Objective Insomnia is prevalent in knee osteoarthritis (KOA). Research indicates that sleep disruption may amplify clinical pain by altering central pain modulation, suggesting that treating insomnia may improve pain. We sought to: 1) evaluate the efficacy of Cognitive-Behavioral Therapy for Insomnia (CBT-I) in KOA, 2) determine whether improvements in sleep predict reduced pain, and 3) determine whether alterations in pain modulation mediate improvements in clinical pain. Methods We conducted a double-blinded, randomized, active placebo-controlled clinical trial of CBT-I in 100 KOA patients with insomnia [Mean Age = 59.5(9.5)]. Patients were randomized to 8-sessions of CBT-I or Behavioral Desensitization-Placebo. We conducted in-home polysomnograms, diary assessment, and sensory tests of pain modulation at baseline, posttreatment, 3-and 6-months. Results Intent-to-treat analyses demonstrated that both groups yielded substantial improvements in sleep. CBT-I demonstrated significantly greater reductions in wake after sleep onset time (WASO), measured via diary and actigraphy [PSG trended, (p=.075)]. Both groups reported significant and comparable reductions in pain over 6 months with a third demonstrating ≥ 30% reduction in pain severity. Baseline-to-posttreatment reductions in Diary and PSG WASO predicted subsequent decreases in clinical pain. This effect was significantly greater for CBT-I compared to BD. We found no significant changes in laboratory measures of pain modulation. Conclusion Compared to active placebo, CBT-I was efficacious in reducing sleep maintenance insomnia. Treatment decreased clinical pain, but not pain modulation, suggesting that CBT-I has potential to augment pain management in KOA. Future work is needed to identify the mechanisms by which improved sleep reduces clinical pain.

IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses.DOI: http://dx.doi.org/10.7554/eLife.21238.001

Objectives: Osteoarthritis, a chronic degenerative joint disorder, is characterized by joint pain. Emerging research demonstrates that a significant number of patients evidence central sensitization (CS), a hyper-excitability in nociceptive pathways, which is known to amplify and maintain clinical pain. The clinical correlates of CS in OA, however, are poorly understood. Insomnia is prevalent in older adults with OA and recent experiments suggest associations between poor sleep and measures of CS. Catastrophizing, a potent predictor of pain outcomes has also been associated with CS, but few studies have investigated possible interactions between catastrophizing, sleep and CS. Methods: We conducted a case controlled study of 4 well characterized groups of adults with insomnia and/or knee osteoarthritis. A total of 208 participants completed multimodal sleep assessments (questionnaire, diary, actigraphy, polysmnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between CS, catastrophizing and insomnia. Descriptive characterization of each measure is presented, with specific focus on sleep efficiency and CS. Results: The KOA-Insomnia group demonstrated the greatest degree of CS compared to controls. In the overall sample, we found that catastrophizing moderated the relationship between sleep efficiency and CS. Specifically those with low sleep efficiency and high catastrophizing scores reported increased levels of CS. In addition, CS was significantly associated with increased clinical pain. Conclusions: These findings highlight the importance of assessing sleep efficiency, CS and catastrophizing in chronic pain patients and have important clinical implications for treatment planning.

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