Risk factors of severe infections in patients with rheumatoid arthritis treated with leflunomide

Abstract

Objectives To determine the risk of severe infection requiring or complicating hospitalization associated with leflunomide therapy in patients with rheumatoid arthritis (RA).

Methods We performed a retrospective study of RA patients who were prescribed leflunomide between 2004 and 2011. Background clinical and laboratory features were compared between patients who suffered severe leflunomide-associated infections and those who did not.

Results Since January 2005, 401 RA patients have started on leflunomide. Among those, 33 (8.2 %) developed severe infections: pneumonia, oral candidiasis, pyelonephritis, pulmonary tuberculosis, cellulitis, disseminated herpes zoster, tonsillitis, and pulmonary cryptococcosis. Logistic regression showed that age at entry, the presence of DM, and daily dosage of corticosteroid were associated with development of severe infections.

Conclusions These results showed that some patients with RA who were taking leflunomide developed severe infections requiring hospitalization, and that older age, DM, and a higher daily dosage of corticosteroid were risk factors associated with leflunomide-associated severe infections.     

Efficacy and safety of leflunomide 10 mg versus 20 mg once daily in patients with active rheumatoid arthritis: multinational double-blind, randomized trial

OBJECTIVE: To compare the efficacy and safety profile of two daily maintenance doses of leflunomide, 10 mg and 20 mg, for the treatment of active rheumatoid arthritis (RA). METHODS: In this multinational, randomized, double-blind, parallel-group study, 402 RA patients were randomized equally to receive daily doses of 10 mg leflunomide (n = 202; loading dose on day 3, 100 mg) or 20 mg leflunomide (n = 200; loading dose on day 1-3, 100 mg) for 24 weeks. The study was designed to demonstrate non-inferiority of the efficacy of 10 mg compared with 20 mg by calculating 95% confidence intervals for differences in changes in tender joint count (TJC), swollen joint count (SJC) and Health Assessment Questionnaire Disability Index (HAQ DI), comparing these confidence intervals with predefined bounds. RESULTS: In the intent-to-treat population, mean improvements at the end-point in the 10 and 20 mg groups respectively were: TJC, -7.57 and -8.89 (P = 0.061); SJC, -6.38 and -6.96 (P = 0.304); and HAQ DI, 0-0.37 and 0-0.49 (P = 0.095). By American College of Rheumatology (ACR) > or =20% criteria, response rates were 49.8 and 56.6% respectively (P = 0.1724). Adverse events (AEs) resulting in treatment withdrawal were higher in the 10 mg (15.3%) than in the 20 mg treatment group (12.0%), as were serious adverse events (SAEs): 12.9 vs 10.0%. CONCLUSIONS: This study rejected the hypothesis of non-inferiority of 10 mg compared with 20 mg daily maintenance doses of leflunomide. More AEs resulting in treatment discontinuation and SAEs in patients receiving 10 mg leflunomide daily also support a better efficacy profile for the 20 mg daily dose.     

Adalimumab,a fully human anti-tumor necrosis factor alpha monoclonal antibody,for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

OBJECTIVE: To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX. METHODS: In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks. RESULTS: An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events. CONCLUSION: The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.     

Safety,tolerability, pharmacodynamics and pharmacokinetics of the soluble guanylyl cyclase activator BI 685509 in patients with diabetic kidney disease: A randomized trial

Aims

Albuminuria is associated with abnormalities in the nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cyclic guanosine monophosphate pathway. We assessed safety and efficacy of the NO-independent sGC activator BI 685509 in patients with diabetic kidney disease and albuminuria.

Materials and methods

In this Phase Ib trial (NCT03165227), we randomized patients with type 1 or 2 diabetes, estimated glomerular filtration rate (eGFR) 20–75 mL/min/1.73 m² and urinary albumin:creatinine ratio (UACR) 200–3500 mg/g to oral BI 685509 (1 mg three times daily, n = 20; 3 mg once daily, n = 19; 3 mg three times daily, n = 20, after final titration) or placebo (n = 15) for 28 days. Changes from baseline in UACR in first morning void (UACR_FMV) and 10-hour (UACR_10h) urine (3 mg once daily/three times daily only) were assessed.

