T. Neogi’s research while affiliated with Boston University and other places

Background Sleep problems represent a modifiable but neglected risk factor for osteoarthritis (OA) pain, and studies show that sleep problems predict more severe long-term pain intensity in people with lower limb OA. Sleep problems may also be associated with central sensitization in OA, which in turn has been linked to more severe pain, but to date, there are no studies exploring such associations in people with hand OA. Objectives To examine whether sleep problems are associated with the severity of pain outcomes and central sensitization in a longitudinal study of people with hand OA. Methods We used data from the Nor-Hand study, which includes people aged 40-70 years with hand OA recruited from secondary care in Oslo, Norway. The participants were examined in 2016-2017 (n=300) and again in 2019-21 (n=213). Pain intensity during the last 24 hours was assessed in the hands and total body on numerical rating scales (NRS, 0=no pain). Self-reported sleep problems were assessed on a Likert scale (none, slight, moderate, severe). Central sensitization was quantified by using measurements of pressure pain thresholds (PPTs, kg/cm²) at the trapezius and tibialis anterior muscles as well as temporal summation (TS) at the wrist. The central sensitization measures were sex-standardized. We performed linear regression analyses to examine associations of baseline sleep problems with 1) pain intensity at baseline and follow-up and 2) the associations between baseline sleep problems and measures of central sensitization at baseline and follow-up. All analyses were adjusted for age, sex, education, body mass index, and self-reported comorbidities. Results The majority was women (87.8%) with mean (SD) age 60.8 (6.2) years. The mean length of follow-up was 3.5 years. At baseline, 76 (25.6%) participants reported no sleep problems, while 101 (33.9%), 78 (26.3%) and 42 (14.1%) reported slight, moderate and severe sleep problems, respectively. The baseline characteristics were similar between those attending baseline only versus both assessments. Compared to persons without sleep problems, persons with moderate and severe sleep problems reported higher adjusted pain levels at both baseline and follow up, with the strongest association observed for people with severe sleep problems (Table 1). Finally, severe sleep problems were significantly associated with lower PPTs (indicating more sensitization) at the trapezius and tibialis anterior muscles at baseline, as well as lower PPT at the trapezius muscle and temporal summation at follow-up (data not shown). As an example, people with severe sleep problems reported 0.79 SD (95% CI -1.50, -0.08) lower PPT than people with no sleep problems.View this table: • View inline • View popup Table 1. The associations between self-reported sleep problems at baseline and NRS pain outcomes (range 0-10) adjusted for age, sex, body mass index, education, and comorbidities. Bold = p<0.05 Conclusion In a hand OA sample, people with sleep problems reported more pain in their hands and overall body in both cross-sectional and longitudinal analyses. Those reporting the most severe sleep problems also exhibited more findings of central sensitization than those without such sleep problems. Due to the observational nature of this study, we cannot conclude whether sleep problems are the cause or consequence of pain and recognize that there could be bidirectional effects. REFERENCES NIL Acknowledgements NIL Disclosure of Interests None declared

Objectives Pain as central symptom of osteoarthritis (OA) needs to be addressed as part of successful treatment. The assessment of pain as feature of disease or outcome in clinical practice and drug development remains a challenge due to its multidimensionality and the plethora of confounders. This article aims at providing insights into our understanding of OA pain-phenotypes and suggests a framework for systematic and comprehensive assessments. Methods This narrative review is based on a search of current literature for various combinations of the search terms “pain-phenotype” and “knee OA” and summarizes current knowledge on OA pain-phenotypes, putting OA pain and its assessment into perspective of current research efforts. Results Pain is a complex phenomenon, not necessarily associated with tissue damage. Various pain-phenotypes have been described in knee OA. Among those, a phenotype with high pain levels not necessarily matching structural changes and a phenotype with low pain levels and impact are relatively consistent. Further subgroups can be differentiated based on patient reported outcome measures, assessments of comorbidities, anxiety and depression, sleep, activity and objective measures such as quantitative sensory testing. Conclusions The complexity of both OA as disease and pain in OA prompt the definition of a set of variables that facilitate assessments comparable across studies to maximize our understanding of pain, as central concern for the patient.

