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Extended report
Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial
  1. Vappu Rantalaiho1,
  2. Hannu Kautiainen2,3,4,
  3. Markku Korpela1,
  4. Pekka Hannonen5,
  5. Oili Kaipiainen-Seppänen6,
  6. Timo Möttönen7,
  7. Markku Kauppi8,
  8. Anna Karjalainen9,
  9. Kari Laiho8,
  10. Leena Laasonen10,
  11. Mikko Hakola5,
  12. Ritva Peltomaa11,
  13. Marjatta Leirisalo-Repo11,12
  14. for the NEO-RACo Study Group
  1. 1Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Tampere, Finland
  2. 2Unit of Primary Health Care, Helsinki University Central Hospital, Helsinki, Finland
  3. 3Department of General Practice, University of Helsinki, Helsinki, Finland
  4. 4Unit of Primary Health Care, Turku University Hospital, Turku, Finland
  5. 5Department of Medicine, Jyväskylä Central Hospital, Jyväskylä, Finland
  6. 6Department of Medicine, Kuopio University Hospital, Kuopio, Finland
  7. 7Division of Medicine and Department of Rheumatology, Turku University Hospital, Turku, Finland
  8. 8Department of Medicine, Päijät-Häme Central Hospital, Lahti, Finland
  9. 9Department of Medicine, Oulu University Hospital, Oulu, Finland
  10. 10Helsinki Medical Imaging Centre, Helsinki University Central Hospital, Helsinki, Finland
  11. 11Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland
  12. 12Department of Clinical Medicine, University of Helsinki, Helsinki, Finland
  1. Correspondence to Dr Vappu Rantalaiho, Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Central Hospital, PO BOX 2000, Tampere FI-33521, Finland; vappu.rantalaiho{at}pshp.fi

Abstract

Objective To study whether adding initial infliximab to remission-targeted initial combination-DMARD treatment improves the long-term outcomes in patients with early rheumatoid arthritis (RA).

Methods Ninety-nine patients with early, DMARD-naïve RA were treated with a triple combination of DMARDs, starting with methotrexate (max 25 mg/week), sulfasalazine (max 2 g/day), hydroxychloroquine (35 mg/kg/week), and with prednisolone (7.5 mg/day), and randomised to double blindly receive either infliximab (3 mg/kg; FIN-RACo+INFL) or placebo (FIN-RACo+PLA) infusions during the first 6 months. After 2 years the treatment strategies became unrestricted, but the treatment goal was strict ACR remission. At 5 years the clinical and radiographic outcomes were assessed.

Results Ninety-one patients (92%) were followed up to 5 years, 45 in the FIN-RACo+INFL and 46 in the FIN-RACo+PLA groups. At 5 years, the respective proportions of patients in strict ACR and in disease activity score 28 remissions in the FIN-RACo+INFL and FIN-RACo+PLA groups were 60% (95% CI 44% to 74%) and 61% (95% CI 45% to 75%) (p=0.87), and 84% (95% CI 71% to 94%) and 89% (95% CI 76% to 96%) (p=0.51). The corresponding mean (SD) total Sharp/van der Heijde scores at 5 years were 4.3 (7.6), and 5.3 (7.3), while the respective mean Sharp/van der Heijde scores changes from baseline to 5 years were 1.6 (95% CI 0.0 to 3.4) and 3.7 (95% CI 2.2 to 5.8) (p=0.13).

Conclusions In early RA, targeted treatment with a combination of traditional DMARDs and prednisolone induces remission and minimises radiographic progression in most patients up to 5 years; adding initial infliximab for 6 months does not improve these outcomes.

  • Early Rheumatoid Arthritis
  • DMARDs (synthetic)
  • DMARDs (biologic)

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Introduction

The current treatment of rheumatoid arthritis (RA) aims at early and sustained remission.1 A considerable proportion of the patients may achieve this target, even in the long term. Previous trials have shown that in the treatment of early RA a combination of disease modifying antirheumatic drugs (DMARDs) is better than DMARD monotherapy,2–5 that targeted therapy is better than routine care,6–8 and that the use of glucocorticoids (GCs) orally,9–11 and intra-articularly12 ,13 improves the results. Further, added induction therapy with infliximab (INFL), has, in combination with methotrexate (MTX), been shown to be more effective than MTX monotherapy,14 a finding confirmed with other tumour necrosis factor-α (TNF) inhibitors,15 ,16 but comparable early response is achieved with a combination of DMARDs and GCs.3 When applying targeted strategies, the clinical outcomes of different initial treatments do not differ in the long term,17 but the early achievement of low disease activity or remission results in lower total radiographic progression and better maintenance of working capacity,18 ,19 emphasising the importance of rapid suppression of inflammation.

