Azathioprine (Imuran)

1. ImmunoGlobulin & Azathioprine combined in MS
   Eur Neurol 1998;39(3):178-81

2. Lesion load quantification in serial MR of early Relapsing Multiple Sclerosis in Azathioprine treatment
   Eur Neurol 1997;38(4):284-90

3. Azathioprine & MoFetil: Emerging treatments for MS
   Mult Scler 1996 Jul;1(6):379-84

4. Immunological Monitoring of Azathioprine in Multiple Sclerosis
   J Neurol 1997 Mar;244(3):167-74

5. Plasma Exchange & Azathioprine in Multiple Sclerosis
   Neurology 1996 Jun;46(6):1620-5

6. Risk of Cancer from Azathioprine in Multiple Sclerosis
   Neurology 1996 Jun;46(6):1607-12

7. Effects of Prednisone & Azathioprine on OligoClonal IGG in Multiple Sclerosis CerebroSpinal Fluid
   Neurol Neurochir Pol 1996 Mar-Apr;30(2):201-11

8. Immunotherapy in Multiple Sclerosis
   Am J Health Syst Pharm 1995 Sep 15;52(18):1985-2000

9. Efficacy of Azathioprine on Multiple Sclerosis new Brain lesions evaluated using Magnetic Resonance Imaging
   Arch Neurol 2005 Dec;62(12):1843-7

10. Azathioprine for Multiple Sclerosis
    Cochrane Database Syst Rev 2007 Oct 17;(4):CD003982

11. Azathioprine and Interferon beta(1a) in Relapsing/Remitting Multiple Sclerosis patients: increasing efficacy of combined treatment
    Eur Neurol 2004;51(1):15-20

In an attempt to prevent exacerbations of Multiple Sclerosis, ImmunoGobulin therapy was combined with Azathioprine (AZA).

IntraVenous ImmunoGobulin (I.V.IG) 2 g/kg was given in divided doses over 3 consecutive days followed by monthly booster doses (0.2 g/kg) for 3 years to 38 patients with Relapsing/Remitting Multiple Sclerosis (MS).

In the 34 patients who completed the trial, the relapse rate decreased (from 1.7 relapses per year to 0 during the 3-year trial period).

The Kurtzke Expanded Disability Status Scale decreased from 3.4 +/- 0.72 to 3.0 +/- 0.70. The results suggest that combined I.V.IG and AZA suppress the ongoing pathologic process in Relapsing/Remitting MS.

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.

Global ImmunoSuppression instead of focused selective or specific ImmunoModulating strategies may still be relevant in diseases with chronic and broad Immune Dysregulation such as Multiple Sclerosis (MS).

Among classical or new ImmunoSuppressive drugs, two of them, both inhibiting Purine Synthesis, show an attractive profile for MS treatment.

Azathioprine (AZA) is the most anciently and widely used global ImmunoSuppressive drug in MS.

Despite founded initial fears, it can be stated today that AZA is usually well tolerated and compatible with normal daily activities, that it requires minimal monitoring and does not significantly increase the risk of Cancer induction after 5 years of continuous usage at the conventional 2.5 mg/kg daily dose.

The only two presently available well conducted trials of AZA in ambulatory patients with Relapsing/Remitting MS show marginally significant beneficial results of AZA treatment on relapse frequency and disability.

Some preliminary data on Brain MRI are also promising.

Mycophenolate MoFetil (MMF) affects mainly the desired cell types, with a good safety profile, a rapidly reversible activity, and an absence of mutagenic effect and Chromosome breakage.

However, it remains to be shown that promising experimental results can be converted into significant clinical results in MS.

It is presently demonstrated for AZA and it is presumable for MMF that neither drug is able to cure MS.

However, it can be anticipated that either drug in combination with other strategies such as recombinant Interferon-ß could represent a significant adjunct for the therapeutic control of MS, at least in early ambulatory Relapsing/Remitting MS.

Presently, the choice between the old, no longer 'sexy', but well-known drug as AZA and a young, appealing, but still to be better evaluated drug (notably for the long run) as MMF is a matter of personal, community, industrial and scientific inclination.

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 Tumor Necrosis Factor-alpha (TNF-).

