***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 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 ) , result ing 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 A prospect i ve , controlled trial of the therapeutic effect of azathioprine in 30 patients with multiple sclerosis was carried out . No significant advantage  of azathioprine over placebo was demonstrated in non‐re‐sponders to corticosteroids or corticotrophin ( p < 0.5 ) . At the present time , it can not be concluded from the trial whether or not azathioprine should be given to corticosteroid‐responsive patients Summary The results of a prospect i ve , long-term controlled study on the treatment of multiple sclerosis with azathioprine are reported . The effect of a daily 2 mg/kg body weight dosage on 56 r and omly chosen patients with multiple sclerosis is compared with a non-treated control group of 51 r and omly selected multiple sclerosis patients . The azathioprine therapy was continued in all cases for more than one year , on average for 732 days . To assess the effect of therapy , the course of the disease was followed by regular examinations evaluating the severity of the disease by use of an objective weighting-scale covering the whole range of neurological signs . The individual course of the disease within the observation period was determined by means of regression analysis . On average , the disease deteriorated less rapidly for those undergoing azathioprine therapy , this being most marked for patients who had had the disease for less than two years . For those who had been affected for longer , no significant differences in the progression of the disease could be detected . The annual relapse rate was the same for both categories . ZusammenfassungEs wird über die Ergebnisse einer prospektiven , langfristigen kontrollierten Therapiestudie berichtet , in der die Wirksamkeit von Azathioprin in einer Dosis von 2 mg/kg Körpergewicht täglich bei 56 zufällig ausgewählten Multiple Sklerose-Kranken i m Vergleich zu 51 zufällig ausgewählten nicht mit Azathioprin beh and elten Multiple Sklerose-Kranken verglichen wurde . Azathioprin wurde in allen Fällen länger als ein Jahr gegeben , i m Mittel 732 Tage . Zur Beurteilung des Therapieerfolges wurde der individuelle Krankheitsverlauf bei beh and elten und unbeh and elten Kranken durch regelmäßige vollständige neurologische Untersuchung und Bewertung des pathologischen neurologischen Befundes mit einer objektivierten Wertskala ermittelt und durch Regressionsanalyse mathematisch beschrieben . I m Mittel schritt die Erkrankung bei den mit  Azathioprin  beh and elten weniger rasch voran als bei den nicht beh and elten Personen . Die günstige Wirkung des Azathioprin auf die weitere Krankheitsprogression war besonders deutlich bei den Kranken , deren Multiple Sklerose nicht länger als zwei Jahre bekannt war . Bei Personen , die schon länger an der Krankheit litten , schritt sie dagegen i m Mittel in beiden Vergleichskollektiven gleich rasch voran . Auch war die mittlere jährliche Schubrate in beiden Therapiegruppen nicht verschieden The results are reported of a small double-blind controlled trial on the effect of azathioprine in multiple sclerosis . Although a trend in favour of the treated group , as regards the effect on the disability , was found , it did not reach statistical significant levels . No influence was found on the relapse rate . The influence of side-effects , which were found in the treated group in a higher percentage than in the placebo group , on the results is discussed As the effectiveness of continuous azathioprine therapy in multiple sclerosis ( MS ) is still controversial , we have conducted a prospect i ve trial of the drug ( 2 mg/kg daily for at least 2 years ) in patients with clinical ly definite MS , ie with remitting , remitting-progressive and progressive MS . At the end of an average 3-year follow-up 65 % of the 40 patients with remitting-progressi had the same EDSS score as they had to start with . This was observed mainly in patients with longst and ing MS and a high baseline EDSS . Of the 22 patients with a remitting course 77 % showed no clinical deterioration and the annual relapse rate declined , although not significantly . In only one case did the remitting disease become remitting-progressive .  Azathioprine would seem to have some efficacy in delaying the progression of remitting MS.SommarioAbbiamo condotto uno studio prospettivo sui pazienti con SM definita clinicamente che assumono azatioprina alla dose di 2 mg/kg/die da almeno 2 anni e che sono stati consecutivamente ammessi al nostro Istituto dal gennaio 1980 al dicembre 1983 . Il farmaco è stato somministrato ai pazienti con malattia progressiva ( primaria e secondaria ) e con poussées frequenti . Al termine del follow-up ( media : 3 aa . ) il 65 % dei 40 pazienti con malattia progressiva secondaria erano rimasti stazionari . Lo stato neurologico non si è deteriorato nel 77 % dei 22 pazienti con forma a poussées , l'ARR è diminuito e un solo paziente ha modificato il decorso della malattia in progressiva . I nostri risultati , da verificare con uno studio controllato , sembrano indicare una certa efficacia dell'azatioprina nella SM A prospect i ve study in the United Kingdom of 1,634 patients without transplants treated with immunosuppressive drugs ( 68 percent with azathioprine , 28 percent with cyclophosphamide )  found an excess of non-Hodgkin 's lymphoma and squamous cell skin cancer , suggesting that the excesses ( although larger ) of the same malignancies found among transplant recipients are not due solely to the foreign antigens of the graft . A separate analysis of the 643 patients with rheumatoid arthritis found a 13-fold increase of non-Hodgkin 's lymphoma ( whether treated with azathioprine or cyclophosphamide ) . This increase is not significantly different from the excess in similarly treated patients with other disorders in the study . In patients with rheumatoid arthritis not receiving immunosuppressive drugs , this excess is greater than that in a Finnish population and lower than that in another United Kingdom