Neuropathic-like pain features and cross-sectional associations in rheumatoid arthritis

This study assessed the occurrence and associations of NP-like symptoms in a cohort of patients with relatively well-controlled RA. Despite almost 75 % of patients being in DAS28 remission, 44 % still reported clinically significant pain. According to the PainDETECT, 17 % of all patients had likely NP, while 21 % had possible NP features. These patients were shown to have more severe pain, used pain medication more often, and reported lower quality of life. Multivariable logistic analysis showed that the occurrence of possible or likely NP-like features was independently associated with worse physical and mental health, even when controlling for pain severity.

Despite the relatively low disease activity in the current cohort, nearly half of the patients still reported clinically significant pain. Clinically significant pain was defined as an average pain score ≥4. This threshold was based on several previous studies that identified pain intensity levels ≥4 out of 10 as moderate to severe or unacceptable [28, 29]. This confirms that, despite improvements in the management of RA, pain control remains inadequate in some patients, even when inflammation is well controlled [3]. Consequently, although inflammation contributes to pain in RA, it may not be the only factor and other pain mechanisms such as NP may also play a role.

The findings of this study suggest that the pain of a substantial number of RA patients may have neuropathic features or a neuropathic component, as has also been shown in other rheumatic conditions. NP symptoms have only been sporadically tested in RA samples. The 17 % proportion of RA patients with likely NP found in this study was very similar to the 19 % prevalence reported by Meirinhos et al. [21]. Conversely, Ahmed et al. [20] reported that 28 % of RA patients had possible NP symptoms and 5 % were likely to be experiencing NP symptoms according to the painDETECT. The relatively high proportion of patients (36 %) with NP in the study by Perrot et al. [22] may have resulted from their use of the DN4 questionnaire, which tends to have a high sensitivity but low specificity in identifying NP [30].

With respect to possible NP symptoms in patients with RA, it should be noted that although inflammatory pain and NP are attributed to different mechanisms, they do have some features in common which may confound the results of NP screeners. Most notably, the painDETECT item dealing with pain with slight pressure may also reflect typical inflammatory joint pain. Removing this item from the total painDETECT score lowered the proportion of patients with possible NP from 38.4 % to 29 % in the current study.

The proportion of RA patients with likely NP was clearly lower than that usually reported in patients with osteoarthritis [9‐11] and much lower than that found in patients with FM [12, 13]. Many recent studies have suggested the NP-like symptoms in rheumatic conditions to be manifestations of dysregulation of central pain processing mechanisms [8, 12, 31‐38]. Central sensitization is the increased responsiveness of nociceptive neurons in the central nervous system to normal input and the recruitment of a response to normally subthreshold inputs [39]. The precise mechanisms behind this pain augmentation are not known as yet, but most likely encompasses multiple changes in the central nervous system. In acute pain, sensitization is a physiological process to induce the body to protect damaged tissue and to give it time to heal and is thus an important mechanism for survival. It is hypothesized that in chronic pain conditions this adaptive pain mechanism persists despite elimination of the original nociceptive input and thus provides a deranged pathological mechanism for persistent pain [40]. The finding that the number of RA patients concurrently fulfilling the current criteria for FM, often considered the prototypical central pain syndrome [41], was substantially higher among those with NP features provides support to this theory for RA patients as well.

No previous studies have thoroughly examined multivariable associations of NP symptoms with sociodemographic, clinical, and quality of life-related factors in patients with RA. In the current study, NP symptoms were not related to any of the sociodemographic characteristics included. Moreover, while the TJC was significantly higher in the NP group, the more objective parameters of disease activity, such as CRP, ESR and the SJC, did not differ between the two groups. The TJC and the global health score are largely subjective measures and thus may not necessarily reflect clinical disease activity. Previous studies have shown that some patients fail to reach RA remission criteria due to poor patient-reported health scores only [42, 43]. When comparing DAS28 scores in RA and FM patients, FM patients tend to score higher on subjective parameters, while RA patients score worse on objective measures [44]. Similarly, Ranzolin et al. [45] found that RA patients with co-existent FM had significantly higher DAS28 scores mostly caused by the TJC and general health scores. As such, this also points to other mechanisms than inflammation as a cause for pain in certain RA patients.

Finally, the finding that NP symptoms were independently associated with physical and mental health status is in accordance with studies in patients with established peripheral or central neuropathology, such as diabetic neuropathy and spinal cord injury. These studies have consistently shown that the presence and severity of NP is associated with substantial impairments in most important health-related quality of life domains [46, 47]. Studies in osteoarthritis also showed that the occurrence of NP-like symptoms was strongly correlated with a worse quality of life, more distress, and higher pain intensity [10, 17].

Taken together, the findings of the current study provide preliminary support of a noninflammatory pain component in RA. This could have important implications for RA treatment strategies. The current goal in the treatment of RA is to reach early sustained remission. This is increasingly done by intensive treat-to-target strategies, aimed at DAS28 remission criteria. When remission is not reached, drug therapy is adjusted. This can range from a dose change, starting combination therapy with a second DMARD or glucocorticoids, or the start of biologicals. These latter are expensive therapies and have, as do all medications, unwanted and in some cases serious side effects. Furthermore, all these strategies specifically target inflammation. If, however, mechanisms other than inflammation, for example hypersensitivity, contribute to a high DAS28 and therefore not reaching remission, these expensive medications will not likely have the desired effect. Overtreatment could therefore be an outcome in some RA patients. In these cases, pain treatment targeting the NP-like symptoms might be more appropriate than intensifying anti-inflammatory treatment. This treatment could comprise neuromodulators and certain antidepressants. Both these drug groups appear to be effective in NP [48]. In FM, a syndrome hypothesized to be caused by central pain processing abnormalities, these drugs have also been shown to have an effect, albeit small, on pain [49, 50]. If effective in RA patients with NP-like symptoms who fail to reach remission, these therapies could be more cost-effective and, more importantly, result in a better quality of life than current treatment strategies.

Our study has several strengths. First, it combines the painDETECT questionnaire with clinical data, the DAS28 score and measurements of FM, quality of life, and disability. This gives insight into the origin of pain in RA patients, but also the effect it has on the daily life of patients. Second, the patients included in this study were recruited from normal daily clinical practice and therefore closely resemble the current ‘well-controlled’ RA patient. The findings, however, may not be applicable to RA populations with less well-controlled disease. Furthermore, since our population consisted of predominately white patients, the findings may not be generalizable to more ethnically diverse populations.

The major limitation of the study is the absence of a gold standard for NP or central sensitization. This is a problem inherent to the field. Central sensitization especially is a relatively new concept, and objective measurements do not yet exist. The gold standard is thus usually based on a combination of quantitative sensory testing and clinical or expert opinion. Additionally, the cross-sectional nature of this study does not allow any determination of the direction of associations between NP symptoms and clinical variables. Finally, the painDETECT was developed as a screening tool for NP, not central sensitization. Although symptoms of NP and central sensitization may be similar, they are by no means the same. The occurrence of NP symptoms according to the painDETECT therefore does not measure central sensitization per se, but may be useful in assisting in the identification of central sensitization [12]. More research, however, is needed to develop validated tools for the specific identification of central sensitization.