Overview of azathioprine treatment in multiple sclerosis

doi:10.1016/0140-6736(91)91909-E

The Lancet

Volume 338, Issue 8774, 26 October 1991, Pages 1051-1055

https://doi.org/10.1016/0140-6736(91)91909-E Get rights and content

Abstract

The efficacy of azathioprine in the treatment of multiple sclerosis was assessed by meta-analysis of the results of all published blind, randomised, controlled trials. 793 patients were enrolled in 5 double-blind and 2 single-blind studies. After 1 year of treatment, the increase in Kurtzke disability status score was no different in treated and control groups, but at 2 years there was a small difference (-0·22; 95% confidence interval [Cl] -0·43, 0·003) in favour of azathioprine treatment; this difference was sustained, but not increased, after 3 years. The probability of freedom from any relapse during 1, 2, and 3 years' treatment was significantly greater in the azathioprine-treated group (relative odds over 3 years 1·97; 95% Cl 1·27, 3·04), but it is debatable whether the slight clinical benefits of azathioprine outweigh its side-effects.

References (27)

Or Hommes et al.
Treatment of the chronic progressive form of multiple sclerosis with a combination of cyclophosphamide and prednisone
Clin Neurol Neurosurg
(1975)
U. Patzold et al.
Azathioprine in treatment of multiple sclerosis: final results of a 4½-year controlled study of its effectiveness covering 115 patients
J Neurol Sci
(1982)
British and Dutch Multiple Sclerosis Azathioprine Trial Group
Double-masked trial of azathioprine in multiple sclerosis
Lancet
(1988)
Lj Kinlen
Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment
Am J Med
(1985)
R. Peto
Why do we need systematic overviews of randomised trials?
Stat Med
(1987)
Pl Yudkin et al.
Immunological treatment for multiple sclerosis
Lancet
(1989)
Jf Kurtzke
The disability status scale for multiple sclerosis: apologia for DSS sua
Neurology
(1989)
Ga Schumacher et al.
Problems of experimental trials of therapy in multiple sclerosis: report by the panel on evaluation of experimental trials of therapy in multiple sclerosis
Ann NY Acad Sci
(1965)
Sl Hauser et al.
Intensive immunosuppression in progressive multiple sclerosis: a randomised three-arm study of high dose intravenous cyclophosphamide, plasma exchange, and ACTH
N Engl J Med
(1983)
D. McAlpine et al.
Some aspects of natural history of disseminated sclerosis
QJ Med
(1952)

Mr Mickey et al.

An illness severity score for multiple sclerosis

Neurology

(1984)

As Rose et al.

Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs placebo

Final report. Neurology

(1970)

U. Patzold et al.

Therapie der multiplen Sclerose mit Levamisol und Azathioprin—Vergleich der Wirksamkeit einer "immunstimulierenden" und "immun-suppressiven" Behandlung

Nervenarzt

(1978)

Cited by (242)