We have previously shown that, in early RA, an intensified initial Finnish Rheumatoid Arthritis combination treatment (FIN-RACo) combination treatment (MTX, sulfasalazine (SASP), hydroxychloroquine and small-dose prednisolone (PRD)) resulted in very low disease activity in most patients, with 82% of the patients being in disease activity score 28 (DAS28) remission at 2 years and only 8% of the patients not reaching an ACR50 response.20 As many as 53% of the patients treated with this combination reached the strict American College of Rheumatology (ACR) remission at 2 years, adding INFL for the first 6 months increased the percentage further to 66%. At 2 years, patients treated with the FIN-RACo combination had minimal radiographic progression; still patients receiving additional INFL for the first 6 months had even less joint damage.

In the present study we report the 5-year outcomes of these patients with early RA treated with the initial FIN-RACo combination for 2 years, and with either INFL or placebo (PLA) infusions for the first 6 months.

Methods

Study design and patients

In this investigator initiated, multicentre, controlled study, 99 patients with early, active RA were treated with an intensified FIN-RACo regimen including MTX, started at a dose of 10 mg/week, and increased by week 14 up to 25 mg/week (subcutaneous/intramuscular, in case of intolerance or inefficacy), SASP up to 2 g/day, hydroxychloroquine 35 mg/kg/week and PRD 7.5 mg/day for 2 years, and double blindly randomised to receive either INFL or PLA infusions at weeks 4, 6, 10, 18 and 26. At all time points the treatment was targeted to ACR remission,21 with the following modification: the patient was considered to be in remission if fulfilling five out of six criteria (morning stiffness <15 min, no fatigue, joint pain, tender joints, swelling in joints or tendons, and erythrocyte sedimentation rate (ESR)<30 mm/h in women and <20 mm/h in men) and having no swollen or tender joints. An active use of intra-articular GC injections to all inflamed joints was part of the protocol. The patient selection criteria as well as the treatment protocol have been described in detail earlier.20

Outcomes and follow-up

The patients were assessed at weeks 0, 4, 6, 10, 14, 18, 22, 26, and at months 8, 10, 12, and thereafter 3 monthly up to 5 years. If, at any time between 6–24 months, the treatment response was less than ACR50 at two consecutive visits, the patient was regarded as a treatment failure, and the therapy became unrestricted, including the opportunity to use TNF-blockers, but the INFL/PLA code was not opened and the patient continued in the study. At 5 years, the patients to whom a biologic had been initiated within 2 years were included, even though they had been excluded from the 2-year analysis. If the treatment response was ≥ACR50, but not remission, the DMARDs could be substituted by others according to a predefined protocol, which was also applied in case of intolerability. Nevertheless, during the first 2 years, it was obligatory to use a combination of three DMARDs, one of which had to be a cytostatic (MTX, leflunomide, azathioprine) or an immunomodulating (cyclosporine) agent.

After 24 months, if the patient was in remission at that point, PRD dose was decreased by 2.5 mg/day every 3 months and tapered off if the patient continued to be in remission. In case of sustained remission without PRD, first SASP could be tapered down by 500 mg/day every 3 months and eventually stopped, and after that the dose of MTX could be decreased by 2.5 mg/week every 3 months. If remission was lost, the preceding DMARD treatment was recommenced. In case of non-remission, the maximum tolerated doses of the combination treatment were continued throughout the follow-up and the therapies modified according to the judgement of the treating rheumatologist, aiming at strict remission at all time points.