Results

Baseline median eGFR and UACR were 47.0 mL/min/1.73 m² and 641.5 mg/g, respectively. Twelve patients had drug-related adverse events (AEs; 16.2%: BI 685509, n = 9; placebo, n = 3), most frequently hypotension (4.1%: BI 685509, n = 2; placebo, n = 1) and diarrhoea (2.7%: BI 685509, n = 2; placebo, n = 0). Four patients experienced AEs leading to study discontinuation (5.4%: BI 685509, n = 3; placebo, n = 1). Placebo-corrected mean UACR_FMV decreased from baseline in the 3-mg once-daily (28.8%, P = 0.23) and three-times-daily groups (10.2%, P = 0.71) and increased in the 1-mg three-times-daily group (6.6%, P = 0.82); changes were not significant. UACR_10h decreased by 35.3% (3 mg once daily, P = 0.34) and 56.7% (3 mg three times daily, P = 0.09); ≥50.0% of patients (UACR_10h 3 mg once daily/three times daily) responded (≥20% UACR decrease from baseline).

Conclusions

BI 685509 was generally well tolerated. Effects on UACR lowering merit further investigation.     

Oral type II collagen treatment in early rheumatoid arthritis. A double-blind,placebo-controlled,randomized trial

Objective. To investigate the efficacy of oral type II collagen in the treatment of early rheumatoid arthritis (RA). Methods. Ninety patients with RA (disease duration ⩽3 years) were treated for 12 weeks with oral bovine type II collagen at 1 mg/day (n = 30) or 10 mg/day (n = 30) or with placebo (n = 30), in a double-blind randomized study. Results. There was no significant difference between the 3 groups in terms of response to treatment. However, we observed a higher prevalence of responders in the type II collagen-treated groups: 7 responders in the 10-mg type II collagen group and 6 in the 1-mg group, versus 4 in the placebo group. Furthermore, 3 patients in the 10-mg type II collagen group and 1 patient in the 1-mg type II collagen group, but no patients in the placebo group, had very good response. A total of 14 patients had to be withdrawn from the study: 2 because of side effects (nausea) and 12 because of lack of efficacy. Conclusion. Only a minority of patients responded to treatment with oral type II collagen. These results justify further efforts to identify which patients will have a good response to such therapy.     

When a DMARD fails,should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide?

OBJECTIVE: To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy. METHODS: Patients with active RA ((DAS28) >3.2) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks. Inadequate responders then entered the double blind phase and received a further 24 weeks' treatment with leflunomide (20 mg once daily) plus sulfasalazine (final dose 2 g once daily), or placebo plus sulfasalazine (dose as above). The primary efficacy variable was the DAS28 response rate, and secondary efficacy outcomes were ACR 20%, 50%, and 70% response rates. Adverse events, including standard laboratory tests, were recorded. RESULTS: 106 inadequate responders entered the double blind phase; 56 received leflunomide plus sulfasalazine, and 50 placebo plus sulfasalazine. In the intention to treat population, more patients receiving leflunomide plus sulfasalazine (25/56 (45%)) achieved a DAS28 response than those receiving placebo plus sulfasalazine (17/50 (34%)) (p = 0.179). In week 24 completers, more patients receiving leflunomide plus sulfasalazine (17/56 (30%)) were DAS28 responders than those receiving placebo plus sulfasalazine (10/50 (20%)) (p = 0.081). Comparable numbers in each group were ACR 20% responders; the ACR 50% response rate was significantly higher in the leflunomide plus sulfasalazine group (8.9%) than in the placebo plus sulfasalazine group (0%) (p = 0.038). The safety profiles of both groups were comparable. CONCLUSION: Patient numbers are small and firm conclusions cannot be reached, but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide.     

Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate

Objective

To compare the efficacy, safety, and tolerability of 4 doses of oral tofacitinib (CP‐690,550) with placebo in Japanese patients with active rheumatoid arthritis (RA) receiving stable background methotrexate (MTX) who had an inadequate response to MTX alone.

Methods

A total of 140 patients were randomized to receive tofacitinib 1, 3, 5, and 10 mg twice a day or placebo in this 12‐week, phase II, double‐blind study. All patients remained on background MTX. Efficacy and safety were assessed at weeks 1, 2, 4, 8, and 12. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.

Results

ACR20 response rates at week 12 were significant (P < 0.0001) for all tofacitinib treatment groups: 1 mg twice a day, 64.3%; 3 mg twice a day, 77.8%; 5 mg twice a day, 96.3%; and 10 mg twice a day, 80.8% versus placebo, 14.3%. A significant dose‐response relationship for the ACR20 was observed (P < 0.0001). Low disease activity was achieved by 72.7% of patients with high baseline disease activity for tofacitinib 10 mg twice a day at week 12 (P < 0.0001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, and Disease Activity Score 28‐3 (C‐reactive protein) were also reported. The most commonly reported adverse events (AEs) were nasopharyngitis (n = 13) and increased alanine aminotransferase (n = 12) and aspartate aminotransferase (n = 9) levels. These AEs were mild or moderate in severity. Serious AEs were reported by 5 patients. No deaths occurred.

Conclusion

In Japanese patients with active RA with an inadequate response to MTX, tofacitinib in combination with MTX over 12 weeks was efficacious and had a manageable safety profile.     

Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data

Abstract

Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We investigated concomitant methotrexate (MTX) dose on tofacitinib efficacy/safety in Japanese RA patients.

Methods: This post hoc analysis pooled data from a 3-month phase 2 study (NCT00603512) and a 24-month phase 3 study (NCT00847613). Patients (N= 254) received tofacitinib (low-dose (1 or 3?mg), 5?mg, 10?mg) twice daily (BID) or placebo, with low-dose (>0 to 8?mg/week) or high-dose (>8?mg/week) MTX. Efficacy (ACR20/50/70 and DAS28-4 (ESR)<2.6 response rates; changes from baseline (CFB) in DAS28-4 (ESR) and HAQ-DI) and safety (adverse events (AEs), discontinuations due to AEs, serious AEs, and deaths) were assessed through month 3.

Results: At month 3, ACR20/50/70 response rates, mean DAS28-4 (ESR) CFB and HAQ-DI CFB were similar across MTX doses and generally greater for all tofacitinib doses versus placebo. AE rates with low-dose/high-dose MTX were: placebo, 28.6%/52.9%; tofacitinib low-dose, 50.0%/66.7%; 5?mg BID, 56.5%/64.3%; 10?mg BID, 73.8%/67.7%.

Conclusion: Tofacitinib efficacy in Japanese RA patients may be unaffected by background MTX dose. AE rates with low-dose versus high-dose MTX were lower with placebo, tofacitinib low-dose or 5?mg BID, but not 10?mg BID, with no apparent differences across system organ class/laboratory parameters.     

Lack of a renal–protective effect of misoprostol in rheumatoid arthritis patients receiving cyclosporin a. results of a randomized,placebo–controlled trial

Objective. To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy. Methods. In this randomized, placebo–controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 μg/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks. Results. A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events. Conclusion. A renal–protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.     

Faldaprevir,pegylated interferon,and ribavirin for treatment-naïve HCV genotype-1: pooled analysis of two phase 3 trials

