Rheumatoid arthritisCentral Sensitization in Patients with Rheumatoid Arthritis: A Systematic Literature Review
Section snippets
Peripheral Sensitization
Any joint pathology can produce severe pain resulting from sensitization of primary afferent nociceptive neurons (4). Peripheral sensitization is mediated by local components of the local inflammatory reaction released by the microenvironment of the inflamed and injured tissue, such as bradykinin, prostaglandin, and probably neuropeptides and cytokines (2, 5). The peripheral terminals of Aδ and C fibers, which are activated only by noxious stimuli under noninflamed conditions, express many
Hypothesis: Central Hyperexcitability in RA
Peripheral sensitization is widely held to be responsible for pain and tenderness over inflamed or damaged joints, but it does not account for other symptoms observed in RA (1) and for enhanced responses to afferent inputs from noninflamed regions adjacent to or even remote from the inflamed site (3). Furthermore, the autonomic dysfunction and bilateral involvement in RA are strongly suggestive for impaired pain processing in the central nervous system (CNS). Continuously increased nociceptive
Objective
In patients with RA, however, neurophysiologic mechanisms underlying pain remain unclear. Experimental animal models of inflammatory arthritis suggest that changes of neuronal sensitivity at both peripheral and central levels may be important (3, 14). Evidence indicating that central plasticity of the nociceptive system is contributing to pain in humans with RA seems, however, less obvious (1, 15).
The goal of the present study is to systematically review the scientific literature addressing
Literature Search Methods
Given the expectancy of chiefly observational studies (given the research question), the review was conducted according to the recommendations of the Meta-Analysis of Observational Studies in Epidemiology group (16).
Qualification of Searchers/Raters
Literature was searched and screened by the first author (MM), who had obtained a PhD with a dissertation regarding central sensitization (in chronic fatigue syndrome), including a systematic review (17).
Methodologic quality was assessed by 2 researchers (MM and SV). The second rater achieved the degree of Master of Science and was trained in assessing methodologic quality. In the case of disagreement, a third opinion was provided by the last author (JN), who obtained a degree of PhD and is
Search Strategy
To identify relevant articles concerning central pain processing in patients with RA, PubMed (http://www.ncbi.nlm.nih.gov/entrez) and Web of Science (http://isiwebofknowledge.com) were searched in October 2009. The search strategy was based on a combination of the search terms, derived from “PICO.” It consisted of the following keywords and MeSH terms: “Rheumatoid arthritis”, inflammatory joint pain or arthritis AND (central) sensitization, (central) hypersensitivity, central hyperexcitability,
Study Selection
To be included in the review, an article had to meet the following criteria: (1) subjects of the study had to be adults (humans) diagnosed with RA to obtain a population as heterogeneous as possible; (2) the author(s) studied the concept of central pain processing in these individuals; (3) the studies were presented in English, Dutch, French, or German; (4) only studies in the last 20 years were allowed; and (5) articles were full-text reports, and not abstracts, letters, or editorials. If any
Study Process
We screened the titles and abstracts of all citations identified in the search. The full-text article was retrieved if the citation was considered potentially relevant. Each full-text article was evaluated whether it fulfilled the inclusion criteria. Articles were categorized by the reviewer following study design (meta-analysis/review/(randomized) clinical trial/longitudinal study/case-control study/cross-sectional/case report).
Assessment of Study Quality
Different checklists were used to assess the methodologic quality of different study designs. Quality assessment of case-control studies or cohort studies was performed using the Newcastle-Ottawa Scale (NOS), a scale specific for the respective studies, which uses a star rating system to judge quality based on 3 aspects of the study: selection of groups, comparability, and ascertainment of the outcomes of interest. The validity of this tool has been previously established (18). The NOS is 1 of
Data Abstraction
Finally, the results were analyzed and the existing knowledge concerning central pain processing in RA was summarized. The methodologic quality of the different studies was taken into account when interpreting the findings of the different studies.
Study Selection
The study selection is presented in Figure 1. Twenty-four full-text articles were included in the qualitative synthesis of the review. Those 24 articles were screened and reviewed. Most studies were excluded based on the first inclusion criterion: adult humans with RA.
Study Characteristics
The properties of the 24 studies that fulfilled all inclusion criteria are presented in Table 3. Of the 24 studies, 12 were case control studies, 2 cross-sectional, 2 case reports, 6 reviews, 1 pilot trial (combined with an animal
Discussion
The goal of the present systematic literature search was to review the scientific literature addressing central nociceptive processing in patients with RA.
Most authors seem to agree with the primary and secondary hyperalgesia in RA, regardless of the method used (25, 26, 27, 28, 29, 30) Generalized hyperalgesia and allodynia may be the result of long-lasting nociceptive bombardment from inflamed joints, giving rise to peripheral and central sensitization of nociceptive afferents, as well as to
Acknowledgment
Mira Meeus has a postdoctoral research fellowship from the Research Foundation Flanders (FWO).
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The authors have no conflicts of interests to disclose.