The clinical assessments included the evaluation of the number of swollen and tender joints (out of 66/68 joints), patient's assessment of pain (10 cm visual analogue scale (VAS)), patient's global assessment of disease activity (10 cm VAS), physician's global assessment of disease activity (10 cm VAS), patient's assessment of physical function (Health Assessment Questionnaire, HAQ),22 and acute-phase reactants (C-reactive protein (CRP), ESR). The DAS according to the state of 28 joints was calculated.23

The medications used, the intra-articular GC injections given, as well as the occurrence of adverse effects were carefully elucidated at each visit.

The small joints of the hands and feet were radiographed at baseline and at 2 years and 5 years, and scored by an experienced radiologist (LL), aware of the chronology of the radiographs, according to the modified Sharp/van der Heijde method (SHS).24

The primary outcome measures were the strict ACR remissions and the radiographic damage in hands and feet at 5 years. The secondary outcome measures were the DAS28 remission and HAQ scores.

Statistical methods

Statistical comparisons between the groups were made by using t test, bootstrap type t test, Mann-Whitney test or χ2 test. The longitudinal remission data was analysed with generalised estimating equations models with unstructured correlation structure, and binomial or Poisson link. Bootstrap type analysis of covariance with the baseline value as a covariate was adapted for radiological progression changes due to the violation of distribution assumption. The 95% CIs for means of radiological outcomes were also obtained by bias-corrected bootstrapping (5000 replications).

Results

The flow chart of the patients is presented in figure 1. Two patients in the original FIN-RACo+INFL group and one in the FIN-RACo+PLA group had been excluded from the 2-year analysis due to lack of efficacy (ACR response <50% on two consequent visits) and subsequent treatment with a TNF-inhibitor,20 but were included in this 5-year analysis. One patient from the original FIN-RACo+PLA group withdrew consent at the 24-month visit and was included in the 2-year analysis, but not after that.

Figure 1

Flow chart of the patients randomised to receive either initial infliximab (FINRACo+INFL) or initial placebo infusions (FIN-RACo+PLA) in addition to a combination of three DMARDs and small-dose prednisolone and followed up for 5 years.

The baseline demographics, the measures of disease activity and function at baseline and at 5 years, and the proportions of patients in DAS28 or strict ACR remission at 5 years are shown in table 1. The proportions of patients in ACR and in DAS28 remission between 2–5 years and over time are presented in figure 2. There was a trend for a difference in the ACR-remission rates between the groups up to 4 years.

Table 1

Demographic data at baseline as well as clinical characteristics and radiographic findings at baseline and at 5 years in patients randomised to receive initial infliximab (FIN-RACo+INFL) or initial placebo infusions (FIN-RACo+PLA) for 6 months in addition to a combination of three DMARDs and small-dose prednisolone

Figure 2

Percentages of patients according to the original patient groups, randomised to receive either initial infliximab (FIN-RACo+INFL) or initial placebo infusions (FIN-RACo+PLA) in addition to a combination of three DMARDs and small-dose prednisolone, in (A) strict ACR remission, and in (B) disease activity score 28 (DAS28) remission between 2–5 years. Data are presented as means and 95% CIs.

The details of radiographic scores at baseline and at 5 years are also presented in table 1. The mean changes in total SHS from baseline to 5 years were 1.6 (95% CI 0.0 to 3.4) and 3.7 (95% CI 2.2 to 5.8) (p=0.13, adjusted for baseline total SHS) in the initial FIN-RACo+INFL and FIN-RACo+PLA group patients, respectively. Thus the respective progression rates were 0.32 (95% CI 0.00 to 0.66) and 0.73 (95% CI 0.39 to 1.08) units per year. The cumulative percentage of the change in the total SHS from baseline to 5 years is shown in figure 3A, and the mean (SD) increase in it from baseline to 2 years and 5 years in figure 3B. From baseline to 5 years the increase in erosive patients was 1.48-fold (95% CI 0.63 to 3.47) in the FIN-RACo+PLA group compared with the FIN-RACo+INFL patients (figure 3C). No radiographic progression during 5 years occurred in 64% (95% CI 48% to 78%) of the FIN-RACo+INFL and in 43% (95% CI 29% to 59%) of FIN-RACo+PLA group patients.