Introduction & aim. Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor. The STARTVerso1 and STARTVerso2 phase 3 studies evaluated faldaprevir plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic HCV genotype-1 infection.Material and methods. Patients were randomized 1:2:2 to receive placebo, faldaprevir 120 mg q.d. (12 or 24 weeks) or faldaprevir 240 mg q.d. (12 weeks) all with PegIFN/RBV (24-48 weeks). Faldaprevir 120 mg for 12 weeks only (STARTVerso1 only) required early treatment success (ETS, HCV RNA < 25 IU/mL at week 4 and undetected at week 8). All faldaprevir-treated patients with ETS stopped PegIFN/RBV at week 24. Primary endpoint: sustained virologic response 12 weeks post-treatment (SVR12).Results. SVR12 rates were significantly higher for patients treated with faldaprevir 120 or 240 mg (72% and 73%, respectively) compared with placebo (50%); estimated differences (adjusted for trial, race, and genotype-1 subtype) faldaprevir 120 mg 24% (95% CI: 17-31%, P < 0.0001), faldaprevir 240 mg 23% (95% CI: 16-30%, P < 0.0001). Subgroup analyses consistently showed higher SVR12 rates for patients receiving faldaprevir compared with placebo. The incidence of adverse events (AEs) was similar in faldaprevir 120-mg and placebo groups and slightly higher in the faldaprevir 240-mg group. Serious AEs were reported in 6%, 7%, and 8% of patients in placebo, faldaprevir 120-mg, and faldaprevir 240-mg groups, respectively.Conclusion. Addition of faldaprevir to PegIFN/RBV increased SVR12 in patients with HCV genotype-1, and was well tolerated. Faldaprevir 120 mg is effective in the treatment of HCV genotype-1. ClinicalTrials.gov: NCT01343888 and NCT01297270.     

Alendronate in rheumatoid arthritis patients treated with methotrexate and glucocorticoids

Rheumatoid arthritis (RA) is a systemic inflammatory disease. Along with synovial joint inflammation, extra-articular involvement is a common feature of RA. Periarticular and generalized osteoporosis are seen both as an extra-articular feature of the disease itself and due to various medications like glucocorticoids and methotrexate (MTX). In this study, we investigated the effects of oral alendronate in RA patients treated with MTX and prednisolone by comparing the effects of “alendronate+calcium” and “only calcium” on bone mineral density (BMD). Fifty RA patients classified according to American Rheumatism Association (ARA) criteria were included in the study. The control group consisted of 20 postmenopausal osteoporotic patients. The RA patients were divided randomly into two groups. All patients were started on MTX 7.5 mg/week, 2.5-mg daily folic acid, and 7.5-mg daily prednisolone. The first group, consisting of 25 female RA patients, was also given 10-mg daily alendronate and 1000-mg daily calcium. The second group also consisted of 25 female patients and was given only 1000-mg calcium per day. The postmenopausal control group was given daily 10-mg alendronate and 1000-mg calcium. Bone mineral densities were measured by dual-energy x-ray absorptiometry (DEXA) and again at the end of the sixth month. At the end of the study, RA patients given only calcium had reduced mean BMD, and patients treated with alendronate and calcium showed increased mean BMD almost in all regions. This increase was significant in the L2 and L1–4 total regions. In postmenopausal osteoporotic patients, we saw statistically significant increases in BMD in all regions. The increase in BMD values in RA patients treated with alendronate was smaller than in those of the control group of postmenopausal osteoporosis patients. In conclusion, RA itself has a risk factor for osteoporosis in addition to the risks of the medications like corticosteroids and MTX. In the prevention and treatment of RA-associated osteoporosis, alendronate and calcium therapy is effective and well tolerated. Received: 16 June 2000 / Accepted: 20 August 2000     

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve‐month results of a phase iib,double‐blind,randomized, placebo‐controlled trial

Objective

To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA‐4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy.

Methods

This was a 12‐month, multicenter, randomized, double‐blind, placebo‐controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial.

Results

A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 1 year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of <2.6) compared with placebo at 1 year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted.

Conclusion

Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy.

