**3. Rheumatoid Arthritis**

#### *3.1. Pain in Clinical RA*

Compared to OA, which is considered a type of noninflammatory arthritis, research endeavors in RA have focused on the regulation of abnormal immune responses and inflammation, with pain considered a byproduct of inflammation that would be controlled by reducing disease activity. Although biological disease-modifying anti-rheumatic drugs (DMARDs) have revolutionized disease control and long-term outcomes of RA, substantial numbers of patients still suffer from pain despite low disease activity. The use of biological DMARDs has provided new insights into the unique qualities of pain manifestations independent of inflammation in RA [134]. The blockade of TNF-α improves pain faster than the resolution of inflammation or tissue damage, indicating a direct role for TNF-α in nociceptor sensitization pathways [135]. This direct analgesic effect is not shared by all cytokine blockers, as neutralization of IL-1β has a less pronounced influence on pain despite its profound role in attenuating inflammation and structural damage [136]. In a study of nociceptive central nervous system (CNS) activity using functional MRI in RA patients treated with a monoclonal antibody to TNF-α, neuronal activity in the thalamus and the somatosensory cortex, areas typically involved in pain perception, was significantly reduced as early as 24 h after the infusion [137]. This indicates that pain in RA is mediated by a mechanism independent of inflammation or joint damage. Pain is an important contributor to the patient global assessment of RA disease activity and discordance between patients and physicians [138].

There has been some speculation on the mechanism underlying persistent pain despite the absence of inflammation. It may result from irreversible joint damage and from changes in the CNS processing signals from the joint [139]. Central sensitization is present in people with RA, such that the prevalence of patients fulfilling fibromyalgia classification increases throughout the course of the disease [140].

Conditioned pain modulation, a measure of inhibitory pathways leading to a diffuse decrease in pain in response to acutely painful stimuli, is impaired in RA patients, and this association is mediated by sleep problems [141]. Patients with established RA also show increased sensitivity to pressure-induced pain at non-joint sites, such as the sternum and anterior tibia, as well as over joints, further indicating that central mechanisms contribute to pain in RA [142]. In a study of 108 RA patients, electrophysiological evidence of neuropathy, including pure sensory or sensory motor axonal neuropathy and demyelinating neuropathy, was present in 57.4% of cases [139]. Local inflammatory responses arising from synovitis as well as systemic inflammation caused by circulating proinflammatory cytokines may augment central pain processing in RA. The potentiation of anti-rheumatic medication is indicated mostly to control inflammation, and a high disease activity score driven by pain should be distinguished to avoid over-treatment. A better understanding of the mechanism of such pain is thus of paramount importance.
