糖皮质激素的撤药方案(英汉对照)

1、糖皮质激素的撤药方案著者：Daniel E Furst, MD Kenneth G Saag, MD, ScM David N Orth, MD 译者：刘湘源由于糖皮质激素有强大的抗炎作用及偶尔因被认为有免疫抑制活性，在多种疾病治疗中采用糖皮质激素 长期治疗。常使用皮质类固醇的风湿病有类风湿关节炎、大和小血管性血管炎、系统性红斑狼疮、风湿性 多肌痛及某些合并炎性肠病的关节炎病例。尽管皮质类固醇激素有强大功效，但它所诱导的副作用一般要求在疾病得到控制后逐渐减量，减量必须仔 细，要防止潜在疾病的复发及因使用类固醇期间导致的下丘脑-垂体-肾上腺（HPA）轴抑制引起的皮质醇 缺乏。如何减类固醇量尚无很

2、好的对照研究，本章节将综述与激素减量相关的主要问题、文献报道的减量方案以 及我们在大多数患者使用的方案。糖皮质激素减量指证一在讨论不同的糖皮质激素减量方案之前，先简单综述一下撤药的指证是有帮助的， 这些指证包括：已获得想要得到的最大治疗益处时在充分的试验性治疗后，已获得不当的治疗益处时当用药时出现的副作用，如腰椎骨质疏松或高血压变得严重或不能控制时另外，有两项并发症需要立即停药，而不能缓慢停药：类固醇激素诱导的急性精神病，对抗精神病药物无效疱疹病毒诱发的角膜溃疡，快速引起角膜穿孔，并可能出现永久性失明时。皮质类固醇制剂一虽然存在有其他皮质类固醇制剂，但以强的松为代表进行讨论（见图1）（见“合成

3、糖 皮质激素的结构-功能关系”章节）。有不同效能的制剂（如1, 2, 5, 10, 20mg的强的松）和不同的 剂型（片剂、静脉制剂、肌肉内注射制剂和肛门栓剂）。这些具有不同效能和剂型的制剂的吸收或代谢的 不同可影响类固醇激素减量的能力，庆幸的是，大多数商业应用的强的松和强的松龙制剂是生物性等效 的，这可通过以下观察数据来说明：应用健康男性进行的交叉研究的体内研究显示，5种不同的强的松口服制剂的任何药代动力学参数均无 统计学差异甲基强的松龙的直肠和口服吸收是等价的，口服对直肠用药的相对生物利用度为90%强的松的全身性生物利用度等于强的松龙（0.77对0.80）,强的松本身无生物活性，而是快速转

4、换为 活性类型强的松龙。然而，有严重肝病的患者转化强的松为强的松龙困难，对于这样的患者，很可能从强 的松得到的疗效与从强的松龙得到的疗效不同。另外，某些药物相互作用可影响强的松的代谢和生物利用 度。类固醇激素的药代动力学一如果强的松不同剂量下的药物搭配发生改变，那么减量方案可受到潜在影响。虽 然其动力学有剂量依赖性趋势，剂量越大，清除越快，但这种作用相对小，通常无重要的临床意义。有一项对54例不同年龄患者进行的有趣研究，这些患者给予口服和静脉用甲基强的松龙和强的松龙，其中 11例患者（占20%）显示有不寻常的动力学，他们的药物清除率几乎是其他人的2倍，其原因尚不清 楚。另外的发现包括：有4例患

5、者的皮质类固醇激素吸收不彻底，强的松龙的清除率与年龄之间呈负相关（r = -0.88）,这意味着所给的剂量在较老的人中有较大的作用。这种关系已被其他研究所证实。此外， 非洲美国人的强的松龙清除率也慢于高加索人。随患者在动力学上相互间变异性的程度不同，可以想象到有些患者可能比另一些患者有较大的撤药症 状，该病症是可出现的，虽然道在血浆皮质类固醇激素动力学和生物活性之间有不同。Chronic corticosteroid therapy is used in the treatment of a variety of disorders because of its potent antiinfl

