Forum

Azathioprine

Hi everybody - do any of you have any evidence or experience of azathioprine (Imuran) being used in the treatment of MS

I am sure there have been a couple of mentions of this on here fairly recently, but I can’t find them. Perhaps I am not using the search facility properly.

My neuro spoke of it many years ago as an option if (as was a real risk back then) there was no funding for the drugs that are now the first-line DMDs. I remember his saying that it was tried and tested, reasonably well-tolerated (although potentially problematical and needed close monitoring) and cheap!

Alison

Hi Liffy I was on Aziathoprine almost 13 yrs ago now after been taken off beta interferon. I managed quite well with no major problems ms wise but again another drug I was taken off as my white & red blood cells were all to pot and there was a fear of liver, kidney failure. Sue

I met someone the other week who has been on this for a long time. She swears it has calmed her MS down - she went from loads of relapses a year to hardly any.

Karen x

All many thanks for the replies - my wife has been on Azathioprine since the late 90’s and has remained fairly stable. Suddenly her GP has announced he wants to take her off it as there is no real evidence to suggest it is beneficial. So I need to pull as much info together as I can before going to talk to him - any links etc you can share would be great. Thanks, Liffy

I do dislike people who use platitudes or tow the party (PCT) line without doing their own research. In which case, I hope the following will give your wife’s GP something to at least make him blush and, with any luck, think again! This is a relatively small sample of what’s available.

Karen x

Etemadifar et al. (2007). Comparison of interferon beta products and azathioprine in the treatment of relapsing-remitting multiple sclerosis. JOURNAL OF NEUROLOGY, 254, 1723-1728

We compared the relative efficacy of interferon beta (IFN beta) products and azathioprine (AZA) in the treatment of relapsing- remitting multiple sclerosis (RRMS). Ninety-four previously untreated patients of short duration with RRMS were randomly allocated to the two treatment groups. The first group received IFN beta products (Betaferon,Avonex or Rebif); the second group received AZA for 12 months. Response to treatment was assessed at 3, 6, and 12 months after starting therapy. The mean number of relapse during one year of the study was lower in the AZA group than in the IFN beta products group (0.28 vs. 0.64, P < 0.05).After 12 months, 57.4% of patients receiving IFN beta products remained relapse free compared with 76.6% of those given AZA. The Expanded Disability Status Scale (EDSS) decreased by 0.30 units in IFN beta-treated patients (P < 0.05) and 0.46 in AZAtreated patients (P < 0.001). Treatment with IFN beta products and AZA significantly reduces the relapse rate and EDSS score in patients with RRMS, while AZA is more effective than the IFN beta formulations.

Casetta et al. (2007). Azathioprine for multiple sclerosis. COCHRANE DATABASE OF SYSTEMATIC REVIEWS, 4

BackgroundAzathioprine is the most widely used immunosuppressive treatment in multiple sclerosis ( MS). It is an alternative to interferon beta for treating MS also because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in multiple sclerosis.ObjectivesTo compare azathioprine versus placebo. To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with multiple sclerosis.Search strategyThe Multiple Sclerosis Group’s Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL- Issue 4, 2006), Cochrane Database of Systematic Reviews (CDSR- Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE searched 28.12.06) MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006). Journals and reference lists were hand searched for relevant articles both to benefit and adverse effects. Regulatory agencies were additional sources of information for adverse effects.Selection criteriaAll parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with multiple sclerosis. Cohorts, case controls, case series and case reports were also used to assess adverse effects.Data collection and analysisPotentially relevant references were evaluated and all data extracted by two independent authors.Main resultsThe five trials that met our criteria included 698 randomised patients: data from 499 (71.5%) were available for analysis of relapse frequency in patients at one year’s, from 488 (70%) at two years’ and from 415 (59.5%) at three years’ follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] = 20%; 95% CI = 5% to 33%), at two years’ ( RRR = 23%; 95% CI = 12% to 33%) and three years’ (RRR = 18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies. Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years’ follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials. Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%).Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g.Authors’ conclusionsAzathioprine is an appropriate maintenance treatment for patients with multiple sclerosis who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating multiple sclerosis. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in multiple sclerosis has not been made.

La Mantia et al. (2007). Azathioprine. Safety profile in multiple sclerosis patients. NEUROLOGICAL SCIENCES, 28, 299-303

