利妥昔单抗
一些零星证据表明利妥昔单抗可作为 CFS/ME 的一种治疗药物。它是一种靶向全 B 细胞抗原 CD20 的嵌合型单克隆抗体。[225]Abdulla NE, Ninan MJ, Markowitz AB. Rituximab: current status as therapy for malignant and benign hematologic disorders. BioDrugs. 2012 Apr 1;26(2):71-82.http://www.ncbi.nlm.nih.gov/pubmed/22339395?tool=bestpractice.com 小型随机安慰剂对照和开放性研究显示，治疗 22 至 83 周后改善率为 60% 至 83%，而安慰剂组为 7% 至 10%。[44]Capelli E, Zola R, Lorusso L, et al. Chronic fatigue syndrome/myalgic encephalomyelitis: an update. Int J Immunopathol Pharmacol. 2010 Oct-Dec;23(4):981-9.http://www.ncbi.nlm.nih.gov/pubmed/21244747?tool=bestpractice.com[46]Fluge Ø, Mella O, Bruland O, et al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016 Dec 22;1(21):e89376.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/http://www.ncbi.nlm.nih.gov/pubmed/28018972?tool=bestpractice.com[84]Fluge Ø, Bruland O, Risa K, et al. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome: a double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198463/http://www.ncbi.nlm.nih.gov/pubmed/22039471?tool=bestpractice.com[226]Fluge Ø, Risa K, Lunde S, et al. B-lymphocyte depletion in myalgic encephalopathy/chronic fatigue syndrome: an open-label phase II study with rituximab maintenance treatment. PLoS One. 2015 Jul 1;10(7):e0129898.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488509/http://www.ncbi.nlm.nih.gov/pubmed/26132314?tool=bestpractice.com 参与者被分层为显著反应者、临界反应者和无反应者，这提示潜在的病理生理存在异质性。然而，一项大型随机安慰剂对照研究显示没有显著的治疗获益，并且有较高程度的安慰剂效应。在撰写本文时，这项研究还未发表。[227]ME Association. Negative phase III clinical trial result from Norway for rituximab in ME/CFS. November 2017 [internet publication].https://www.meassociation.org.uk/2017/11/me-association-statement-negative-phase-iii-clinical-trial-result-from-norway-for-rituximab-in-mecfs-27-november-2017/ 这一系列构思良好的临床试验表明，需要适当推进随机安慰剂对照临床研究、适当的参与者选择标准、严格遵守研究方案、除自诉指标外的客观治疗结果，以及透明地公布研究目标和结局。该研究的一项分支发现为证实了 CFS/ME 患者的代谢组学改变，并且提出了一种循环线粒体抑制剂。[46]Fluge Ø, Mella O, Bruland O, et al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016 Dec 22;1(21):e89376.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/http://www.ncbi.nlm.nih.gov/pubmed/28018972?tool=bestpractice.com[47]Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5472-80.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027464/http://www.ncbi.nlm.nih.gov/pubmed/27573827?tool=bestpractice.com目前尚未批准在 CFS/ME 中使用利妥昔单抗。
KPAX002
在 12 周时，盐酸哌甲酯联合线粒体支持营养素 KPAX002 可使个人疲劳强度问卷 (Checklist Individual Strength) 评分改善 34% (P＜0.0001)。[228]Kaiser JD. A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome. Int J Clin Exp Med. 2015 Jul 15;8(7):11064-74.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565289/http://www.ncbi.nlm.nih.gov/pubmed/26379906?tool=bestpractice.com 超过 50% 的人报告在疲劳和集中注意力方面有某些改善。
安普利近