6、ammatory effects and occasionally because it is thought to have therapy in the nephrotic syndrome is more similar to regimens used in most rheumatic diseases. As a result, short tapering regimens are not generally recommended in patients with rheumatic or renal disease.SUGGESTED TAPERING REGIMEN- Sh

7、ort-term corticosteroid therapy (up to three weeks), even if at a fairly high dose, can simply be stopped and need not be tapered. HPA suppression of this duration will not persist and is highly unlikely to have any clinical consequence. However, in a frail or dangerously ill patient, the clinician

8、may elect to proceed more cautiously as noted below.In patients who have taken a corticosteroid for a longer time, we suggest the following regimen which is largely based on experience and rests upon certain assumptions:The above factors (age, frailty, concomitant illnesses, dangerousness and likeli

9、hood of flare of underlying illness, psychological factors, and duration of previous use) are taken into account.The rheumatic disease is sufficiently stable so that tapering of the dose is appropriate.The patient has received long-term steroid therapy, not recurrent pulses as might be used in asthm

10、a.The observation that HPA suppression is uncommon at prednisone doses below 5 mg/day means that most patients on a daily dose of 5 mg/day do not have to be tapered 12.Our regimen also assumes that repeated morning cortisol determinations are too expensive for routine use (although this might change

11、 if properly designed studies showed that such an approach is better) and that the appropriate end-points are the patients signs and symptoms.The goal of tapering is to use a rate of change that will prevent both recurrent activity of the underlying disease and symptoms of cortisol deficiency due to

12、 persistent HPA suppression. We generally aim for a relatively stable decrement of 10 to 20 percent, while accommodating convenience and individual patient response. The dose is tapered by:10 mg/day every one to two weeks at an initial dose above 60 mg of prednisone or equivalent per day.5 mg/day ev

13、ery one to two weeks at prednisone doses between 60 and 20 mg/day.2.5 mg/day every one to two weeks at prednisone doses between 19 and 10 mg/day.1 mg/day every one to two weeks at prednisone doses between 9 and 5 mg/day.0.5 mg/day every one to two weeks at prednisone doses below 5 mg/day. This can b

14、e achieved by alternating daily doses, eg, 5 mg on day 1 and 4 mg on day 1.This regimen will generally prevent symptoms of cortisol deficiency. At some point, however, many patients with rheumatic diseases complain of recurrent symptoms of the underlying disease. If the symptoms are not major, we tr

15、y to wait seven to 10 days, and use a nonsteroidal antiinflammatory drug or other analgesic. If the symptoms do not subside within this period, we increase the prednisone dose by 10 to 15 percent (to the next convenient mg tablet regimen) and maintain that dose for two to four weeks. If the symptoms

16、 resolve, the above tapering regimen can be resumed, using two to four weeks between decrements rather than one to two weeks.Should this modest increase in dose not be sufficient to alleviate symptoms, we double the prednisone dose. The disease flare is allowed to subside and the taper is reinstitut

17、ed at a slower rate (eg, once monthly) or at smaller decrements (eg, one-half of the original decrement). There arez to our knowledge, no data supporting one method or another.It should also be appreciated that incremental change is inappropriate if life-threatening flares occur (as in acute recurre

18、nce of lupus nephritis, severe hemolysis, acute polymyositis, or vasculitis). In these settings, a return to the original, highest dose of steroids should be instituted. Tapering which is slowed in rate or decrement can be undertaken after the flare subsides.Alternate-day regimen- We are not aware o

19、f any evidence-based data relating to steroid tapering on an alternate-day regimen. We do, however, use the following alternate-day approach (in which the entire dose is given on the alternate days) in some patients. After the daily regimen has reached 20 to 30 mg of prednisone per day, we decrease

20、the alternate day dose by 5 mg every one to two weeks until the dose is 20 to 30 mg alternating with 10 mg. We then decrease the alternate day dose by 2.5 mg every one to two weeks until the prednisone dose on the alternate day has fallen to zero. At that point we decrease the remaining drug in the

