John Tesser

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Combination Therapy with Cyclosporine and Methotrexate in Severe Rheumatoid Arthritis

BACKGROUND Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement. METHODS In a six-month randomized, double-blind trial, we compared combination therapy with cyclosporine (2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals) and methotrexate (at the maximal tolerated dose) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment. The primary outcome measure was the change in the number of tender joints. RESULTS The mean (+/- SD) dose of cyclosporine at the final treatment was 2.97 +/- 1.02 mg per kilogram per day. As compared with the placebo group, the patients in the treatment group had a net improvement in the tender-joint count of 25 percent, or 4.8 joints (95 percent confidence interval, 0.7 to 8.9; P = 0.02), and in the swollen-joint count of 25 percent, or 3.8 joints (95 percent confidence interval, 1.3 to 6.3; P = 0.005); improvement in overall disease activity as assessed by the physician (19 percent, P < 0.001) and the patient (21 percent, P < 0.001); and improvement in joint pain (23 percent, P = 0.04) and in the degree of disability (26 percent, P < 0.001). The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group (P = 0.006). Thirty-six patients (48 percent) in the cyclosporine group and 12 patients (16 percent) in the placebo group (P < 0.001) met the 1993 criteria for improvement of the American College of Rheumatology (more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables). Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study; 2 patients in the cyclosporine group died, 1 from viral pneumonia and the other in a motor vehicle accident. Serum creatinine concentrations increased by a mean of 0.14 +/- 0.27 mg per deciliter (12 +/- 24 mmol per liter) in the cyclosporine group and by 0.05 +/- 0.19 mg per deciliter (4 +/- 17 mmol per liter) in the placebo group (P = 0.02). CONCLUSIONS In a six-month study, patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinically important improvement after combination therapy with cyclosporine and methotrexate. Side effects were not substantially increased. Long-term follow-up of patients treated with this combination is needed.

Safety of extended treatment with anakinra in patients with rheumatoid arthritis

Objective: To determine the safety profile of anakinra after extended exposure in a diverse clinical trial population of patients with rheumatoid arthritis. Methods: A six month, randomised, double blind phase comparing anakinra (100 mg/day) with placebo was followed by open label anakinra treatment for up to three years in patients with rheumatoid arthritis. Concomitant non-steroidal anti-inflammatory drugs, corticosteroids, and other disease modifying antirheumatic drugs were permitted. Results: In all 1346 patients with rheumatoid arthritis received anakinra for up to three years. Patients had varying levels of disease severity, concomitant drug use, and comorbid conditions. Cumulative, exposure adjusted event (EAE) rates for all adverse events (AEs), serious AEs, and deaths were similar during each year of anakinra treatment; the overall rate (0 to 3 years) was similar to that observed for controls during the blinded phase. The most frequent AEs were injection site reactions (122.26 events/100 patient-years), rheumatoid arthritis progression (67.80 events/100 patient-years), and upper respiratory infections (26.09 events/100 patient-years). The EAE rate of serious infections was higher for patients treated with anakinra for 0 to 3 years (5.37 events/100 patient-years) than for controls during the blinded phase (1.65 events/100 patient-years). However, if the patient was not receiving corticosteroid treatment at baseline, the serious infection rate was substantially lower (2.87 event/100 patient-years). The overall incidence of malignancies was consistent with expected rates reported by SEER. Neutralising antibodies developed in 25 patients, but appeared to be transient in 12; neutralising antibody status did not appear related to occurrence of malignancies or serious infections. There were no clinically significant trends in laboratory data related to anakinra. Conclusion: Anakinra is safe and well tolerated for up to three years of continuous use in a diverse population of patients with rheumatoid arthritis.

Tramadol for the treatment of joint pain associated with osteoarthritis: a randomized, double-blind, placebo-controlled trial☆