有低质量的证据显示，Rintatolimo（免疫调节性聚肌胞苷酸双链 RNA ）有 Toll 样受体 3 (toll-like receptor 3) 激动剂特性，可改善 CFS/ME 患者的运动能力。[208]Mitchell W. Review of Ampligen clinical trials in chronic fatigue syndrome. J Clin Virol. 2006;37(suppl 1):S113.[209]Strayer DR, Carter WA, Brodsky I, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18(suppl 1):S88-95.http://www.ncbi.nlm.nih.gov/pubmed/8148460?tool=bestpractice.com[210]Strayer DR, Carter WA, Stouch BC, et al. A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303772/http://www.ncbi.nlm.nih.gov/pubmed/22431963?tool=bestpractice.com[229]Mitchell WM. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Expert Rev Clin Pharmacol. 2016 Jun;9(6):755-70.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917909/http://www.ncbi.nlm.nih.gov/pubmed/27045557?tool=bestpractice.com
其他药物治疗
已研究了抗病毒药（单用或与静脉注射免疫球蛋白联用）、[230]Tirelli U, Lleshi A, Berretta M, et al. Treatment of 741 Italian patients with chronic fatigue syndrome. Eur Rev Med Pharmacol Sci. 2013 Nov;17(21):2847-52.http://www.europeanreview.org/wp/wp-content/uploads/2847-2852.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/24254550?tool=bestpractice.com[118]Kogelnik AM, Loomis K, Hoegh-Petersen M, et al. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol. 2006 Dec;37(suppl 1):S33-8.http://www.ncbi.nlm.nih.gov/pubmed/17276366?tool=bestpractice.com[119]Montoya JG, Kogelnik AM, Bhangoo M, et al. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013 Dec;85(12):2101-9.http://onlinelibrary.wiley.com/doi/10.1002/jmv.23713/fullhttp://www.ncbi.nlm.nih.gov/pubmed/23959519?tool=bestpractice.com 单用静脉注射免疫球蛋白、[115]Attard L, Bonvicini F, Gelsomino F, et al. Paradoxical response to intravenous immunoglobulin in a case of Parvovirus B19-associated chronic fatigue syndrome. J Clin Virol. 2015 Jan;62:54-7.http://www.ncbi.nlm.nih.gov/pubmed/25542471?tool=bestpractice.com[231]Kerr JR, Cunniffe VS, Kelleher P, et al. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis. 2003 May 1;36(9):e100-6.http://cid.oxfordjournals.org/content/36/9/e100.longhttp://www.ncbi.nlm.nih.gov/pubmed/12715326?tool=bestpractice.com[232]Rowe KS. Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents. J Psychiatr Res. 1997 Jan-Feb;31(1):133-47.http://www.ncbi.nlm.nih.gov/pubmed/9201655?tool=bestpractice.com 可乐定、[26]Sulheim D, Fagermoen E, Winger A, et al. Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: a combined cross-sectional and randomized clinical trial. JAMA Pediatr. 2014 Apr;168(4):351-60.http://archpedi.jamanetwork.com/article.aspx?articleid=1827799http://www.ncbi.nlm.nih.gov/pubmed/24493300?tool=bestpractice.com[204]Hall DL, Lattie EG, Milrad SF, et al. Telephone-administered versus live group cognitive behavioral stress management for adults with CFS. J Psychosom Res. 2017 Feb;93:41-7.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270375/http://www.ncbi.nlm.nih.gov/pubmed/28107891?tool=bestpractice.com[233]Fagermoen E, Sulheim D, Winger A, et al. Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial. BMC Pediatr. 2015 Sep 10;15:117.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566847/http://www.ncbi.nlm.nih.gov/pubmed/26357864?tool=bestpractice.com西酞普兰（用于无抑郁的患者）、[234]Hartz AJ, Bentler SE, Brake KA, et al. The effectiveness of citalopram for idiopathic chronic fatigue. J Clin Psychiatry. 2003 Aug;64(8):927-35.http://www.ncbi.nlm.nih.gov/pubmed/12927008?tool=bestpractice.com 氢化可的松、[235]Cleare AJ, Miell J, Heap E, et al. Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy. J Clin Endocrinol Metab. 