Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist

OBJECTIVE: To evaluate the efficacy and safety of interleukin-1 receptor antagonist (IL-1Ra) in patients with rheumatoid arthritis (RA). METHODS: Patients with active and severe RA (disease duration <8 years) were recruited into a 24-week, double-blind, randomized, placebo-controlled, multicenter study. Doses of nonsteroidal antiinflammatory drugs and/or oral corticosteroids (< or =10 mg prednisolone daily) remained constant throughout the study. Any disease-modifying antirheumatic drugs that were being administered were discontinued at least 6 weeks prior to enrollment. Patients were randomized to 1 of 4 treatment groups: placebo or a single, self-administered subcutaneous injection of IL-1Ra at a daily dose of 30 mg, 75 mg, or 150 mg. RESULTS: A total of 472 patients were recruited. At enrollment, the mean age, sex ratio, disease duration, and percentage of patients with rheumatoid factor and erosions were similar in the 4 treatment groups. The clinical parameters of disease activity were similar in each treatment group and were consistent with active and severe RA. At 24 weeks, of the patients who received 150 mg/day IL-1Ra, 43% met the American College of Rheumatology criteria for response (the primary efficacy measure), 44% met the Paulus criteria, and statistically significant improvements were seen in the number of swollen joints, number of tender joints, investigator's assessment of disease activity, patient's assessment of disease activity, pain score on a visual analog scale, duration of morning stiffness, Health Assessment Questionnaire score, C-reactive protein level, and erythrocyte sedimentation rate. In addition, the rate of radiologic progression in the patients receiving IL-1Ra was significantly less than in the placebo group at 24 weeks, as evidenced by the Larsen score and the erosive joint count. IL-1Ra was well tolerated and no serious adverse events were observed. An injection-site reaction was the most frequently observed adverse event, and this resulted in a 5% rate of withdrawal from the study among those receiving IL-1Ra at 150 mg/day. CONCLUSION: This study confirmed both the efficacy and the safety of IL-1Ra in a large cohort of patients with active and severe RA. IL-1Ra is the first biologic agent to demonstrate a beneficial effect on the rate of joint erosion.     

Long-term treatment of destructive rheumatoid arthritis with methotrexate

OBJECTIVE: To evaluate the tolerability and efficacy of methotrexate (MTX) treatment in patients with longstanding, progressive, active rheumatoid arthritis (RA) who had failed one or more disease modifying antirheumatic drugs (DMARD). METHODS: Two hundred seventy-one consecutive patients with RA in whom MTX treatment was introduced were followed at regular intervals for up to 108 months. Evaluations included the number of swollen joints, grip strength, patient assessment of pain and mobility, erythrocyte sedimentation rate (ESR), and hemoglobin. Radiographs of hands and feet were taken once a year and 32 joints were evaluated according to a modified Larsen score. RESULTS: Of the 271 patients, 269 had prior treatment with one DMARD, primarily parenteral gold, and 58% with 2 or more DMARD. MTX was started parenterally in all patients in doses between 15 and 25 mg weekly and continued by oral medication in most of the cases. Eighty-three percent of patients complained of adverse events. The most common side effects were nausea, hair loss, transaminase increase, and stomatitis. In 45 patients (16.5%), MTX was withdrawn because of side effects, mostly during the first year. Sixteen patients (5.9%) died during followup, mainly due to myocardial infarction, heart failure, stroke, or cancer. After one year, 78.7% and after 5 years 60.3% of the patients were still taking MTX. Number of swollen joints, ESR, grip strength, patient assessment of pain, and mobility improved significantly at all measurement points. Improvement in the swollen joint count and the ESR of over 50% was seen in more than 50% of patients. Inactivation of the disease, defined as < 2 swollen joints, ESR < 20 mm, and no concomitant steroid use, occurred in 8-14% of patients. Steroid intake was significantly reduced. In spite of clinical improvement the modified Larsen score showed a progression in the vast majority of patients. CONCLUSION: Even in patients with longstanding, active, destructive RA who failed one or more DMARD, MTX treatment is well tolerated and improves clinical and biochemical disease activity significantly, while radiographic progression is still present.     

