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Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.

Fibromyalgia is a common, high-impact condition of chronic widespread pain and sensory dysfunction associated with altered central and peripheral sensory processing. A growing body of evidence supports the role of neuroinflammation and immune changes in fibromyalgia, and a narrative review of this literature was undertaken. Published data suggest that the interactions between the neural pain networks and the immune system in fibromyalgia appear to be bidirectional and operate both centrally and peripherally. There is a growing focus on processes occurring in the dorsal root ganglia and the role of maladaptive microglial cell activation. Ongoing insight into neuroinflammatory mechanisms in fibromyalgia opens potential avenues for the development of mechanism-based therapies in what is, at present, a challenging-to-manage condition.

Fibromyalgia is a common illness characterized by chronic widespread pain, sleep problems (including unrefreshing sleep), physical exhaustion and cognitive difficulties. The definition, pathogenesis and treatment are controversial, and some even contest the existence of this disorder. In 1990, the American College of Rheumatology (ACR) defined classification criteria that required multiple tender points (areas of tenderness occurring in muscles and muscle–tendon junctions) and chronic widespread pain. In 2010, the ACR preliminary diagnostic criteria excluded tender points, allowed less extensive pain and placed reliance on patient-reported somatic symptoms and cognitive difficulties. Fibromyalgia occurs in all populations worldwide, and symptom prevalence ranges between 2% and 4% in the general population. The prevalence of people who are actually diagnosed with fibromyalgia (‘administrative prevalence’) is much lower. A model of fibromyalgia pathogenesis has been suggested in which biological and psychosocial variables interact to influence the predisposition, triggering and aggravation of a chronic disease, but the details are unclear. Diagnosis requires the history of a typical cluster of symptoms and the exclusion of a somatic disease that sufficiently explains the symptoms by medical examination. Current evidence-based guidelines emphasize the value of multimodal treatments, which encompass both non-pharmacological and selected pharmacological treatments tailored to individual symptoms, including pain, fatigue, sleep problems and mood problems. For an illustrated summary of this Primer, visit: http://go.nature.com/LIBdDX Fibromyalgia is characterized by chronic widespread pain, unrefreshing sleep, physical exhaustion and cognitive difficulties. The definition, pathogenesis and treatment of fibromyalgia are controversial, with some physicians contesting its existence. In this Primer, Häuser et al . explain these controversies.

The promulgation of the American College of Rheumatology (ACR) 1990 criteria for fibromyalgia (FM) classification has significantly contributed to an era of increased research into mechanisms that underlie the disorder. The previous emphasis on putative peripheral nociceptive mechanisms has advanced to identifying of changes in central neural networks that modulate pain and other sensory processes. The influences of psychosocial factors on the dynamic and complex neurobiological mechanisms involved in the fibromyalgia clinical phenotype are now better defined. This review highlights key milestones that have directed knowledge concerning the fundamental mechanisms contributing to fibromyalgia.

Key Points Fibromyalgia and complex regional pain syndrome (CRPS) have distinct clinical phenotypes but share features such as pain, allodynia and peripheral dysaesthesia Factors involving the brain and spinal cord lead to central sensitization, which has a dominant role in both disorders Neurogenic inflammation, resulting from the release of proinflammatory neuropeptides from C-fibres, is also prominent in both disorders and contributes to allodynia, tissue swelling and dysaesthesia Neurogenic inflammation involves interactions of the innate immune system with the peripheral and central nervous systems of patients with fibromyalgia or CRPS Although the pathogenesis of both fibromyalgia and CRPS is dominated by central mechanisms, components of neurogenic neuroinflammation might be useful therapeutic targets in patients with these disorders Fibromyalgia and complex regional pain syndrome (CRPS) share many pathophysiological mechanisms. Central mechanisms predominate in both disorders, although peripheral mechanisms such as neurogenic neuroinflammation also contribute to their clinical features, albeit to differing degrees. This article discusses the evidence suggesting that neurogenic neuroinflammation is an important and potentially targetable link between the two disorders. Although fibromyalgia and complex regional pain syndrome (CRPS) have distinct clinical phenotypes, they do share many other features. Pain, allodynia and dysaesthesia occur in each condition and seem to exist on a similar spectrum. Fibromyalgia and CRPS can both be triggered by specific traumatic events, although fibromyalgia is most commonly associated with psychological trauma and CRPS is most often associated with physical trauma, which is frequently deemed routine or minor by the patient. Fibromyalgia and CRPS also seem to share many pathophysiological mechanisms, among which the most important are those involving central effects. Nonetheless, peripheral effects, such as neurogenic neuroinflammation, are also important contributors to the clinical features of each of these disorders. This Review highlights the differing degrees to which neurogenic neuroinflammation might contribute to the multifactorial pathogenesis of both fibromyalgia and CRPS, and discusses the evidence suggesting that this mechanism is an important link between the two disorders, and could offer novel therapeutic targets.

