Trial Information

Pain Modulation in RA - Influence of Adalimumab. A Randomized, Placebo-controlled Study Using Functional Magnetic Resonance Imaging (PARADE)

Background

Rheumatoid arthritis (RA) RA is characterized by joint inflammation causing peripheral pain,
however the relation between peripheral pathology and pain intensity is weak. There is
substantial evidence that also pain modulation mechanisms are dysregulated in RA. For
example, generalized pain frequency is higher in RA than in normal population, about 15%
compared to 3%. Earlier data from our group show a changed pattern of pain-modulation in
established RA compared to early RA and controls (Keystone 2004).

There are several treatments in RA directed at relieving symptoms (NSAIDs) as well as
modifying disease (DMARDs and biologics). One of the established biologics is the Tumor
Necrosis Factor (TNF)-blocking agent adalimumab which has proven efficacious for decreasing
disease activity and retardation of joint destruction in RA (Keystone 2004, Weinblatt 2006).
In addition, adalimumab has proven efficient in reduction of fatigue in RA (Yount 2007)

Pain mechanisms in rheumatoid arthritis

Pain in RA has traditionally been regarded as nociceptive pain due to peripheral
inflammation of joints (arthritis). However, although affected joints are typically inflamed
and swollen, peripheral pathology cannot fully explain the amount of pain a patient
experiences (Thompson 1997). Central nervous system (CNS) mechanisms have been implicated in
the pain experience by RA patients and we have previously been able to demonstrate a
generalised increase in pain sensitivity in RA patients (Leffler 2002). The importance of
CNS changes in endogenous pain modulation (i.e, facilitation, central
sensitisation/disinhibition) is further underscored by the high co-morbidity between RA and
generalised pain syndromes such as fibromyalgia (FM)(Neumann and Buskila 2003), where
specific dysfunctions of endogenous pain modulation have been documented. The pronounced
co-morbidity between FM and rheumatic inflammatory diseases, and the fact that a generalised
increase in pain sensitivity has been reported in patients with long (> 5 years) but not
short (< 1 year) duration of RA (Leffler 2002) suggest that disturbances in pain modulation
can also be important for pain perception in many patients with RA. Endogenous pain
inhibitory mechanisms are physiologically closely linked to autonomic nervous system
activity. The same type of autonomic nervous system dysfunction (i.e., basal sympathetic
hyperactivity and hyporeactivity) has been reported in RA patients (Evrengul 2004, Goldstein
2007) and FM patients (Cohen 2001).

Besides pain regulation, recent studies have focused on the involvement of autonomic tone
also in systemic inflammatory responses. A major breakthrough was the characterization of
the cholinergic anti-inflammatory pathway. Efferent activity in the vagus nerve leads to
systemic release of acetylcholine (ACh). Specific binding to alfa 7 nicotinic ACh receptors
on tissue macrophages efficiently inhibits the release of proinflammatory substances such as
TNF, IL-1, IL-6 and IL-8 (Tracey 2002). This inflammatory reflex pathway is rapid, localized
and integrated in contrast to the well defined humoral regulation of inflammation.
Dysfunction of autonomic regulation, with a relative reduction of vagal tone is a feature of
RA and proven to correlate with systemic levels of inflammatory cytokines (Goldstein 2007).
The importance of interaction between autonomic pain regulation and neural anti-inflammatory
pathways is indicated by several findings. Flight-or-fight responses activated by pain can
result in increase of epinephrine and norepinephrine, that can inhibit macrophage activation
and regulate TNF secretion (Tracey 2002). Moreover, a reduction of antiinflammatory
cytokines (IL-4 and IL-10) (Uceyler 2006) and an increase in pro-inflammatory cytokines
(TNF, IL-1, IL6, IL-8) have been shown in syndromes characterized by generalized pain
(Salemi 2003, Bazzichi 2007). Thus, these data indicate that modulation of systemic and
chronic inflammation may have significant effects on pain processing.

In recent years increasing focus has been placed upon the interactions between the immune
system and the CNS with the recognition of an immune - to brain pathway activating the
sickness response. In addition to blood-borne signalling, neural pathways via the sensory
vagus and glossopharyngeal nerves have been identified (Watkins 2005). Recent animal studies
have revealed that peripheral inflammation, nociceptive input as well as pronounced mental
stress can activate microglia cells throughout the CNS and that these stimulated microglia
cells start to produce pro-inflammatory substances (TNF, IL-

1, IL-6). These substances initiate central inflammatory changes with increased pain
sensitivity (allodynia, hyperalgesia and most likely spontaneously ongoing pain) as a result
(Milligan 2009, Beattie 2002). Moreover, intrathecal administration of substances
potentiating release of antiinflammatory cytokines such as IL-10, have been proven
efficiently analgesic (Johnston 2004).