tRNA-guanine transglycosylase from Escherichia coli: recognition of full-length ''queuine-cognate'' tRNAs

OBJECTIVE: To determine clinical variables useful in predicting the prognosis of patients with early rheumatoid arthritis (RA) by investigating the relationship between clinical variables and radiological progression. METHODS: One hundred eighteen patients with early RA whose symptoms developed within the previous year were enrolled in a prospective study. Data from the 98 patients who completed the 2 year study were analyzed, using the number of erosive joints and Larsen's score as the outcome of RA. RESULTS: Increases in the number of erosive joints at 12 months after entry into the study were significantly correlated with the number of swollen joints (r = 0.510), erythrocyte sedimentation rate (ESR) (r = 0.404), and C-reactive protein (CRP) (r = 0.487) at 6 months. The same results were seen using Larsen's score as the measure of outcome. The average number of erosive joints or mean Larsen's score at 12 months was higher in patients whose levels of CRP were high at 6 months and suppressed by 12 months, but increased much less in patients whose levels of CRP were successfully suppressed by 6 months. More joint erosions were noted in patients with positive rheumatoid factor (RF) than in RF negative patients. CONCLUSION: Joint erosions appeared with a certain time lag after active synovitis. Earlier introduction of effective treatment is recommended for the prevention of RA joint damage. The presence of RF, number of swollen joints, ESR, and levels of CRP at 6 months after starting therapy are the most useful variables to predict radiological progression in patients with early RA.     

Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells

OBJECTIVE: To evaluate tolerability and efficacy of combination therapy with methotrexate (MTX)/parenteral gold or MTX/other disease modifying antirheumatic drug (DMARD, d-penicillamine or chloroquine) in comparison with MTX monotherapy in patients with longstanding destructive active rheumatoid arthritis (RA). METHODS: In an open prospective trial all consecutive MTX-naive patients with active RA starting MTX treatment alone or in combination between January 1980 and December 1987, after failing one or more DMARD, were followed at regular intervals up to 108 months. Evaluations included the number of swollen joints (0-32), grip strength, patient assessment of pain and mobility, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and hemoglobin. Group 1, treated with MTX monotherapy (n = 97), was compared with Group 2, with combination therapy MTX/parenteral gold (n = 126) and Group 3 with MTX + other DMARD (n = 48). RESULTS: There were no significant differences between the groups in mean age (59/57/56 yrs), disease duration (9.6/7.7/8.3 yrs), seropositivity (80/88/82%), or ACR anatomical disease stage (2/3 in stage III and IV). The number of swollen joints (16.8/19.3/16.1 of 32) and the CRP (4.4/5.1/4.7 mg/dl) was significantly greater in Group 2; other disease activity variables were not significantly different. The mean MTX dose at baseline (mostly parenteral) was 16.8/17.0/12.8 mg and could be reduced to around 12 mg (predominantly oral) in the 3 groups. Frequency of adverse events (80/83/88%), nature of clinical (nausea, hair loss, stomatitis) and laboratory (liver enzyme elevation, slight proteinuria) side effects, and withdrawal rate for side effects (20.6/15.0/12.5%) were not significantly different between the groups. After 5 years 54/54/80% of patients continued their treatment. All efficacy variables improved significantly (p < 0.001) in all groups without significant intergroup difference. Improvement > 50% in the ESR was achieved in 63/68/41% and in the swollen joint count in 70/85/48% of patients after 3 years. The number of patients taking oral steroids decreased from 63/59/65% to 22/31/48% after 3 years. In half the patients hemoglobin increased by at least 1 g/dl. CONCLUSION: Combination therapy of MTX with parenteral gold or other DMARD is effective in reducing clinical and biochemical disease activity in patients with longstanding destructive RA with no greater risk of toxicity compared with MTX alone; our study however, did not show clear advantages of combination therapy versus monotherapy for effectiveness.     