     

Leflunomide increases the risk of early healing complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery

The aim of this object is to study whether treatment with biological or leflunomide increases the risk of wound-healing complications after elective orthopedic surgery. Between March 2002 and September 2003, 201 patients participated in this study with the following inclusion criteria: (a) Rheumatoid arthritis (RA) or psoriatic arthritis (psA), (b) therapy with: MTX, leflunomide, etanercept, infliximab, adalimumab, anakinra, (c) undergoing elective orthopedic surgery. The incidence of early postoperative wound-healing complications was compared among the different groups. In comparison with patients who received MTX therapy (n = 59), the risk of postoperative wound-healing complications in patients undergoing leflunomide therapy (n = 32) was significantly higher: 13.6% in the MTX group, 40.6% in the leflunomide group (P = 0.01). It is recommended that leflunomide medication for patients with RA undergoing elective orthopedic surgical procedure is interrupted preoperatively to reduce the risk of early wound-healing complications or infections.     

Comparative efficacy and tolerability of monotherapy with leflunomide or tacrolimus for the treatment of rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials

We aimed to assess the relative efficacy and tolerability of monotherapy with leflunomide or tacrolimus at recommended dosages in rheumatoid arthritis (RA) patients. Randomized controlled trials (RCTs) examining the efficacy and tolerability of leflunomide 20 mg, leflunomide 10 mg, tacrolimus 3 mg, tacrolimus 1.5–2 mg, and placebo, based on the number of withdrawals of RA patients, were included. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs. Six RCTs including 1510 patients met the inclusion criteria. The proportion of patient withdrawals owing to lack of efficacy was significantly lower in the leflunomide 20 mg (OR 0.17, 95% credible interval (CrI) 0.08–0.34); leflunomide 10 mg (OR 0.16, 95% CrI 0.02–0.75); and tacrolimus 3 mg (OR 0.41, 95% CrI 0.21–0.74) groups than in the placebo group. Rank probability based on the surface under the cumulative ranking curve (SUCRA) values indicated that leflunomide 20 mg had the highest probability of being the best treatment based on the number of withdrawals owing to lack of efficacy (SUCRA = 0.8530), followed by leflunomide 10 mg (SUCRA = 0.8321), tacrolimus 3 mg (SUCRA = 0.4965), tacrolimus 1.5–2 mg (SUCRA = 0.3035), and placebo (SUCRA = 0.0150). Patient withdrawals owing to adverse events did not differ significantly among the groups; however, withdrawals in the placebo group were fewer than those in the leflunomide 20 mg group (OR 0.22, 95% CrI 0.07–0.74). Placebo had the highest probability of being the most tolerable treatment (SUCRA = 0.8161) followed by tacrolimus 3 mg (SUCRA = 0.6490), tacrolimus 1.5–2 mg (SUCRA = 0.4857), leflunomide 10 mg (SUCRA = 0.4651), and leflunomide 20 mg (SUCRA = 0.0841). Leflunomide 20 mg, leflunomide 10 mg, and tacrolimus 3 mg were more efficacious than placebo, while leflunomide 20 mg was less tolerable than placebo. Leflunomide is likely to be more efficacious but less tolerable than tacrolimus for RA treatment.     

Evaluation of the efficacy and safety of oral tiludronate in paget's disease of bone

Objective. To assess the optimal dosage of oral tiludronate in Paget's disease of bone. Methods. We studied 149 patients with Paget's disease, in a double-blind, randomized, placebo-controlled trial. Patients were randomly assigned to 1 of 5 therapeutic groups: a daily dose of 100 mg, 200 mg, 400 mg, or 800 mg of oral tiludronate, or a placebo. Treatment was for 3 months, followed by 3 months of placebo-controlled followup. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatinine (OH/Cr) were measured monthly, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale and a global pain index. Results. Statistical analysis revealed that beginning at a dosage of 200 mg/day, there was a direct dose-dependent effect on the reduction of SAP and OH/Cr levels. Reduction of SAP levels was clinically significant at a dosage of 400 mg (44.9 ± 4.2% reduction at 90 days and 49.2 ± 4.5% at 180 days, mean ± SEM) and at 800 mg (53.4 ± 5% at 90 days and 59.3 ± 4.6% at 180 days). There was a significant reduction in pain in all groups, including the group taking placebo. In only those taking 800 mg/day of tiludronate was there a significant frequency of complete resolution of pain (versus placebo). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance of all 5 regimens was good. Exhaustive biochemical investigations failed to reveal significant toxicity of tiludronate up to the 800-mg daily dose investigated. Conclusion. Because of its significantly better antiresorptive effects and greater analgesic properties (compared with lower dosages), combined with the excellent clinical and biochemical tolerance, the 800-mg daily dose of tiludronate appears to be optimal for the treatment of Paget's disease of bone.     

