human
***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: Sulphasalazine ( SASP ) and methotrexate ( MTX ) are well-established treatments for RA but the use of these drugs in combination has been avoided as both have antifolate activity . In this paper we report our experience with 32 patients treated with the combination MTX/SASP and compare the toxicity and tolerability of the combination with 63 patients treated with MTX alone .  The median duration of exposure to the combination was 23 months . Nineteen patients have continued this regime for over 18 months . Five patients on MTX/SASP combination discontinued MTX , in four cases due to toxicity and in one because MTX/SASP was ineffective . In 17 patients on MTX alone  , the drug was withdrawn permanently . In seven cases the cause was toxicity including two patients with severe reactions . In patients known to tolerate SASP alone , the combination of MTX/SASP is also well tolerated . In our experience of 48 patient-years of such combination therapy , there is no increase in toxicity compared to therapy with MTX alone in RA In recent years , therapeutic strategies for patients with rheumatoid arthritis have been discussed in detail [ 1 - 8 ] . Traditional therapy , usually referred to as the pyramid model , begins with nonsteroidal anti-inflammatory drugs ( NSAIDs ) . If these are insufficiently effective , they are later replaced or supplemented with second-line antirheumatic drugs , which are distinguished from NSAIDs primarily by their assumed disease-modifying potential and delayed onset of action . These second-line drugs are also referred to as slow-acting antirheumatic drugs ( SAARDs ) or disease-modifying antirheumatic drugs ( DMARDs ) . Traditionally , the SAARDs of first choice have been hydroxychloroquine or intramuscular gold followed by D-penicillamine , methotrexate , or azathioprine . The traditional therapeutic pyramid is based on the principle of primum non nocere : Because of their potential toxicity , SAARDs should only be given when milder therapies have failed . Recently , the beneficial effects of the pyramid strategy have been question ed because the long-term outcome of rheumatoid arthritis continues to be disappointing . Patients with rheumatoid arthritis have increased mortality [ 9 , 10 ] , and their quality of life is seriously affected by functional impairment and loss of employment [ 11 , 12 ] . The pyramid model might be undesirable because administering SAARDs only after milder regimens prove to be insufficiently effective delays the suppression of inflammation . It is preferable that the disease process be controlled as soon as possible , because radiologic abnormalities appear in the joints early in the course of the disease [ 13 , 14 ] and are related to the extent of inflammation [ 15 , 16 ] . Toxicity indices for NSAIDs and most SAARDs have recently been shown to be similar ; thus , exposure of patients to possible adverse reactions is probably not in itself a reason to withhold treatment with SAARDs [ 17 ] . However , the ability of SAARDs to modify the course of disease and prevent radiologic damage is often question ed [ 18 , 19 ] . The poor long-term outcome of rheumatoid arthritis might be caused not by a delay in effective treatment but by the low disease-modifying power of both first- and second-line drugs . The short courses of SAARDs ( short because of adverse reactions or impatience with a delay in effect ) might also play a role [ 20 , 21 ] . Combinations of SAARDs have not been shown to be superior to single drugs [ 21 , 22 ] . Current clinical practice is shifting toward the earlier introduction of second-line treatment for rheumatoid arthritis , but thus far no clinical trials have shown this strategy to be beneficial . We investigated the consequences of ignoring the treatment pyramid for patients with recent-onset rheumatoid arthritis . In this report , we describe the first-year results of a r and omized clinical trial in which the delayed and the immediate introduction of SAARDs were compared . Effectiveness was measured by disease activity and progression of radiologic abnormalities . The various SAARDs are considered as a single group in this report ; comparisons among the second-line therapies will be reported in detail later . Methods Patients As of January 1990 , all patients with recent-onset rheumatoid arthritis ( diagnosed according to the 1987 American College of Rheumatology criteria [ [ 23 ] ] from six rheumatologic centers in the region of Utrecht , the Netherl and s , were asked to participate in a r and omized , prospect i ve clinical trial . Disease duration had to have been less than 1 year , and most patients were enrolled shortly after diagnosis . The following exclusion criteria were applied : 1 ) age younger than 17 years , 2 ) comorbid conditions that might interfere with one of the therapeutic strategies , 3 ) previous or current treatment with any SAARDs , glucocorticosteroids , or cytotoxic or immunosuppressive therapy , 4 ) the possibility of pregnancy or breast feeding , and 5 ) psychiatric or mental disturbances that would make adherence to the study protocol unlikely . All