The most relevant changes included a decrease in CD3- CD56⁺ Cells, an increase in CD4⁺ CD45RA⁺ Cells and a decrease in TNF- levels only in treated patients, while no changes occurred in untreated patients over a 1-year period.

The decrease in TNF- levels and the increase in "Suppressor-inducer" Lymphocytes could reduce chronic inflammation in Multiple Sclerosis, and paralleled an overall favorable clinical response to Azathioprine treatment in our patients.

We enrolled 11 patients with Secondary/Progressive MS in a randomized single-masked cross-over study of Plasma Exchange (PE) in combination with Azathioprine 2 mg/kg.

PE was performed once a week for 4 weeks and thereafter every second week for 20 weeks (14 treatments).

Eight patients completed the whole trial, and three patients discontinued the trial, two during the run-in period of Azathioprine treatment and one at the introduction of PE.

The primary efficacy variables were the number of Gadolinium-enhancing lesions and the occurrence of new enhancing lesions on serial MRI performed every 3 weeks during the PE and the control period.

Secondary efficacy variables were the total MS lesion load on T₂-weighted MRI, multimodal Evoked Potentials, and Clinical Neurologic Ratings.

No significant differences were found regarding the number of enhancing lesions or occurrence of new enhancing lesions in the two periods.

Although the total MS lesion load on MRI was significantly lower (p < 0.02) and Central Motor Conduction Times decreased significantly (p < 0.05) during PE.

This small study did not provide sufficient evidence for a significant beneficial effect of PE or encourage a subsequent large randomized parallel group study.

An increased risk of Cancer has been reported in patients treated with Azathioprine.

To assess the long-term risk of Neoplasia in Azathioprine treated Multiple Sclerosis (MS) patients, we conducted a case control study using the Lyon Multiple Sclerosis Database.

From the 1,191 MS patients included in the database, we identified patients who developed Cancer before December 31, 1991.

Each case was then matched to three Cancer-free MS controls by gender, date of birth, and date of MS onset. A matched analysis was performed to compare cases and controls for exposure to Azathioprine therapy during the same follow-up period.

Twenty-three MS patients with Cancer were identified:
1. 17 solid Tumors
2. 2 Skin Carcinomas
3. 4 Hematopoietic Cancers

Cases had a mean age of 34.5 years +/- 10.2 (+/- SD) at clinical onset of MS and have been followed up for an average 13.8 years +/- 8.1 before being diagnosed with Cancer

Fourteen cases (61%) and 34 controls (49%) had been treated with Azathioprine for at least 1 month after being diagnosed with MS (adjusted odds ratio = 1.7; 95% confidence interval [CI], 0.6 to 4.6).

When assessing risk associated with different durations of Azathioprine therapy compared with no treatment at all, we found that MS patients had an increase in Cancer risk of:

1. 1.3 (95% CI, 0.4 to 4.0) when treated less than 5 years
2. 2.0 (95% CI, 0.4 to 9.1) when treated 5 to 10 years
3. 4.4 (95% CI 0.9 to 20.9) when treated more than 10 years

Similar results were obtained when assessing Cancer risk associated with cumulative doses of Azathioprine ever taken. This case control study suggests that the overall long-term risk of Cancer from Azathioprine is low in MS patients.

The results are suggestive of a dose response relationship with no significant risk during the first years of treatment and a possible increased risk after about 10 years of continuous therapy.

Further studies are needed to better assess the risk-benefit ratio of Azathioprine in MS.

The influence of high-dose Prednisone and Azathioprine therapy on OligoClonal IgG in the CSF of MS patients was studied.

The OligoClonal Bands were present in 93% of patients treated with Prednisone and in 90% of patients treated with Azathioprine.

After the treatment with Prednisone, the OligoClonal Bands density was diminished in 3 patients, and after the treatment with Azathioprine in 1 patient. The number of bands and their pattern remained the same.

Part 1
The efficacies of CorticoSteroids and Azathioprine (part 1) and of Cyclophosphamide, Immune Gobulin, Cyclosporine, Interferons, Copolymer-1, and Cladribine (part 2) in patients with Multiple Sclerosis (MS) are reviewed.