Fibromyalgia is a high impact chronic pain disorder with a well-defined and robust clinical phenotype. Key features include widespread pain and tenderness, high levels of sleep disturbance, fatigue, cognitive dysfunction and emotional distress. Abnormal processing of pain and other sensory input occurs in the brain, spinal cord and periphery and is related to the processes of central and peripheral sensitization. As such, fibromyalgia is deemed to be one of the central sensitivity syndromes. There is increasing evidence of neurogenically derived inflammatory mechanisms occurring in the peripheral tissues, spinal cord and brain in fibromyalgia. These involve a variety of neuropeptides, chemokines and cytokines with activation of both the innate and adaptive immune systems. This process results in several of the peripheral clinical features of fibromyalgia, such as swelling and dysesthesia, and may influence central symptoms, such as fatigue and changes in cognition. In turn, emotional and stress-related physiological mechanisms are seen as upstream drivers of neurogenic inflammation in fibromyalgia.

IntroductionThe aim of this study was to describe the real-world evidence for effectiveness, treatment persistence, and treatment patterns among patients in the community with rheumatoid arthritis treated with the JAK inhibitor tofacitinib.MethodsThis was a retrospective, non-interventional cohort study that extracted data for new users of tofacitinib or biologic disease-modifying antirheumatic drugs (bDMARDs) from the Australian Optimizing Patient outcomes in Australian RheumatoLogy (OPAL) dataset between March 2015 and September 2018. Patients were propensity score matched at a 1:2 tofacitinib to bDMARD ratio based on age, sex, and selected baseline treatment combinations. Treatment effectiveness was evaluated using disease status measures. Treatment persistence was calculated and the percentage of patients receiving monotherapy or combination therapy at treatment initiation was evaluated.ResultsData from 2810 patients were extracted and 1950 patients were included in the matched population (1300 bDMARD initiators and 650 tofacitinib initiators). Patients were predominantly aged 55 to 74 years (57.8%) and female (81.2%). After 18 months of treatment, 52.4% and 57.8% of patients had achieved disease activity score (DAS) remission in the bDMARD and tofacitinib groups, respectively. The median treatment persistence for tofacitinib was similar to that for bDMARDs: 34.2 months (95% CI 32.2 to not reached) and 33.8 months (95% CI 28.8 to 40.4), respectively. In the overall population, more patients were prescribed tofacitinib as monotherapy (43.4%) compared with bDMARD monotherapy (33.4%).ConclusionsTofacitinib demonstrated treatment effectiveness and persistence similar to bDMARDs. Overall, there was a trend for more use of tofacitinib as monotherapy than bDMARDs.Key Points• This study provides real-world evidence regarding effectiveness, treatment persistence, and treatment patterns, among patients with rheumatoid arthritis (RA) in the community being treated with tofacitinib.• The study suggests that tofacitinib is an effective and enduring intervention in RA with tofacitinib persistence and effectiveness comparable to bDMARDs.

Introduction This study sought to describe treatment patterns, persistence, and effectiveness of upadacitinib (UPA) alone and compared to other Janus kinase inhibitors (JAKis) or tumor necrosis factor inhibitors (TNFis) in patients with rheumatoid arthritis (RA). Methods This retrospective, non-interventional study used the OPAL dataset, derived from electronic medical records. Patients initiated UPA ( N  = 2624), other JAKis (baricitinib and tofacitinib [ N  = 925]), or TNFis (adalimumab, etanercept, certolizumab, golimumab, infliximab [ N  = 3540]) between May 2020 and March 2023. Median persistence (Kaplan-Meier, log rank test) and effectiveness (Disease Activity Score 28-joint C-reactive protein, three variables [DAS28CRP{3}]) were evaluated for UPA-treated patients and in three propensity score-matched cohorts: UPA monotherapy versus combination therapy, UPA versus other JAKis, and UPA versus TNFis. Results In patients prescribed UPA, 41.3% were ≥ 65 years old, 33.8% were prescribed as first-line advanced therapy, and 27.2% were prescribed monotherapy. Median persistence on UPA was 26.6 months (95% confidence intervals: 24.4, 29.9) and longest in earlier lines of therapy. The DAS28CRP(3) remission rate was 73% at 3 months, with improvements observed across lines of therapy. UPA monotherapy and combination therapy had similar median persistence (27.8 [23.5, 33.4] versus 30.4 months [22.1, 35.3], p  = 0.84) and effectiveness. UPA showed longer median persistence than other JAKis (28.8 [25.6, 32.4] versus 17.2 months [14.9, 19.8], p  < 0.001) and TNFis (26.6 [24.9, 30.8] versus 13.3 months [11.5, 14.5], p  < 0.001). DAS28CRP(3) remission rates were greater at 3 months for UPA than other JAKis (75.0% versus 61.5%) and TNFis (72.7% versus 59.5%). In unmatched subgroups, compared to cycling between TNFis, switching to UPA from other JAKis or TNFis resulted in longer median persistence (months: JAKi-to-UPA: 25.3 [16.1, not reached]; TNFi-to-UPA: 27.8 [23.2, 35.4]; TNFi-to-TNFi: 9.6 [8.4, 10.7]) and greater DAS-28CRP(3) remission rates over 9 months. Conclusions Overall, the breadth and depth of data from this large real-world dataset continue to support a favorable clinical profile of UPA for the treatment of RA and may inform treatment choices in everyday clinical practice. Plain Language Summary This study of patients treated in clinical practice looked at how a targeted medication, a Janus kinase inhibitor (JAKi) called upadacitinib, was used to treat rheumatoid arthritis, a disease that causes joint pain and damage. The researchers wanted to see how long patients continued treatment with upadacitinib, how effective it was at reducing symptoms, and how these outcomes compared to other JAKis (baricitinib and tofacitinib) and tumor necrosis factor inhibitors, a different type of advanced medication. Patients continued upadacitinib treatment for a median time of over 2 years. Those patients who had never previously used JAKis or tumor necrosis factor inhibitors continued upadacitinib treatment longer than those patients with previous experience. Patients treated with upadacitinib alone or in combination with less advanced medications like methotrexate continued treatment for a similar length of time. Compared to other JAKis and tumor necrosis factor inhibitors, patients prescribed upadacitinib stayed on their treatment the longest. Upadacitinib helped to lessen the symptoms of rheumatoid arthritis, whether patients took it alone or in combination with medications like methotrexate. After 3 months, more patients treated with upadacitinib experienced reduced symptoms than patients treated with other JAKis or tumor necrosis factor inhibitors. Additionally, patients who switched to upadacitinib after using other JAKis or tumor necrosis factor inhibitors reduced their symptoms and continued treatment for longer than those switching between tumor necrosis factor inhibitors. Overall, patients treated with upadacitinib continued treatment for longer and saw greater improvements in the symptoms of rheumatoid arthritis than patients prescribed other advanced medications.