Incidence and prevalence of different uveitis entities in Finland

A prospective, open, multicentre study was performed to investigate the efficacy and safety of long-term treatment with cyclosporin in adults with severe atopic dermatitis. Subjects were treated for a maximum of 48 weeks. For the first 8 weeks, cyclosporin was administered at 2.5 mg/kg per day. The dose was then adjusted according to response. Disease activity was monitored using the six-area, six-sign score and the proportion of skin involved. Pruritus and sleep disturbance were assessed using four-point scales. Response was further evaluated on a five-point scale. Adverse events, blood pressure and serum biochemistry were monitored. Tolerability was assessed on a five-point scale. One hundred subjects were enrolled and 65 completed 48 weeks of treatment. Withdrawals occurred due to remission (three), inadequate response (seven), protocol violations (11) and adverse events (14, of which seven were probably treatment related). Cyclosporin produced rapid and highly significant improvements in all indices of disease activity. Sixty-five subjects considered that they had shown a considerable improvement or complete clearance of disease. Most patients relapsed after cessation of treatment, but neither signs nor symptoms had returned to baseline severity 8 weeks later. Blood pressure and serum creatinine levels increased slightly, and in one subject renal impairment was a major factor contributing to withdrawal of the drug. Overall, 85 subjects rated the tolerability of cyclosporin as good or very good. The results indicate that cyclosporin has a place in the long-term treatment of severe atopic dermatitis provided that appropriate patients are selected and careful monitoring is performed.     

Safety and tolerability of conversion from stable Sandimmun maintenance treatment to Sandimmun Neoral in patients with rheumatoid arthritis

OBJECTIVE: To assess the safety and tolerability of converting patients with rheumatoid arthritis (RA) taking a stable dose of cyclosporin A (CyA) maintenance treatment (Sandimmun, SIM) to a new microemulsion capsule formulation, Sandimmun Neoral (Neoral), at an initial dose of 2.5 mg/kg/day. METHODS: In this single arm, open multicenter study, 28 patients were recruited to enter a 6 week pre-conversion period; of these, 22 patients completed 12 weeks' treatment with Neoral. RESULTS: During the 12 week post-conversion period, 11 patients experienced adverse events considered to be drug related; most were mild to moderate in severity and reflected the known safety profile for CyA. Only slight differences in efficacy variables were observed after conversion. The mean Neoral dose at Week 12 (2.84 mg/kg/day) was lower than the mean SIM pre-conversion dose (3.38 mg/kg/day). The study showed that, in patients with RA undergoing stable SIM maintenance treatment, conversion to an initial Neoral dose of 2.5 mg/kg/day did not give rise to any clinically relevant safety and tolerability concerns, and efficacy of the treatment was maintained compared with SIM. CONCLUSION: This conversion strategy constitutes a clinically acceptable alternative to a 1:1 dose conversion.     

A proposed 30-45 minute 4 page standard protocol to evaluate rheumatoid arthritis (SPERA) that includes measures of inflammatory activity, joint damage, and longterm outcomes

A proposed 4 page, 30-45 minute standard protocol to assess rheumatoid arthritis (SPERA) is described that includes all relevant measures of inflammatory activity such as joint swelling, measures of joint damage such as joint deformity, and outcomes such as joint replacement surgery, to monitor patients in longterm observational studies. Forms are included: (1) a patient self-report modified health assessment questionnaire (MHAQ) to assess function, pain, fatigue, psychological distress, symptoms, and drugs used; (2) assessor-completed forms: "RA clinical features" --criteria for RA, functional class, family history, extraarticular disease, comorbidities, joint surgery, radiographic score, and laboratory findings. (3) A 32 joint count with 5 variables: (a) a "shorthand" normal/abnormal so that normal joints require no further detailed assessment; (b) tenderness or pain on motion; (c) swelling; (d) limited motion or deformity; (e) previous surgeries; physical measures of function, i.e., grip strength, walk time, and button test. (4) Medication review of previous disease modifying antirheumatic drugs (DMARD), work history, and years of education. The forms allow cost effective acquisition of all relevant measures of activity, damage, and outcomes in routine clinical care, and allow recognition that measures of activity may show similar or improved values over 5-10 years, while measures of damage and outcomes indicate severe progression in the same patients. The SPERA is feasible to acquire most known relevant measures of activity, damage, and outcomes in RA in 30-45 min in usual clinical settings, to provide a complete database for analyses of longterm outcomes.     

Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine

OBJECTIVE: To evaluate the ability of hydroxychloroquine sulfate (HCQ) to extend the response to combination therapy with HCQ and methotrexate (MTX) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis (RA). METHODS: Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks. First, all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks. Then, responders were randomized into 3 groups: (1) HCQ with MTX as needed for disease flare (n = 40), (2) HCQ 400 mg/day (n = 41), or (3) placebo with MTX as needed for disease flare (n = 40), each for 36 weeks. RESULTS: Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX. After MTX withdrawal, HCQ-containing maintenance regimens delayed the onset of disease flare (p = 0.023). There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment. CONCLUSION: Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks. After withdrawal of MTX, HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks. Initial therapy with HCQ and MTX, followed by maintenance HCQ, may be a useful alternative for the treatment of RA.     

A comparative evaluation of the treatment results with cyclosporin A, methotrexate and azathioprine in rheumatoid arthritis patients (a preliminary report)

In a randomized trial 43 patients with RA systemic manifestations received for 6 months immunodepressants: azathioprine, methotrexate and cyclosporin A (12.15 and 16 patients, respectively). Ten more patients resistant to immunodepressants were given cyclosporin A. The drugs were found to produce a positive effect on clinical symptoms and laboratory indices of the disease. Cyclosporin A is thought a basic immunodepressant without serious hematological or infectious complications. Occasionally it can be useful in failure of other immunodepressants administered to RA patients.     

Salvage of urea-nitrogen in the large bowel: functional significance in metabolic control and adaptation

OBJECTIVE: To assess the safety, tolerability and efficacy of a new cyclosporin A (CyA) microemulsion formulation, Sandimmun Neoral (Neoral), in patients with severe psoriasis that was stable on CyA administered as Sandimmun (SIM). METHODS: In this 24-week, open, randomized, prospective, multicentre trial, 28 patients continued on the same dosage of SIM, while 30 converted to Neoral at 2.5 mg/kg/day or a dosage equivalent to their pre-conversion SIM dosage. During the study, dosages could be adjusted to maintain efficacy, because of adverse events or after disease stabilization. The maximum permitted dosage for either formulation was 5.0 mg/kg/day. Primary efficacy criteria were change in Psoriasis Area and Severity Index (PASI) from baseline and time to relapse. RESULTS: The dosage was increased to maintain efficacy in 22 patients (Neoral 13; SIM 9) and 20 dose reductions for safety were required (Neoral 14, SIM 6). In both groups, PASI scores remained stable throughout and relapses were primarily a result of dosage reduction after disease stabilization. No significant difference was found between groups in the proportion of patients remaining relapse-free. Adverse events were recorded in 20 patients receiving Neoral and 14 receiving SIM. Most drug-related events were of mild or moderate severity and reflected the known CyA side-effect profile. Dose titration guidelines ensured that mean blood pressure and serum creatinine concentrations remained stable in both groups. CONCLUSIONS: If the guidelines for CyA use are followed and the Neoral dosage does not exceed 5 mg/kg/day, conversion of stable patients with severe psoriasis from SIM to Neoral should present no clinically relevant safety or tolerability problems and efficacy of treatment is maintained.     

A prospective comparison of four study designs used in assessing safety and effectiveness of drug therapy in hypertension management

