Arthritis is a well-known chronic disease with many symptomatic manifestations, which includes the induction of a chronic inflammatory response in affected joints. This response attributes to cardinal signs of inflammation, including vasodilation, increased vascular permeability and pain. Patients with OA, gout and RA presenting with painful joints are often physically and mentally affected. Concurrent with elevated inflammatory biomarkers present in circulation, synovial hypertrophy and elevated synovial fluid levels as detected on US, our study indicates the important role of inflammation in arthritis.
Whilst the three arthritides have distinct clinical representations, manifestations and differing pathogenic origins, the tissue inflammatory process is understood to differ only by the intensity of the inflammatory picture.14, 15 This is consistent with our findings, where systemic inflammatory markers CRP and sTNFR1 were notably higher in gout and RA as compared to OA. Furthermore, other plasma cytokines including IL-1β, IL-6 and IL-10 were significantly higher in RA than OA, while TNFα was higher in gout than RA. Though OA was historically regarded as a non-inflammatory degenerative joint disease, the critical contribution of inflammatory mechanisms towards the pathogenesis of OA is increasingly recognised, consistent with our findings.23, 24 Inflammation is therefore present in arthritides, with elevated inflammatory cytokine profiles in gout and RA as compared to OA.
There is increasing evidence that the KKC is involved in sustaining joint inflammation.7, 8 Bradykinin receptors, when bound to their respective ligands, are widely known to contribute to the cardinal signs of inflammation: vasodilation, increased vascular permeability and pain.25 We noted higher expression of B1R on circulating blood neutrophils of RA patients as compared to other arthritides, but no significant differences in B2R neutrophil expression. On the other hand, OA had higher neutrophil expression of plasma kallikrein (PK) K1B and tissue kallikrein (TK) KLK1 as compared to RA and gout. We previously showed a loss of kinin moiety on the surface of synovial neutrophils of rheumatoid arthritis patients, resulting in lower neutrophil expression of TK and PK, while synovial levels of kallikreins are elevated showing that kallikreins are actively involved in the generation of kinins by circulating and synovial neutrophils, to promote synovial tissue remodelling and to sustain joint inflammation.8 Concurrent with increased inflammatory cytokines and plasma biomarkers, our results suggest that the KKC may have higher functional roles in RA and gout as compared to OA.
US evidence of hypertrophy and synovial fluid was non-discriminatory between RA, gout, and OA. A significantly higher percentage of RA patients reported Global SH and PD-GE2 scores as compared to OA and gout, respectively (Table 3). When correlated with inflammatory and KKC biomarkers, B1R expression on neutrophils was associated with increased PD and PD-GE2 scores, indicating that B1R may contribute to structural changes in arthritic joints. This further suggests different intensities of inflammation between different arthritides.
We also reported higher expression of B1R in RA and gout compared to OA, however, equivalent levels of B2R were found across all cohorts. It is of interest that a study assessing the analgesic effects of B2R antagonists improved pain at rest and during activity, but showed no changes in synovitis as assessed by contrast-enhanced ultrasound.11 Though B2R antagonists have shown promising results for alleviating pain in painful knee OA, its constitutive expression and involvement in acute phase inflammation may hinder its therapeutic benefits in the context of a chronic inflammatory response.11, 26–28. Contrastingly, B1R is upregulated in chronic inflammatory conditions, secondary to inflammatory mediator release.28 Additionally, our study demonstrated similar expressions of B2R in OA and inflammatory arthritides, suggesting that blocking B2R may not alleviate pain in arthritis. Inhibiting B1R to mitigate pain and manage chronic inflammation in arthritides should therefore be further investigated. In the setting of acute inflammatory pain, this may be consistent with the knowledge that B1R is involved in nociceptor activation, whereas B2R is involved in nociceptor sensitisation.
In our study, differences in expression of KKC proteins and receptors found on blood neutrophils show potential as biomarkers for arthritides, presenting clinics with a less invasive and more efficient method to identify inflammation in arthritis patients. Differences in KKC on blood neutrophils may therefore be a good biomarker to assess pain and a patient’s response to therapies that block B1R. Targeting B1R to modulate the kinin-kallikrein system may pose as a new therapeutic target in the treatment of arthritis.
Although our cohort of patients were relatively class, our study was the first to observe differences in pain between OA, gout and RA, as well as its association with circulating inflammatory biomarkers, and the role of the KKC in the pathophysiology of disease. Our study was unable to examine the level of KCC proteins in synovial fluid of patients, which would be an area of interest for future studies. Given that the relationship between symptoms and pathology in arthritis is complex, and poorly understood, this pilot study adds to the current knowledge whilst raising interesting questions that warrants future investigations to better understand pain in arthritis. Furthermore, our data supports the targeting of B1R to treat painful knee arthritis.