Identification of inflammatory mediators in spinal liquor and the knee in relation to synovial nerve sprouting and pain in osteoarthritis

Pain is the predominating clinical feature of osteoarthritis (OA), is often
hard to manage effectively, and is a major reason for patients to undergo total
knee replacement (TKR). Yet, OA pain is still understood poorly; it is highly
variable, can be widespread, can only partly be explained by the extent of
joint damage, and persists after TKR in considerable numbers of patients. This
disconnect between joint pathology and the magnitude, persistence and
widespreadness of pain could be explained by neuroplastic changes in the
sensory nervous system, spinal cord neuro-inflammation and local inflammatory
(synovitis) characteristics.

Our key objective of this study is to elucidate potential peripheral and
central mechanisms that determine chronic pain characteristics in humans with
OA.

Design: An observational, longitudinal clinical study, with detailed pain
phenotyping determined by pain questionnaires and QST, combined with sampling
of CSF, SF and ST at the time of TJR in regular practice.

Setting: Collection of spinal cerebral fluid, synovial fluidand tissue, bone,
and cartilage tissues will be performed at the St. Antonius Ziekenhuis.
Questionnaires and QST will be performed within 1-6 weeks before TKR, and 6
weeks and 6 months post TKR. Questionaires will also be performed 1 years after
TKR. Multiplex analyses and metabolomics of fluids and tissue homegenates and
all statistical analyses, including coded patient data, will be performed at
the University Medical Center Utrecht.

Duration: Inclusion is estimated to take 30 months (~50 inclusions/year, ~10%
of total population undergoing TKR) with one year follow-up after the last
inclusion.

After informed consent (see 9.1 for exact detail on recruitment and consent),
patients are asked to fill out the ICOAP (intermittent and Constant
Osteoarthritis Pain ), KOOS (pain stiffness and physical function) and
PAINDETECT (neuropathic pain components) questionnaires, and Graded Chronic
Pain Scale (CPGS)

Data collection:
After consent, patients will be asked prior to (1-6 weeks) TKR, and6 weeks, 6
months, and 1 year after TKR to:
i) Provide a pain VAS (visual analogue scale) for the affected knee. The pain
VAS is a validated, widely used unidimensional measure of pain intensity.
ii) Fill out 4 pain questionnaires (KOOS, PAINDETECT, ICOAP, GCPS). Details
provided under 6.1.2.
iii) Report widespread pain by checking-off body areas where they experienced
pain (head, neck, hands, arms, chest, shoulders, stomach, upper and lower back,
legs, and feet). This will be used to determine if participants fulfill
criteria for widespread pain, according to the American College of Rheumatology
criteria (pain present in upper and lower quadrants and on both sides of the
body).

i-iii) Estimated time: 15 minutes


iv) Undergo quantitative sensory testing (QST) and pressure cuff algometry to
assess the nociceptive and non-nociceptive afferent systems in detail and
identify loss-of-function and gain-of-function. QST of the affected knee will
help reveal subgroups of sensitized OA patients by performing QST of the index
knee. Specific elements of QST (pressure pain; thermal pain; windup) will also
be measured at 2 distant body regions (arm, lower leg) to reveal subgroups of
generalized pain phenotypes. Total duration of the assement is 60 minutes .
v) At the day of surgery, CSF (500 uL) will be collected prior to the spinal
anesthesia that is part of the standard operation procedures for TKR. Knee
tissues will be collected (waste material of TKR). More specific, synovial
fluid (SF) and synovial tissue (ST), cartilage and bone will be collected and
stored for further analysis.

Benefit: Patients have no direct benefit of participating in this study.
Results will elucidate the underlying mechanisms of osteoarthritis pain and may
provide insights for novel pain treatment strategies. Based on the pilot study
the lack of a direct benefit for the participating patients is not considered
to be a risk.

Burden: Patients will undergo 3 times QST procedures and have to fill out
questionnaires. Prior to spinal anaesthesia, 500 ul cerebral spinal fluid will
be obtained in a syringe. Since the aspiration can be performed with the same
needle as injection of the spinal anaesthesia requires no additional burden is
introduced. The aspiration will take approximately maximum 5 minutes.
Risks: Postdural headache or infection is negligible