2001 Aug;86(8):3545-54.http://press.endocrine.org/doi/10.1210/jcem.86.8.7735?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmedhttp://www.ncbi.nlm.nih.gov/pubmed/11502777?tool=bestpractice.com 氟氢可的松、[212]Blockmans D, Persoons P, Van Houdenhove B, et al. Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study. Am J Med. 2003 Jun 15;114(9):736-41.http://www.ncbi.nlm.nih.gov/pubmed/12829200?tool=bestpractice.com 哌甲酯、[236]Blockmans D, Persoons P, Van Houdenhove B, et al. Does methylphenidate reduce the symptoms of chronic fatigue syndrome? Am J Med. 2006 Feb;119(2):167.e23-30.http://www.amjmed.com/article/S0002-9343%2805%2900656-X/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/16443425?tool=bestpractice.com 褪黑素、[237]van Heukelom RO, Prins JB, Smits MG, et al. Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome and late melatonin secretion. Eur J Neurol. 2006 Jan;13(1):55-60.http://www.ncbi.nlm.nih.gov/pubmed/16420393?tool=bestpractice.com[238]Williams G, Waterhouse J, Mugarza J, et al. Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Eur J Clin Invest. 2002 Nov;32(11):831-7.http://www.ncbi.nlm.nih.gov/pubmed/12423324?tool=bestpractice.com 加兰他敏、[211]Blacker CV, Greenwood DT, Wesnes KA, et al. Effect of galantamine hydrobromide in chronic fatigue syndrome: a randomized controlled trial. JAMA. 2004 Sep 8;292(10):1195-204.http://jama.jamanetwork.com/article.aspx?articleid=199392http://www.ncbi.nlm.nih.gov/pubmed/15353532?tool=bestpractice.com 单用血清烟酰胺腺嘌呤二核苷酸[239]Forsyth LM, Preuss HG, MacDowell AL, et al. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol. 1999 Feb;82(2):185-91.http://www.ncbi.nlm.nih.gov/pubmed/10071523?tool=bestpractice.com 以及联合辅酶 Q10 使用、[240]Castro-Marrero J, Cordero MD, Segundo MJ, et al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal. 2015 Mar 10;22(8):679-85.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346380/http://www.ncbi.nlm.nih.gov/pubmed/25386668?tool=bestpractice.com 葡萄球菌毒素、[241]Zachrisson O, Regland B, Jahreskog M, et al. Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome: a randomised controlled trial. Eur J Pain. 2002;6(6):455-66.http://www.ncbi.nlm.nih.gov/pubmed/12413434?tool=bestpractice.com 白细胞介素-1 受体抑制剂阿那白滞素、[242]Roerink ME, Bredie SJH, Heijnen M, et al. Cytokine inhibition in patients with chronic fatigue syndrome: a randomized trial. Ann Intern Med. 2017 Apr 18;166(8):557-64.http://www.ncbi.nlm.nih.gov/pubmed/28265678?tool=bestpractice.com 胍基乙酸[243]Ostojic SM, Stojanovic M, Drid P, et al. Supplementation with guanidinoacetic acid in women with chronic fatigue syndrome. Nutrients. 2016 Jan 29;8(2):72.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772036/http://www.ncbi.nlm.nih.gov/pubmed/26840330?tool=bestpractice.com 以及皮下给予人胎盘提取物[244]Park SB, Kim KN, Sung E, et al. Human placental extract as a subcutaneous injection is effective in chronic fatigue syndrome: a multi-center, double-blind, randomized, placebo-controlled study. Biol Pharm Bull. 2016 May 1;39(5):674-9.https://www.jstage.jst.go.jp/article/bpb/39/5/39_b15-00623/_html/-char/enhttp://www.ncbi.nlm.nih.gov/pubmed/26911970?tool=bestpractice.com 对 CFS/ME 的疗效，但结果不确切，或者显示疗效有限或无效。[245]Yancey JR, Thomas SM. Chronic fatigue syndrome: diagnosis and treatment. Am Fam Physician. 2012 Oct 15;86(8):741-6.http://www.aafp.org/afp/2012/1015/p741.htmlhttp://www.ncbi.nlm.nih.gov/pubmed/23062157?tool=bestpractice.com 由于样本量较小及较差的研究设计，这些研究可能提供误导性结果；因此应谨慎解读结果。