The 20-year history: Change of multiple sclerosis patient profile over 20 years
2019, Multiple Sclerosis and Related Disorders
Citation Excerpt :
Multiple sclerosis (MS) has for years been one of the most intensively studied neurological diseases in terms of both etiopathogenesis and therapeutic options, and in which perhaps the greatest progress has been made. Until 1993, the treatment of MS consisted of alternatives such as corticosteroid, azathioprine, and ACTH (Von Reis et al., 1953; Yudkin et al., 1991), of which only corticosteroid continues to be effectively employed today. The conclusion of the phase 3 interferon beta 1b study, one potential option in disease progression and MRI activity and progression, other than attack treatment, and its entry into therapeutic use occurred in 1993.
Patients attending multiple sclerosis (MS) clinics experience less disability compared to previous years.
This study was conducted retrospectively examining the patient records of our MS Clinic. The patient records in 1996 were compared to those in 2016.
Demographic data, duration of disease, time to diagnosis, course of the disease, Expanded Disability Status Scale (EDSS) scores, and whether or not patients used disease modifying therapies were recorded in both 1996 and 2016.
The mean frequency of visits were significantly higher in 1996 compared to 2016 (p = 0.003). There were significantly more number of patients with clinically isolated syndrome (p = 0.004) and secondary progressive MS (p = 0.001) in 1996; however, significantly less number of patients with relapsing-remitting MS (p < 0.001). EDSS scores of ≤3 were significantly higher in 2016 (p < 0.001). On the other hand, the number of patients with the EDSS scores of 6–6.5 and ≥7 were significantly less in 2016 (p < 0.001). Significantly more patients with secondary progressive MS, EDSS scores of 6–6.5 and ≥7 (wheel-chair dependent patients) came to the clinic in 1996 compared to 2016.
The emergence of treatment options in MS and the increasing availability of new treatment options for patients with no/inadequate treatment response have changed the MS patient profile over the 20 years. The number of wheelchair-dependent patients dramatically reduced.
Indirect meta-analytical comparison of azathioprine and of beta interferon effectiveness in all forms of multiple sclerosis pooled together
2014, Journal of the Neurological Sciences
Multiple sclerosis as an adverse effect of anti-tumor necrosis factor agents: An infrequent but important complication of infliximab in Crohn's disease
2013, Gastroenterologia y Hepatologia
Los agentes antifactor de necrosis tumoral alfa (TNF-α) son efectivos en el tratamiento de la enfermedad inflamatoria intestinal. Su perfil de efectos adversos es bien conocido y son seguros, adecuadamente utilizados. En la práctica su riesgo más importante son las infecciones. Otras reacciones adversas son también posibles, pero mucho menos frecuentes. Sin embargo, la generalización del uso de estos agentes hace que sus efectos adversos menos frecuentes también puedan aparecer en la práctica clínica. Presentamos el caso de uno de ellos, la esclerosis múltiple, infrecuente pero muy relevante por sus consecuencias. Ante la aparición de síntomas neurológicos durante el tratamiento con un anti-TNF-α, es necesario descartar activamente un proceso desmielinizante. Su manejo diagnóstico y terapéutico, dirigido por el neurólogo con nuestra colaboración, obliga a suspender definitivamente los anti-TNF-α. La azatioprina, el interferón e incluso natalizumab serán las alternativas en aquellos casos que lo requieran.
Anti-tumor necrosis factor alpha (TNF-α) agents have been a great advantage in the treatment of inflammatory bowel disease. The safety profile of these agents is well-known and they can be considered safe when properly used. In clinical practice, the most important adverse events are infections. Other adverse effects are also possible but are much less frequent. However, because of the widespread use of these drugs, these uncommon adverse effects may also occur in clinical practice. We report one of these infrequent adverse events, multiple sclerosis, which is rare but important because of its severity. When neurological symptoms appear during treatment with anti-TNF-α, multiple sclerosis must be ruled out. The diagnosis and therapeutic management of this entity, led by a neurologist with our collaboration, required permanent cessation of anti-TNF-α therapy. Azathioprine, interferon, and even natalizumab, may be used as alternatives in patients who require therapy.
Treatment of multiple sclerosis
2011, Medicine
Spinal Cord Injury and its Relationship to the Development or Worsening of Clinical Multiple Sclerosis
2011, Neuroinflammation
This chapter highlights the clinical features noted by distinguished physicians of the occurrence of clinical multiple sclerosis (MS) or its exacerbation following trauma, particularly of the cervical cord. Multiple sclerosis is one of the most common causes of chronic neurologic disease in young adults. It has long been pointed out by a number of investigators that the plaques of MS bear a special relationship to blood vessels. Döring was one of the first to voice the opinion that the plaques, which are found adjacent to the lateral ventricles, also have a specific relationship to blood vessels. These early investigators also drew attention to the fact that the small blood vessels within plaques may or may not have inflammatory cells, but virtually all active plaques will have macrophages. Dawson, one of the first serious students of MS, showed that there was a clear relationship between the development of plaques and blood vessels. The proximity of the plaque to the ventricular system and the fact that it has a central vein or venule has led many investigators to speculate about the possibility of a pathogenic agent, such as an enzyme or immunoagent, that diffuses from the cerebrospinal fluid (CSF) or blood into the brain. All investigators of MS have come to the same conclusion that the plaque is based around small blood vessels, usually venules.
Animal models of multiple sclerosis-Potentials and limitations
2010, Progress in Neurobiology
Experimental autoimmune encephalomyelitis (EAE) is still the most widely accepted animal model of multiple sclerosis (MS). Different types of EAE have been developed in order to investigate pathogenetic, clinical and therapeutic aspects of the heterogenic human disease. Generally, investigations in EAE are more suitable for the analysis of immunogenetic elements (major histocompatibility complex restriction and candidate risk genes) and for the study of histopathological features (inflammation, demyelination and degeneration) of the disease than for screening of new treatments. Recent studies in new EAE models, especially in transgenic ones, have in connection with new analytical techniques such as microarray assays provided a deeper insight into the pathogenic cellular and molecular mechanisms of EAE and potentially of MS. For example, it was possible to better delineate the role of soluble pro-inflammatory (tumor necrosis factor-α, interferon-γ and interleukins 1, 12 and 23), anti-inflammatory (transforming growth factor-β and interleukins 4, 10, 27 and 35) and neurotrophic factors (ciliary neurotrophic factor and brain-derived neurotrophic factor). Also, the regulatory and effector functions of distinct immune cell subpopulations such as CD4⁺ Th1, Th2, Th3 and Th17 cells, CD4⁺FoxP3⁺ Treg cells, CD8⁺ Tc1 and Tc2, B cells and γδ⁺ T cells have been disclosed in more detail. The new insights may help to identify novel targets for the treatment of MS. However, translation of the experimental results into the clinical practice requires prudence and great caution.

View all citing articles on Scopus

View full text

CLINICAL PRACTICEOverview of azathioprine treatment in multiple sclerosis

Abstract

Clin Neurol Neurosurg

J Neurol Sci

Lancet

Am J Med

Why do we need systematic overviews of randomised trials?

Stat Med

Immunological treatment for multiple sclerosis

Lancet

The disability status scale for multiple sclerosis: apologia for DSS sua

Neurology

Problems of experimental trials of therapy in multiple sclerosis: report by the panel on evaluation of experimental trials of therapy in multiple sclerosis

Ann NY Acad Sci

Intensive immunosuppression in progressive multiple sclerosis: a randomised three-arm study of high dose intravenous cyclophosphamide, plasma exchange, and ACTH

N Engl J Med

Some aspects of natural history of disseminated sclerosis

QJ Med

An illness severity score for multiple sclerosis

Neurology

Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs placebo

Final report. Neurology

Therapie der multiplen Sclerose mit Levamisol und Azathioprin—Vergleich der Wirksamkeit einer "immunstimulierenden" und "immun-suppressiven" Behandlung

Nervenarzt

CLINICAL PRACTICE
Overview of azathioprine treatment in multiple sclerosis