21、same manner as was suggested for the daily dosing regimen. Although this regimen is generally effective in most rheumatic diseases, patients with rheumatoid arthritis often do not tolerate alternate-day dosing.immunosuppressive activity 1. Among the rheumatic diseases in which corticosteroids are of

22、ten used are rheumatoid arthritis, large- and small-vessel vasculitis, systemic lupus erythematosus, polymyalgia rheumatica, and, in some cases, the arthritis associated with inflammatory bowel disease 1.Despite its efficacy, steroid-induced side effects generally require tapering as soon as the dis

23、ease being treated is under control. Tapering must be done carefully to avoid both recurrent activity of the underlying disease and possible cortisol deficiency resulting from hypothalamic-pituitary-adrenal (HPA) axis suppression during the period of steroid therapy.There are no well controlled stud

24、ies examining how best to taper steroids. This card will review the major issues related to tapering, the regimens that have been reported in the literature, and the regimen(s) we use in most patients.INDICATIONS FOR WITHDRAWING GLUCOCORTICOIDS- Before discussing the different glucocorticoid withdra

25、wal regimens, it is helpful to first briefly review the indications for such withdrawal. These include the following:When the maximum desired therapeutic benefit has been obtainedWhen inadequate therapeutic benefit has been obtained after an adequate trialWhen side effects, such as lumbar spine oste

26、oporosis or hypertension, become serious or uncontrollable with medicationIn addition, there are two complications that require immediate cessation of steroid therapy, not tapering:Steroid-induced acute psychosis, which is often unresponsive to antipsychotic medicationsHerpesvirus-induced corneal ul

27、ceration, which can rapidly lead perforation of the cornea and possibly permanent blindnessCORTICOSTEROID PREPARATIONS- Prednisone will be the agent discussed, although other corticosteroid preparations are available (show figure 1). (See card “Structure-function relationships of synthetic glucocort

28、icoids). These preparations are available in various strengths (eg, 1, 2, 5, 10, 20 mg for prednisone) and in various formulations (tablet, intravenous preparations, intramuscular preparations, and rectal suppositories). Differences in the absorption or metabolism of these various strengths and form

29、ulations could affect the ability to taper steroids. Fortunately, most commercially available prednisone and prednisolone preparations appear to be bioequivalent. This can be illustrated by the following observations:In vivo studies using healthy males in a crossover study revealed no statistical di

30、fference in any pharmacokinetic parameter with five different oral prednisone preparations 2.Rectal and oral absorption of methylprednisolone are equivalent, with the relative bioavailability of oral to rectal administration being 90 percent 3.The systemic bioavailability of prednisone is equivalent

31、 to that of prednisolone (0.77 to 0.80) 4. Prednisone itself is biologically inactive, but it is rapidly converted to the active form prednisolone. However, patients with severe liver disease may have difficulty converting prednisone to prednisolone; in such patients, it is possible that one might n

32、ot get the same effect from prednisone as from prednisolone. In addition, certain drug interactions can affect the metabolism and bioavailability of prednisone.Steroid pharmacokinetics- Tapering regimens could potentially be influenced if drug disposition changed at varying prednisone doses. Althoug

33、h there is a trend toward dosedependent kinetics, with larger doses being cleared more rapidly, the effect is relatively small and usually not of great clinical importance 5-7.One interesting study examined 54 patients of varying ages who were given oral and intravenous methylprednisolone and predni

34、solone 8. Eleven patients (20 percent) demonstrated unusual kinetics. Their drug clearance was approximately twice that of the rest of the population without an identifiable cause. Other findings included incomplete absorption of corticosteroids in four patients and an inverse correlation (r = -0.88

35、) between prednisolone clearance and age, which means that a given dose may have a greater effect in older persons. This relation to age has been confirmed in other studies 9. In addition, prednisolone clearance is also slower in African-Americans compared to Caucasians 10.With this degree of interp

