Photoacoustic detection and monitoring of synovitis in finger joints with rheumatoid arthritis.

Current methods to detect or diagnose rheumatoid arthritis (RA) are based on
physical examination and ultrasound (US) imaging, while x-ray imaging and MRI
imaging are used in problem-solving situations.
Physical examination is not sensitive enough for early stage diagnostics. US
imaging is moderately sensitive to the synovium of the joint where the first
changes are expected to be witnessed. These indicators are thickening of the
synovial membrane, hypertrophy, edema (swelling) in the joint capsule and an
increased blood volume. The latter is detectable using the power Doppler mode.
However the technique suffers from subject-to-subject and inter-observer
variation. X-ray imaging is limited to changes in bony structures, that occur
only after months to years of joint inflammation. MRI imaging is sensitive and
specific, but requires contrast agents, is expensive and because of that
relatively less accessible.
Photoacoustic imaging is a new modality that has the capacity to visualize
blood vessels in soft tissue without the use of contrast agents. Pulsed light
is absorbed by haemoglobin in blood which produces ultrasound by the
photoacoustic effect. This ultrasound can be measured with high resolution
ultrasound transducers. An increased density of blood vessels and/ or increased
blood flow are hallmarks of joint inflammation which constitutes an early step
in the progression of RA. Photoacoustic imaging promises visualization of
synovial vascularity, since it reflects the presence of haemoglobin.
This method is expected to improve sensitivity and specificity of imaging in
early arthritis. We will investigate the feasibility of using the method on a
small population of patient volunteers.

-To determine the feasibility of detection of synovitis by photoacoustic
imaging using three discrete wavelengths of pulsed light as an early indicator
of the presence of RA.
-To correlate the photoacoustic markers that are indicative for inflammation
with conventional RA imaging modalities and clinical examination.
-To make/propose technological changes based on clinical experiences, and to
use the results in the development of new generations of photoacoustic imaging
devices that will be used in phase 2. (amendment)
-To find appropriate image analysis methods in order to get the best contrast
and resolution within the investigated finger joint.

Two proximal interphanlengeal finger joints of a total of 30 patients and 20
healthy volunteers will be investigated by ultrasound imaging and photoacoustic
imaging (three wavelengths). The total duration of the study is 2 years.

In phase 1, which will last for 1 to 3 months, 10 patients with highly inflamed
PIP joints and 10 healthy volunteers are measured. Those measurements and
results will be used for optimization of the measurement protocol and analysis
algorithms that we use for the design and modification of the systems used in
phase 2.

In phase 2, which will last till the end of 2015, new generations of imaging
devices will be tested. Two new improved versions have been developed. Each of
these versions requires 10 patients and 10 healthy subjects to test the main
question of the research. This results in a total of 20 patients and 20 healthy
subjects in phase 2.

A total of 30 patients and 30 healthy volunteers will be included in the whole
project (fase1 +2)

The only burden for the patients is a 2 hour visit at the University of Twente.
The rheumatologist will clinically investigate finger joints of the patient
first. Followed by ultrasound and Doppler imaging of the finger joints (total
5-10 min).
The photoacoustic measurements will consist of two scans of approximately 15
minutes.

A thorough risk analysis was performed by the clinical physician and the
medical instrumentation group of the ZGT.
The clinical physicians assessed the possible risks that are related to the use
of laser sources. Based on their advice we improved the laser safety on several
topics. All advices were included into the user protocol. The nominal ocular
hazard distance (NOHD) and the hazard distance are taken into account.
Additional warning signs were placed and the required safety level of the laser
safety goggles is checked according to the most strict rules: EN 207. The EN
207 rules include a high optical density and a high damage threshold of the
used safety glasses.

The medical instrumentation group looked into the electrical safety of the
whole setup. No harm can be done to the patients because of the used isolation
transformer which protects against current leakages. The isolation transformer
does this by separating the setup from the grid main power. (IEC60601-1 en
IEC60601-1-1)
Only after written permission from the Clinical physician and the medical
instrumentation group we will be allowed to start with patient measurements.

Level of knowledge about mechanism of action
Due to light absorption, tissue experiences a temperature rise when exposed to
laser light. To prevent tissue injury, the maximum permissible laser energy
output is restricted to standards. These values are dependent on the used
wavelength, beam geometry, scale and duration of measurement. This calculation
is based on the following two conditions from the international standard IEC
60825-1,and the Dutch norm (Richtlijn) 2006/25/EG:

1. The exposure from any single pulse within a pulse train shall not exceed the
MPE for a single pulse.
2. The average exposure for a complete pulse train of exposure duration T shall
not exceed the MPE for a single pulse of exposure duration T.

Photoacoustics has been intensively investigated for medical purposes for the
past decade. The most important risk factor is the used amount of light in from
the laser source. International safety rules apply for all uses of laser light.
MPE levels for skin and eyes were carefully defined for medical use.
During the experiments of this research the used laser will not exceed not
exceed the MPE levels for the skin. Safety measures have been taken in the user
protocol to ensure the safety of both user and patient.