may lead to
the identification and validation of new biomarkers that bring "personalized
medicine" in myositis a step closer. In addition, new insights into the
pathogenesis can lead to the development of new therapies or therapeutic
strategies. In view of the relatively small risk of complications, we consider
this study justified.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
- Adult patients (18-80 years) with idiopathic inflammatory myopathy (IIM),
according to diagnostic criteria:
• Dermatomyositis
• Overlapmyositis
• Antisynthethase syndrome
- Informed consent
Exclusion criteria
Exclusion criteria:
- Patients who are not able to give informed consent
- Pregnancy
- Present or previous (< 2 year) treatment with any cell depleting therapies,
including anti-B-cell therapy or other investigational agents (e.g., abetimus
sodium, anti CD40L antibody, BG9588/ IDEC 131).
- Immunosuppressive treatment within the last 24 months with the exception of:
• Oral prednisone with a maximum dose of 60mg/day since one week, without
clinical response
• Oral prednisone with a maximum dose of 20mg/day since two weeks, without
clinical response
- History of infection:
• Currently on any suppressive therapy for a chronic infection (such as
tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes
zoster and atypical mycobacteria)
• Hospitalization for treatment of infection within 60 days of Day 0.
• Use of parenteral (IV or IM) antibiotics (anti-bacterial, antiviral,
anti-fungal, or anti-parasitic agents)
- History of malignancies neoplasm within the last 5 years except basal cell or
squamous cell carcinoma of the skin treated with local resection only or
carcinoma in situ of the uterine cervix treated locally and with no evidence of
metastatic disease for 3 years
- Have a history of a primary immunodeficiency, including significant IgG
deficiency (IgG level < 400 mg/dL) or IgA deficiency (IgA level < 10 mg/dL)
- Have current drug or alcohol abuse or dependence, or a history of drug or
alcohol abuse or dependence within 365 days prior to Day 0
- Have a historically positive HIV test or test positive at screening for HIV
- Have any other clinically significant abnormal laboratory value in the
opinion of the investigator
Design
Recruitment
Medical products/devices used
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 | NL85907.018.24 |