36、atient variability in kinetics, it is conceivable that some patients may show greater withdrawal symptoms than others. This may occur despite the known difference between plasma corticosteroid kinetics and biologic activity.下丘脑-垂体-肾上腺轴的抑制一虽然有一种重要变量（在试验前曾治疗的疗程）总不能清楚地说明，但大 多数研究已显示，当强的松剂量超过5mg/d时，可出现下丘

37、脑-垂体-肾上腺轴的抑制。40mg/m2/d或 该剂量以上的强的松治疗5天（尤其是分次给予时）即可开始出现下丘脑-垂体-肾上腺轴的抑制。即使甲 基强的松龙单次进行关节内注射时，也可引起短暂的抑制。另一方面，在强的松撤药时，剂量在5mg/d 或5mg/d以下（每天早上一次）通常不引起下丘脑-垂体-肾上腺轴的抑制。另外，许多研究显示，隔日治 疗方案（如隔2天用2次）比每日疗法对下丘脑-垂体-肾上腺轴的抑制和对白细胞反响的损害小。然而，对这种治疗剂量和疗程下的具体患者并不能准确预测到下丘脑-垂体-肾上腺轴受抑制的可能性及程 度。例如有一项对279例患者应用5-30mg/d强的松或其等效物治疗1周至1

38、5年的评价，通过最后一 次应用强的松24小时后早上一次性注射促皮质激素释放激素100mg来测定下丘脑-垂体-肾上腺轴功能（见下面），结果发现针对促皮质激素释放激素产生血浆ACTH和皮质醇的反响缺乏者有43例患者 （15%）,迟钝者有133例（占48%）,正常患者有103例（占37%）。这种反响性与激素剂量或疗 程的相关性差，因此下丘脑-垂体-肾上腺轴不同抑制程度的决定因素尚不清楚。生物节律的丧失 皮质醇分泌有昼夜节律，可被强的松的应用所打破。如有一项评价用强的松治疗34例 RA患者的研究，采用的是敏感的皮质类固醇激素抑制试验（加压素，美替拉酮，或胰岛素诱导性低血糖） 而非测定血浆皮质醇，有16

39、例患者出现皮质类固醇激素昼夜节律异常（见“枯兴综合征的原因确定”章 节），这种异常节律与激素应用时间的长短有关，而与每天的剂量无关。另一项研究发现，低剂量的强的 松龙（平均5.6mg/d）对昼夜节律无影响，然而，该研究应用的肾上腺抑制测定方法（血浆皮质醇测定 法）相对不敏感。很可能长期应用皮质类固醇激素引起了某些内源性皮质类固醇昼夜节律的受抑。下丘脑-垂体-肾上腺轴抑制程度一有人可能预测如应用强的松的患者的下丘脑-垂体-肾上腺轴的抑制程度 高，撤药更为困难。抑制程度可通过测定恢复正常下丘脑-垂体-肾上腺反响性所需的时间来估计，对两项 长期用皮质类固醇治疗患者的研究已提出了这个问题。一项研究对1

40、2例患者在终止应用强的松后一年间内进行了反复检测，发现剂量超过7.5mg/d时恢复期延 长，且获得胰岛素诱导性低血糖正常反响的时间需1年，然而，除所有患者1年内有恢复以外，抑制时间 的长短未明确说明。第二项研究综述了 50例长期应用强的松、而剂量已减少到10mg/d以下的患者，患者输注ACTH进行刺 激试验，服用5mg/d以下的23例患者中有3例患者（13%）受到抑制，而剂量超过5mg/d的患者中 这种抑制更为普遍。因此，对日剂量减量到这种低水平并保持至少数天无病症出现或无既往疾病复发的患 者在激素减量过程中，一般不需转换为隔日疗法。短程治疗后的恢复较快。象上面提到的那样，应用短至5天的大剂量

41、强的松后即可见到下丘脑-垂体-肾上 腺轴的受抑。如果强的松的应用未超过7-10天，虽然某些患者的肾上腺功能恢复正常需7天或7天以 上，但大多数患者仅需2-4天。例如给予数天大剂量的强的松然后再在数天内快速减量，那么强的松停止治 疗1周后下丘脑-垂体-肾上腺轴的功能恢复正常。HYPOTHALAMIC-PITUITARY-ADRENAL AXIS SUPPRESSION- Most studies have shown that HPA axis suppression occurs at prednisone doses above 5 mg/day, although an important