Azathioprine (Aza) has been proposed in the treatment of multiple sclerosis (MS) since 1971 and continues to be used in MS Clinical Centres. Recent data, suggesting its efficacy in reducing MRI lesion load and in refractory IFN-treated MS patients, has renewed interest in this drug. Its therapeutic index over other immunosuppressive agents is generally considered favourable, but concerns about a possible risk of malignancy have limited its use. On the other hand, the occurrence of unexpected adverse events (AEs) in clinical trials in recent years has aroused the interest in the safety profile of the drugs. No systematic review of AEs in patients affected by MS is available. The aim of this study is to review the safety profile of the drug in patients affected by MS, in order to support a correct management of these patients in the clinical practice. The controlled and observational clinical studies published between 1971 and 2007 have been included. The AEs have been registered in ad hoc form and the frequency has been calculated. The risk of cancer and toxicity on reproductive function has been also considered. Gastrointestinal complaints and leukopenia are the most frequent AEs of Aza therapy in MS, occurring in more than 10% of the patients, while infections, allergy, anaemia, thrombocytopenia and pancytopenia are common (> 1%-< 10%). Pancreatitis is not common (> 0.1%-< 1%). Most of them are easily managed by dosage adjustment or therapy interruption. The cancer risk increases with the treatment duration and cumulative dose. No data on reproductive toxicity in MS treated with Aza are available. The safety profile of Aza is acceptable, if strategies for management of expected AEs are adopted, following dosage and treatment duration indications, and if long-term monitoring to evaluate the risk of cancer is warranted.

Massacesi et al (2005). Efficacy of azathioprine on multiple sclerosis new brain lesions evaluated using magnetic resonance imaging. ARCHIVES OF NEUROLOGY, 62, 1843-1847

Background: Azathioprine is an immunosuppressive agent that reduces relapse rates in patients with multiple sclerosis (MS), but its efficacy in suppressing new brain lesions has never been evaluated.Objective: To evaluate the efficacy of azathioprine therapy on new brain lesion suppression in MS.Design: Open-label treatment vs baseline study.Setting: Outpatient MS clinical center at a university hospital.Patients: Fourteen patients with relapsing-remitting MS of shortduration and at least 3 gadolinium-enhancing (Gd+) brain lesions observed within 6 months before treatment.Intervention: Azathioprine, up to 3 mg/kg daily, individually adjusted according to blood lymphocyte number and the occurrence of adverse events.Main Outcome Measures: Brain Gd+ lesions evaluated by monthly magnetic resonance imaging for 6 months before and 6 months during treatment and new T2 lesions evaluated during the same periods and after an additional 6 months.Results: The treatment reduced to 0 the median Gd+ lesion number and volume per magnetic resonance image (P<.001 for both), resulting in a Gd+ lesion number reduction of 50% or more in 12 of 14 patients (P<01). An equivalent reduction in the new T2 lesion number was observed (P<02); this activity also persisted during the additional treatment period evaluated using this outcome measure (P<01). The median azathioprine dose administered (2.6-2.8 mg/kg daily) reduced the mean blood lymphocyte count to 57% of the baseline value. Adverse events were transient or reversible with dose adjustment.Conclusions: This study indicates for the first time that azathioprine, administered at lymphocyte-suppressing doses, is effective in reducing MS new brain inflammatory lesions and is well tolerated.

Rubio-Terres & Hurle (2005). Cost-utility analysis of relapsing-remitting multiple sclerosis treatment with azathioprine or interferon beta in Spain. REVISTA DE NEUROLOGIA, 40, 705-710

Aim. To carry out a cost-utility analysis of the treatment of relapsing-remitting multiple sclerosis (RRMS) with azothioprine (Imurel) or beta interferon (all, Avonex, Rebif and Betaferon). Material and methods. Pharmacoeconomic Markov model comparing treatment options by simulating the life of a hypothetical cohort of women aged 30, from the societal perspective. The transition probabilities, utilities, resource utilisation and costs (direct and indirect) were obtained from Spanish sources and front bibliography. Univariant sensitivity analyses of the base case were performed. Results. In. the base case analysis, the average cost per patient (euros in 2003) of a life treatment, considering a life expectancy of 53 years, would be 620,205, 1,047,836, 1,006,014, 1,161,638 and 968,157 euros with Imurel, all interferons, Avonex, Rebif and Betaferon, respectively Therefore, the saving with Imurel would range between 327,000 and 520,000 euros approximately, The quality adjusted life years (QALY) obtained with Imurel or interferons would be 10.08 and 9.30, respectively, with an average gain of 0.78 QALY per patient treated with Imurel. The sensitivity analyses confirmed the robustness of the base case. The cost of one additional QALY with interferons would range between 413,000 and 1,308,000 euros approximately in the hypothetical worst scenario,for Imurel. Conclusions. For a typical patient with RRMS, treatment with Imurel would be more efficient than interferons and would dominate (would be more efficacious with lower costs) beta interferon.

Milder (2002). Partial and significant reversal of progressive visual and neurological deficits in multiple sclerosis: a possible therapeutic effect. CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 30, 363-366.

A 24-year-old woman developed over 18 months fluctuating and progressively increasing visual and cerebellar deficits, due to multiple sclerosis. The minimum visual acuities were 3/19 on the right and the perception of finger movement at 1 m on the left. She became able to walk only with a wide base and with support. Her condition deteriorated despite the use of methylprednisolone, prednisone and interferon beta-1b, so these were ceased. Azathioprine, 25 mg daily increasing to 100 mg daily, reducing following abnormal liver function tests to 50 mg daily, and glatiramer acetate 20 mg daily were commenced. The visual acuities two months later were 3/7.5 on the right and 3/6 on the left and after 4 months 3/4.5 on the right and 3/3 on the left. She was able after 2 months to walk unaided on a narrow base and after 4 months to jog half a kilometre without difficulty. Progressive multiple sclerosis has been held to be irreversible. The response in the present case therefore raises the possibility of a drug effect. It indicates the need for trials of combined immunomodulatory and immunosuppressive therapies in progressive multiple sclerosis.