Figure 3

(A) The cumulative percentage of increase in the total Sharp/van der Heijde scores (SHS) from baseline to 5 years, (B) the mean (SD) increase in the total SHS from baseline to 2 years and 5 years, and (C) the percentage (95% CI) of erosive patients in the original patient groups, randomized to receive either initial infliximab (FIN-RACo+INFL) or initial placebo infusions (FIN-RACo+PLA) in addition to a combination of three DMARDs and small-dose prednisolone. The statistical analyses are adjusted for baseline total SHS.

From 2 years to 5 years, the median (IQR) cumulative PRD doses were 1.5 (0.7–4.4) mg/day and 1.2 (0.8–3.3) mg/day in the FIN-RACo+INFL and FIN-RACo+PLA groups (p=0.83), respectively, while during the total follow-up of 5 years, the respective median (IQR) numbers of intra-articular glucocorticoid injections were 4 (0–15) and 7 (3–12) (p=0.23). After 6 months any biologic drug was initiated to three (6%) and seven patients (15%) (p=0.20), and the median (IQR; range) number of synthetic or biologic DMARDs used was 3 (3, 4; 3–10) and 3 (3, 4; 3–11), in the FIN-RACo+INFL and FIN-RACo+PLA groups, respectively. The percentages of treatment time on different DMARDs are presented in figure 4. At 5 years three patients in the initial FIN-RACo+INFL group were in drug-free remission, but none from the FIN-RACo+PLA patients (p=0.12).

Figure 4

Percentages of follow-up time between 2 years and 5 years on different synthetic DMARDs, prednisolone and biologic DMARDs for the patients originally randomised to receive either initial infliximab (FIN-RACo+INFL) or initial placebo infusions (FIN-RACo+PLA) in addition to a combination of three DMARDs and small-dose prednisolone.

The occurrence of adverse events did not differ between the groups, and the number of serious adverse events, especially of those possibly related to the study medications, was small (table 2).

Table 2

Adverse events between 2–5 years in patients randomised to receive initial infliximab (FIN-RACo+INFL) or initial placebo infusions (FIN-RACo+PLA) for 6 months in addition to a combination of three DMARDs and small-dose prednisolone

Discussion

This study shows that excellent sustained clinical results can be achieved with early, remission-targeted treatment with a combination of traditional DMARDs and systemic (if needed, intra-articular) GC therapy in patients with recent-onset RA. At 5 years 60% of the patients have no RA symptoms, 87% fulfil the DAS28 criterion for remission, and the radiographic progression is marginal.

The 2-year results of the current NEO-RACo trial revealed that treating all patients with a triple combination of DMARDs as well as with systemic and intra-articular GCs, and aiming to strict remission led to clinical remission and minimal radiographic progression in most patients. Initial INFL increased the proportion of patients achieving strict remission by 3 months, after that it had only small additive effect on clinical outcomes, but halted the otherwise marginal radiographic progression totally.20 At 5 years, possibly due to the small study population size, all statistically significant differences between the groups had resolved. Still, there was a trend for fewer new erosive patients and for less need of consequent biologics and intra-articular injections in the original FIN-RACo+INFL group; also, all patients in drug-free remission belonged to this group.

Evidently, the main limitation of our study is the small study population size. While the original population was calculated to have the power to demonstrate a 30% difference in the remission rates between the groups within 2 years, smaller differences may not have been distinguished, especially at 5 years.

Nevertheless, even the original FIN-RACo+PLA patients had excellent outcomes, and approximately 87% of all patients with initially highly active RA were in DAS28 remission at 5 years, a result superior to any other long-term follow-up trial of early RA. In the Ciclosporine, Methotrexate, Steroid in RA (CIMESTRA) study active, targeted treatments and intra-articular GC injections to all inflamed joints were used. Consequently, almost comparable results with our present study were achieved: at 5 years 78% of the patients were in DAS remission and 56% had achieved ACR remission.13 In the original FIN-RACo trial 55% of the patients initially treated with the FIN-RACo combination were in DAS28 remission at 5 years.25 Further, in the Behandel Strategieën (BeSt) trial, comparing four different treatment strategies, 48% of all patients were in DAS remission at 5 years.17 In the Better Anti-rheumatic Farmacotherapy (BARFOT) trial, assessing the effect of initial oral GC treatment, 40% of the patients were in DAS28 remission at 4 years.26 In the 5-year extension of the PREMIER study, DAS28 remission was achieved by 67% of the patients who had received the combination of adalimumab and MTX for 2 years, and adalimumab for up to 5 years.27