population . The findings are consistent with other evidence that immunosuppression favors the development of non-Hodgkin 's lymphoma , which includes the excess of malignancies found among transplant recipients , long-term renal dialysis patients , and patients with certain primary immunodeficiency disorders . The higher risk among transplant recipients may reflect the effects of the foreign antigens , the more intensive immunosuppressive therapy , or both of these factors . In addition , the predilection for the brain , which is a well-known feature of the lymphomas after transplantation , may also apply ( to a lesser extent ) to other patients after immunosuppressive treatment , judging from the increasing numbers of case reports in such patients of this exceedingly rare type of malignancy . In view of the evidence of an increase of non-Hodgkin 's lymphoma in rheumatoid arthritis in the absence of immunosuppressive treatment , any additional increase is likely to be small in absolute terms . Nevertheless , it needs to be weighed against the clinical benefits Ninety-eight patients with multiple sclerosis ( MS ) in the chronic progression phase entered a 3-year clinical trial to determine if azathioprine ( AZ ) alone or with adrenal cortical steroids stabilizes the course of MS . In group AM , the patients took AZ throughout and methylprednisolone ( MP ) for the first 36 weeks . Group AP received AZ and placebo instead of MP . Group PP took placebos for both drugs . We adjusted the AZ to maintain the total white blood cell count within 3,000 to 4,000/mm3 ; we gave the MP in a fixed dose “ pulse ” and alternate-day regimen . The “ intent-to-treat ” groups had no statistically significant differences in the rates of progression among the 3 treatments . Subgroup analysis suggests that patients in the AM group who completed treatment exactly according to protocol did statistically significantly better than the placebo recipients using the sum of St and ard Neurological Examination scores , slightly better using the quantitative neuro-performance tests , but no better using Mickey 's Illness Severity Scores or Kurtzke 's Disability Status Scale . Also , the AZ-treated groups had half the relapse rate of the placebo-treated group . Adverse reactions to AZ accounted for most withdrawals . Hematologic and hepatic abnormalities were significantly associated with AZ , but serious non-MS abnormalities were uncommon and were equally distributed among the 3 groups . Addition of MP to the AZ slightly improved the efficacy of the treatment , but also increased the adverse effects . The benefits of AZ with or without steroids did not outweigh the risks , and therefore we do not recommend this treatment for patients with chronic progressive MS Forty patients , affected by multiple sclerosis with remitting-relapsing or progressive course , were included in a double blind study of treatment with azathioprine ( 2 mg/kg/day ) lasting 3 years . The mean changes on the Exp and ed Disability Status Scale and in the survival analysis show a trend in favour of azathioprine both in slowing disease progression and reducing relapse frequency . These findings , repeatedly observed in similar trials , indicate that azathioprine should be used in the treatment of multiple sclerosis In an open , r and omised , controlled follow-up study the effectiveness of continuous azathioprine therapy of multiple sclerosis with a dosage of 2 mg/kg/day was tested against a control group that was not treated with cytostatics . In the treated group the disease progressed less rapidly than in the untreated group . Statistically significant differences were only seen in patients having an intermittent-progressive course .  The effect of azathioprine on the course was not dependent on the period or severity of illness nor on the patient 's sex . In chronically progressive disease and with an intermittent disease course no influence of azathioprine was observed 30 multiple sclerosis patients in a double-blind , controlled trial were given immunosuppressive treatment consisting of antilymphocyte globulin , prednisolone , and azathioprine , or placebo . After 15 months of treatment the immunosuppressed group had a reduction in the number of relapses and some retardation of the clinical course of the disease ( p < 0.06 ) . The beneficial effect was seen only in females We r and omized 59 patients with relapsing-remitting multiple sclerosis to receive azathioprine ( AZA ) 3.0 mg/kg daily or placebo in a double-masked therapeutic trial . Analysis of data for predetermined primary outcome measures demonstrated a significant difference favoring AZA for observed mean exacerbation rate after 2 years of therapy and time to deterioration in both Ambulation Index and Kurtzke Exp and ed Disability Status Scale score . This study confirms a modest therapeutic benefit for azathioprine previously reported by other investigators In a double-blind controlled trial 43 patients with relapsing-remitting multiple sclerosis were treated either with anti-lymphocyte globulin , prednisolone , and azathioprine , or with placebo preparations . Treatment began with a combination of the three medicaments but after 1 month was continued for another 14 months with azathioprine ( 3 mg/kg dialy ) only . There was a marginally beneficial effect of immunosuppression on the overall relapse rate and clinical progression . However , there were significant effects on in-vitro lymphocyte function and in the visual evoked potentials in favour of the group receiving suppressive treatment . Placebo-treated patients of the HLA A3 tissue type had significantly more relapses than placebo-treated patients who were not of type HLA A3 . Nevertheless , HLA-A3-positive patients treated with immunosuppression had significantly fewer relapses than A3-positive placebo-treated patients 
    Output:
    
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 .
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 .
Considering the trade off between the benefits and harms , azathioprine is a fair alternative to interferon beta for treating multiple sclerosis .