IgG4:IgG mRNA ratio as disease activity marker in vasculitis

Vasculitis is a heterogeneous group of inflammatory diseases that primarily
affects blood vessels. The pathogenesis of the inflammation is largely unknown.
The vascular inflammation impairs blood flow which causes hypoxia, necrosis and
organ failure with devastating consequences. The fluctuating course of primary
vasculitides together with difficulties in reliable assessment of disease
activity on the individual patient level leads to periods of over- and
undertreatment with associated side-effects, morbidity and mortality. Clinical
scores (such as BVAS-v3 (1)) assume that a physician is certain that symptoms
are attributable to vasculitis which is often not the case. Notably, the
differentiation of active vasculitis and infection may be difficult. As a
result, patients regularly need to undergo intensive additional investigations.
Specific and sensitive of current biomarkers are lacking in vasculitis (2): the
ones that serve as diagnostic biomarkers (e.g. ANCA) do not serve very well as
disease activity markers. Thus, from the current clinical perspective, there is
a pressing need for specific biomarkers that sensitively reflect disease
activity. In addition, more understanding of the pathogenesis of these diseases
is needed to further improve clinical care and treatment regimes.
We recently completed a pilot study that indicated that a qPCR test which
indirectly measures the presence of immunoglobulin-G4 positive B-cells and
plasmacells (Hereafter: IgG4+ cells) might be a good disease activity marker in
vasculitis. Historically, IgG4 is regarded as an immunomodulator (e.g. in
controlling allergies), but recent work on IgG4-RD and pemphigus also raised
the hypothesis that IgG4 might be pro-inflammatory (3). Multiple studies have
implicated IgG4 in the pathogenesis of vasculitis, in particular
ANCA-associated vasculitis (4-9), while clinically, there is overlap between
large vessel vasculitis and IgG4-RD (10). However, so far, the presence of
IgG4+ mRNA has not been tested as a disease activity marker in vasculitis.

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Modification and validation of the Birmingham Vasculitis Activity Score
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2. Monach PA. Biomarkers in vasculitis. Curr Opin Rheumatol. 2014;26(1):24-30.
3. Hubers LM, Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL,
Verheij J, Rauws EA, et al. IgG4-associated cholangitis: a comprehensive
review. Clin Rev Allergy Immunol. 2015;48(2-3):198-206.
4. Perez Alamino R, Martinez C, Espinoza LR. IgG4-associated vasculitis.
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(formerly Wegener*s) Lung Biopsies. ACR/ARHP Annual Meeting 20122012.
7. Yamamoto M, Takahashi H, Suzuki C, Tabeya T, Ohara M, Naishiro Y, et al.
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Value of serum IgG4 in the diagnosis of IgG4-related disease and in
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Aim 1:
Confirm the hypothesis that the IgG4 qPCR test score correlates with disease
activity in vasculitis as observed in the pilot study.
Aim 2:
Study IgG4-expressing B-cells from blood of vasculitis patients to understand
their role in the pathogenesis
Aim 3:
By conducting the studies under aim 1 and 2 we will build a unique cohort which
contains detailed clinical data and blood samples. These will be used for the
current project, but will also help in addressing future questions in
vasculitis. To this end we will store serum, PBMCs and RNA from blood at each
time point. If biopsies are performed, RNA from these samples will be added
following patient consent.

Longitudinal observational study with two arms. We will collect clinical
information and blood to study biomarkers. If left-over tissue is present from
standard diagnostic tests, this will also be analysed for biomarkers.
- Arm A (120-140 patients): 2 visits within 1 year
- Arm B (60-80 patients): Visits every 6 months for 2 years and extra visit in
case of suspected new disease activity

Patients will be seen for blood withdrawals related to the study. 2 to 5-7
times 77ml is the average (depending on the study arm).

There are hardly any risks to blood withdrawals (<1% chance of
infection/bleeding).

For biopsy materials that we will receive from the pathology department after
diagnostic routine analysis, there will be no prior research related actions.