patients gave informed consent before study entry and were told that the study was intended to compare the unsure outcome of treatment with NSAIDs alone with that of treatment with NSAIDs and a SAARD for rheumatoid arthritis at an early stage . The study design was approved by the ethical committees of all participating hospitals . The baseline characteristics of patients who were eligible for the study but who objected to r and omization were compared with those of r and omly assigned patients to determine whether any selection bias had occurred . Treatment Patients entering the study were r and omly assigned to one of two therapeutic groups . All r and omization procedures were done by drawing sealed envelopes from blocks of 100 with equal numbers of patients for each of the four treatments per hospital ; the person doing the procedures was blinded to treatment assignments . This method was used because eligible patients were not distributed equally among the centers . The assigned therapeutic strategy was continued for at least 1 year . In the non-SAARD group , patients began receiving NSAID therapy , the dose and type of which could be modified at any time . For this group , initiation of SAARD treatment during the study was regarded as discontinuation of the therapeutic strategy . In the SAARD group , patients were r and omly assigned ( by persons blinded to treatment assignments ) to treatment with one of the following SAARDs : hydroxychloroquine ( 400 mg/d ) , intramuscular gold ( aurothioglucose , 50 mg/wk ) , or oral methotrexate ( 7.5 to 15 mg/wk ) . Therapy with the initial SAARD was continued for 12 months unless adverse reactions necessitated discontinuation ; if this occurred , another SAARD was given . Hydroxychloroquine was followed by auranofin ( 6 to 9 mg/d ) ; intramuscular gold was followed by D-penicillamine ( 500 to 750 mg/d ) ; and methotrexate was followed by sulfasalazine ( 2000 to 3000 mg/d ) . Discontinuation of therapy with the second SAARD was regarded as discontinuation of the therapeutic strategy . Use of NSAIDs was allowed in the SAARD group ; as in the non-SAARD group , the dose and type could be changed at any time . Patients were assigned to the non-SAARD group and the SAARD group in a ratio of 1:3 , and power calculations for the primary end point disability ( equals 0.05 ; equals 0.20 ; difference to be detected , 25 % ) indicated that group sizes of 40 and 120 , respectively , would be sufficient . The ratio of 1:3 was chosen to enable later comparisons of results within the SAARD group , which were thought to be similar . The use of analgesics was allowed in both groups ; the use of oral glucocorticosteroids was avoided if possible ; and intraarticular injections were not allowed within 2 months of a scheduled visit . Criteria for discontinuation or dose adjustment of a SAARD because of adverse reactions were described in detail in the study protocol . Discontinuation of any treatment because of sustained disease activity was done only if the patient and the attending physician ( who had to discuss the patient with a colleague ) judged it to be unavoidable . Primary End Points Assessment s were done at the start of the trial and were repeated every 3 months . Clinical variables were assessed by the same physician or research nurse for each patient on each occasion . Primary end points were functional disability , pain , joint score , erythrocyte sedimentation rate , and radiologic abnormalities [ 24 ] . Radiologic abnormalities and erythrocyte sedimentation rate were determined by persons blinded to treatment assignments ; functional disability and pain were self-assessed scores ; and determination of the joint score was not blinded to treatment . Functional disability was assessed using a vali date d Dutch version of the Health Assessment Question naire Disability Score [ 25 - 27 ] . The question naire scores range from 0 to 3 ; 0 is the best score ( no problems ) , and 3 is the worst . Pain was measured on two horizontal visual analog scales of 100 mm ; the mean of the scores for pain during the night and pain during the morning was calculated . The joint score according to Thompson and colleagues [ 28 , 29 ] assessed the simultaneous presence of joint tenderness and swelling in a selection of joints weighed for joint size ( range , 0 to 534 ) [ 28 , 29 ] . Erythrocyte sedimentation rate ( mm/h ) was measured using Westergren method . Radiography of h and s and feet was done at the start of the study and at 12 months . A modified version of the method of Sharp and coworkers [ 30 , 31 ] was used to score radiologic abnormalities . According to this method , erosions and joint space narrowing in h and and foot joints are scored and added together to obtain a total radiologic damage score ( range , 0 to 448 ) . All radiographs were evaluated by two investigators who were blinded to treatment assignments . The scores of the first investigator were used in the analyses , and the scores of the second investigator were used to vali date the scores of the first . Correlation between the two sets of scores was satisfactory ( Spearman correlation coefficients for scores at baseline and