Morning Light Treatment for Inflammatory Bowel Disease: A Pilot Clinical Trial

摘要 炎症性肠病（IBD）是一种致残性慢性炎症性疾病，包括两种亚型， 溃疡性结肠炎（UC）和克罗恩病（CD）。IBD引起胃肠道症状，如腹部 疼痛、直肠出血和腹泻，以及肠外症状如睡眠和情绪障碍。IBD 影响超过300万美国人，并且具有高达50%的患者的复发和缓解过程 每年都在经历恶化。免疫靶向治疗如生物制剂有助于控制IBD，但 患者继续遭受高比率的次优疾病控制和肠外症状， 疲劳、抑郁和生活质量受损。迫切需要发展预防性治疗 更好地管理IBD症状和疾病活动的方法，副作用最小， 容易获得和负担得起。昼夜节律紊乱（“生物钟”的紊乱）是促炎性的， 肠道功能受损，并与疾病活动增加、胃肠道和 肠外症状和IBD生活质量受损。因此，昼夜节律紊乱可能是一个重要的 IBD的治疗目标。晨光治疗，提前（更早转移）和稳定 昼夜节律定时可能有潜力改善IBD的症状和疾病严重程度。然而，没有研究 已经探索了晨光治疗IBD的潜在治疗益处。最近，我们测试了一个4- 在纤维肌痛患者中进行为期一周、每天1小时的晨间光照治疗（R21 NR 016930），使用 可商购获得的可穿戴光设备。我们发现晨光疗法是可行的， 提前和稳定的睡眠时间，并显着改善抑郁症，睡眠质量和生活质量（所有 p≤0.02），均具有最小的副作用。在这一成功的鼓舞下，我们建议测试同样的晨光， IBD患者的治疗，响应PAS-20-160：临床试验的小R 01，其不 需要初步数据。68例经活检证实患有IBD、临床活动性疾病和受损的 IBD生活质量将随机分配至4周晨间光照治疗（1小时/天）或4周治疗， 通常（TAU），每组中具有等同的研究联系人（完成样本n=50）。患者报告结局 (IBD生活质量、情绪、睡眠）、临床医生评定的疾病严重程度和胃肠道疾病的生物标志物。 将在治疗之前和之后评估炎症（粪便钙卫蛋白）。目标1将决定 晨光治疗与TAU对患者报告结局的影响，目标2将确定对 临床医生评定的疾病严重程度。我们还将探讨晨光治疗与TAU治疗对 胃肠道炎症的生物标志物（粪便钙卫蛋白），以及类固醇的潜在调节作用 使用，不宁腿综合征和生物性别。该项目将是第一个测试晨光治疗， IBD患者，结果将为开发晨光治疗作为一种新的非免疫疗法提供基础。 药理学连续治疗具有增强IBD现有治疗结果的潜力。

ABSTRACT Inflammatory bowel disease (IBD) is a disabling chronic inflammatory condition that includes two subtypes, ulcerative colitis (UC) and Crohn’s disease (CD). IBD causes gastrointestinal symptoms such as abdominal pain, rectal bleeding, and diarrhea, and extraintestinal symptoms such as sleep and mood disturbances. IBD affects over 3 million Americans and has a relapsing and remitting course with up to 50% of patients experiencing exacerbations each year. Immune targeted therapies such as biologics help control IBD, but patients continue to suffer from high rates of suboptimal disease control and extraintestinal symptoms such as fatigue, depression, and impaired quality of life. An urgent need exists to develop adjunctive treatment approaches to better manage IBD symptoms and disease activity, which have minimal side effects, and are readily available and affordable. Circadian disruption (disruption of the “body clock”), is proinflammatory, worsens intestinal function, and is associated with increased disease activity, worse gastrointestinal and extraintestinal symptoms and impaired quality of life in IBD. Thus, circadian disruption may be an important modifiable treatment target for IBD. Morning light treatment, which advances (shifts earlier) and stabilizes circadian timing, may have potential to improve symptoms and disease severity in IBD. However, no studies have explored the potential therapeutic benefits of morning light treatment for IBD. Recently, we tested a 4- week, 1-hour daily morning light treatment in individuals with fibromyalgia (R21NR016930), using a commercially available wearable light device. We found the morning light treatment was feasible, reliably advanced and stabilized sleep timing, and significantly improved depression, sleep quality and quality of life (all p≤0.02), all with minimal side effects. Encouraged by this success, we propose to test the same morning light treatment in individuals with IBD, in response to PAS-20-160: Small R01s for Clinical Trials, which does not require preliminary data. Sixty-eight individuals with biopsy-proven IBD, clinically active disease and impaired IBD quality of life will be randomized to 4 weeks of morning light treatment (1 h/day) or 4 weeks of treatment as usual (TAU), with equivalent study contact in each group (completed sample n=50). Patient-reported outcomes (IBD quality of life, mood, sleep), clinician-rated disease severity, and a biomarker of gastrointestinal inflammation (fecal calprotectin) will be assessed before and after treatment. Aim 1 will determine the effect of morning light treatment versus TAU on patient-reported outcomes and Aim 2 will determine the effects on clinician-rated disease severity. We will also explore the effect of morning light treatment versus TAU on a biomarker of gastrointestinal inflammation (fecal calprotectin), and the potential moderating effects of steroid use, restless leg syndrome and biological sex. This project will be the first to test morning light treatment in people with IBD, and results will provide a foundation for developing morning light treatment as a novel non- pharmacological adjunctive treatment with potential to enhance existing treatment outcomes for IBD.