Objective As part of the first phase of the OARSI Early-stage Symptomatic Knee Osteoarthritis (EsSKOA) initiative, we explored the first symptoms and experiences recalled by individuals with knee osteoarthritis (OA). Design This qualitative study, informed by qualitative description, was a secondary analysis of focus groups (n = 17 groups) and one-on-one interviews (n = 3) conducted in 91 individuals living with knee OA as part of an international study to better understand the OA pain experience. In each focus group or interview, participants were asked to describe their first symptoms of knee OA. We inductively coded these transcripts and conducted thematic analysis. Results Mean age of participants was 70 years (range 47–92) and 68 % were female. We developed four overarching themes: Insidious and Episodic Onset, Diverse Early Symptoms, Must be Something Else, and Adjustments. Participants described the gradual and intermittent way in which symptoms of knee OA developed over many years; many could not identify a specific starting point. Participants described diverse initial knee symptoms, including activity-exacerbated joint pain, stiffness and crepitus. Most participants dismissed early symptoms or rationalized their presence, employing various strategies to enable continued participation in recreational and daily activities. Few sought medical attention until physical functioning was demonstrably impacted. Conclusions The earliest symptoms of knee OA are frequently insidious in onset, episodic and present long before individuals present to health professionals. These results highlight challenges to identifying people with knee OA early and support the development of specific classification criteria for EsSKOA to capture individuals at an early stage.

Objective To characterize dual-energy computed tomography (DECT) changes depicting hyaline cartilage changes in gout patients with and without osteoarthritis (OA) and in comparators without gout. Design Patients with suspected crystal-associated arthropathy were enrolled and underwent bilateral DECT scans of the knees. Standardized regions of interest were defined in the femorotibial hyaline cartilage. Five DECT parameters were obtained: CT numbers in Hounsfield units (HU) at 80 and 140 kV, the electron density (Rho), the effective atomic number (Zeff), and the dual-energy index (DEI). Zones were compared between patients with gout, with and without knee OA, and between patients with gout and comparators without gout, after adjustment for confounders. Results A total of 113 patients with gout (mean age 63.5 ± 14.3 years) and 15 comparators without gout (mean age 75.8 ± 11.5 years) were included, n = 65 (51%) had knee OA, and 466 zones of hyaline cartilage were analyzed. Older age was associated with lower attenuations at 80 kV (P < 0.01) and 140 kV (P < 0.01), and with Rho (P < 0.01). OA was characterized by lower attenuation at 140 kV (P = 0.03), but the lower Rho was nonsignificant after adjustment for confounders. In gout, hyaline cartilage exhibited lower Rho values (adjusted P = 0.04). Multivariable coefficients of association with Rho were −0.21 [−0.38;−0.04] (P = 0.014) for age, −4.15 [−9.0;0.7] (P = 0.093) for OA and 0.73 [−0.1;1.56] (P = 0.085) for monosodium urate volume. Conclusion Gout was associated with DECT-detected changes in cartilage composition, similar to those observed in older patients, with some similarities and some differences to those seen in OA. These results suggest the possibility of potential DECT biomarkers of OA.

Objective: Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field. Method: The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development. Results: Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions. Conclusions: The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.