42、 variable, the underlying duration of treatment prior to testing, was not always clearly delineated 11-15. Suppression can begin after as little as five days with prednisone doses of 40 mg/m2 per day or higher, particularly if given in multiple daily doses 14. Even a single intraarticular injection

43、of methylprednisolone can cause transient suppression 15. On the other hand, doses of 5 mg/day or less given once daily in the morning are generally not associated with pituitary-adrenal suppression when prednisone is withdrawn. In addition, a number of studies have demonstrated that alternate-day t

44、herapy (ie, giving twice the daily dose once every two days) produces less HPA suppression and/or less impairment of the leukocyte response than daily prednisone 16-18.However, the likelihood and degree of HPA suppression cannot be accurately predicted in an individual patient from the dose or durat

45、ion of therapy. One report, for example, evaluated 279 patients who had been treated with 5 to 30 mg/day of prednisone or its equivalent for one week to 15 years 19. HPA axis function was assessed by the administration oflOO fit of CRH (corticotropin releasing hormone) as a bolus morning injection 2

46、4 hours after the last prednisone dose (see below). The plasma ACTH and cortisol responses to CRH were absent in 43 patients (15 percent), blunted in 133 (48 percent), and normal in 103 (37 percent). There was a poor correlation with dose or duration of therapy. The factors determining the variable

47、degree of suppression are not well understood.Loss of circadian rhythm- Cortisol secretion undergoes a diurnal rhythm, which can be disrupted by the use of prednisone 20. One report, for example, evaluated 34 prednisone- treated patients with rheumatoid arthritis. Using sensitive tests of corticoste

48、roid suppression (vasopressin, metyrapone, or insulin-induced hypoglycemia) rather than plasma cortisol, sixteen of the patients were found to have an abnormal circadian corticosteroid rhythm 21. (See card Establishing the cause of Cushings syndrome). The abnormality was related to the duration of u

49、se, not to the daily dose. Another trial found no effect of low doses of prednisolone (mean 5.6 mg/day) on the diurnal rhythm; however, this study used a relatively insensitive measure of adrenal suppression (plasma cortisol measurement) 22. It is probable that some suppression of the endogenous cor

50、ticosteroid diurnal rhythm is caused by long-term corticosteroid usage.Degree of HPA suppression- One might expect more difficulty in withdrawing patients from prednisone if they have profound HPA suppression. The degree of suppression can be estimated by the time required to recover normal HPA resp

51、onsiveness. Two studies have addressed this issue in patients treated with chronic corticosteroid therapy.One report repeatedly examined 12 patients during the year after prednisone was discontinued 13. Doses in excess of 7.5 mg/day delayed recovery; attainment of a normal response to insulin-induce

52、d hypoglycemia required one year. However, the duration of suppression was not clearly defined except that recovery had occurred in all patients by one year.The second study reviewed 50 charts of patients who had been on long-term prednisone therapy but whose dose had been tapered to 10 mg/day or le

53、ss 12. The patients were given a stimulation test using ACTH infusion. Three of 23 patients (13 percent) who had been on 5 mg/day or less were suppressed. Suppression was more common in patients receiving more than 5 mg/day. Thus, patients who can be tapered to this low daily dose and maintained on

54、it for at least a few days without developing symptoms or a flare of the underlying disease do not generally require switching to alternate-day therapy during the tapering process.Recovery is much more rapid after short-term therapy. As noted above, HPA suppression can be seen after as little as fiv

55、e days of high-dose prednisone administration 14. Adrenal function returns to normal in most of these patients within two to four days, although some require seven or more days, provided the prednisone has not been given for more than seven to ten days. As an example, large doses of prednisone given

