Spotlight series: pivotal trials through today's knowledge--adrenocorticotrophic hormone.
Forty-five years ago the first large multicentre, randomized,
double-blinded, controlled trial of a potential therapy for multiple
sclerosis (MS) was completed--testing corticotrophin versus placebo. It
demonstrated the feasibility of such a trial in an illness which is as
variable, from patient to patient, as MS. Adrenocorticotrophic hormone
was soon replaced by intravenous methylprednisolone (IVMP) as therapy
for acute exacerbations, to control acute inflammatory responses.
Long-term therapy with corticosteroids is fraught with complications.
Pulsed IVMP has been widely used as an alternative, but few formal
studies have been done. One, however, suggested that treated patients
had less brain atrophy, and further study of this technique may be
ADRENOCORTICOTROPHIC HORMONE AND MULTIPLE SCLEROSIS; HISTORY OF MULTIPLE SCLEROSIS TREATMENT; RANDOMIZED CONTROLLED TRIALS
Multiple sclerosis (Drug therapy)
Multiple sclerosis (Diagnosis)
Methylprednisolone (Dosage and administration)
ACTH (Dosage and administration)
ACTH (Complications and side effects)
|Publication:||Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 PAREXEL MMS Europe Ltd. ISSN: 1352-8963|
|Issue:||Date: July, 2009 Source Volume: 16 Source Issue: 2|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
Prior to the 1960s, most treatment trials in multiple sclerosis (MS) were uncontrolled, and a wide variety of agents were reported to be efficacious, due to the numbers of patients improving. In a disease in which recent worsening will go on to improve in about 50% of cases, such trials were generally not informative, and the need for controlled trials, with emphasis on prevention of exacerbation or progression, was recognized. (1) Principles to be used in designing such a trial were suggested by an ad hoc committee chaired by GA Schumacher. (2)
The Schumacher report, issued in 1965, suggested diagnostic criteria, defined various phases of MS, reviewed standardized methods of evaluating and following patients in treatment protocols, including the standard neurological examination, and also the semi-quantitation of the standard neurological examination using the Kurtzke scoring system (the Expanded Disability Status Scale [EDSS]). (2,3) The report also recommended certain quantitative tests of neurological function, which could be performed by paramedic personnel, and a symptom scoring system. (4) Most of these methods, or variations of them, have been incorporated in subsequent treatment trials and are now quite familiar to those physicians who participate in such endeavours.
In 1965 there was no therapeutic agent proven to alter the course of MS, although the benefit of corticosteroids in acute exacerbations had been noted in isolated reports. The non-specific effect of corticosteroids, including adrenocorticotrophic hormone (ACTH), in reducing inflammation and their effect in quieting allergic reactions, made these compounds attractive as a possible treatment for acute exacerbations. Pathological studies showed that MS lesions were occasionally associated with marked inflammatory responses. (5)
An early exception to the lack of controlled trials was a study of ACTH or placebo treatment in 40 patients with recent exacerbations, over a 3-week period, by Miller and associates. (6) This controlled trial showed more rapid improvement in the group of 20 ACTH-treated patients. Miller noted that this trial was not well randomized, however, since there were more patients with initial attacks of MS in the ACTH-treated group. This may have biased the study somewhat, since there is almost universal improvement after a first MS exacerbation. (7)
The National Cooperative Trial of ACTH in Acute Exacerbations of MS
With this background, a large multicentre study of the effect of ACTH in acute exacerbations of MS was launched in the USA in 1965. This trial was performed in 10 medical centres in the USA, and took place from 1965-1968. Randomization resulted in 103 patients being assigned to the ACTH-treated group, and 93 patients to the placebo-treated group. The protocol of the trial incorporated many of the principles and recommendations of the Schumacher Committee, including diagnostic criteria, provision for repeated quantitative tests of neurological function, the standard neurological exam, a symptom-scoring system and the Kurtzke scoring system. (2,3)
Of some interest is that in 1965 the Committee noted that 'the system of Kurtzke seems the simplest and least subject to error'. (2,3) More than 40 years later the Kurtzke EDSS, in spite of its limitations, continues to be useful, and is incorporated in the data collection systems of most clinical trials of therapeutic agents in MS.
Patients experiencing acute exacerbations were hospitalized for 2 weeks in clinical research centres at each participating centre. They were randomized to receive either 40 IU of ACTH gel, or identical-appearing placebo, by intramuscular injection twice daily for the first week. During the second week, dosage was reduced to 20 IU twice daily for 4 days, and once daily for 3 days. After this, patients were discharged from the hospital, but examined in detail weekly for the next 2 weeks. There were thus five detailed examinations, recorded on pre-printed forms: a pre-treatment exam, and one at the end of each treatment week.