低强度行为治疗
与常规治疗相比，采用低强度替代方法给予循证治疗（例如，电话、互联网、简短的初级医疗保健随访和认知行为疗法 [CBT] 的引导式自我指导方案）使身体功能、疲劳和患者满意度取得了程度相当的改善。[246]Burgess M, Andiappan M, Chalder T. Cognitive behaviour therapy for chronic fatigue syndrome in adults: face to face versus telephone treatment: a randomized controlled trial. Behav Cogn Psychother. 2012 Mar;40(2):175-91.http://www.ncbi.nlm.nih.gov/pubmed/21929831?tool=bestpractice.com[247]Tummers M, Knoop H, van Dam A, et al. Implementing a minimal intervention for chronic fatigue syndrome in a mental health centre: a randomized controlled trial. Psychol Med. 2012 Oct;42(10):2205-15.http://www.ncbi.nlm.nih.gov/pubmed/22354999?tool=bestpractice.com此外，一项关于青少年的随机试验发现，相对于常规治疗，基于互联网的 CBT 结合分级运动（基于互联网的青少年疲乏治疗 - FITNET）可显著减少症状主诉和功能障碍；这种改善在第 4 年的随访时得以保持，[248]Nijhof SL, Bleijenberg G, Uiterwaal CS, et al. Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial. Lancet. 2012 Apr 14;379(9824):1412-8.http://www.ncbi.nlm.nih.gov/pubmed/22385683?tool=bestpractice.com 目前正在进行另一项以英国为基础的研究，旨在招募 700 多名青少年。在一项针对成人的研究中，与支持性倾听或常规治疗相比，家庭式（护士亲自走访或电话指导）“实用性康复”干预 20 周，改善了自述的疲劳程度。[141]Wearden AJ, Dowrick C, Chew-Graham C, et al. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ. 2010 Apr 23;340:c1777.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859122/http://www.ncbi.nlm.nih.gov/pubmed/20418251?tool=bestpractice.com 然而，在 70 周随访时未发现组间差异。在初级保健机构进行的一项随机试验发现，与 2 次症状监测或常规治疗相比，2 次疲劳自我管理干预措施改善了自诉的疲劳。然而，高退出率限制了对该研究的解读。[249]Friedberg F, Napoli A, Coronel J, et al. Chronic fatigue self-management in primary care: a randomized trial. Psychosom Med. 2013 Sep;75(7):650-7.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785003/http://www.ncbi.nlm.nih.gov/pubmed/23922399?tool=bestpractice.com 为帮助改善行为干预措施，将需要进一步的研究以探索不同治疗的作用方式的效力。
心率变异性生物反馈疗法和分级运动训练
心率变异性生物反馈疗法 (heart rate variability biofeedback therapy, HRV-BF) 联合分级运动训练可减轻疲劳。HRV-BF 对抑郁有额外作用，而分级运动训练 (GET) 可改善躯体健康。[250]Windthorst P, Mazurak N, Kuske M, et al. Heart rate variability biofeedback therapy and graded exercise training in management of chronic fatigue syndrome: an exploratory pilot study. J Psychosom Res. 2017 Feb;93:6-13.http://www.ncbi.nlm.nih.gov/pubmed/28107894?tool=bestpractice.com 在研究受试者招募期间，使用了美国疾病预防控制中心 (Centers for Disease Control and Prevention) 标准。
替代和补充疗法
维生素 D、必需脂肪酸和镁补充剂、[206]Bagnall AM, Whiting P, Richardson R, et al. Interventions for the treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis. Qual Saf Health Care. 2002 Sep;11(3):284-8.