Highlights From EULAR 2008, The Annual European Congress Of Rheumatology

Main Category: Arthritis / Rheumatology
Also Included In: Pain / Anesthetics;  Conferences
Article Date: 03 Jul 2008 - 3:00 PDT

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Half of patients with early rheumatoid arthritis treated with the anti-tumour necrosis factor inhibitor (anti-TNF) infliximab plus methotrexate achieve remission, and up to one in five achieve drug-free remission, according to five-year follow-up results from the BeSt study.

Patients treated initially with a combination of infliximab plus methotrexate achieved significantly better functional ability than those given other treatment regimens.

The Dutch BeSt (Behandel Strategieën) study randomised 508 patients with recent-onset rheumatoid arthritis to one of the four most frequently used treatment strategies:

1. Sequential monotherapy - starting with one drug, then trying other types of drug on their own

2. Step-up combination therapy - starting with one drug, then adding on a second, and third or fourth drug

3. Initial combination including tapered high-dose prednisone

4. Initial combination therapy with infliximab plus methotrexate

The patients were monitored intensively and their treatment adjusted to keep their disease activity score (DAS) low (i.e. below 2.4).

At the end of five years, 51% of patients treated with initial combination therapy with infliximab plus methotrexate and a similar number of those give sequential monotherapy were in remission (Disease Activity Score < 1.6), compared to 45% of those treated with step-up combination therapy and 42% of patients treatment with initial combination including prednisone.

Of these remissions, 39%, 46%, 65% and 81% was achieved with the initial treatment step in treatments groups 1 to 4 respectively (p<0.001 group 4 vs groups 1 and 2). Nearly one in five (19%) of patients treated initially with the infliximab combination were in drug-free remission after five years, compared to 14%, 16%, and 10% for groups 1 to 3, and this was for a mean duration of 22 months.

A longitudinal analysis of the data showed that patients treated initially with combination therapy (either with infliximab or high-dose prednisone) had significantly better scores on the health assessment questionnaire (HAQ), a widely used measure of physical function, over time compared to patients on monotherapy or step-up combination therapy (p<0.001). In addition, infliximab-treated patients had better HAQ scores than those initially treated with the prednisone combination (p=0.01).

"The follow-up data clearly demonstrate that the outlook for patients with early, active rheumatoid arthritis are much better than previously thought possible. It is important to introduce effective treatment as soon as possible and keep the disease activity low all the time," said Dr Renee Allaart, from the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands, and one of the BeSt investigators.

"Rheumatologists should be encouraged to frequently monitor the disease activity and adjust medication accordingly. Given the better clinical response and the fact that so many patients can stop all drugs, initial combination with infliximab and methotrexate appears to be the best treatment option. For the first time, we have a treatment that is disease-course altering," added Dr Allaart.

Reporting the findings at EULAR, Dr Naomi Klarenbeek, also from Leiden University, said: "Over time, patients treated with an initial combination of infliximab plus methotrexate have significantly better functional ability than patients on other treatment strategies."

Dr Andrew Ostör, consultant rheumatologist at Addenbrooke's Hospital, Cambridge, UK, commented: "Patients with aggressive early rheumatoid arthritis potentially do better when treated with initial combination therapy including a biologic. They clearly improved more rapidly than patients treated with sequential monotherapy or step-up combination therapy. Early improvement is important for patients' confidence in their treatment." He added: "Continuous monitoring and tight disease control - based on DAS score - is important in optimising therapy for individual patients."1

Infliximab better than DMARDs in RA patients failing on methotrexate

Adding infliximab achieves significantly better response than adding the conventional disease modifying antirheumatic drugs (DMARDs) sulfasalazine plus hydroxychloroquine in patients with early rheumatoid arthritis failing initial methotrexate monotherapy, a Swedish study has shown.

The SWEFOT trial was designed to compare two strategies in patients with early RA who had failed an initial 3-4 months treatment with methotrexate monotherapy. Researchers initially treated 487 patients with early RA, with symptoms for less than one year, with methotrexate (up to 20mg/week).

