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).