The role of musculoskeletal ultrasonography (MSUS) in investigating pain in patients with inflammatory arthritis

Rheumatoid arthritis (RA) is a prevalent and enduring inflammatory joint disorder characterised by autoimmune responses and persistent joint inflammation. This inflammation results in pain, which is regarded as the hallmark symptom of RA. Numerous patients with RA continue to experience pain despite effectively controlled inflammation. This chronic pain is linked to musculoskeletal conditions that can diminish quality of life. Various mechanisms underlie the clinical pain experienced in RA, including nociceptive and nociplastic pathways. Nociceptive pain in RA has predominantly been associated with inflammatory changes within the joints, whereas nociplastic pain is considered non-inflammatory and related to central sensitisation. A comprehensive understanding of the nature of pain in RA could facilitate the development of improved pain management strategies. The primary objective of this thesis is to investigate the pain mechanisms in RA through the utilisation of musculoskeletal ultrasonography (MSUS). MSUS is valuable for detecting peripheral inflammation that causes nociceptive pain. Furthermore, when pain persists despite inflammation management, MSUS can be used to confirm the absence of inflammatory changes within the joints. The data used in this thesis were collected from six clinical studies. The initial phase involved assessing the prevalence of persistent pain in early RA using the SERA dataset. Subsequently, the study examined the relationship between Ultrasound power Doppler (USPD) and pain intensity, as measured by the pain visual analogue scale (VAS), within the TaSER dataset. Given that the TaSER dataset comprises a reduced sample of patients with early RA who underwent ultrasound examinations, the third chapter focused on analysing the correlation between MSUS findings and pain measures using the larger Spanish RA cohort dataset (Naredo), which also includes diverse MSUS metrics and a wider range of joints. In the following chapter, the validation of the findings from the previous chapter (the correlation between pain and MSUS) within a population afflicted by a different form of inflammatory arthritis, specifically Psoriatic Arthritis (PsA), has been explored, utilising the CENTAUR dataset. This dataset includes subjective pain measures, such as the pain VAS, as well as semi-objective pain assessments, namely Quantitative Sensory Testing (QST). In the concluding chapter, the relationship between pain and MSUS metrics was analysed, this time utilising objective pain measurement tools, specifically neuroimaging via functional Magnetic Resonance Imaging (fMRI), as objective indicators of pain signal processing. The capability of ultrasound to detect nociceptive pain was evaluated by establishing correlations with the traditional pain pathway, specifically the sensorimotor network (SMN)-Thalamus connectivity. Furthermore, the effectiveness of MSUS in identifying inflammation that contributes to the mixed pain state was assessed by correlating MSUS metrics with the nociplastic pain marker, namely the Default Mode Network (DMN)-Insula. Within the SERA chapter, it was observed that a portion of patients reported experiencing pain during follow-up. Among those who reported pain, few participants exhibited a negative swollen joint count (SJC), while a notable proportion had normal erythrocyte sedimentation rate (ESR) levels. In the TaSER chapter, no significant correlation was identified between ultrasound power Doppler (USPD) and the pain visual analogue scale (VAS). These findings might be due to the reduced sample size and the limited number of joints included in the TaSER dataset. However, within the Spanish RA cohort, which had a larger sample size, more MSUS metrics, and a broader range of joints included, a notable correlation was established between MSUS metrics, namely USPD, ultrasound synovial hypertrophy (USSH), and ultrasound joint effusion (USJE), and pain VAS at both baseline and follow-up visits. In the CENTAUR analysis, no substantive correlations emerged between USSH, enthesitis metrics, and pain VAS scores, nor between QST, namely pressure pain threshold algometry (PPT) and MSUS parameters. Furthermore, no significant associations were detected linking MSUS findings with fibromyalgia (FM). FM serves as a prototype for nociplastic pain. In a distinct examination of the CENTAUR dataset, a negative correlation was observed between US enthesitis and SMN-thalamus connectivity. A correlation was not observed between MSUS and DMN-insula connectivity. Notably, significant correlations were established in the SOAR and TEMPO datasets between MSUS parameters, including USPD and ultrasound bone erosion (USBE), and DMN-insula connectivity, albeit no significant association was found between MSUS and SMN-thalamus metrics. This thesis substantiates the reliability of ultrasound as an investigative tool in assessing inflammatory changes within the joints of patients with inflammatory arthritis. It demonstrates that MSUS can effectively evaluate nociceptive pain, evidenced by significant correlations in the extensive Spanish RA cohort. Furthermore, MSUS holds promise as a diagnostic tool to discern the presence or absence of peripheral inflammation contributing to non-inflammatory pain in this patient population. Finally, the findings indicate that MSUS can identify the contributions of nociceptive pain to the overall mixed pain experience in patients with RA and FM.