After three to four months, the 258 patients who had not achieved remission (defined as DAS28 < 3.2) and who were unable to tolerate methotrexate were randomised to DMARD therapy with sulfasalazine plus hydroxychloroquine or to infliximab (3mg/kg/infusion, given at 0, 2, 6 weeks, then every 8 weeks). Patients were allowed to switch therapy once (to cyclosporine in the DMARD group and to etanercept in the anti-TNF group) if they were unable to tolerate their treatment.

Results reported at EULAR showed that just over one-quarter (26%) of patients treated with DMARD therapy achieved a EULAR good response after 12 months, compared to 42% of those treated with infliximab (p<0.01). ACR 20, 50 and 70 responses were higher with infliximab, at 49%, 29% and 13%, compared to DMARD treatment (33%, 16% and 8%; p<0.05 for ACR 20 and 50; not significant for ACR 70).

"On the assumption that an initial trial of methotrexate monotherapy is reasonable, the subsequent addition of an anti-TNF is clinically superior to the addition of conventional DMARDs," suggested the researchers, led by Dr R. van Vollenhoven, from the Karolinska Institute, Stockholm, Sweden. They added: "In patients with early RA who do not achieve remission after 3-4 months on methotrexate, the addition of infliximab yields significantly better EULAR and ACR responses at 12 months than the addition of DMARDs."2

Study indicates the value of a six-month trial of anti-TNFs

More than half of RA patients on anti-TNF therapy who fail to meet EULAR response criteria after three months of treatment, go on to achieve a response at six months, according to a UK study.

Different guidelines currently have conflicting recommendations on how long to treat with an anti-TNF before determining whether or not a patient has responded and treatment is worth continuing. NICE recommends continuation if a response is achieved by six months, but British Society for Rheumatology guidance states that non-response at three months warrants re-evaluation of treatment. EULAR and ACR both maintain a three-month cut-off, even though no evidence exists to support this.

Researchers at Addenbrooke's Hospital, Cambridge, retrospectively assessed all patients (n=253) commencing anti-TNFs for RA in their hospital over a five-year period. They analysed their response to therapy at three and six months, defined by EULAR criteria of either a 1.2 or greater reduction in 28-joint Disease Activity Score (DAS28) or a reduction of > 0.6 and a DAS28 of < 5.2.

The results for 194 patients who had DAS responses recorded at three months showed that 83% had met the response criteria at this time point, while 33 patients (17%) had not. Of these 33 patients, 20 continued with anti-TNF therapy and responses were available for 15 of them at six months. Just over half (53%) of them achieved a EULAR response, with none requiring an increase in dose to reach this.

Dr Andrew stör, consultant rheumatologist at Addenbrooke's Hospital, Cambridge, and one of the study authors, said: "These results support a six-month therapeutic trial over three months. They showed that a substantial proportion of RA patients on anti-TNF therapy who fail EULAR response criteria at three months and continue on treatment to six months achieve a response."3

Early treatment with infliximab increases remissions and prevents radiological progression

Early treatment with infliximab, as part of intensive combination therapy, achieves higher rates of remission and prevents radiological progression, a Finnish study revealed.

The NEO-RACO Study included 100 patients with early, active RA. They were started on combination therapy with three DMARDs (methotrexate, sulfasalazine and hydrochloroquine) plus prednisolone - a regimen the researchers call the FIN-RACo strategy, which has previously been shown to achieve early remission in 37% of patients. The patients were also randomised to infliximab or placebo, to see if the anti-TNF increased remission rates further.

Results showed significantly more patients treated with infliximab achieved remission after two years. More than two-thirds (70%) were in remission, compared to just over half (53%) of those treated with the FIN-RACo regimen (p=0.08). Remission rate over time was nearly twice as high with infliximab (odds ratio 1.97; p=0.04). Sustained remission was achieved in 31% of the FIN-RACo group, and 40% of the patients also treated with infliximab.

Radiological progression was also better with the infliximab combination. Just over half (54%) had a Sharp/van der Heijde score (SHS) - a measure of joint damage on X-ray - of 0 at two years, compared to 41% of patients treated with the FIN-RACo. The mean change of SHS over the two years was 1.4 in patients treated with FIN-RACo, compared to -0.2 in those also treated with infliximab (p=0.005).