MS is an inflammatory, DeMyelinating disease of the CNS that commonly affects young adults. The involvement of various Immune mechanisms in MS suggests a role for ImmunoModulating therapy.

The goals of ImmunoTherapy vary with the clinical stage of the disease and include:

1. Improving recovery from exacerbations
2. Decreasing the number or severity of relapses
3. Preventing the development of Chronic/Progressive disease from a Relapsing/Remitting course
4. Decreasing further progression in patients with Chronic/Progressive disease

In clinical trials, CorticoTropin and CorticoSteroids have been found to accelerate recovery from exacerbations. Tapering is often effective after high-dose induction therapy.

Long-term maintenance regimens do not alter disease progression and are not recommended.

Azathioprine produces modest benefits with respect to relapse rates and disease progression after two or more years of treatment; adverse effects are mild to moderate.

Azathioprine should not be used in patients with aggressive disease who may approach severe disability in 6-18 months.

Cyclophosphamide, because of its modest impact on disease progression and its potentially severe adverse effects, including Cancer, should be reserved for patients with aggressive Relapsing/Remitting or Chronic/Progressive disease in whom other treatments have failed to work; maintenance therapy is necessary after induction.

IntraVenous Immune Gobulin may benefit patients with severe relapses; however, its efficacy remains unproven.

Cyclosporine also cannot be recommended because of its modest efficacy, marked adverse effects, and high cost. Interferon-ß-1b is a more specific ImmunoTherapy that has been found to decrease the number and severity of relapses.

This treatment should be considered in patients with Relapsing/Remitting disease who are having two or more exacerbations per year. Copolymer-1 and Cladribine have shown some promising early results.

Although various ImmunoTherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progression, and some can cause serious adverse effects.

Better understanding of the Immunologic basis of MS may lead to more specific ImmunoTherapies with more lasting benefits.

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, Design & Setting
To evaluate the efficacy of Azathioprine therapy on new Brain lesion suppression in MS. Open-label treatment vs baseline study. Outpatient MS clinical center at a university hospital.

Patients
Fourteen patients with Relapsing/Remitting MS of short duration 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.

Background
Azathioprine 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.

Objectives
To 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 Strategy
The 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 Criteria
All parallel group randomized 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 Analysis
Potentially relevant references were evaluated and all data extracted by two independent authors.

Main Results
The 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' Conclusions
Azathioprine 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-ß 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.

Current treatments of Relapsing/Remitting Multiple Sclerosis (RRMS) with ImmunoSuppressive or ImmunoModulatory Drugs have been shown to modify the course of the disease in a significative number of patients.

However, in many cases, the response to either Interferon-beta (IFN-ß) or Azathioprine (AZA) treatments was not satisfactory and new therapeutic approaches are needed.

We studied clinical and MRI efficacy, safety and tolerance of AZA and IFN-beta-1a combined therapy in 23 patients with clinically definite RRMS, who had not previously been responsive to either monotherapies.

Our cases were divided into three subgroups:
1. 8 previously untreated patients (subgroup A) with at least 2 years of natural course of the disease
2. 8 patients (subgroup B) previously treated with AZA for 2 years
3. 7 patients (subgroup C) previously treated with IFN-ß-1a for 2 years

The baseline Expanded Disability Status Scale (EDSS) ranged from 2 to 4 in all subgroups.

All patients completed 2 years of combined treatment with a dose of AZA adjusted to reduce Lymphocyte count down to 1,000 +/- 100/microl in association with IFN-ß-1a at a dose of 6 MIU every other day.

The mean number of relapses during the combined treatment period was significantly lower than that observed before combined therapy in all the three subgroups.

Also, the mean Delta EDSS score was significantly lower during combined treatment than in monotherapy in subgroups B and C.

Moreover, after 2 years of combined treatment, the number of new T₁ HypoIntense lesions, the number and volume of proton density/T₂ HyperIntense lesions and the Gadolinium enhancement of T₁ HypoIntense lesions were significantly lower than before combined treatment.

After 2 years of treatment, this combination therapy appears to be safe and well tolerated and no serious side effects were reported.

Despite some limitations of our study design, the information regarding efficacy, safety and tolerance of the association of AZA and IFN-ß is most encouraging.

Copyright 2004 S. Karger AG, Basel