The objective of the study was to compare prospectively the impact of study design on drug therapy safety and effectiveness data obtained in hypertension management. The main study was a randomized controlled clinical trial of four different prospective study designs used in postmarketing assessment involving 1008 primary care practices in nine Canadian provinces. Two thousand nine hundred sixty-four patients with mild to moderate hypertension received an angiotensin converting enzyme (ACE) inhibitor daily for 14 weeks in one of four postmarketing studies--a randomized double-blind clinical trial (RCT) (10 to 40 mg fosinopril daily v 5 to 20 mg enalapril daily), two structured open label trials of 10 to 40 mg fosinopril daily (one with free drugs), or an unstructured open label trial of 10 to 40 mg fosinopril daily. Patient demographic and baseline characteristics, systolic and diastolic blood pressures, adverse events reported, and data quality were recorded as the outcome measures. The results showed that the RCT patients were titrated to higher doses of ACE inhibitor than patients in the open studies, P < .008; patients in the open studies were more likely to receive adjuvant diuretic therapy, P < .008. The decrease in blood pressure was similar for patients in all four studies, mean decrease in systolic BP was between 18 and 20 mm Hg, mean decrease in diastolic BP was between 11 and 13 mm Hg. Fewer patients in the unstructured open trial reported adverse events than patients in the RCT; a 55% relative reduction in reported adverse events (P < .008) was associated with the unstructured trial. There were also fewer drug-related adverse events per patient reported in the unstructured study (17 per 100 patients) than in the other studies (27 to 41 per 100 patients), P < .008. Physician preference for rounding off blood pressure measurements to 0 or 5 occurred most often in the unstructured open trial (P < .008). In conclusion, despite differences in dose titration and in the use of adjuvant therapy, antihypertensive drug therapy effectiveness observed in an RCT may be similar to uncontrolled postmarketing studies. Open trials with scheduled follow-up visits are as effective in detecting severe adverse events as RCT, but postmarketing studies with unstructured schedules of follow-up are insufficient in identifying drug-related adverse events and have poorer quality data.     

Radiologic progression in early rheumatoid arthritis treated with methotrexate

OBJECTIVE: To evaluate radiologic progression in patients with early rheumatoid arthritis (RA) receiving methotrexate (MTX) as the first slow acting drug. METHODS: An open, prospective study of 29 patients with RA (21 F, 8 M, mean age 48.5+/-15.4 yrs). The mean duration of RA was 6.6 (2-60) months; and rheumatoid factor was present in 11 cases. Clinical, biological, and radiographic evaluations were done before the start of MTX treatment and after 13+/-3.8 months. Radiographs of hands and wrists were blindly studied by 2 physicians, using Larsen's and modified Sharp's methods. There was a significant correlation for the scores of the 2 physicians evaluated by kappa coefficient. Radiographic evolution was defined as an increase of 15 points in the radiologic score by each method used. RESULTS: Patients showed significant clinical improvement after one year of MTX treatment. Despite clinical and biological improvement, significant mean radiographic progression was noted, with Larsen's method (p = 0.001) and Sharp's method (p = 0.034), without reaching the maximum score. However, using the definition of radiographic progression, the radiologic scores indicated stabilization in 23 patients with Larsen's method and in 24 patients with Sharp's method. CONCLUSION: This study revealed mild radiographic progression in early RA patients treated with MTX for one year. Further controlled studies are needed.     

Olsalazine versus mesalazine in the treatment of mild to moderate ulcerative colitis

AIM: To compare the efficacy and tolerability of olsalazine sodium with enteric-coated mesalazine in inducing endoscopic remission in patients with mild to moderate active ulcerative colitis. PATIENTS AND METHODS: Patients with mild to moderate active ulcerative colitis were randomized to receive either olsalazine sodium, 3 g/day (n = 88), or mesalazine, 3 g/day (n = 80), for up to 12 weeks. RESULTS: Of the patients treated with olsalazine sodium, 52.2% achieved endoscopic remission, compared with 48.8% of patients treated with mesalazine. This difference was not significant (P = 0.67). There was a nonsignificant trend for patients with left-sided colitis or a more severe endoscopic grade to achieve remission if they were treated with olsalazine sodium than if they were treated with mesalazine. Both treatments were comparable with respect to clinical activity index and an investigator's global assessment. Seventy patients reported one or more adverse events; adverse events were seen in 45% of olsalazine sodium-treated patients and in 36% of mesalazine-treated patients. Eleven patients treated with olsalazine sodium and nine patients treated with mesalazine withdrew from the study because of adverse events. One patient treated with olsalazine sodium compared with two treated with mesalazine stopped treatment because of diarrhoea. Serious adverse events occurred in three patients treated with olsalazine sodium and in four treated with mesalazine. CONCLUSION: Therapeutic effectiveness and tolerance to the treatment did not differ between olsalazine sodium, 3 g/day, and mesalazine, 3 g/day, in inducing endoscopic remission in patients with mild to moderate active ulcerative colitis within 12 weeks of treatment.     

