Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine

OBJECTIVE: To compare the efficacy of minocycline with that of a conventional disease-modifying antirheumatic drug (DMARD), hydroxychloroquine, in patients with early seropositive rheumatoid arthritis (RA). METHODS: Sixty patients with seropositive RA of <1 year's duration who had not been previously treated with DMARDs were randomized to receive minocycline, 100 mg twice per day, or hydroxychloroquine, 200 mg twice per day, in a 2-year, double-blind protocol. All patients also received low-dose prednisone. The primary end points of the study were 1) the percentage of patients with an American College of Rheumatology (ACR) 50% improvement (ACR50) response at 2 years, and 2) the dosage of prednisone at 2 years. RESULTS: Minocycline-treated patients were more likely to achieve an ACR50 response at 2 years compared with hydroxychloroquine-treated patients (60% compared with 33%, respectively; P = 0.04). Minocycline-treated patients were also receiving less prednisone at 2 years compared with the hydroxychloroquine group (mean 0.81 mg/day compared with 3.21 mg/day, respectively; P < 0.01). In addition, patients treated with minocycline were more likely to have been completely tapered off prednisone (P = 0.03). Trends favoring the minocycline treatment group were seen when outcomes were assessed according to components of the ACR core criteria set, with the differences reaching statistical significance for patient's global assessment of disease activity (P = 0.004). CONCLUSION: Minocycline is an effective DMARD in patients with early seropositive RA. Patients treated with minocycline were more likely to achieve an ACR50 response and did so while receiving less prednisone. In addition, minocycline-treated patients were more likely to have discontinued treatment with prednisone at 2 years.     

Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine,methotrexate and sulfasalazine,or a combination of the three medications: Results of a two‐year,randomized, double‐blind,placebo‐controlled trial

Objective

To compare the efficacy of combination therapy with methotrexate (MTX) and hydroxychloroquine (HCQ), MTX and sulfasalazine (SSZ), and MTX, HCQ, and SSZ in patients with rheumatoid arthritis (RA).

Methods

RA patients (n = 171) who had not previously been treated with combinations of the study medications were randomized to receive 1 of the 3 treatment combinations in this 2‐year, double‐blind, placebo‐controlled protocol. HCQ was given at a dosage of 200 mg twice a day. The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission. Similarly, the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission. The primary end point of the study was the percentage of patients who had a 20% response to therapy according to the American College of Rheumatology (ACR) criteria at 2 years.

Results

Intent‐to‐treat analysis revealed that patients receiving the triple combination responded best, with 78% achieving an ACR 20% response at 2 years, compared with 60% of those treated with MTX and HCQ (P = 0.05) and 49% of those treated with MTX and SSZ (P = 0.002). Similar trends were seen for the ACR 50% response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years (P = 0.005 for the triple combination group versus the MTX and SSZ group). All combination treatments were well‐tolerated. Fourteen patients (evenly distributed among the 3 groups) withdrew from the protocol because of symptoms that were potentially related to the study medication.

Conclusion

The triple combination of MTX, SSZ, and HCQ is well‐tolerated, and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ.

     

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 ∼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.

     

Treatment of rheumatoid arthritis with humanized anti–interleukin‐6 receptor antibody: A multicenter,double‐blind,placebo‐controlled trial

Objective

Interleukin‐6 (IL‐6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL‐6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL‐6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti–IL‐6 receptor antibody, MRA, in patients with RA.

Methods

In a multicenter, double‐blind, placebo‐controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria.

Results

Treatment with MRA reduced disease activity in a dose‐dependent manner. At 3 months, 78% of patients in the 8‐mg group, 57% in the 4‐mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8‐mg group versus placebo). Forty percent of patients in the 8‐mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4‐mg, and 8‐mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti‐DNA antibodies. Anti‐MRA antibodies were detected in 2 patients.

Conclusion

Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

     

A home‐based two‐year strength training period in early rheumatoid arthritis led to good long‐term compliance: A five‐year followup

Objective

To evaluate the impact of a 2‐year home‐based strength‐training program on physical function in patients with early rheumatoid arthritis (RA) after a subsequent 3‐year followup.

