Handscan optical measurements in Rheumatoid Arthritis: an inventory comparing serum levels of CRP, ESR, IL-6, clinical arthritis and reproducibility of DAS28.

DAS28 is an internationally accepted composite measurement of RA disease
activity. There is one composite for BSE and one for CRP. There are several
reasons why a better method for RA disease monitoring should be developed.
The first reason is that in the pivotal DAS study in 1990, the indices for the
DAS28 were determined in a group of 113 *early* RA patients with a mean swollen
joint count of 14, a tender joint count of 11 and a mean CRP of 30 (2). This
group of patients is not representative for our current practice and a more
sophisticated measuring tool for the current *early phase* of the disease is
needed. In future, our therapeutic intervention might even move forward into
the spectrum of clinically suspect arthralgia.
Secondly, the reproducibility of DAS28 measurements in clinical practice is
known to vary between rheumatologists(3) (Cheung et al 2013). The concordance
in DAS28 (remission/ mild/severe/active) varied between 71% and 87%, with only
a kappa of 0.50 of agreement on swollen joint level.
Thirdly, the objective part of the indices may cause overtreatment of patients
with chronic pain without inflammation (4)
Another plea for an alternative method for measurement of disease activity is
the predicted problematic shortage of health care workers in rheumatology care
in the US. In table 1 it is shown that this shortage will be 4000 health care
workers in 2030 (5) An automated method (robotica) for measurement of disease
activity in RA might be a solution.

The Handscan is a new (Dutch) non invasive imaging device that visualizes
inflammation in the joints of hands and wrists in patients with rheumatoid
arthritis (RA). The technique is based on optical spectral transmission
measurements (www.hemics.com). By using this technique, the Handscan is
supposed to be an objective measurement tool.
The Handscan already demonstrated its ability to visualize subclinical
inflammation in studies when compared to ultrasound imaging and DAS28 scores
(Onna et al 2015).
At this time, only a few institutes (including both MCL and LUMC) have access
to and experience with this new device. Until now no data exist comparing the
Handscan with systemic parameters of inflammation such as ESR, CRP, IL-6 and
arthritis activity. Also, the range of the optical score in different patients
is not known.
With this study proposal we will gather data which may lead to more specific
clinical Handscan studies. First we have to define its association with current
objective inflammatory parameters and its quality to sense small (subclinical)
changes in a short treatment period. If this quality exists, than the Handscan
might be a new tool for objective and better measurement of disease activity.
A secondary objective of this study is to evaluate the relationship between
serum Interleukin-6 levels with CRP, ESR, swollen joint count over time during
treatment with different treatment modes. It is expected that serum IL-6 levels
in the Sarilumab treatment group better predict clinical response than in the
other treatment groups.
Another secondary objective is to describe the effects of Sarilumab therapy in
MTX naïve patients (% remission after 12 weeks and time to remission, compared
to the monotherapy MTX group).
If this study shows that the Handscan indeed can measure both subclinical
arthritis activity and is more sensitive to change than DAS28 measurement, then
more studies are justified. One intriguing application could be the use of the
Handscan as a classification tool for early RA patients, who would benefit most
from rapid onset biologic treatment at the early stages of the disease (6)
Furthermore, use of the Handscan as an instrument for substitution of medical
healthcare workers in controlling disease activity could be an important answer
to the expected shortage of healthcare workers in rheumatology.

2.1 Primary Objective
Describing the association between Handscan optical scores, markers of
inflammation (levels of CRP, serum IL-6) and clinical swollen joint score in
three treatment groups with different pharmacokinetic modes of action for RA
activity. Each of these groups has its own time to response due to differences
in pharmacodynamic properties of the used medication. If the Handscan is really
sensitive to early response then a difference between treatment groups should
be detected in Handscan scores.

2.2 Secondary Objectives
- Comparing differences in time to response in the three treatment groups for
swollen joint count, tender joint count, DAS28, CRP, ESR and IL-6
- Defining the Handscan optical scores in untreated early RA patients at
baseline
- Establish reproducibility of Handscan measurements with interobserver
variability of DAS28.
- Association between Handscan total optical score and DAS28
- Describing the effects of Sarilumab therapy in MTX naïve patients compared to
the monotherapy MTX group
- Establish IL-6 levels with rate of severity of arthritis activity, DAS28
categories.

The HANDRAIL study is a randomised open label trial with three different
treatment groups. This study compares the characteristics of different modes
for measuring disease activity in three randomized treatment groups with
expected different spatial response patterns during 12 weeks.

Investigational product/ treatment
Early MTX naive RA patients will be randomized in three subgroups:
I. methotrexate 15 mg once a week monotherapy
II. methotrexate plus methylprednisolone 120 mg IM (depomedrol )
III. methotrexate 15 mg once a week plus Sarilumab 200 mg SC every 2 weeks
After randomisation the study is an open label observational study, which
focusses on the characteristics of different modes for scoring RA disease
activity during 12 weeks.

Participation in this study entails a total of 7 study visits at Screening,
baseline, week 1, 3, 6, 9 en 12.
This means 3 to 4 visits more than patients would have had in standard of care
in the same period after starting a csDMARD. This is a time burden but also a
chance for early detection of persisting disease activity and an oppertunity to
adjust medication if necessary.
Blood drawal is slightly more frequent than in regular care, but at the start
of methotrexate patients also have to draw blood every three to four weeks in
the first three months. ( and sometimes more frequently, for example if they
start csDMARDs leflunomide of sulfasalazine)
Patients do not experience the Handscan measurements as painful.
Repeating the Joint examination for showing interobserver variability of the
DAS28 can be experienced as unpleasant, particularly if patients have a lot of
tender joints
All patients have active RA for which a DMARD would be started, regardless of
if the patient decides or not to participate in a study. In this study all
patients will receive medication with proven efficacy and known side effects,
which are deemed acceptable. The therapeutic effect (and the burden of
persisting active disease without starting medication) weighs up to the chance
of potential side effects.
Also patients have the chance of reaching early remission of RA as a result of
the start of Sarilumab early in the course of the disease, this has been shown
to have the benificial effect of reaching and maintaining longterm remission.