The profusion of data accumulated during the study was computerized and analyzed in detail. Randomization resulted in 103 patients being in the ACTH-treated group, and 93 patients in the placebo-treated group. The results of the trial were reported in a series of publications, (8,9) and indicated that ACTH treatment significantly hastened improvement, by almost all methods of measurement. However, the differences between ACTH-treated and placebo-treated patients became progressively less marked, as dosage of ACTH was reduced in the second week and with discontinuation of treatment at the end of the second week. While equivalence in patient measurements in the two groups was not achieved at the end of the 4-week study, the results suggest that it is likely that this would have been achieved had the study been continued slightly longer.
Perspective through Today's Knowledge
The importance of this National Cooperative ACTH Trial is not so much in the results achieved, but rather in showing, 45 years ago, that a randomized, multicentre, placebo-controlled trial of a putative MS treatment could be successfully accomplished in an illness showing marked variability in both course and severity. Now, treatment trials of this kind are commonplace, and scores of medications have been evaluated using similar principles and methodology. A number of partially effective treatments have been identified in such trials, most notably the beta-interferons, glatiramer acetate, and, more recently, the monoclonal antibodies natalizumab and rituximab.
Current Treatment of MS Exacerbations
The results of the national ACTH trial were widely accepted, and for many years remained a common treatment for acute exacerbations. However, even prior to the trial, some authors found prednisone equally useful. (10) Later authors compared the results in patients treated either with ACTH or methylprednisolone, and noted that the results were comparable, or even superior, when high-dose methylprednisolone was administered in 3-5-day courses intravenously. (11-13) The latter has now become the most frequently used treatment for serious acute exacerbations, and is the prescribed 'rescue treatment' when serious exacerbations occur during the course of treatment trials with other agents.
The use of ACTH has declined markedly over the years. The definite therapeutic effects of corticosteroids can all be achieved more conveniently using prednisone or intravenous methylprednisolone (IVMP), with less retention of salt and water, and less virilization. (14) When ACTH is used, it is usually given intramuscularly in a repository form, as a gel, and this was the mode of administration in the National Cooperative ACTH study. Intravenous ACTH has a very short half-life and requires prolonged intravenous administration for effective use. A few authors have maintained that ACTH is superior to methylprednisolone, but this is a minority view. (15,16)
Long-term Therapy with ACTH or Corticosteroids
Shortly after the introduction of cortisone, a trial suggested that it did not possess the ability to either prevent exacerbation or progression of MS. Thus in 1954, Merritt et al. showed that 19 patients receiving 100 mg cortisone daily for 13 months all developed a hyperadrenal state, and eight had exacerbation or progression in disability during this period. (17) Most subsequent controlled long-term trials of adrenal steroids have reached the conclusion that improvement of recent worsening is hastened, but the degree of improvement is no greater than that which would ultimately be achieved naturally. A rather clear demonstration of this fact is illustrated by the results of the large Optic Neuritis Treatment Trial: at the end of 5 years, the visual functions of those treated with high-dose methylprednisolone were similar to those of patients in the placebo group. (18)
One unwelcome result of showing an effect of ACTH in acute exacerbations was that it stimulated trials of long-term administration of either ACTH or corticosteroids, despite earlier evidence that such use is ineffective. In many instances this resulted in a high rate of corticosteroid complications such as compression fractures, gastrointestinal haemorrhage and cataracts. (19)
Pulsed administration of IVMP administered intermittently has been used in an effort to diminish such complications, and still allow chronic steroid treatment. (20,21) Our own experience in using this method with a few rapidly progressive MS patients has been disappointing, but only a few formal studies have been done. At the present time there is still a consensus that long-term steroid administration does not alter the course of MS. (22,23)
This consensus was challenged in 2001, however, by workers at the University of Trieste, Italy. (24) Approximately 40 patients were treated every 4 months with pulsed IVMP 1 g daily for 5 days. An additional randomly selected group of patients received IVMP only if exacerbation occurred. At the end of 3 years there was significantly less brain atrophy, fewer 'black holes' by MRI and less disability progression in the patients receiving IVMP every 4 months. Earlier, a marginally significant delay in onset of sustained disability was reported by Goodkin et al. in 108 patients with secondary progressive MS treated with pulsed IVMP. (25)
A recent report of a select committee of the National Multiple Sclerosis Society in the USA has concluded that the use of steroid for acute relapses is ' ... well established ... but ... the indications for longterm intermittent pulse therapy [are] ... less clear'. (23) Further organized trials of pulsed long-term IVMP may be indicated. (26)
Possible Reasons for Failure of Long-term Glucocorticoid Therapy
Recent studies using diffusion-weighted imaging (DWI) and magnetic transfer ratio (MTR) imaging suggest that the inflammation seen in MS, instead of being an early event in lesion formation, (27) may be, instead, a late phenomenon. Werring et al., at the National Hospital in London, UK, did monthly diffusion scans for 1 year on five MS patients with active disease. They showed that the site of new lesions (subsequently shown by conventional MRI) could be identified as early as 6 months prior to new lesion development--by a continuous increase in the diffusion coefficient. (27)
Likewise, Filippi and associates studied 10 patients having 48 new lesions over a 3-month period. Using MTR imaging, they could show that the areas of normal-appearing white matter (NAWM) at the sites destined to have new lesions all had abnormal readings 3 months prior to blood-brain barrier (BBB) breakdown and new lesion formation. (28)
These and similar studies indicate that BBB breakdown, and new lesion formation (by conventional MRI) are both events initiated months prior to new symptoms and detection of new lesions in the conventional way. The BBB breakdown (inflammation) is actually a late event in lesion formation, rather than the initiating cause. This may help explain why chronic suppression of inflammation has a limited effect, or none, on the course of MS.