at 12 months were 0.84 for both ) ; the second investigator was found to have given lower scores ( means at baseline were 4.2 and 3.4 , respectively ; means at 12 months were 11.2 and 9.7 , respectively ) . Therefore , in individual cases , differences in total scores of 25 % or more were discussed until an agreement was reached on the appropriate score . That score was then used in the analyses . Additional Assessment s Secondary end points were grip strength ( mean of three measurements of each h and with a vigorimeter [ Martin , Tuttlingen , Germany ] in kPa ) , duration of morning stiffness ( maximum , 720 min ) , and general well-being ( horizontal visual analog scale of 100 mm ) . Additional laboratory variables were serum level of C-reactive protein ( mg/L ) , hemoglobin concentration ( mmol/L ) , and platelet count ( times 109/L ) . Rheumatoid factor status was determined to be positive or negative , as indicated by either the OBJECTIVE To obtain additional safety and efficacy data on leflunomide ( LEF ) treatment in combination with methotrexate ( MTX ) therapy in an open-label extension study in patients with rheumatoid arthritis ( RA ) . METHODS Following a 24 week , r and omized , double-blind trial of adding placebo ( PLA ) or LEF to stable MTX therapy , patients could enter a 24 week extension . Subjects r and omized to LEF and MTX  continued treatment [ ( LEF/LEF ) + MTX ] . Subjects r and omized to PLA and MTX switched to LEF ( 10 mg/day , no loading dose ) and MTX [ ( PLA/LEF ) + MTX ] . The double-blind regarding initial r and omization was maintained . RESULTS For subjects in the extension phase , American College of Rheumatology 20 % ( ACR20 ) responder rates for the ( LEF/LEF ) + MTX group were maintained from Week 24 ( 57/96 , 59.4 % ) to Week 48 ( 53/96 , 55.2 % ) . ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [ ( PLA/LEF ) + MTX ] from 25.0 % ( 24/96 ) at Week 24 to 57.3 % ( 55/96 ) at Week 48 . Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially r and omized to LEF . Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose . CONCLUSION Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension . Importantly , ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose , and those who received a loading does of LEF ( 100 mg/day x 2 days ) at r and omization . Fewer adverse events were reported in patients switched to LEF without a loading dose OBJECTIVE To evaluate tolerability and efficacy of combination therapy with methotrexate (MTX)/parenteral gold or MTX/other disease modifying antirheumatic drug ( DMARD 
    Output:
    
agent
***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: Sulphasalazine ( SASP ) and methotrexate ( MTX ) are well-established treatments for RA but the use of these drugs in combination has been avoided as both have antifolate activity . In this paper we report our experience with 32 patients treated with the combination MTX/SASP and compare the toxicity and tolerability of the combination with 63 patients treated with MTX alone .  The median duration of exposure to the combination was 23 months . Nineteen patients have continued this regime for over 18 months . Five patients on MTX/SASP combination discontinued MTX , in four cases due to toxicity and in one because MTX/SASP was ineffective . In 17 patients on MTX alone  , the drug was withdrawn permanently . In seven cases the cause was toxicity including two patients with severe reactions . In patients known to tolerate SASP alone , the combination of MTX/SASP is also well tolerated . In our experience of 48 patient-years of such combination therapy , there is no increase in toxicity compared to therapy with MTX alone in RA In recent years , therapeutic strategies for patients with rheumatoid arthritis have been discussed in detail [ 1 - 8 ] . Traditional therapy , usually referred to as the pyramid model , begins with nonsteroidal anti-inflammatory drugs ( NSAIDs ) . If these are insufficiently effective , they are later replaced or supplemented with second-line antirheumatic drugs , which are distinguished from NSAIDs primarily by their assumed disease-modifying potential and delayed onset of action . These second-line drugs are also referred to as slow-acting antirheumatic drugs ( SAARDs ) or disease-modifying antirheumatic drugs ( DMARDs ) . Traditionally , the SAARDs of first choice have been hydroxychloroquine or intramuscular gold followed by D-penicillamine , methotrexate , or azathioprine . The traditional therapeutic pyramid is based on the principle of primum non nocere : Because of their potential toxicity , SAARDs should only be given when milder therapies have failed . Recently , the beneficial effects of the pyramid strategy have been question ed because the long-term outcome of rheumatoid arthritis continues to be disappointing . Patients with rheumatoid arthritis have increased mortality [ 9 , 10 ] , and their quality of life is seriously affected by functional impairment and loss of employment [ 11 , 12 ] . The pyramid model might be undesirable because administering SAARDs only after milder regimens prove to be insufficiently effective delays the suppression of inflammation . It is