Bryant et al (2001). Systematic review of immunomodulatory drugs for the treatment of people with multiple sclerosis: Is there good quality evidence on effectiveness and cost? JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 70, 574-579

Objective-To review the clinical effectiveness and costs of a range of disease modifying drugs in multiple sclerosis. Drugs included are azathioprine, cladribine, cyclophosphamide, intravenous immunoglobulin, methotrexate, and mitoxantrone. Methods-Electronic databases and bibliographies of related papers were searched for randomised controlled trials (RCTs) and systematic reviews, and experts and pharmaceutical companies were contacted for further information. Inclusion and quality criteria were assessed, data extraction undertaken by one reviewer and checked by a second reviewer, with discrepancies being resolved through discussion. Costs were obtained and cost-effectiveness papers sought. Results-Seventeen studies met the inclusion criteria for the review. Evidence for the clinical effectiveness of the drugs showed some reductions in relapse rates and/or progression to disability for people with MS, although benefits may be lessened by wide ranging side effects. Annual drug costs/patient are estimated to range from pound 60 to pound 10 200. No cost effectiveness studies were found. Conclusion-Evidence for the effectiveness of these drugs in multiple sclerosis is problematic because there are few good quality trials for each drug. Trials often have methodological Limitations and use different treatment regimes, patient groups, and outcome measures. Well conducted trials using outcome measures with clinical significance for groups of patients with different types of multiple sclerosis and long term follow up are needed if the evidence base of treatment for the disease is to be improved.

NB: There are some interesting data in this paper that are not obvious from the above abstract. You can find the full paper here: http://jnnp.bmj.com/content/70/5/574.full.pdf+html (Send me a pm if you can’t access it and I can send it to you by email.)

Salmaggi et al (1997). Immunological monitoring of azathioprine treatment in multiple sclerosis patients. JOURNAL OF NEUROLOGY, 244, 167-174

Despite the longstanding clinical use of azathioprine as an immunosuppressive agent in multiple sclerosis, little is known about the action of this drug on a number of parameters of putative pathogenic relevance in the disease. Eleven patients with multiple sclerosis, treated with azathioprine 2.5-3 mg/kg per day, and six untreated patients were studied with serial blood sampling for 1 year. The following immunological parameters were investigated: peripheral blood lymphocyte subsets, natural killer activity, serum IgG, IgM, ICAM-1 and tumour necrosis factor alpha (TNF-alpha). The most relevant changes included a decrease in CD3-CD56(+) cells, an increase in CD4(+)CD45RA(+) cells and a decrease in TNF-alpha levels only in treated patients, while no changes occurred in untreated patients over a 1-year period. The decrease in TNF-alpha levels and the increase in ‘‘suppressor-inducer’’ lymphocytes could reduce chronic inflammation in multiple sclerosis, and paralleled an overall favourable clinical response to azathioprine treatment in our patients.

Cavazzuti et al (1997). Lesion load quantification in serial MR of early relapsing multiple sclerosis patients in azathioprine treatment - A retrospective study. EUROPEAN NEUROLOGY, 38, 284-290

Azathioprine (AZA) has a slight but consistent effect on clinical outcome in multiple sclerosis (MS), but very few data are available on magnetic resonance imaging (MRI) changes. We performed a retrospective study aimed to quantify changes of lesion load in two serial proton density weighted MRI sequences (TR 2500, TE 30, 1.5 T) at a mean interval of 2.5 years in 36 relapsing-remitting (RR) MS patients: 19 had been treated with AZA, beside steroids after relapses (AZA group), and 17 had been treated with steroids only (control group). All but 3 patients were in the early phase of the disease. Total lesion area (TLA) was measured by manual outlining method and the arbitrary score proposed by Ormerod (total score) was also calculated from the number and diameter of lesions. Lesion load was the same at baseline, but median percentage difference of TLA between first and second scan was +15.6% in control, -43.7% in the AZA group (p < 0.05, Mann-Whitney test). The distribution of patients according to TLA change, assuming that an increase or decrease was significant if larger than 50%, was found to be significantly different in favor of AZA-treated patients (chi(2) = 35.92, p < 0.001). These results suggest an effect of AZA treatment on MRI lesion load in early RR MS: a larger prospective study is worthwhile.

Again very many thanks for the information and the research; I will spend the weekend digesting before contracting said GP, much better informed and confident. Other concern being the suddenness of his request which begs the obvious question of why now - cost maybe, but all indications are that AZ is one of the cheaper options out there. Food for thought, will post the conclusion following talks with GP - thanks again; Liffy

Hi all my neurologist has prescribed me Azathioprine, I’ve got to have all my vaccinations Then wait six weeks before I start taking it,has anyone got any experience Of this medication? Any feedback much appreciated. Thanks Mark