Perspective for Future Studies
Important questions raised by these MRI studies include the following: 1) Do all MTR imaging and DWI changes seen in NAWM eventually develop into T2 lesions by conventional MRI?, and 2) What finally triggers the inflammatory response in what appear to be slowly developing changes in NAWM? Is the inflammation due to re-contact with an environmental antigen, or is it the inevitable acute culmination of a smouldering autoimmune process, the antigen of which is unknown (perhaps the current consensus)?
While the numerous medication trials currently ongoing to find better treatments for MS are important and necessary, it would perhaps be well also to search as diligently for an environmental factor. The cause of MS remains elusive, but an environmental factor is generally agreed to be involved, based on identical-twin studies.
Concordance of MS in monozygotic twins is only about 25%, limiting the importance of genetic factors. (29,30) While acknowledging the importance of immune factors in pathogenesis, we continue to favour the idea that an external antigen, perhaps a common virus, may trigger the occurrence of new areas of inflammation, and hence new lesions. Evidence in favour of this hypothesis relies on epidemiological studies, and certain seasonal data. It has been reviewed in several publications. (31-33)
Conflicts of Interest
No conflicts of interest were declared in relation to this article.
* A large multicentre treatment trial with ACTH 45 years ago served as a model for future medication trials
* Use of ACTH in MS is largely of historical interest. For acute exacerbations it has mostly been replaced by IVMP
* Failure of chronic glucocorticoid treatment to alter the course of MS may be explained by recent evidence that inflammation may be a late secondary result, rather than an initiating cause of new lesions
* Whether all changes in normal-appearing white matter develop eventually into MRI-T2 lesions is an unanswered question at present, however. Thus the exact cause of the inflammatory response remains an enigma
(1.) Sibley WA: Drug treatment of multiple sclerosis. In: Handbook of Clinical Neurology, Multiple Sclerosis and Other Demyelinating Diseases, Vol. XIII (Vinken PJ, Bruyn GW, eds). Amsterdam: North-Holland Publishing Co. 1970; pp383-407.
(2.) Schumacher GA, Beebe G, Kibler RF, Kurlund LT, Kurtzke JF, McDowell F et al. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965; 122: 552-568.
(3.) Kurtzke JF. On the evaluation of disability in multiple sclerosis. Neurology 1961; 11: 686-694.
(4.) Tourtellotte WW, Haerer AF, Simpson JF, Kuzma JW, Sikorski J. Quantitative neurological testing. I. A study of a battery of tests designed to evaluate in part the neurological function of patients with multiple sclerosis and its use in a therapeutic trial. Ann NY Acad Sci 1965; 122: 480-487.
(5.) Adams CW. Inflammatory vasculitis in multiple sclerosis. J Neurol Sci 1985; 69: 269-283.
(6.) Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (ACTH). Lancet 1961; 2(7212): 1120-1122.
(7.) Miller H. Discussion. In: Rose AS, Kuzma JW, Kurtzke JF, Sibley WA, Tourtellotte WW. Cooperative study in evaluation of therapy in multiple sclerosis: ACTH vs placebo in acute exacerbations. Trans Am Neurol Assn 1969; 94: 126-133.
(8.) Rose AS, Kuzma JW, Kurtzke JF, Sibley WA, Tourtellotte WW. Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs placebo in acute exacerbations. Preliminary report. Neurology 1968; 18(Suppl): 1-10.
(9.) Rose AS, Kuzma JW, Kurtzke JF, Sibley WA, Tourtellotte WW. Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs placebo-final report. Neurology 1970; 20: 1-59.
(10.) Jonsson B, Von Reis G, Sahlgren E. Experience of ACTH and cortisone treatment in some organic neurological cases. Acta Psychiatr Neurol Scand 1951; 74: 60-65.