preferable that the disease process be controlled as soon as possible , because radiologic abnormalities appear in the joints early in the course of the disease [ 13 , 14 ] and are related to the extent of inflammation [ 15 , 16 ] . Toxicity indices for NSAIDs and most SAARDs have recently been shown to be similar ; thus , exposure of patients to possible adverse reactions is probably not in itself a reason to withhold treatment with SAARDs [ 17 ] . However , the ability of SAARDs to modify the course of disease and prevent radiologic damage is often question ed [ 18 , 19 ] . The poor long-term outcome of rheumatoid arthritis might be caused not by a delay in effective treatment but by the low disease-modifying power of both first- and second-line drugs . The short courses of SAARDs ( short because of adverse reactions or impatience with a delay in effect ) might also play a role [ 20 , 21 ] . Combinations of SAARDs have not been shown to be superior to single drugs [ 21 , 22 ] . Current clinical practice is shifting toward the earlier introduction of second-line treatment for rheumatoid arthritis , but thus far no clinical trials have shown this strategy to be beneficial . We investigated the consequences of ignoring the treatment pyramid for patients with recent-onset rheumatoid arthritis . In this report , we describe the first-year results of a r and omized clinical trial in which the delayed and the immediate introduction of SAARDs were compared . Effectiveness was measured by disease activity and progression of radiologic abnormalities . The various SAARDs are considered as a single group in this report ; comparisons among the second-line therapies will be reported in detail later . Methods Patients As of January 1990 , all patients with recent-onset rheumatoid arthritis ( diagnosed according to the 1987 American College of Rheumatology criteria [ [ 23 ] ] from six rheumatologic centers in the region of Utrecht , the Netherl and s , were asked to participate in a r and omized , prospect i ve clinical trial . Disease duration had to have been less than 1 year , and most patients were enrolled shortly after diagnosis . The following exclusion criteria were applied : 1 ) age younger than 17 years , 2 ) comorbid conditions that might interfere with one of the therapeutic strategies , 3 ) previous or current treatment with any SAARDs , glucocorticosteroids , or cytotoxic or immunosuppressive therapy , 4 ) the possibility of pregnancy or breast feeding , and 5 ) psychiatric or mental disturbances that would make adherence to the study protocol unlikely . All patients gave informed consent before study entry and were told that the study was intended to compare the unsure outcome of treatment with NSAIDs alone with that of treatment with NSAIDs and a SAARD for rheumatoid arthritis at an early stage . The study design was approved by the ethical committees of all participating hospitals . The baseline characteristics of patients who were eligible for the study but who objected to r and omization were compared with those of r and omly assigned patients to determine whether any selection bias had occurred . Treatment Patients entering the study were r and omly assigned to one of two therapeutic groups . All r and omization procedures were done by drawing sealed envelopes from blocks of 100 with equal numbers of patients for each of the four treatments per hospital ; the person doing the procedures was blinded to treatment assignments . This method was used because eligible patients were not distributed equally among the centers . The assigned therapeutic strategy was continued for at least 1 year . In the non-SAARD group , patients began receiving NSAID therapy , the dose and type of which could be modified at any time . For this group , initiation of SAARD treatment during the study was regarded as discontinuation of the therapeutic strategy . In the SAARD group , patients were r and omly assigned ( by persons blinded to treatment assignments ) to treatment with one of the following SAARDs : hydroxychloroquine ( 400 mg/d ) , intramuscular gold ( aurothioglucose , 50 mg/wk ) , or oral methotrexate ( 7.5 to 15 mg/wk ) . Therapy with the initial SAARD was continued for 12 months unless adverse reactions necessitated discontinuation ; if this occurred , another SAARD was given . Hydroxychloroquine was followed by auranofin ( 6 to 9 mg/d ) ; intramuscular gold was followed by D-penicillamine ( 500 to 750 mg/d ) ; and methotrexate was followed by sulfasalazine ( 2000 to 3000 mg/d ) . Discontinuation of therapy with the second SAARD was regarded as discontinuation of the therapeutic strategy . Use of NSAIDs was allowed in the SAARD group ; as in the non-SAARD group , the dose and type could be changed at any time . Patients were assigned to the non-SAARD group and the SAARD group in a ratio of 1:3 , and power calculations for the primary end point disability ( equals 0.05 ; equals 0.20 ; difference to be detected , 25 % ) indicated that group sizes of 40 and 120 , respectively , would be sufficient . The ratio of 1:3 was chosen to enable later comparisons of results within the SAARD group , which were thought to be similar . The use of analgesics was allowed in both groups ; the use of oral glucocorticosteroids was avoided if possible ; and intraarticular injections were not allowed within 2 months of a scheduled visit . Criteria for discontinuation or dose adjustment of a SAARD because of adverse reactions were described in detail in the study protocol . Discontinuation of any treatment because of sustained disease activity was done only if the patient and the attending physician ( who had to discuss the patient with a colleague ) judged it to be unavoidable . Primary End Points Assessment s were done at the start of the trial and were repeated every 3 months . Clinical variables were assessed by the same physician or research nurse for each patient on each occasion . Primary end points were functional disability , pain , joint score , erythrocyte sedimentation rate , and radiologic abnormalities [ 24 ] . Radiologic abnormalities and erythrocyte sedimentation rate were determined by persons blinded to treatment assignments ; functional disability and pain were self-assessed scores ; and determination of the joint score was not blinded to treatment . Functional disability was assessed using a vali date d Dutch version of the Health Assessment Question naire Disability Score [ 25 - 27 ] . The question naire scores range from 0 to 3 ; 0 is the best score ( no problems ) , and 3 is the worst . Pain was measured on two horizontal visual analog scales of 100 mm ; the mean of the scores for pain during the night and pain during the morning was calculated . The joint score according to Thompson and colleagues [ 28 , 29 ] assessed the simultaneous presence of joint tenderness and swelling in a selection of joints weighed for joint size ( range , 0 to 534 ) [ 28 , 29 ] . Erythrocyte sedimentation rate ( mm/h ) was measured using Westergren method . Radiography of h and s and feet was done at the start of the study and at 12 months . A modified version of the method of Sharp and coworkers [ 30 , 31 ] was used to score radiologic abnormalities . According to this method , erosions and joint space narrowing in h and and foot joints are scored and added together to obtain a total radiologic damage score ( range , 0 to 448 ) . All radiographs were evaluated by two investigators who were blinded to treatment assignments . The scores of the first investigator were used in the analyses , and the scores of the second investigator were used to vali date the scores of the first . Correlation between the two sets of scores was satisfactory ( Spearman correlation coefficients for scores at baseline and at 12 months were 0.84 for both ) ; the second investigator was found to have given lower scores ( means at baseline were 4.2 and 3.4 , respectively ; means at 12 months were 11.2 and 9.7 , respectively ) . Therefore , in individual cases , differences in total scores of 25 % or more were discussed until an agreement was reached on the appropriate score . That score was then used in the analyses . Additional Assessment s Secondary end points were grip strength ( mean of three measurements of each h and with a vigorimeter [ Martin , Tuttlingen , Germany ] in kPa ) , duration of morning stiffness ( maximum , 720 min ) , and general well-being ( horizontal visual analog scale of 100 mm ) . Additional laboratory variables were serum level of C-reactive protein ( mg/L ) , hemoglobin concentration ( mmol/L ) , and platelet count ( times 109/L ) . Rheumatoid factor status was determined to be positive or negative , as indicated by either the OBJECTIVE To obtain additional safety and efficacy data on leflunomide ( LEF ) treatment in combination with methotrexate ( MTX ) therapy in an open-label extension study in patients with rheumatoid arthritis ( RA ) . METHODS Following a 24 week , r and omized , double-blind trial of adding placebo ( PLA ) or LEF to stable MTX therapy , patients could enter a 24 week extension . Subjects r and omized to LEF and MTX  continued treatment [ ( LEF/LEF ) + MTX ] . Subjects r and omized to PLA and MTX switched to LEF ( 10 mg/day , no loading dose ) and MTX [ ( PLA/LEF ) + MTX ] . The double-blind regarding initial r and omization was maintained . RESULTS For subjects in the extension phase , American College of Rheumatology 20 % ( ACR20 ) responder rates for the ( LEF/LEF ) + MTX group were maintained from Week 24 ( 57/96 , 59.4 % ) to Week 48 ( 53/96 , 55.2 % ) . ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [ ( PLA/LEF ) + MTX ] from 25.0 % ( 24/96 ) at Week 24 to 57.3 % ( 55/96 ) at Week 48 . Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially r and omized to LEF . Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose . CONCLUSION Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension . Importantly , ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose , and those who received a loading does of LEF ( 100 mg/day x 2 days ) at r and omization . Fewer adverse events were reported in patients switched to LEF without a loading dose OBJECTIVE To evaluate tolerability and efficacy of combination therapy with methotrexate (MTX)/parenteral gold or MTX/other disease modifying antirheumatic drug ( DMARD 
    Output:
    