Background Pain sensitization is an important component of the pain experience in many persons with osteoarthritis (OA). Knee OA studies have suggested that pain sensitization is associated with functional limitations, but the evidence in hand OA is sparse. Objectives To assess whether pain sensitization is associated with physical function in people with hand OA. Methods We included 206 participants in cross-sectional analyses from the follow-up visit of the Nor-Hand study. Measures of pain sensitization included pressure pain thresholds (PPTs) by a handheld algometer, and temporal summation (TS) defined as increased pain during repeated stimuli. Pain and function in hands and knees/hips were self-reported on the AUSCAN and WOMAC indices, respectively. Performance-based measures of physical function included hand grip strength, the 30-second chair stand test and the 40-meter walk test (reported as walking speed). Associations between sex-standardized PPT and TS values and physical function were assessed using linear regression adjusted for potential confounders (see Table 1). The possible mediating effect of self-reported pain severity was examined with causal inference-based mediation analyses. Results The median (IQR) age was 65 (60-69) years and 86% were female. People with higher PPTs at or near the hand or knee, which may represent less peripheral and/or central sensitization, reported better function in hands and knees/hips and performed better on the performance tests than people with lower PPTs (Table 1), although not statistically significant for all outcomes. Also, a higher PPT at the trapezius muscle, representing less central sensitization, was associated with better function in the lower extremities (Table 1). No associations were found between pain sensitization and the chair stand test (data not shown), or between TS (measure of central sensitization) and hand or lower extremity function. The effects of PPTs on self-reported AUSCAN hand function appeared to be largely mediated through self-reported hand pain (e.g., indirect effect of PPT at the wrist mediated through hand pain: -1.19, 95% CI -1.95, -0.43, and direct effect: -0.20, 95% CI -0.90, 0.51). Effects of PPTs on grip strength were mediated through pain to a lesser extent (e.g., indirect effect of PPT at the wrist mediated through hand pain: 0.12, 95% CI -0.10, 0.34, and direct effect: 1.21, 95% CI 0.29, 2.13). Similarly, the mediating effects of knee/hip pain were larger in analyses of self-reported function than for performance-based measures of lower extremity function (data not shown). Conclusion Our results suggest that peripheral sensitization and possibly also central sensitization, are associated with impaired function in hands and lower extremities. For both the hand and lower extremities, measures of sensitization may have direct effects on performance-based measures of function, whereas the effect of sensitization on self-reported function appears to be mediated through self-reported pain severity. Table 1. Associations between measures of sensitization and function AUSCAN hand function (range 0-36) Grip strength (kg) WOMAC knee/hip function (range 0-68) 40-meter walk test (m/s) PPT finger joint -1.42 (-2.42, -0.43 ) 1.25 (0.35, 2.14 ) -1.73 (-3.40, -0.05 ) 0.03 (-0.01, 0.06) PPT wrist -1.39 (-2.38, -0.39 ) 1.33 (0.41, 2.24 ) -1.66 (-3.37, 0.04) 0.03 (-0.01, 0.06) PPT trapezius muscle -0.80 (-1.81, 0.22) 0.66 (-0.25, 1.57) -1.76 (-3.47, -0.05 ) 0.04 (0.00, 0.07 ) PPT tibialis anterior muscle -0.76 (-1.77, 0.26) 0.74 (-0.17, 1.65) -1.57 (-3.29, 0.14) 0.05 (0.01, 0.08 ) Temporal summation -0.08 (-1.07, 0.91) -0.28 (-1.17, 0.61) 0.96 (-0.75, 2.67) -0.01 (-0.05, 0.02) Adjusted for age, sex, body mass index, education, physical activity, and Kellgren-Lawrence sum score of the hands in the analyses of hand function or ultrasound-detected osteophytes in the knees, hips and feet in the analyses of lower extremity function. Presented as beta (95% CI) per standard deviation of sex-standardized PPT and TS. Acknowledgements The authors would like to thank the study participants, the project coordinator Heidi Gammelsrud, as well as the user representative, physicians and medical students who were involved in the Nor-Hand study. Disclosure of Interests Marthe Gløersen: None declared, Pernille Steen Pettersen: None declared, Tuhina Neogi Consultant of: Novartis, Pfizer-Lilly, Regeneron, Grant/research support from: Pfizer, Joe Sexton: None declared, Tore K. Kvien Speakers bureau: Grünenthal, Sandoz, UCB, Consultant of: AbbVie, Amgen, Celltrion, Gilead, Novartis, Pfizer, Sandoz, UCB, Grant/research support from: AbbVie, Amgen, BMS, Galapagos, Novartis, Pfizer, UCB, Hilde Berner Hammer Speakers bureau: AbbVie, UCB, Lilly, Novartis, Grant/research support from: AbbVie, Pfizer, Roche, Ida K. Haugen Consultant of: Novartis, GSK, Grant/research support from: Pfizer/Lily.