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January 2010

Index

  1. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review.

  2. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis:

  3. Can Tumor Necrosis Factor Inhibitors Be Safely Used in Pregnancy?

  4. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry

Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review.  Ann Rheum Dis 2010;69:20-28.
G Ruiz-Irastorza,  M Ramos-Casals,  P Brito-Zeron,  M A Khamashta

Background: 

Antimalarial drugs (AMs), chloroquine (CQ) and hydroxychloroquine (HCQ), are frequently withdrawn in patients with lupus with either severe or remitting disease. However, additional effects beyond immunomodulation have been recently described. The aim of the present work was to analyse all the published evidence of the beneficial and adverse effects of AM therapy in systemic lupus erythematosus (SLE).

Methods: 

A systematic review of the English literature between 1982 and 2007 was conducted using the MEDLINE and EMBASE databases. Randomised controlled trials (RCTs) and observational studies were selected. Case reports were excluded except for toxicity reports. The GRADE system was used to analyse the quality of the evidence.

Results: 

A total of 95 articles were included in the systematic review. High levels of evidence were found that AMs prevent lupus flares and increase long-term survival of patients with SLE; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss. Toxicity related to AMs is infrequent, mild and usually reversible, with HCQ having a safer profile. In pregnant women, high levels of evidence were found that AMs, particularly HCQ, decrease lupus activity without harming the baby. By contrast, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak. Individual papers suggest effects in preventing the evolution from SLE-like to full-blown SLE, influencing vitamin D levels and protecting patients with lupus against cancer.

Conclusions: 

Given the broad spectrum of beneficial effects and the safety profile, HCQ should be given to most patients with SLE during the whole course of the disease, irrespective of its severity, and be continued during pregnancy.

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Comparison of Tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study Ann Rheum Dis 2010;69:88-96 G. Jones, A Sebba et al

Background: 

The anti-interleukin (IL) 6 receptor antibody Tocilizumab inhibits signaling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. Objective:  To evaluate through the AMBITION study the efficacy and safety of Tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed.

Methods: 

This 24-week, double-blind, double-dummy, parallel-group study, randomized 673 patients to either Tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by Tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24.

Results: 

The intention-to-treat analysis demonstrated that Tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs. 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs. 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with Tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with Tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs. 0.4%) and increased total cholesterol ≥240 mg/dl (13.2% vs. 0.4%), and a lower incidence of alanine aminotransferase elevations >3×–<5× upper limit of normal (1.0% vs. 2.5%), respectively.

Conclusion: 

Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit–risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.

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Can Tumor Necrosis Factor Inhibitors Be Safely Used in Pregnancy?
The Journal of Rheumatology 2010 vol. 37 no. 1 9-17 .

Objective. 

We review available safety data for use of currently approved tumor necrosis factor (TNF) inhibitors during pregnancy and lactation and suggest guidelines for use of these agents among women of reproductive age.

Method. 

Although regulatory agencies encourage the inclusion of pregnant women and those of child-bearing age in randomized controlled trials, pregnant and lactating women have universally been excluded from studies because of unknown or potential risks to the fetus. Thus, strong evidence-based treatment recommendations during pregnancy are usually lacking and safety information is derived from voluntary reports of adverse events during post marketing surveillance or via uncontrolled, observational studies, reviewed here.

Results. 

Uncommon adverse pregnancy outcomes observed with TNF inhibitor therapy appear to approximate those seen in women not receiving such therapy and may include premature birth, miscarriage, low birth weight, hypertension, and preeclampsia. There are rare reports of fetal malformations or congenital anomalies in patients exposed to TNF inhibitors during conception or pregnancy. However, the incidence of these events appears to be far below the 3% rate of congenital anomalies in the general population.

Conclusion. 

If the activity or disease severity precludes the cessation of a TNF inhibitor and/or DMARD, uncontrolled observations suggest that conception and early pregnancy are not adversely affected by use of TNF inhibitors. Nearly 70% of pregnant patients can discontinue their TNF inhibitor early in the pregnancy (or with determination of pregnancy) without augmenting maternal or fetal risks.

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Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with Adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry

Arthritis & Rheumatism 2010 Volume 62 Issue 1, Pages 22 - 32. Merete Lund Hetlad, Ib Jarle Christensen, Ulrik Tarp et al

Objective

To compare tumor necrosis factor alpha inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response.
 Methods

The nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received Adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease-modifying drugs, center, and functional status (Health Assessment Questionnaire score).
Results

Seventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52-2.76) for Adalimumab versus infliximab, 1.78 (95% CI 1.28-2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82-1.60) for Adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63-2.40), 1.35 for infliximab versus Adalimumab (95% CI 1.15-1.58), and 1.47 for Adalimumab versus etanercept (95% CI 1.20-1.80).
Conclusion

Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, Adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and follow up times.
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