Methods

Seventy patients with early RA were randomized to perform either strength training (experimental group [EG]) or range‐of‐motion exercises (control group [CG]). Maximal strength values were recorded by dynamometers. The Modified Disease Activity Score (DAS28), pain, Health Assessment Questionnaire (HAQ), walking speed, and stair‐climbing speed were also measured.

Results

The maximum strength of assessed muscle groups increased by 19–59% in the EG during the training period and remained at the reached level throughout the subsequent 3 years. Muscle strength improved in the CG by 1–31%, but less compared with the EG. During the 2‐year training period, DAS28 decreased by 50% and 45% and pain by 67% and 39% in the EG and CG, respectively. The differences in muscle strength, DAS28, and HAQ were significantly in favor of the EG both at the 2‐year and 5‐year followup assessments.

Conclusions

The improvements achieved during the 2‐year strength‐training period were sustained for 3 years in patients with early RA.

     

The effects of intravenous doxycycline therapy for rheumatoid arthritis: A randomized,double‐blind,placebo‐controlled trial

Objective

To determine the feasibility, safety, and potential clinical efficacy of intravenous (IV) doxycycline therapy for rheumatoid arthritis (RA), as well as its possible effects on serum and urinary markers of collagen breakdown.

Methods

The exploratory trial was designed as a 16‐week, single‐center, randomized, double‐blind, placebo‐controlled trial. Eligible subjects with active seropositive or erosive RA were randomly allocated into 3 treatment groups: doxycycline 200 mg IV, azithromycin 250 mg orally, or placebo. The blinded IV study drug was administered once daily for the first 3 weeks by home self‐infusion and then weekly for the next 8 weeks, concurrent with the blinded oral study drug at the prescribed doses. The primary end points were the change between baseline and week 4 in the tender joint count, erythrocyte sedimentation rate, and urinary excretion of pyridinoline.

Results

The trial was stopped prematurely after enrollment of 31 patients. Three subjects were withdrawn because of worsening arthritis, and 1 patient was withdrawn when newly diagnosed with breast cancer. Infusion‐related events occurred in 13 (42%) of 31 patients, but none were serious. There were 4 serious adverse events unrelated to the study drug, including a new diagnosis of breast cancer in 3 cases and hospitalization for abdominal pain in 1 case. No significant differences were observed across treatment groups in any of the 3 primary clinical end points.

Conclusion

Although IV doxycycline therapy was generally well‐tolerated by patients in this trial, it did not show any evidence of reducing disease activity or collagen crosslink production.

     

Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double‐blind,randomized, placebo‐controlled trial

Objective

To determine whether patients with undifferentiated arthritis (UA; inflammatory, nontraumatic arthritis that cannot be diagnosed using current classification criteria) benefit from treatment with methotrexate (MTX).

Methods

The PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment (PROMPT) study was a double‐blind, placebo‐controlled, randomized, multicenter trial involving 110 patients with UA who fulfilled the American College of Rheumatology (ACR) 1958 criteria for probable RA. Treatment started with MTX (15 mg/week) or placebo tablets, and every 3 months the dosage was increased if the Disease Activity Score was >2.4. After 12 months, the study medication was tapered and discontinued. Patients were followed up for 30 months. When a patient fulfilled the ACR criteria for RA (primary end point), the study medication was changed to MTX. Joint damage was scored on radiographs of the hands and feet.

Results

In 22 of the 55 patients (40%) in the MTX group, UA progressed to RA compared with 29 of 55 patients (53%) in the placebo group. However, in the MTX group, patients fulfilled the ACR criteria for RA at a later time point than in the placebo group (P = 0.04), and fewer patients showed radiographic progression over 18 months (P = 0.046).

Conclusion

This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.

     

A comparison of patients with seropositive and seronegative rheumatoid arthritis

Summary It has recently been suggested that a subpopulation of patients with rheumatoid arthritis, diagnosed on clinical, radiologic and pragmatic grounds, but with negative rheumatoid factor tests, represents a clinical entity quite distinct from that of seropositve rheumatoid arthritis. We have studied 60 sequentially presenting patients, 30 of whom were selected because they were seronegative, and 30 selected because they were seropositive in regard to IGM rheumatoid factor. The only major differences detected between the two groups on blind assessment were a greater tendency to deformity, a greater degree of erosion and the presence of subcutaneous nodules in the seropositive group. Seronegative and seropositive rheumatoid arthritis appear to have very similar clinical features, but differing degrees of severity.     

Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone

OBJECTIVE: To compare the efficacy of doxycycline plus methotrexate (MTX) versus MTX alone in the treatment of early seropositive rheumatoid arthritis (RA), and to attempt to differentiate the antibacterial and antimetalloproteinase effects of doxycycline. METHODS: Sixty-six patients with seropositive RA of <1 year's duration who had not been previously treated with disease-modifying antirheumatic drugs were randomized to receive 100 mg of doxycycline twice daily with MTX (high-dose doxycycline group), 20 mg of doxycycline twice daily with MTX (low-dose doxycycline group), or placebo with MTX (placebo group), in a 2-year double-blind study. Treatment was started with an MTX dosage of 7.5 mg/week, which was titrated every 3 months until remission was reached (maximum dosage of 17.5 mg/week). The primary end point was an American College of Rheumatology 50% improvement (ACR50) response at 2 years. RESULTS: ACR50 responses were observed in 41.6% of patients in the high-dose doxycycline group, 38.9% of those in the low-dose doxycycline group, and 12.5% of patients in the placebo group. Results of chi-square analysis of the ACR50 response in the high-dose doxycycline group versus that in the placebo group were significantly different (P = 0.02). Trend analysis revealed that the ACR20 response and the ACR50 response were significantly different between groups (P = 0.04 and P = 0.03, respectively). MTX doses at 2 years were not different among groups. Four patients in the high-dose doxycycline group, 2 patients in the low-dose doxycycline group, and 2 patients in the placebo group were withdrawn because of toxic reactions. CONCLUSION: In patients with early seropositive RA, initial therapy with MTX plus doxycycline was superior (based on an ACR50 response) to treatment with MTX alone. The therapeutic responses to low-dose and high-dose doxycycline were similar, suggesting that the antimetalloproteinase effects were more important than the antibacterial effects. Further studies to evaluate the mechanism of action of tetracyclines in RA are indicated.     

A 48‐week,randomized, double‐blind,double‐observer,placebo‐controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: Results of the METGO study

Objective

To evaluate the efficacy and safety of adding intramuscular (IM) gold to the treatment regimen of patients with rheumatoid arthritis (RA) who have a suboptimal response to methotrexate (MTX).

Methods

A randomized, double‐blind, double‐observer, placebo‐controlled multicenter trial of 48 weeks was conducted. Sixty‐five RA patients who had a suboptimal response to ≥12 weeks of MTX therapy were randomly assigned to receive weekly IM gold or placebo in addition to MTX. Gold was administered according to a standard protocol developed for the study. The primary outcome measure was the percentage of patients who met the American College of Rheumatology (ACR) 20% improvement criteria (achieved an ACR20 response) at week 48. Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses, the individual criteria that make up the primary outcome, quality of life, direct and indirect health care costs, intraarticular steroid use, and adverse events, among other measures. Statistical analyses were based on an intent‐to‐treat strategy.

Results

Sixty‐one percent of patients receiving gold achieved an ACR20 response compared with 30% of patients receiving placebo (χ² = 6.04, P = 0.014; logistic regression odds ratio 3.64 [95% confidence interval 1.3, 10.4], P = 0.016). Twenty‐six percent of patients receiving gold achieved an ACR50 response compared with 4% of patients receiving placebo (P = 0.017), and 21% of patients receiving gold achieved an ACR70 response compared with 0% of patients receiving placebo (P = 0.011). From both clinical and cost‐effectiveness perspectives, gold was the preferred and dominant strategy. Study treatment was discontinued in 23 patients (14 in the placebo group compared with 9 in the gold group; P = 0.022) due to loss to followup, adverse events, or lack of efficacy.

Conclusion

In RA patients with a suboptimal response to MTX, adding weekly IM gold causes significant clinical improvement. Adverse events were minor, and IM gold–related adverse events led to discontinuation in only 11% of the gold group over 48 weeks.