These data are in accordance with recent results where collagen induced arthritis resulted
in a decrease in the threshold for thermal and mechanical stimuli, beginning on the day of
onset. This was accompanied by increased inflammatory response in spinal cord astrocytes,
and treatment with anti-TNF was both profoundly analgesic and also restored inflammatory
changes in astrocytes (Inglis JJ 2007). These results thus indicate that pain regulation may
be influenced by peripheral inflammation and can also be reversed by potent
anti-inflammatory therapy.

Altogether, understanding the relationship between peripheral nociceptive input (due to
inflamed joints), autonomic NS activity, endogenous pain modulatory systems and CNS
inflammation for the symptoms in patients with RA is important and can lead to improved
strategies in treatment of pain mechanisms as well as fatigue.

Imaging Pain can be conceptualised as a primarily motivational state to induce a behavioural
drive with the purpose to restore homeostasis. The multidimensionality of pain perception is
supported by studies using functional magnetic resonance imaging (fMRI) to assess cerebral
activation during stimulus-evoked pain in human subjects. These studies have documented
activation of brain areas traditionally associated with the perception of sensory features
(e.g. somatosensory cortices) and regions associated with emotional and motivational aspects
of pain (prefrontal cortex (PFC), anterior cingulate cortex (ACC) and insular cortex (IC)).
In addition, brain areas involved in the regulation of autonomic nervous system and
endogenous pain modulation are also activated. In a recent fMRI study of patients with
chronic low back pain (LBP) activation of the somatosensory cortex was only seen during
brief periods of spontaneously increasing pain intensity. During periods of ongoing LBP only
brain regions of importance for emotional and cognitive aspects of pain (i.e. prefrontal
cortex and cingulate) were activated (Baliki 2006). These findings indicate that the
perception of chronic, ongoing pain requires very limited involvement of the pure
somatosensory areas. These results are in accordance with two recent positron emission
tomography (PET) studies of joint pain. In patients with pain due to knee osteoarthritis,
increased activity was reported in the prefrontal cortex, cingulate and insula during
arthritic pain compared to experimental heat pain (Kulkarni 2007). Accordingly, in another
PET study, Schweinhardt et al.

(Schweinhardt 2008) reported a stronger activation in the dorsolateral prefrontal cortex in
response to provoked joint pain in RA patients compared to experimental heat pain. The
results were interpreted as increased activation of areas implicated in emotional and
cognitive processing of noxious stimuli, reflecting the greater emotional salience of
clinical pain compared to experimental pain and the importance of coping strategies
potentially influencing the perception of chronic pain. In healthy volunteers, activation of
the prefrontal cortex is related to the degree of anxiety during the experience of
experimental pain (Ochsner 2006) and the prefrontal cortex has been reported to be more
consistently activated in studies of clinical pain compared to studies of experimental pain
(Apkarian 2005). Little is known about the relation between cerebral pain related activity,
clinical symptoms, degree of systemic inflammation and various coping strategies.

The aim of the study We hypothesise that RA patients have a generalised increase in pain
sensitivity (i.e., not restricted to inflamed joints) and that this increase in pain
sensitivity is mediated through increased central nervous system inflammation affecting the
ability to recruit endogenous pain modulatory mechanisms in a negative way. Furthermore, we
hypothesise that treatment with TNF antagonists, in addition to reductions in peripheral
inflammation, also affect central nervous system inflammation and improve the ability to
activate endogenous pain modulatory mechanisms thus reducing pain and other symptoms (i.e.,
fatigue).

The study adresses the following questions:

1. Do patients with RA exhibit an increased sensitivity to randomized painful stimulation
at an inflamed joint and at a neutral painfree area, resp., compared to healthy
controls?

2. Does the cerebral activation pattern assessed by fMRI differ between patients and
controls during experimental painful stimulation at a painful (inflamed joint) and a
non-painful (thumbnail) area?

3. Can disturbances in autonomic nervous system activity be linked to the pain
sensitivity, cerebral processing of noxious stimuli and/or the degree of inflammation
in RA patients?

4. Can the subjective perception of fatigue be related to any of the following; pain
sensitivity, abnormalities in cerebral pain processing, inflammatory parameters and
autonomic activity?

5. How are the above parameters affected by treatment with a TNF antagonist (adalimumab)
compared to placebo?

Patients with active RA and incomplete response to methotrexate (MTX) will be recruited to
the study as well as healthy clinical subjects. RA patients and controls will be compared
concerning pain pressure thresholds, pain processing using brain fMRI, activity in the
autonomous nerve system and inflammatory markers in blood samples as well as assessment of
pain, fatigue using standardized assessments. Following inclusion, patients with RA will be
randomized into active treatment (A) and placebo control group (B) using standardized
procedures for randomized, double blind, placebo controlled studies. The treatment group
will receive adalimumab directly following the baseline assessment and subsequently eow
during the study. The placebo control group will receive placebo injections at baseline, two
weeks and at four weeks and subsequently adalimumab. The overall aim with the study is to
obtain increased knowledge concerning pain processing and fatigue in RA, and how these
conditions are influenced by treatment with TNF blockade with adalimumab.