The research group, led by M. Leirisalo-Repo, from Helsinki University Central Hospital, Helsinki, Finland, said: "Adding infliximab to intensive use of FIN-RACo in early active RA during the first six months reflected in higher frequencies of remissions over time and prevented radiological progression during two years."4

Initial combination therapy prevents bone loss in RA

Initial combination therapy with infliximab or prednisone is associated with less reduction in bone mineral density (BMD) in the hand than other treatment strategies, show further results from the BeSt Study.

The Dutch study randomised 508 patients with recent onset, active RA to sequential monotherapy or step-up combination therapy, both starting with methotrexate, combination therapy with a tapered high dose of prednisone, sulphasalazine and methotrexate, or infliximab plus methotrexate. Bone density was measured by digital X-ray radiogrammetry in both hands, in the hip and spine in 218 patients, at baseline and after one and two years.

Results showed significantly greater BMD loss in the hands (-2.5%) at two years, than in the hip (-0.5%) and spine (-1.0%), indicating that it provides a useful measure over a relatively short time period. Initial combination therapy with infliximab or prednisone was associated with less hand BMD loss than initial monotherapies ( -1.6% with infliximab combination therapy and -1.4% with prednisone-based treatment vs -3.6% with sequential monotherapy and -3.3% with step-up combination therapy).

Progression of erosions was independently associated with increased BMD loss in the hands and hip after one year.

The research group, from Leiden University Medical Center, Leiden; Haga Hospital, the Hague, and VU Medical Center, Amsterdam, the Netherlands, commented: "Initial combination therapy with infliximab or prednisone is associated with less hand BMD loss due to more rapid, adequate suppression of disease activity compared to initial monotherapy." They added: "The association between progressive joint damage and both hand and hip BMD loss suggests common pathways between these processes in RA."5

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References

1. Klarenbeek, NB, Güler-Yüksel M, van der Kooij SM, van der Heijde DMFM, Huizinga TWJ, Kerstens PJSM, Peeters AJ, Ronday HK, Westedt ML, Dijkmans BAC, Allaart CF. Clinical Outcomes Of Four Different Treatment Strategies In Patients With Recent-Onset Rheumatoid Arthritis: 5-Years Results Of The BEST-Study. EULAR 2008: Abstract [THU0162]

2. van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Cöster L, Waltbrand E, Zickert A, Theander J, Thörner A, Hellström H, Teleman A, Dackhammar C, Akre F, Forslind K, Ljung L, Oding R, Wörnert M, Bratt J. In Patients With Early RA Who Failed Initial MTX, The Addition Of Anti-TNF Yields Better EULAR And ACR Responses Than The Addition Of Conventional DMARDs: 1-Year Results Of The SWEFOT Clinical Trial. EULAR 2008: Abstract [LB0001]

3. Pocock JM, Ostör AJK. Anti-TNF Efficacy in Rheumatoid Arthritis - Three or Six Month Trial. EULAR 2008: Abstract [FRI0131]

4. Leirisalo-Repo M, Kautiainen H, Laasonen L, Möttönen T, Hannonen P, Korpela M, Kauppi M, Kaipiainen-Seppänen O, Luosujärvi R, Blåfield H, Ilva K, Julkunen H, Uutela T, Moilanen E. A Randomized, Double-Blind, Placebo-Controlled Study On Addition Of Infliximab To The FIN-RACO DMARD Combination Therapy For Initial Six Months In Patients With Early Active Rheumatoid Arthritis. The NEO-RACO Study. EULAR 2008: Abstract [OP-0009]

5. Güler-Yüksel M, Allaart CF, Huizinga TWJ, de Beus WM, Ewals JAPM, Hulsmans HMJ, Dijkmans BAC, Lems WF. Initial Combination Therapy Prevents Bone Mineral Density (BMD) Loss In The Hands In Patients With Recent-Onset Rheumatoid Arthritis (RA) EULAR: Abstract [OP-0029]

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