     

Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: A double‐blind,placebo‐controlled study

Objective

To examine the safety and efficacy of an extract of Tripterygium wilfordii Hook F (TWHF) in the treatment of patients with rheumatoid arthritis (RA).

Methods

An ethanol/ethyl acetate extract from the roots of TWHF was prepared and used in a prospective, double‐blind, placebo‐controlled study in patients with longstanding RA in whom conventional therapy had failed. Patients were randomly assigned to receive either placebo or low‐dose (180 mg/day) or high‐dose (360 mg/day) extract for 20 weeks, followed by an open‐label extension period. Clinical responses were defined as 20% improvement in disease activity according to the American College of Rheumatology criteria. Side effects were actively queried and recorded at each visit.

Results

A total of 35 patients were enrolled in the trial; 21 patients completed the 20‐week study. One patient from each group withdrew because of side effects. Twelve, 10, and 10 patients in the placebo, low‐dose, and high‐dose groups, respectively, completed at least 4 weeks of treatment. Of these patients, 8 and 4 in the high‐dose and low‐dose groups, but none in the placebo group, met criteria for clinical response. Four, 4, and 7 patients in the placebo, low‐dose, and high‐dose groups, respectively, were enrolled in the open‐label extension; of these, 2, 4, and 5 patients, respectively, met criteria for clinical response. The most common side effect was diarrhea, which caused 1 patient in the high‐dose group to withdraw from the trial. No patients withdrew because of adverse events during the open‐label extension.

Conclusion

The ethanol/ethyl acetate extract of TWHF shows therapeutic benefit in patients with treatment‐refractory RA. At therapeutic dosages, the TWHF extract was well tolerated by most patients in this study.

     

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.

     

Survey of the use and effect of assistive devices in patients with early rheumatoid arthritis: A two‐year followup of women and men

Objective

To identify activity limitation in early rheumatoid arthritis (RA) to detect patients needing assistive devices. To evaluate the effects of assistive devices.

Methods

A multicenter cohort of 284 early RA patients was examined using the Evaluation of Daily Activity Questionnaire 12 and 24 months after diagnosis.

Results

The extent of activity limitation was stable over time for both women and men. Most limitations concerned eating and drinking. Women reported more difficulties than did men. The use of assistive devices was related to subgroups with severe disease and more disability. Use of assistive devices reduced difficulties significantly. For both women and men, assistive devices were mostly used in activities related to eating and drinking.

Conclusion

Already 1 year after diagnosis, RA patients reported activity limitation that remained stable over time. Use of assistive devices was related to more severe disease and more pronounced disability. Use of devices reduced difficulties significantly.

     

A randomized,double‐blind,multicenter, controlled clinical trial of chicken type II collagen in patients with rheumatoid arthritis

Objective

To assess the efficacy and safety of chicken type II collagen (CCII) in rheumatoid arthritis (RA) compared with methotrexate (MTX).

Methods

We conducted a prospective, 24‐week, followup, multicenter, double‐blind, controlled study of CCII (0.1 mg/day) versus MTX (10 mg/week) in patients with active RA. Clinical assessments were performed at screening and at 12, 18, and 24 weeks of treatment.

Results

A total of 236 RA patients were included; 211 patients (89.4%) completed the 24‐week followup. In both groups there was a decrease in pain, morning stiffness, tender joint count, swollen joint count, Health Assessment Questionnaire score, and investigator and patient assessment of function; all differences were statistically significant. In the MTX group, erythrocyte sedimentation rate and C‐reactive protein level decreased. Rheumatoid factor did not change in either group. At 24 weeks, 68.57% of patients in the CCII group and 83.02% in the MTX group met the American College of Rheumatology 20% improvement criteria (ACR20), and 40.95% and 57.54%, respectively, met the ACR50 criteria. The ACR20 and ACR50 response rates in the CCII group were lower than those in the MTX group, and this difference was statistically significant (P < 0.05). Gastrointestinal symptoms were common in both groups. There were fewer and milder side effects in the CCII group than the MTX group. The difference in incidence of adverse events between the 2 groups was statistically significant (P < 0.05).

Conclusion

CCII is effective in the treatment of RA. CCII is well tolerated, and the incidence of adverse events of CCII is lower than that of MTX.