T-cell clonal expansion in chronic demyelinating inflammatory polyradiculoneuropathy (CIDP)

Corticosteroids, intravenous immunoglobulin (IVIg) and plasma exchange are the
only proven effective therapies in CIDP. Still, around 20% of patients do not
or insufficiently respond to treatment. Most patients need long-term treatment
such as daily prednisolone and/or interval infusions with IVIg which have their
specific drawbacks. Corticosteroids frequently results in serious adverse
events such as diabetes, hypertension and osteoporosis. IVIg is relatively
difficult to administer as it has to be given intravenously at regular
intervals and is very expensive. Long-term maintenance treatment is further
complicated by the difficulty in identifying patients that require lower doses
or no treatment at all as most patients have no or only minor symptoms during
maintenance treatment. This has been illustrated by a recent trial in which
maintenance doses could be significantly reduced in almost half of patients
with placebo add-on treatment. Alternatively, clinical deterioration is often a
late manifestation of active disease due to under treatment and can lead to
permanent axonal damage.

The key mechanisms in the pathogenesis have not been identified although
several studies have highlighted the role of T-cells in CIDP. Better
understanding of the pathogenesis is needed to identify new treatment
strategies and to develop biomarkers that correlate with disease activity that
could help guide maintenance treatment. Recently, our Genome Analysis
Department developed a new method for TCR repertoire typing based on high
throughput sequencing (HTS) using T-cel RNA. Using this method we will explore
whether expanded T-cell clones can be observed in both nerve biopsies as in
peripheral blood of newly diagnosed CIDP patients.

1) The primary objective of this pilot study is to compare the clonal
composition of the TCR repertoire in anterior fascicular sural nerve biopsies
with the TCR repertoire in peripheral blood of CIDP patients with active
disease in order to identify disease-associated T-cell clones.
2) The second objective is to compare the frequency of expanded T-cell clones
in peripheral blood during different disease activity states.

Observational pilot study.

The main risk of anterior sural fascicle biopsies is the occurrence of a
persistent sensory deficit in about 1/3 of patients corresponding with the
territory innervated by the nerve (sensation loss in lateral foot). Other
immediate complications of sural nerve biopsies (whole and anterior fascicle
sural nerve biopsies) are postoperative pain, parasthesia and dysesthesia
(unpleasant feeling of touch) in about 1/3 of patients and wound infection
(8%). Long-term follow-up studies have suggested a decrease in symptoms up to 5
years after biopsy. In almost all patients sural biopsy complications were
judged to be mild and did not lead to functional impairment.

Nerve biopsy will be only performed in patients with clinical and
electrophysiological signs suggesting already severely impaired sural nerve
function. This is important not only to avoid sampling error (absence of
T-cells in sural nerve) but also because it would strongly reduce the chance
that permanent sensory deficit is caused by the anterior fascicle biopsy. Most
patients responding to treatment improve in muscle strength whereas distal
sensory residual symptoms normally persist.