Further, the perceived function remained excellent in most patients of the current trial, with only one patient having a HAQ score above 1.0 and approximately 70% having it at zero, findings comparable with normal, non-RA, population.28 For comparison, in the CIMESTRA trial 57% of the patients had the HAQ score <0.25 at 5 years,13 and in the BeSt trial the mean HAQ at 5 years was 0.58 in all groups.17

Also the radiographic progression was marginal in both groups. In the FIN-RACo+PLA group the increase in the total SHS score was 0.73 units per year, which is clearly below the limit for the minimal clinically important difference,29 and even the smallest detectable change.30 Adding initial INFL decelerated the progression further, halting it during the first 2 years, and lessening the progression of new erosive patients. However, the real life relevance of the difference between the groups remains ambiguous. For comparison, in the CIMESTRA trial the radiographic progression in the total SHS score was also just below 1 unit per year,13 in the BeSt trial it was around 1 unit per year for the combination groups,17 and in the BARFOT trial the progression was 1.1 units per year for those in remission with initial GC, and 3 units per year for those not in remission. In the PREMIER trial, for the patients receiving the combination of adalimumab and MTX for the first 2 years, and adalimumab after that the progression in the modified total SHS score was approximately 0.6 units per year.27

Originally, all trials comparing the combination of a biologic agent and MTX to the single MTX therapy in early RA have shown the combination to be more effective.14–16 However, in strategy trials with predefined treatment goals in remission or low disease activity, the biologics have not been superior to synthetic DMARDs at least in the primary outcome measures, even though they may have proven beneficial for some secondary outcomes.17 ,31 ,32 In any case, it appears evident that regardless of the specific medications used, the stricter the treatment goal, the higher the proportion of patients reaching remission and a non-progressive state of disease.

There is a broad international consensus among rheumatologists about treating RA to early remission,1 as it predicts consequent remissions,33–35 less radiographic progression,13 ,18 ,36–38 better maintenance of working capacity19 ,33 and thus savings in indirect costs of the disease.39 However, the definitions of remission vary,40 most probably as in daily clinical practice strict remissions have been rare. Also, opinions on the means to achieve remission diverge and there is a great variation in the treatments used and in the treatment recommendations given.41 Thus far the European guideline recommends the use of MTX monotherapy in active early RA, and if this fails, the use of biologics,42 DMARD combinations are not seen as an option even in RA with markers of poor prognosis. Other recommendations have given a role to initial combination DMARDs,43 ,44 and the Finnish ones even underline their importance in active RA,45 which is reflected in real life practices.46

Different inclusion criteria in the various meta-analyses have led to diverging conclusions on the role of combination DMARD therapy.47 ,48 Nevertheless, recently published studies have confirmed the importance of early combination treatment,4 ,49 ,50 and the Swedish Farmacotherapy (SWEFOT) trial demonstrated that with initial MTX only 30% of the patients reach low disease activity within 4 months, and that of these responders 72% were in DAS28 remission at 2 years but some still progressed radiographically.51 Therefore, first, MTX monotherapy does not seem to be the ideal initial treatment of early RA, as only a minority of patients achieve an adequate response. And second, low disease activity does not seem to be a sufficient goal, as it still allows substantial disease activity, which may lead to progressive disease.

The wide use of initial combination DMARDs may be restricted by a concern of ‘overtreatment’, a poorly defined concept supposedly meaning that one causes more harm than benefit to the early RA patients.52 In that respect the findings of the current study are reassuring; serious adverse events were very uncommon, proving this aggressive treatment strategy safe. Undoubtedly, however, further analyses are required to elucidate the side effects especially of GCs in detail.53 The GCs were tapered down and off similarly in both groups, and the use of intra-articular GC injections, DMARDs or biologics after 2 years did not significantly differ between the groups. One justification of the step-down strategies has been the idea of tapering the medication once remission is achieved. To a certain point this may be possible in some patients, but it has been shown that totally drug-free remissions are often transient, and that the reintroduction of DMARD therapy may be less efficient than continuing the treatments.54 Therefore, the protocol of the NEO-RACo trial allowed the tapering of the DMARDs, but did not recommend a total discontinuation of the medications despite reaching remission. Thus, only a few patients were in drug-free remission at 5 years.