We hypothesized that fibromyalgia (FM) patients would report lower levels of psychological control mechanisms and that higher levels of control would moderate key symptoms associated with FM, such as pain, fatigue, perceived stress, and mood disturbance. Ninety-eight women with FM diagnosed according to American College of Rheumatology criteria and 35 matched pain-free women were identified. Applied questionnaires included the Fibromyalgia Impact Questionnaire, Profile of Mood States, Perceived Control of Internal States Scale, Perceived Stress Scale, and Mastery Scale. Differences were sought using t-tests, one-way analysis of variance, bivariate correlations, and multiple regression analysis. Comparison between FM patients and healthy individuals found significant differences in control (Perceived Control of Internal States Scale and Mastery Scale), pain, perceived stress, fatigue, confusion, and mood disturbance (all P < 0.001). There were significant associations found between both high and low levels of control on stress, mood, pain, and fatigue (P < 0.001-0.05). Strong negative correlations were present between internal control and perceived stress (P < 0.0005). FM patients use significantly different control styles compared with healthy individuals. Levels and type of psychological control buffer mood, stress, fatigue, and pain in FM. Control appears to be an important \"up-stream\" process in FM mechanisms and is amenable to intervention.

Objective To analyze comparative treatment persistence for first‐line baricitinib (BARI) versus first‐line tumor necrosis factor inhibitor (TNFi) in patients with rheumatoid arthritis (RA) and for first‐line BARI initiated as monotherapy versus first‐line BARI initiated with at least one conventional synthetic disease‐modifying antirheumatic drug (csDMARD). Methods Patients with RA who initiated BARI or TNFi as first‐line biologic or targeted synthetic DMARD from October 1, 2015, to September 30, 2021, were identified in the OPAL data set. Drug survival times to 6, 12, and 24 months were analyzed using restricted mean survival time (RMST). Multiple imputation and inverse probability of treatment weighting were used to address missing data and nonrandom treatment assignment. Results A total of 545 patients initiated first‐line BARI, including 118 as monotherapy and 427 as csDMARD combination therapy. Three thousand five hundred patients initiated first‐line TNFi. There was no difference in drug survival to 6 or 12 months for BARI compared with TNFi; differences in RMST were 0.02 months (95% CI: −0.08 to 0.013; P = 0.65) and 0.31 months (95% CI: −0.02 to 0.63; P = 0.06), respectively. Patients in the BARI group had 1.00 month (95% CI: 0.14 to 1.86; P = 0.02) longer drug survival to 24 months. There was no difference in drug survival for BARI monotherapy compared with combination therapy, with differences in RMST to 6, 12, and 24 months of −0.19 months (95% CI: −0.50 to 0.12; P = 0.12), −0.35 months (95% CI: −1.17 to 0.42; P = 0.41), and −0.56 months (95% CI: −2.66 to 1.54; P = 0.60), respectively. Conclusion In this comparative analysis, treatment persistence up to 24 months was significantly longer for first‐line BARI compared with TNFi, but the effect size of 1.00 month is not clinically meaningful. There was no difference in persistence for BARI monotherapy versus combination therapy.