Heart Rate Variability in pre-clinical and clinical arthritis

Rheumatoid Arthritis and Pre-Clinical Arthritis
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease in which
specific auto-antibodies can be detected years before RA becomes clinically
manifest. These serum auto-antibodies, IgM rheumatoid factor (RF) and
anti-citrullinated protein antibodies (ACPA) are first seen at a median of 5
years before clinical symptoms appear. People with these specific rheumatoid
auto-antibodies have a chance of 40-70% of developing RA within 5 years.
Histological studies in early rheumatoid arthritis patients have shown all
features of chronic synovial inflammation to be present in clinically affected
joints and extensive inflammation is found in clinically unaffected joints of
RA-patients. In addition, a notable percentage of RA patients have signs of
joint destruction at the time of initial diagnosis.
Taken together, these data form strong evidence that early RA in fact
represents chronic synovitis and that clinical signs and symptoms may be
preceded by a preclinical phase for several years. Patients in this preclinical
phase positive for IgM-RF and/or ACPA and having arthralgias are currently
being included in clinical observational trials at the Department of Clinical
Immunology and Rheumatology in the Academic Medical Center (AMC) Amsterdam

Autonomic dysfunction in Rheumatoid Arthritis
It is known that part of the patients with active RA have autonomic
dysfunction, which is a imbalance between the parasympathetic and sympathetic
nervous system. Heart rate variability (HRV) is a validated method to assess
autonomic nervous system imbalance. RA patients have an increased sympathetic
control and decreased parasympathetic control of the heart rate, which results
in the finding of a lower heart rate variability. A high variability in heart
rate is generally a sign of good adaptability, as to be found in a healthy
individual with a well-functioning autonomic nervous system.
HRV can be measured with a Holter 24-hour electrocardiogram (ECG), after
which the heart beat (R-R interval) variation is analyzed in two domains, the
time-domain and frequency-domain analysis. Analysis in the time domain includes
the standard deviation of the mean of R-R intervals (SDNN), which reflects the
autonomic nervous system balance and the percentage of R-R intervals differing
from each other more than 50 milliseconds (pNN50), which reflects
parasympathetic activity. Analysis in the frequency-domain is done by spectral
analysis of R-R intervals, resulting in defining a high (HF) and low frequency
(LF) component. HF is seen as a marker of parasympathetic activity and LF is a
marker of sympathetic activity. The LF/HF ratio reflects the sympathovagal
balance.
To assess the adaptability of the autonomic nervous system in the subjects
they will be asked to change from supine to standing position during
HRV-measurement. The orthostatic stress from standing up will unveil a shift
from the mainly parasympathetic supine state to a more sympathetically
dominated state in the upright position.

HRV as a biomarker
We suspect that HRV can be used in clinical practice as an indicator for
the development of RA. We hypothesize that persons with pre-clinical arthritis
will have a lower HRV compared to healthy persons and but still a higher HRV
compare to active RA-patients. Follow-up of individuals with pre-clinical
arthritis will give insight in the change of HRV over time in relation to the
activity and thereby progression of arthritis.

Day/Night HRV
The influence of the autonomic nervous system on HRV changes during the day.
Being asleep gives the parasympathetic nervous system the upper hand, resulting
in a higher HRV compare to a lower HRV while being awake in healthy subjects.
It is known that RA-patients have a mostly sympathetic control of the heart
rate, which results in a lower HRV. Our question is if RA patients demonstrate
a change in HRV between day and night or that the sympathetic control over the
heart does not decrease at night and leaves the HRV unchanged during the whole
24 hour period.

Neuroendocrine hormones
In the last decade increasing evidence has been published about the
relationship between neuroendocrine hormones, especially prolactin, and
autoimmune diseases such as RA. RA is more common in females and this is
possibly due to the role of neuroendocrine hormones. Furthermore, it has been
shown that during pregnancy disease activity is relatively low and that after
delivery and the start of lactation RA relapses. This phenomenon could possibly
be explained by changes in prolactin levels during these episodes.
Recently, our group has studied the prolactin receptor in synovium of RA,
psoriatic arthritis (PsA) and osteoarthritis (OA) patients. The expression of
the prolactin receptor was higher in RA and PsA patients as compared to OA
patients. The prolactin levels in blood of RA patients was decreased in group
of responders compared to the non-responders to TNF-treatment. Also higher
tertiles of prolactin levels were associated with reumafactor positivity.
Therefore, prolactin can be a possible new biomarker in RA, but it*s prognostic
value needs to be determined in (pre-)arthritis vs healthy volunteers.

With the experimental set-up of this study we would like to address the three
following objectives:
* Investigate HRV baseline levels in individuals with pre-clinical arthritis,
healthy subjects and active RA, to evaluate if pre-clinical arthritis patients
already have an autonomic imbalance, comparable to patients with active RA
patients and in contrast to healthy subjects
* Evaluate if HRV can predict progression to active arthritis in the follow-up
of individuals with pre-clinical arthritis
* Evaluate if there is a imbalance in day/night autonomic rhythm in patients
with active RA

Visits to outpatient clinic:
* HRV will be measured in individuals with pre-clinical arthritis at three
timepoints:
a. Baseline: Subject have been found to have arthralgias and a positive ACPA
and/or IgM-RF
b. Timepoint one: At first manifestation of arthritis, characterized by pain
and swelling
c. Timepoint two: meets ACR criteria or 5 years after baseline
* HRV in Patients with active RA and healthy subjects will be measured at
baseline only

The burden for the participants will be minimal. There are no direct benefits
for the subjects participating in this study.