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA). METHODS: This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg. RESULTS: A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by >/=40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients. CONCLUSION: Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates.     

Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group

OBJECTIVE: To evaluate the efficacy and safety of diacerein, a drug with interleukin-1beta--inhibitory activity in vitro, in patients with knee osteoarthritis (OA). METHODS: A total of 484 patients fulfilling the American College of Rheumatology criteria for knee OA were enrolled in this 16-week, randomized, double-blind, placebo-controlled, parallel study group with 3 diacerein dosages of 50 mg/day, 100 mg/day, and 150 mg/day (administered twice daily). RESULTS: In the intent-to-treat population, 100 mg/day diacerein (50 mg twice daily) was significantly superior (P < 0.05) to placebo using the primary criterion (visual analog scale [VAS] assessment of pain on movement). Significant improvement (P < 0.05) was also observed for the secondary criteria, which included the Western Ontario and McMaster Universities OA Index (WOMAC), the WOMAC subscores, and the VAS assessment of handicap. In patients treated with diacerein dosages of 50 mg/day and 150 mg/day, favorable but not significant results were observed for the primary criterion. The best daily dosage of diacerein, calculated from the effect on the VAS assessment of pain on movement, was 90.1 mg. In the per-protocol population, the analysis of the primary criterion showed significant dose-dependent differences (P < 0.05) between each of the 3 diacerein dosages and the placebo. No differences were observed among the 3 diacerein groups. A significantly higher incidence (P < 0.05) of adverse events (AEs), as well as a higher rate of dropoout due to AEs, was observed in patients treated with 150 mg/day diacerein versus those treated with placebo, 50 mg/day diacerein, or 100 mg/day diacerein. Mild-to-moderate transient changes in bowel habits were the most frequent AEs, increasing with the dosage. CONCLUSION: Diacerein, a drug for the treatment of OA, was shown to be an effective treatment for symptoms in patients with knee OA. Taking into account both efficacy and safety, the optimal daily dosage of diacerein for patients with knee OA is 100 mg/day (50 mg twice daily).     

Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind,randomized, placebo-controlled trial

OBJECTIVE: To evaluate whether treatment with prasterone (dehydroepiandrosterone [DHEA]) would allow the dosage of prednisone (or an equivalent corticosteroid) to be reduced to < or = 7.5 mg/day for 2 months or longer while maintaining stable or reduced disease activity in steroid-dependent women with systemic lupus erythematosus (SLE). METHODS: In a double-blind, randomized trial, 191 female SLE patients receiving prednisone (10-30 mg/day) were treated daily with either placebo, 100 mg of oral prasterone (an adrenal androgen), or 200 mg of oral prasterone for 7-9-months. At monthly intervals, corticosteroid dosages were reduced by algorithm in patients whose SLE Disease Activity Index (SLEDAI) score was stable or improved. Patients for whom a sustained reduction in the dosage of prednisone (< or = 7.5 mg/day) was achieved for at least the last 2 months of the 7-9-month treatment period were classified as responders. RESULTS: Response rates were 41% in the placebo group, 44% in the 100-mg prasterone group, and 55% in the 200-mg group (P = 0.110, 200 mg versus placebo). Among the 137 subjects (45 in the placebo group, 47 in the 100-mg group, and 45 in the 200-mg group) who had active disease at baseline (defined as SLEDAI score >2), 29%, 38%, and 51%, respectively, were responders (P = 0.031 for 200 mg prasterone versus placebo). Acne was the most common adverse event but was generally mild. Clinical and laboratory changes primarily reflected androgenic effects of prasterone. CONCLUSION: Among women with lupus disease activity, reducing the dosage of prednisone to < or = 7.5 mg/day for a sustained period of time while maintaining stabilization or a reduction of disease activity was possible in a significantly greater proportion of patients treated with oral prasterone, 200 mg once daily, compared with patients treated with placebo.     