Effect of gold treatment on the progression of erosions in RA patients

The progressive of erosive X-ray changes over a period of 5-6 years was evaluated in RA patients with a low or high dose of gold during the follow-up period. The "low gold" group included 18 patients whose treatment was discontinued because of side effects at a mean dose of 254 mg of Myocrisin. The "high gold" group included 32 patients who received a mean dose of 1858 mg of Myocrisin. Both the number of eroded joints in the hands and feet and the X-ray stage had deteriorated more in the "low gold" group. The inter-group difference was statistically significant. Thus, gold treatment has a retarding effect on the progression of erosions in RA patients.     

Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression

OBJECTIVE: To describe the longitudinal radiographic course of rheumatoid arthritis (RA), and to identify and quantitate predictors of radiographic progression. METHODS: This prospective, longitudinal study of radiographic progression and clinical predictors of RA involved 256 patients with RA who were seen within the first 2 years of disease (mean 0.77 years) and were followed up for up to 19 years. Participants underwent a total of 6,278 clinical assessments (mean 24.5) and 934 paired radiographs (mean 3.1, range 2-6). Clinical assessments at every visit included determination of the erythrocyte sedimentation rate (ESR), grip strength, pain scores, tender joint counts, and anxiety and depression measurements. Regression analyses utilized time-integrated predictors. RESULTS: Overall, radiographic progression rates, as measured by the summary Sharp scores, appeared constant over the course of RA. The strongest correlate of progression was the time-integrated ESR (rho=0.53). This association grew stronger with time. At 0-5 years, 5-10 years, 10-15 years, and 15-20 years, correlations were 0.40, 0.50, 0.65, and 0.74, respectively, and for the period 10-20 years, the correlation was 0.67. In multivariate models, the mean ESR, mean grip strength, rheumatoid factor positivity, and tender joint count were independent predictors of radiographic progression. CONCLUSION: Radiographic damage occurs at a constant rate in RA, and is not greater early in RA or reduced later in the course of the illness. Acute-phase reactants are, by far, the strongest determinants of progression.     

A T cell receptor beta chain variable region polymorphism associated with radiographic progression in rheumatoid arthritis

OBJECTIVE: In rheumatoid arthritis (RA) genetic factors influence susceptibility to disease and progression. Identifying these genetic factors may give more insight into the aetiology and pathogenesis of this disease. Furthermore, if these genetic markers can predict progression in an early stage of disease, timely institution of more aggressive treatment in patients with a bad prognosis may help to prevent joint damage. Several studies have shown that HLA-DRB1 alleles are associated with RA, whereas others have indicated that genes not linked to the HLA complex are also involved. Candidates for such genes are the T cell receptor (TCR) alpha/beta genes. METHODS: The association of a polymorphism in a TCR beta chain variable region gene (TCR-V beta 8) with both risk for RA and radiographic progression of joint disease was analysed after a three year follow up. A cohort of 118 white patients with a duration of disease shorter than one year at entry, and 110 white controls were typed for this (BamHI) TCR-V beta 8 polymorphism. RESULTS: The distribution of the two alleles, 2.0 and 23.0 kb, was identical in patients and controls. Radiographic progression (modified Sharp method) after a three year follow up, studied in 111 patients, was significantly less in the group possessing the 2.0 kb allele (p = 0.03). CONCLUSION: This does not confirm the reported association of the (BamHI) TCR-V beta 8 2.0 kb allele with RA. By contrast with previous findings in smaller studies, in the present study this 2.0 kb allele was protective against radiographic progression. Because well known prognostic variables in RA were corrected for, the findings indicate that the TCR-V beta 8 polymorphism studied is a new prognostic marker for this disease.     