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1743629/http://www.ncbi.nlm.nih.gov/pubmed/12486997?tool=bestpractice.com[251]Maes M, Mihaylova I, Leunis JC. In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation. Neuro Endocrinol Lett. 2005 Dec;26(6):745-51.http://www.ncbi.nlm.nih.gov/pubmed/16380690?tool=bestpractice.com多种营养元素、[252]Brouwers FM, Van Der Werf S, Bleijenberg G, et al. The effect of a polynutrient supplement on fatigue and physical activity of patients with chronic fatigue syndrome: a double-blind randomized controlled trial. QJM. 2002 Oct;95(10):677-83.http://qjmed.oxfordjournals.org/content/95/10/677.longhttp://www.ncbi.nlm.nih.gov/pubmed/12324640?tool=bestpractice.com 顺势疗法、[253]Weatherley-Jones E, Nicholl JP, Thomas KJ, et al. A randomised, controlled, triple-blind trial of the efficacy of homeopathic treatment for chronic fatigue syndrome. J Psychosom Res. 2004 Feb;56(2):189-97.http://www.ncbi.nlm.nih.gov/pubmed/15016577?tool=bestpractice.com 中医、[254]Wang YY, Li XX, Liu JP, et al. Traditional Chinese medicine for chronic fatigue syndrome: a systematic review of randomized clinical trials. Complement Ther Med. 2014 Aug;22(4):826-33.http://www.ncbi.nlm.nih.gov/pubmed/25146086?tool=bestpractice.com静力瑜伽、[255]Oka T, Tanahashi T, Chijiwa T, et al. Isometric yoga improves the fatigue and pain of patients with chronic fatigue syndrome who are resistant to conventional therapy: a randomized, controlled trial. Biopsychosoc Med. 2014 Dec 11;8(1):27.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269854/http://www.ncbi.nlm.nih.gov/pubmed/25525457?tool=bestpractice.com 光疗、[238]Williams G, Waterhouse J, Mugarza J, et al. Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Eur J Clin Invest. 2002 Nov;32(11):831-7.http://www.ncbi.nlm.nih.gov/pubmed/12423324?tool=bestpractice.com 色氨酸耗竭、[256]The GK, Verkes RJ, Fekkes D, et al. Tryptophan depletion in chronic fatigue syndrome, a pilot cross-over study. BMC Res Notes. 2014 Sep 16;7:650.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176591/http://www.ncbi.nlm.nih.gov/pubmed/25227994?tool=bestpractice.com 气功疗法、[257]Ho RT, Chan JS, Wang CW, et al. A randomized controlled trial of qigong exercise on fatigue symptoms, functioning, and telomerase activity in persons with chronic fatigue or chronic fatigue syndrome. Ann Behav Med. 2012 Oct;44(2):160-70.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442161/http://www.ncbi.nlm.nih.gov/pubmed/22736201?tool=bestpractice.com[258]Chan JS, Ho RT, Wang CW, et al. Effects of qigong exercise on fatigue, anxiety, and depressive symptoms of patients with chronic fatigue syndrome-like illness: a randomized controlled trial. Evid Based Complement Alternat Med. 2013;2013:485341.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747479/http://www.ncbi.nlm.nih.gov/pubmed/23983785?tool=bestpractice.com按摩疗法[206]Bagnall AM, Whiting P, Richardson R, et al. Interventions for the treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis. Qual Saf Health Care. 2002 Sep;11(3):284-8.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1743629/http://www.ncbi.nlm.nih.gov/pubmed/12486997?tool=bestpractice.com 以及顺势疗法干预[259]Alraek T, Lee MS, Choi TY, et al. Complementary and alternative medicine for patients with chronic fatigue syndrome: a systematic review. BMC Complement Altern Med. 2011 Oct 7;11:87.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201900/http://www.ncbi.nlm.nih.gov/pubmed/21982120?tool=bestpractice.com的疗效不明确，或者显示疗效有限或无效。由于这些干预措施缺乏充足证据，通常不建议对 CFS/ME 患者使用。此外，由于样本量较小及研究设计较差，这些研究可能提供误导性结果；因此应谨慎解读结果。