(11.) Barnes MP, Bateman DE, Cleland PG, Dick DJ, Walls TJ, Newman PK et al. Intravenous methylprednisolone for multiple sclerosis in relapse. J Neurol Neurosurg Psychiatry 1985: 48: 157-159.
(12.) Thompson AJ, Kennard C, Swash M, Summers B et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology 1989; 39: 969-971.
(13.) Milligan NM, Newcombe R, Compston DA. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis. 1. Clinical effects. J Neurol Neurosurg Psychiatry 1987; 50: 511-516.
(14.) Schimmer BP, Parker KL. ACTH, adrenocortical steroids and their synthetic analogs. In: Goodman & Gilman's The Pharmacologic Basis of Therapeutics (Hardman JG, Limbird LE, eds). London/New York: McGraw Hill 2001; pp1649-1677.
(15.) Davis FA, Stefoski D. Is steroid therapy in multiple sclerosis superior to corticotrophin therapy? Arch Neurol 1988; 45: 1180 (Letter).
(16.) Poser CM. Coricotropin is superior to corticosteroids in the treatment of MS. Arch Neurol 1989; 46: 946.
(17.) Merritt HH, Glaser GH, Herrmann C. A study of the short- and long-term effects of adrenal steroids on the clinical course of multiple sclerosis. Ann NY Acad Sci 1954; 58: 625-629.
(18.) Optic Neuritis Study Group. Visual function 5 years after optic neuritis; experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1997; 115: 1545-1552.
(19.) Cass LJ, Alexander L, Enders M. Complications of corticotrophin therapy in multiple sclerosis. JAMA 1966; 197: 173-178.
(20.) Pirko I, Rodriguez M. Pulsed intravenous methylprednisolone therapy in progressive multiple sclerosis: need for a controlled trial. Arch Neurol 2004; 61: 1148-1149.
(21.) Uttner I, Muller S, Zinser C, Maier M, Sussmuth S, Claus A et al. Reversible impaired memory induced by pulsed methylprednisolone in patients with MS. Neurology 2005; 64: 1971-1973.
(22.) Ciccone A, Beretta S, Brusaferri F, Galea I, Protti A, Spreafico C. Corticosteroids for the long-term treatment in multiple sclerosis. Cochrane Database Syst Rev 2008; Jan. 23: CD006264.
(23.) National Multiple Sclerosis Society. Expert Opinion Paper. Recommendations regarding corticosteroids in the management of multiple sclerosis. Available at: http// www.nationalmssociety.org/for professionals/healthcareprofessi onals/publications/expert opinionpapers/download.aspx? id=553. Accessed 16 April 2008.
(24.) Zivadinov R, Rudick RA, De Masi R, Nasuelli D, Ukmar M, Pozzi-Mucelli RS et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 2001; 57: 1239-1247.
(25.) Goodkin DE, Kinkel RP, Weinstock-Guttman B, VanderBrug-Medendorp S, Secic M, Gogol D et al. A phase II study of IV methylprednisolone in secondary progressive multiple sclerosis. Neurology 1998; 51: 239-245.
(26.) Kermode AG, Tofts PS, Thompson AJ, MacManus DG, Rudge P, Kendall BE et al. Heterogeneity of blood-brain barrier changes in multiple sclerosis: an MRI study with gadolinium-DTPA enhancement. Neurology 1990; 40: 229-235.
(27.) Werring DJ, Brassat D, Droogan AG, Clark CA, Symms MR, Barker GJ et al. The pathogenesis of lesion and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study. Brain 2000; 123: 1667-1676.
(28.) Filippi M, Rocca MA, Martino G, Horsfield MA, Comi G. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol 1998; 43: 809-814.
(29.) Hansen T, Skytthe A, Stenager E, Petersen HC, Brennum-Hansen H, Kyvik KO. Concordance for multiple sclerosis in Danish twins: an update of a nationwide study. Mult Scler 2005; 5: 504-510.
(30.) Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC; Canadian Collaborative Study Group. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003; 100: 12877-12882.
(31.) Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet 1985; 1: 1313-1315.
(32.) Sibley WA. The effect of virus-like infections on the course of multiple sclerosis. In: Genes and Viruses in Multiple Sclerosis (Hommes OR, Clanet M, Wekerle H, eds). Amsterdam/ New York: Elsevier 2001; pp89-95.
(33.) Kriesel JD, Sibley WA. The case for rhinoviruses in the pathogenesis of multiple sclerosis. Editorial. Mult Scler 2005; 11: 1-4.
Address for Correspondence
William A Sibley, University of Arizona,
College of Medicine, Tucson, Arizona 85724, USA
Phone: +1 520 326 3489
Fax: +1 520 881 3891
Received: 23 July 2008
Accepted: 20 November 2008
|Gale Copyright:||Copyright 2009 Gale, Cengage Learning. All rights reserved.|