Central Sensitization in Patients with Rheumatoid Arthritis: A Systematic Literature Review

doi:10.1016/j.semarthrit.2011.08.001

Seminars in Arthritis and Rheumatism

Volume 41, Issue 4, February 2012, Pages 556-567

https://doi.org/10.1016/j.semarthrit.2011.08.001 Get rights and content

Objective

The goal of the present study is to systematically review the scientific literature addressing central sensitization and central nociceptive processing in patients with rheumatoid arthritis (RA).

Methods

To identify relevant articles, we searched PubMed and Web of Science. The search strategy was a combination of terms of the following groups: “Rheumatoid arthritis,” inflammatory joint pain, or arthritis; AND (central) sensitization, (central) hypersensitivity, central hyperexcitability, pain modulation, pain processing, neural inhibition, or pain physiopathology; AND pain, nociception, hyperalgesia, pain threshold, or algometry. Articles fulfilling the inclusion criteria were screened for methodologic quality with specific checklists to evaluate different study designs (2 independent raters).

Results

Twenty-four full-text articles were included, of which the majority were case-control studies, followed by nonsystematic reviews, cross-sectional studies, and case reports. Methodologic quality was very heterogeneous. Preliminary evidence for generalized hyperalgesia in RA is available. In addition, the mechanism behind impaired central nociceptive processing remains rather obscure. The role of cytokines and neuropeptides especially remains to be elucidated. Windup appears to develop more easily in RA, but evidence in support of impaired nociceptive inhibition and cognitive emotional sensitization (sensitization due to cognitive bias) is scarce.

Conclusions

The symmetrical manifestation of the disease, the poor relation between disease activity and symptoms, and the generalized hyperalgesia at both articular and nonarticular sites for different kinds of stimuli are indicative of the presence of central sensitization in RA patients. Further research is required to provide firm evidence in support of various aspects of central sensitization in humans with RA.

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.

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Rheumatoid arthritisCentral Sensitization in Patients with Rheumatoid Arthritis: A Systematic Literature Review

Objective

Methods

Results

Conclusions

Section snippets

Peripheral Sensitization

Hypothesis: Central Hyperexcitability in RA

Objective

Literature Search Methods

Qualification of Searchers/Raters

Search Strategy

Study Selection

Study Process

Assessment of Study Quality

Data Abstraction

Study Selection

Study Characteristics

Discussion

Acknowledgment

Pain

Pain

Pain

J Clin Neurosci

Eur J Pain

Control Clin Trials

Lancet

Pain

Eur J Pain

J Pain

Int J Psychophysiol

NeuroImage

Trends Pharmacol Sci

DREAMing about arthritic pain

Ann Rheumat Dis

The molecular basis of pain and its clinical implications in rheumatology

Nat Clin Pract

[Neuroendocrine-immunologic mechanisms in rheumatic diseases—a congress report]

Z Rheumatol

Why does an inflammation in the joint hurt?

Br J Rheumatol

Neuropeptides in experimental and degenerative arthritis

Ann NY Acad Sci

Peripheral and spinal neural mechanisms in arthritis, with particular reference to treatment of inflammation and pain

Arthritis Rheum

Evidence of augmented central pain processing in idiopathic chronic low back pain

Arthritis Rheum

Evidence for generalized hyperalgesia in chronic fatigue syndrome: a case control study

Clin Rheumatol

Rheumatoid arthritis
Central Sensitization in Patients with Rheumatoid Arthritis: A Systematic Literature Review