To conclude, this study proves that we have the means and knowledge to accompany the majority of patients with early RA into remission and non-progressive state of the disease. It is up to the clinicians to adopt this comprehension and consider which is more harmful: risking of ‘overtreating’ occasional patients with traditional, inexpensive, well-known and relatively safe DMARDs in combination, or knowingly undertreating the majority of patients with MTX monotherapy, and then, after failing to reach the target, overtreating them with new, highly expensive biologics, which still have an unclear long-term safety profile. Evidently, a minority of patients fails even the aggressive initial DMARD combinations, and therefore future efforts should concentrate on identifying these patients as early as possible, and on finding an efficient treatment for them as well.

Acknowledgments

The authors would like to thank all participating patients, study nurses and other members of the NEO-RACo Study Group.

References

Footnotes

  • Handling editor Tore K Kvien

  • Collaborators Other members of the NEO-RACo Study Group: Eeva Alasaarela, Harri Blåfield, Kari K Eklund, Kirsti Ilva, Heikki Julkunen, Aulikki Kononoff, Maija-Liisa Krogerus, Riitta Luosujärvi, Reijo Luukkainen, Timo Malmi, Helena Niinisalo, Leena Paimela, Kari Puolakka, Jari Pöllänen, Tea Uusitalo, Toini Uutela, Heikki Valleala, and Kaisa Vuori (rheumatologists), and Eeva Moilanen, Riina Nieminen, and Katariina Vuolteenaho (pharmacologists). The administrative board of the study consisted of Marjatta Leirisalo-Repo, Timo Möttönen, Markku Korpela, Markku Kauppi, Oili Kaipiainen-Seppänen, and Riitta Luosujärvi.

  • Contributors The study was designed by the principal investigator, ML-R, in collaboration with other investigators of the NEO-RACo Study Group, and all data were collected by the Study Group. LL evaluated the radiographs. Data collection and statistical analysis were done by HK. All authors contributed to the conception and design of the study and participated in the analysis and interpretation of the data. VR, HK, MK and ML-R drafted the article and the other authors revised it critically for intellectual content. All authors approved the final version of this article.

  • Funding This study was financially supported by the Competitive Research Funding of the Tampere University Hospital (Grants 9M124 and 9M128), by the Helsinki University Central Hospital Research Funds, by Finska Läkaresällskapet, and by Orion-Farmos Research Foundation. At baseline an unrestricted grant was provided by Schering-Plough Finland, which was used for the purchase of infliximab.

  • Competing interests VR has received honoraria from Abbott, BMS, Pfizer, Roche, UCB Pharma. HK has received honoraria from Abbott, Pfizer and Schering-Plough. MMK has received honoraria and consulting fees from Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB Pharma. PH has received honoraria and consulting fees from Abbott, Astra-Zeneca, BMS, GSK, MSD Finland, Mundipharma, Pfizer, Roche, UCB Pharma. OK-S has received honoraria from Abbott, Actelion, BMS, GSK, MSD Finland, Pfizer, Roche, UCB Pharma. TM has received honoraria and consulting fees from Abbott, Amgen, Astra, BMS, Ely Lilly, GSK, MSD, Pfizer, Schering-Plough, Servier, Roche, UCB Pharma. MJK has received honoraria from Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB Pharma. AK has received honoraria from Abbott, Actelion, BMS, GSK, MSD, Pfizer, Roche, Schering-Plough, UCB Pharma. LL has received consulting fees from Abbott and Pfizer. RP has received honoraria and consulting fees from Abbott, Actelion, BMS, MSD, Pfizer, Roche, Schering-Plough, UCB Pharma. ML-R has received honoraria and consulting fees from Abbott, BMS, GSK, MSD, Pfizer, Roche, Schering-Plough, UCB Pharma. KL and MH have nothing to disclose.

  • Ethics approval The study was conducted according to the declaration of Helsinki and its protocol was approved by the national health authorities and by the ethics committee of the Hospital District of Helsinki and Uusimaa. All the patients gave informed written consent. The study has been registered at http://www.clintrials.gov (NCT00908089).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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