56、 for a few days and then tapered rapidly over a few more days result in normal HPA function one week after stopping the prednisone 23.下丘脑-垂体-肾上腺轴抑制的估计一在临床上要识别下丘脑-垂体-肾上腺轴抑制程度并不简单，可用许多 的试验，每一项试验对类固醇撤药患者均有某些限制。血浆或尿中所分泌的游离皮质醇不能定量下丘脑-垂体-肾上腺轴功能的储存情况。然而，如测定到的数值 在正常范围的上半区，那么下丘脑-垂体-肾上腺轴不太可能有明显受抑，当下丘脑-垂体-肾上腺轴

57、恢复后， 这些指标可最快地恢复正常，但它们不是肾上腺对应急反响的最好测试法（见“尿皮质类固醇激素和游离 皮质醇分泌的测定”章节）。对人工合成ACTH （促肾上腺皮质激素）的反响是评估肾上腺皮质功能最好的方法。然而，这不能提供 有关下丘脑功能的信息，及下丘脑或垂体功能不全的患者测得的肾上腺皮质功能可能正常（见“肾上腺功 能不全对ACTH反响的评价”章节）。美替拉酮刺激测定整个下丘脑-垂体-肾上腺轴，但测定应急反响并不重要（见“美替拉酮刺激试验”）测定应急反响的最好方法是在胰岛素诱导性低血糖期间测定血浆皮质醇水平（如果测定仔细的话），这 很可能是测定肾上腺抑制最敏感的试验，长期应用皮质类固醇激素后

58、最常出现长时间的异常（见“胰岛素 诱导性低血糖试验”章节）。然而，胰岛素诱导性低血糖难以实施，如果进行不合适，会带来某些危险， 目前在临床实践中未普遍使用。促皮质激素释放激素试验也可用于评估ACTH和肾上腺的反响，且无胰岛素诱导的低血糖相关的危险。 然而，该试验昂贵，在类固醇激素逐渐减量前不能广泛使用。因此，临床上评估下丘脑-垂体-肾上腺轴功能所用的每项试验均有其局限性。目前，类固醇激素撤药最常 用的方法是经验性撤药，类似于下面所描述的一种方案。类固醇激素依赖性的其它形式一已证实其他形式的类固醇激素依赖性（并非因下丘脑-垂体-肾上腺轴受 抑引起的病症和生化改变）可阻碍类固醇激素的逐渐减量，这些

59、因素包括：对类固醇激素精神性依赖疾病的复燃，需开该药治疗尽管下丘脑-垂体-肾上腺轴功能正常，也无疾病的复燃，但有明显的肾上腺功能不全病症。总结一在考虑皮质类固醇激素治疗逐渐减量之前，评估下丘脑-垂体-肾上腺轴功能是否明显受抑是很重要 的。以下患者无下丘脑-垂体-肾上腺轴的受抑，无需进行评价这种可能性的测试：任何剂量的糖皮质激素应用时间不到3周的患者糖皮质激素长期隔日疗法罕有下丘脑-垂体-肾上腺轴功能的抑制。相反，应考虑进行下丘脑-垂体-肾上腺轴功能的抑制功能测试情况包括：强的松口服剂量在20mg/d以上、持续时间超过3周的任何患者临床上发生枯兴综合征的任何患者对于不需进行下丘脑-垂体-肾上腺轴

60、功能测试的患者，应象对待继发性肾上腺功能不全患者一样处理，包 括让他们带上医药紧急救护手卡或项卡，在其钱包或皮夹内放置紧急医疗信息，最可靠的是，预先带上内 含4mg磷酸地塞米松的1ml注射器，以防在紧急的时候注射（见“肾上腺功能不全的治疗”章节）。下丘脑-垂体-肾上腺轴受抑居中类型的患者包括服用强的松10-20mg/d超过3周者。这些患者不需检 测，除非需紧急停药或急性应急反响如手术。对于后一种情况，可预防性给予应急剂量的糖皮质激素，或 者如时间容许，象我们喜欢采用的用低剂量的二十四肽促皮质素刺激试验来检测肾上腺的反响。下丘脑-垂体-肾上腺轴中度受抑类型也包括强的松（或等效物）剂量在10mg/