Abstract Background: Results from short-term, non—placebo-controlled clinical trials suggest that tramadol is effective as adjunctive therapy for the treatment of joint pain associated with osteoarthritis (OA). Objective: We assessed the efficacy and tolerability of tramadol monotherapy versus placebo in the treatment of joint pain associated with OA. Methods: Patients with symptomatic OA of the knee and at least moderate pain at the end of a 10-day analgesic washout period were randomized to receive tramadol or placebo. After a 7-day titration period (50-mg increments every 2 days to a target dosage of 200 mg/d), patients were permitted to increase their dose up to 400 mg/d as needed for 84 days. Likert scale scores to assess pain intensity (none = 0 to extreme=4) and pain relief (complete relief=3 to severely worse=−3) as well as Western Ontario and McMaster Universities (WOMAC) OA Index scores were obtained at visits on days 14, 28, 56, and 91 of the study. Patient and investigator global assessments of treatment effectiveness were recorded at the final visit (day 91 or at the time of discontinuation). Results: Baseline characteristics were similar for the tramadol (n = 63) and placebo (n = 66) groups; more than half of the patients (mean age 62.5 years) were women (65.1% and 59.1% in the tramadol and placebo groups, respectively). Mean final pain intensity scores were 2.10 in the tramadol group and 2.48 in the placebo group ( P = 0.082, analysis of covariance). Tramadol was significantly more effective than placebo for all secondary outcomes: mean final pain intensity scores ( P = 0.045, t test), pain relief scores ( P = 0.004), patient and investigator global assessments ( P = 0.038 and P = 0.001, respectively), median time to failure of effectiveness ( P = 0.042), and all WOMAC scores ( P ≤ 0.033). Fourteen tramadol and 10 placebo patients discontinued the study because of adverse events (AEs). Other reasons for discontinuation included lack of efficacy (26 tramadol and 43 placebo patients) and patient choice (10 tramadol and 11 placebo patients). The most common AEs during tramadol therapy were nausea, constipation, dizziness, pruritus, and headache; no serious AEs, seizures, or cases of abuse were reported in the tramadol group. Conclusion: Tramadol may be useful as monotherapy in the treatment of joint pain associated with OA.

Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks: an open-label extension study. The Methotrexate-Cyclosporine Combination Study Group.

OBJECTIVE To determine whether the clinical benefit and favorable safety profile previously noted with the combination of cyclosporine (CSA) and methotrexate (MTX) given for 24 weeks in patients with rheumatoid arthritis (RA) would be maintained for a further 24 weeks, and whether the addition of CSA in patients who had previously been randomized to receive placebo + MTX would result in clinical benefit. METHODS Eligible subjects from the initial study (weeks 0-24), in which the addition of placebo or CSA to MTX therapy was compared in patients with RA that was partially responsive to MTX, were enrolled. Patients who had received CSA + MTX continued this regimen for a further 24 weeks (weeks 24-48) (group 1; n = 48), and patients who had initially received placebo + MTX now received CSA + MTX for 24 weeks (weeks 24-48) (group 2; n = 44), in an open-label extension study. The primary outcome measures were the number of tender joints, number of swollen joints, physician and patient global assessments, pain, functional disability as measured by the modified Health Assessment Questionnaire, and erythrocyte sedimentation rate. RESULTS Of the 92 patients enrolled, 80 (87%) completed the extension study. In patients in group 1, the clinically and statistically significant improvement in response outcomes previously noted at week 24, ranging from 25% to 50%, was maintained through week 48. In patients in group 2, the addition of CSA resulted in significant clinical improvement. By week 48, most outcome measures in group 2 patients were similar to those in group 1 patients. CSA treatment resulted in a small increase in serum creatinine levels, but only 1 patient was withdrawn from the study for this reason. CONCLUSION The clinical improvement previously observed in patients treated with the CSA + MTX combination for 24 weeks was maintained for 24 subsequent weeks, without serious adverse effects, and was also observed in the patients whose treatment was switched from placebo + MTX to CSA + MTX.

The liver in rheumatic diseases

HE HEPATIC manifestations of the rheumatic diseases are not well described. The frequency, significance, and the specific hepatic pathology varies with each rheumatic illness. Abnormalities of liver tests in this setting may lead to diagnostic confusion and the need for extensive evaluation. Additionally, many of the drugs used in the treatment of these diseases are hepatotoxic. The aim of this contribution is to review the current published data regarding liver involvement in the rheumatic diseases and discuss the hepatic complications of medications commonly prescribed. RHEUMATOID ARTHRITIS Hepatic involvement in adult rheumatoid arthritis (RA) is incompletely described. Early observations included the apparent improvement in joint disease with the onset of jaundice. Still,’ in 1897, noted “catarrhal jaundice to be followed by distinct improvement of the joint symptoms” and Hench,’ in 1940, noted remission in articular symptoms when patients with “chronic infectious arthritis” became jaundiced. Because of these observations, attempts were made to induce jaundice in patients with RA. Oral ingestion of ox and human bile, and intravenous administration of liver extracts and jaundice blood were ineffective.3 Temporary improvement in joint symptoms occurred in 25 of 32 patients who were inoculated with serum from patients with hepatitis and became jaundiced.4 The joint improvement was transient and the mechanism for the improvement was not determined. Biochemical evidence of hepatic involvement in RA has been described in several studies. Elevation in serum transaminases (SGOT, SGPT) have not been noted but serum alkaline phosphatase elevation has been found in 25%50% of patients with RA.‘16 This elevation in serum alkaline phosphatase is hepatic in origin since simultaneous elevations in five prime nucleotidase and gamma glutamyl transpeptidase have been noted.’ Serum alkaline phosphatase elevation correlates with disease activity and decreases with improvement in the arthritis.’

Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase

Objective To study the efficacy and safety of certolizumab pegol (CZP) in patients with active rheumatoid arthritis (RA) who had discontinued an initially effective TNF inhibitor (TNF-IR). Methods A randomised 12-week double-blind trial with CZP (n=27) or placebo (n=10) followed by an open-label 12 week extension period with CZP. Results Baseline characteristics ofthe 2 groups were similar. ACR20 response (primary end point) at week 12 was achieved in 61.5%, and none of CZP and placebo-treated patients, respectively. Weeks 12–24 showed a maximum effect for CZP at 12 weeks, and that placebo patients switched blindly to CZP attained similar results seen with CZP in weeks 0–12. Since this result was highly significant, study inclusion was terminated after entry of 33.6% of the originally planned 102 patients. Adverse events occurred in 16/27 (59.3%) CZP subjects and 4/10 (40%) placebo subjects. There were no serious adverse events, neoplasms, opportunistic, or serious infections. Conclusions This first, prospective, blinded trial of CZP in secondary TNF-IR shows that the ACR20 response rate observed with CZP was higher than that reported in most previous studies of TNF-IR. Additionally, CZP demonstrated good safety and tolerability. This study supports the use of CZP in RA patients who are secondary non-responders to anti-TNF therapies.

The evolution of biomarkers in rheumatoid arthritis: from clinical research to clinical care.

Background: Treatment efficacy in rheumatoid arthritis (RA) has been measured by clinical response, gross radiological results and some biochemical markers. With the new biologic treatments, markers for disease development, progress, severity and therapy response have evolved. Objectives: This review focuses on a selection of current markers and the need for better markers for determining RA treatment susceptibility and success. Methods: A review of the literature was conducted and expert opinions expressed. Results/conclusion: Current biomarkers mainly focus on disease activity and severity. Biomarkers for treatment response and susceptibility that help clinicians make initial treatment decisions are lacking or insufficient, yet required for optimal control of RA. A combination of biomarkers is necessary to classify a complex immune disease, such as RA.

How Often Does Lateral Spine DXA Detect Low Bone Mass in Patients with Both Normal PA Spine and Hip

The clinical utility of lateral bone mineral density (BMD) measurement for the diagnosis of osteoporosis remains controversial. Since both posterior-anterior (PA) spine and hip scans are universally performed, the true clinical utility of lateral dual-energy X-ray absorptiometry (DXA) should lie in its ability to detect low bone mass independent of both PA spine and hip. We examined lateral, PA and hip BMDs in 2134 referred Caucasian females aged 25-89 using the Hologic 2000. Compared only to PA scans, the additional percentages of women with very low BMD (T-score below -2.5 utilizing the National Health and Nutrition Examination Survey [NHANES] III normative database) on lateral were 7.3, 16.4, 28.2, 33.7, and 26.2% for age groups 25-49, 50-59, 60-69, 70-79, and 80-89, respectively. When the results from both PA and total hip measurements were combined, lower but still significant percentages were found: 5.4, 14.9, 24.4, 26.6, and 17.8% for age groups 25-49, 50-59, 60-69, 70-79, and 80-89, respectively. Utilizing the original Hologic normative database, the additional yield in women with a nonosteoporotic PA spine and femoral neck was quite low: 4.6, 8.5, 13.3, 10.0, and 2.5% for women age 25-49, 50-59, 60-69, 70-79, and 80-89, respectively. Thus, the lateral scans now add more additional patients into the very low BMD category. Whether the relationship to future fracture risk of low BMD and T-scores on lateral is similar to that of PA spine remains to be established.

Ethnographic Observational Study of the Biologic Initiation Conversation Between Rheumatologists and Biologic-Naive Rheumatoid Arthritis Patients

This ethnographic market research study investigated the biologic initiation conversation between rheumatologists and biologic‐naive patients with rheumatoid arthritis to assess how therapy options, particularly mode of administration, were discussed.