Diagnostics and mechanisms of titanium allergy

Titanium is one of the most commonly used materials for implantation in the
human body. It is widely used especially in dentistry, as well as in
orthopaedic surgery and cardiology. Evidence is accumulating that at least 4-5%
of patients with titanium implants develop type IV sensitivity to titanium.
Importantly, the current tests (skin patch test with titanium derivatives) are
found not to be accurate nor sensitive. Identification of the best diagnostic
test, or a combination of diagnostic tests, is of important clinical relevance
and needed for adequate patient advice. In addition to the common skin patch
tests, two in vitro tests are described for the diagnosis of type IV metal
hypersensitivity. However, the potential diagnostic value of recently developed
in vitro tests is still being examined. This full study has the aim to improve
clinical diagnostics for titanium hypersensitivity via comparison and
examination of the in vivo (with novel titanium derivatives) and in vitro
tests. Before the start of the full study, several novel titanium derivatives
will be tested in a pilot study for their ability to penetrate skin in a
limited patient group. Penetration is in fact necessary for the development of
a hypersensitivity reaction. Only derivatives which are capable of penetrating
the skin will be used in the full study.

Primary Objective:
Pilot study: Selection of the titanium derivatives which are capable of
penetrating the skin, and thus can be used in the full study as patch test
materials.
Full study: To compare the results of three different diagnostic tests used for
identifying titanium allergy and to find the best combination of these tests
which are needed to identify the titanium allergic patient.

Secondary Objectives:
Full study: to study the immunological mechanisms underlying titanium
sensitivity and to validate different new evaluation methods for the objective
interpretation of patch test results. Also, to obtain a view on the symptoms
and patient characteristics related to titanium sensitivity.

Pilot study: Single-centre experimental study.
Pilot study intervention(s): Cutaneous penetration test by sequential adhesive
tape stripping (to obtain evidence of cutaneous penetration by the tested
derivative).

Full study: multi-centre observational cross-sectional study (prospective test
comparison study).
Full study intervention(s): All participants are offered skin patch tests with
routine read-outs and read-outs with new evaluation methods known as
non-invasive optical diagnostic tools (NODT) and a skin irritability test. The
test group and negative control group are offered two venipunctures (for in
vitro tests). The allergens that will be used during epicutaneous skin tests
are commercial and novel titanium derivatives.

Minor discomforts can occur from the patch tests and skin irritability tests.
For example local itching, redness of the skin, sometimes with vesicles, can
occur. The study procedures are routine procedures in dermatological
diagnostics. The substances to be tested in this study are either routine
diagnostic titanium derivatives, commercially available titanium derivatives or
a newly selected titanium derivate (developed by the department of Dental
Materials Science laboratory under supervision of dr. C.J. Kleverlaan) or a
combination of them. These diagnostic substances are unlikely to cause serious
unexpected adverse reactions. Peripheral blood is collected by venipuncture,
which is a very low risk and routine procedure. Non-invasive optical diagnostic
tools are imaging techniques with very minimal risks and no ionizing radiation.
Cutaneous penetration tests by adhesive tape strips can cause minor discomfort
on removal and moderate erythema resulting from application and removal.
Normally, four regular visits to the Dermatology outpatient clinic are needed
for the diagnostic allergy work-up. Due to this study, full study participants
will have to visit one extra time. The negative control group will also have
five visits to the Dermatology outpatient clinic. Participants could benefit
from the additional advice they receive about their allergy. They will have
gained more specific information about their allergy, and, if possible, safe
implant material alternatives.