Validation of rheumatoid arthritis improvement criteria that include simplified joint counts

OBJECTIVE: To study the validity of response criteria for rheumatoid arthritis (RA) that included 28-joint counts instead of more comprehensive joint counts. METHODS: In a double-blind, placebo-controlled trial of 105 patients treated with methotrexate, sulfasalazine, or both, response was evaluated at week 52. Both European League Against Rheumatism and American College of Rheumatology definitions of response, with comprehensive as well as simplified joint counts, were calculated. We studied the differences between the criteria with and without simplified joint counts, the discriminating capacity between treatment groups, and the association with change in functional capacity and joint damage. RESULTS: Response criteria that included 28-joint counts classified patients' responses more conservatively. No differences between treatment groups were found with either set of response criteria. The association with change in functional capacity was significant in all cases. All response criteria were significantly associated with radiographic progression of RA. CONCLUSION: Improvement criteria that include 28-joint counts are as valid as the original improvement criteria that included more comprehensive joint counts.     

Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomized prospective trial

BACKGROUND: Parenteral nutrition is well established for providing nutritional support in acute pancreatitis while avoiding pancreatic stimulation. However, it is associated with complications and high cost. Benefits of enteral feeding in other disease states prompted a comparison of early enteral feeding with total parenteral nutrition in this clinical setting. METHODS: Thirty-eight patients with acute severe pancreatitis were randomized into two groups. The first (n = 18) received enteral nutrition through a nasoenteric tube with a semi-elemental diet, while the second group (n = 20) received parenteral nutrition through a central venous catheter. Safety was assessed by clinical course of disease, laboratory findings and incidence of complications. Efficacy was determined by nitrogen balance. The cost of nutritional support was calculated. RESULTS: Enteral feeding was well tolerated without adverse effects on the course of the disease. Patients who received enteral feeding experienced fewer total complications (P < 0.05) and were at lower risk of developing septic complications (P < 0.01) than those receiving parenteral nutrition. The cost of nutritional support was three times higher in patients who received parenteral nutrition. CONCLUSION: This study suggests that early enteral nutrition should be used preferentially in patients with severe acute pancreatitis.     

Salsalate, a nonacetylated salicylate, is as efficacious as diclofenac in patients with rheumatoid arthritis. Salsalate-Diclofenac Study Group

OBJECTIVE: To investigate the efficacy of salsalate, a nonacetylated salicylate, in the treatment of patients with rheumatoid arthritis (RA). METHODS: Three hundred and one patients meeting the ACR criteria for RA were drawn from 16 centers. After withdrawal of nonsteroidal antiinflammatory drugs (NSAID) and subsequent flare, patients were randomized to receive either salsalate or diclofenac for 8 weeks, according to a double blind, double dummy protocol. Initial doses of salsalate 3.0 g/day and diclofenac 75 mg/day were titrated for the first 5 weeks. The primary outcome measure was a multivariate analysis at 8 weeks of tender joint count, pain, visual analog scale score, and physician's global assessment. RESULTS: One hundred and ninety patients completed the study. The mean stabilized dose of salsalate was 3.55 g/day, and that of diclofenac 112 mg/day. Discontinuations were due to lack of efficacy (17 salsalate vs 15 diclofenac); adverse events [19 salsalate (mainly tinnitus and hearing loss; p = 0.0001 and p = 0.04, respectively) vs 9 diclofenac]; laboratory abnormalities (3 salsalate vs 1 diclofenac); and other reasons, including protocol violations, intercurrent illness, and personal factors (24 salsalate vs 23 diclofenac). Both treatments produced significant improvement from flare (p < 0.0001). Post hoc power analysis showed that the study had sufficient power (0.60 to 0.90) to detect clinically important differences between the 2 drugs in the primary outcome measures; however, no statistically significant (p = 0.29) or clinically important treatment differences were recorded. Other than a difference in erythrocyte sedimentation rate that favored salsalate, there were no significant differences in secondary outcome measures between the 2 groups. All outcomes showed a tendency for more improvement with salsalate. CONCLUSION: Salsalate is as efficacious as diclofenac. Salsalate may be considered an alternative to other NSAID in the first line treatment of patients with RA.