Actemra Succeeds as Monotherapy

A real-world study offers evidence for tocilizumab as monotherapy in patients with rheumatoid arthritis.

by Nancy Walsh
Senior Staff Writer, MedPage Today
December 19, 2014

A real-world study supported the use of tocilizumab (Actemra) as monotherapy in patients with rheumatoid arthritis, in that discontinuation rates and clinical responses didn’t appear to be affected by concomitant treatment with disease-modifying anti-rheumatic drugs (DMARDs).

Factors that predicted discontinuation of tocilizumab in a multivariate analysis were a low baseline level of C-reactive protein (HR 0.76, 95% CI 0.63-0.91), a high score on the Health Assessment Questionnaire (HR 1.23, 95% CI 1.06-1.44), and previous treatment with other biologics (HR 1.43, 95% CI 1.12-1.83), according to Helena Forsblad-d’Elia, MD, of the University of Gothenburg in Sweden, and colleagues.

In contrast, no association with treatment discontinuation was seen for concomitant DMARD therapy (HR 0.96, 95% CI 0.72-1.29), the researchers reported online in Rheumatology.

In a substudy of a clinical trial known as ACT-RAY, patients receiving tocilizumab alone had similar MRI findings at week 12 as did those receiving this interleukin-6 receptor antagonist in combination with methotrexate.
However, clinical trial results are limited by their short duration and strict eligibility criteria. “It is therefore important to also follow and report drug adherence, effectiveness, and side effects in a real-world setting,” the researchers wrote.

In addition, while most recommendations call for biologics to be given with methotrexate, experience has shown that up to one-third of patients are given them as monotherapy.

To further examine the effects of monotherapy versus combinations, Forsblad-d’Elia and colleagues analyzed data from the Anti-Rheumatic Therapies in Sweden registry for patients receiving tocilizumab between 2008 and 2012.
Their analysis included 530 patients. Most were women, mean age was 58, and mean disease duration was 14 years.
Mean C-reactive protein (CRP) level at baseline was 26.7, mean Disease Activity Score in 28 joints (DAS28) was 5.4, and mean score on the Health Assessment Questionnaire (HAQ) was 1.4.

A total of 35.3% patients initiated tocilizumab as monotherapy, while 64.7% were given concomitant DMARDs, most often methotrexate.

Only 12% had not previously received a biologic, and more than one-third had already received a tumor necrosis factor (TNF) inhibitor plus either rituximab (Rituxan) and/or abatacept (Orencia).
During the 2-year follow-up period, 199 patients discontinued treatment. In 44%, the reason was a lack of efficacy, in 36% it was because of side effects, and the remainder were for various reasons such as remission or pregnancy.
At 6 months, 79% of patients were still on tocilizumab, as were 64% and 50% at years 1 and 2. These continuation rates were influenced by prior use of biologics, with biologic-naive patients having 1-year continuation rates of 81% versus 66% for those who had already received a TNF inhibitor and 54% for those who had received a TNF inhibitor and abatacept or rituximab (P<0.0003). Having a high level of CRP was associated with longer treatment continuation, but concomitant treatment with a DMARD was not. In a univariate analysis, factors associated with treatment discontinuation were female sex, low levels of CRP or erythrocyte sedimentation rate, higher score on the HAQ, and use of additional biologics. Again, concomitant DMARD treatment was not a factor. For clinical responses according to the good, moderate, and no response criteria of the European League Against Rheumatism (EULAR), the rates were 46.7%, 33.8%, and 19.5%, respectively, during an assessment between months 2 and 8. Rates for low disease activity and remission were 52% and 37.3%. In a multiple regression analysis, predictors of a good EULAR response (versus no response) were low HAQ score (OR 0.56, 95% CI 0.40-0.78), high DAS28 scores (OR 2, 95% CI 1.44-2.78), and baseline avoidance of steroids (OR 0.47, 95% CI 0.25-0.88). Use of DMARDs was not associated with a good EULAR response (OR 0.81, 95% CI 0.45-1.44). "Concomitant DMARDs did not have significant impact on drug termination or response to treatment, supporting tocilizumab as an effective monotherapy biologic drug," the researchers observed. Overall continuation rates in this study were lower than what has been seen in studies of patients receiving anti-TNF therapies, most likely because of channeling bias and patients having longstanding, refractory disease, according to the authors. A limitation of the study was its observational design, which can permit confounding by indication.

Less aggressive therapy still works

Treating patients at an early stage of rheumatoid arthritis is key and can potentially alter the course of the disease. However, in reality, it is sometimes close to impossible to convince patients to be very aggressive early on in their disease, despite all the disabilities that we describe could happen.

So this trial is a welcomed proof that we may not need to be too aggressive early on, with a clear caveat that we MUST adopt a “treat-to-target” approach. Starting DMARDs early is beyond question. In this trial methotrexate(MTX) + steroids achieves comparable results with MTX+Sulfasalazine+steroids or MTX+Leflunomide+steroids, in high risk patients. It was also associated with less side effects.

Having said this, it is an open label study over a relatively short period of time, i.e. 1 year. There is also no direct comparison with starting biologics early where it was proven that we can even achieve a drug free remission. So treating early aggressively can potentially alter the course of the disease with biologics. Unfortunately, the high cost of biologics will likely deter many from taking this option at an early stage.



Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial

Patrick Verschueren, Diederik De Cock, Luk Corluy, Rik Joos, Christine Langenaken, Veerle Taelman, Frank Raeman, Isabelle Ravelingien, Klaas Vandevyvere, Jan Lenaerts, Elke Geens, Piet Geusens, Johan Vanhoof, Anne Durnez, Jan Remans, Bert Vander Cruyssen, Els Van Essche, An Sileghem, Griet De Brabanter, Johan Joly, Sabrina Meyfroidt, Kristien Van der Elst, Rene Westhovens
Annals of the Rheumatic Diseases 2016 July 18

OBJECTIVES: Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year.

METHODS: The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness ( identifier NCT01172639).

RESULTS: 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals.

CONCLUSIONS: MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed.

TRIAL REGISTRATION NUMBERS: EudraCT-number 2008-007225-39 and NCT01172639; Results.