Assessment of the effectiveness of golimumab 50-mg and 100-mg regimens in patients with rheumatoid arthritis in daily practice

Abstract

Objectives. To assess the effectiveness of the golimumab (GLM) 50-mg and 100-mg regimens in patients with rheumatoid arthritis (RA) in daily practice. Methods. We retrospectively analyzed RA patients who started GLM between September 2011 and July 2012. Patients were divided into three groups: a 50-mg group; a 50/100-mg group (had a dose increase to 100 mg); and a 100-mg group (started GLM at 100 mg). We assessed Disease Activity Score 28 (DAS28) and treatment continuation rate. Risk factors associated with time to discontinuation of the 50-mg regimen were determined with proportional hazards analysis. Results. We analyzed 74 patients: 43 in the 50-mg group, 23 in the 50/100-mg group, and 8 in the 100-mg group. DAS28 improved from 4.0 ± 1.0, 4.8 ± 1.0, and 4.7 ± 1.9, respectively, at baseline to 2.4 ± 1.2, 3.3 ± 1.5, and 2.5 ± 0.7, respectively, at week 52. Treatment continuation rates at week 52 were 73.7%, 60.9%, and 87.5%, respectively. In the 50/100-mg group, the mean DAS28 improved significantly from 4.4 ± 1.2 before to 3.6 ± 1.3 12 weeks after the dose increase. Oral corticosteroid therapy ≥ 5 mg/day, previous use of two biologic agents, and DAS28 > 5.1 at initiation of GLM were significantly associated with discontinuation of the 50-mg regimen. Conclusions. Both GLM 50-mg and 100-mg regimens are effective in patients with RA in daily practice.     

Double-blind,placebo-controlled multicenter trial using chimeric monoclonal anti-cd4 antibody,cm-t412, in rheumatoid arthritis patients receiving concomitant methotrexate

Objective. To evaluate the clinical response to and safety of single and repeat doses of a chimeric anti-CD4 monoclonal antibody, cM-T412, in patients with rheumatoid arthritis (RA) concomitantly treated with a stable regimen of low-dose methotrexate. Methods. Sixty-four patients with refractory RA, who were already receiving stable doses of methotrexate, were randomized into a multicenter, double-blind, placebo-controlled trial to receive 3 monthly treatments with either a placebo, or 5, 10, or 50 mg cM-T412, given intravenously. Results. Using ≥50% improvement in swollen joint counts as a criterion for clinical response, 13%, 13%, 18%, and 13% of patients receiving 50, 10, or 5 mg cM-T412, or the placebo, respectively, exhibited a clinical response at 3 months of therapy. Using ≥50% improvement in tender joint counts as a measure of clinical efficacy at 3 months, 19%, 13%, 12%, and 6% of patients receiving 50, 10, or 5 mg cM-T412, or the placebo, respectively, exhibited a clinical response. “Flu-like” symptoms (fever, chills, rigor) within 24 hours of the infusion occurred more frequently in the groups receiving 50-mg (29%) and 10-mg (31%) doses of cM-T412 than those receiving 5 mg cM-T412 (12%) or the placebo (13%). Significant CD4+ T cell depletion occurred in the 50-mg group (mean of 353 CD4+ T cells/mm³ at 6 months versus 856 CD4+ T cells/mm³ at baseline). All patients were followed up for 12 months after the final treatment; no opportunistic infectious complications occurred. Conclusion. Treatment with cM-T412 in this cohort of RA patients who were also taking methotrexate was not associated with clinical efficacy or enhanced toxicity from infectious complications, despite significant peripheral CD4+ T cell depletion.