Skip Navigation


Rheumatology Advance Access originally published online on June 28, 2008
Rheumatology 2008 47(9):1384-1388; doi:10.1093/rheumatology/ken223
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
47/9/1384    most recent
ken223v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Karanikolas, G.
Right arrow Articles by Sfikakis, P. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Karanikolas, G.
Right arrow Articles by Sfikakis, P. P.
Related Collections
Right arrow Pharmacology
Right arrow Rheumatoid Arthritis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or cyclosporin-A monotherapy: a 48-week, comparative, prospective study

G. Karanikolas1, D. Charalambopoulos1, G. Vaiopoulos2, A. Andrianakos3, A. Rapti4, D. Karras5, E. Kaskani6 and P. P. Sfikakis1

1First Department of Propedeutic and Internal Medicine, 2First Department of Internal Medicine, Laiko Hospital, Athens University Medical School, 3Hellenic Foundation for Rheumatological Research, Athens, 4Hellenic Rheumatology Society, Corfu, 5Hellenic Rheumatology Society and 6IKA Health Center, Athens, Greece.

Correspondence to: G. Karanikolas, 39 Alopekis Str, Athens, Greece. E-mail: gkaranikgr{at}yahoo.gr


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To assess the efficacy and safety of anakinra (ANK) as an add-on therapy in RA patients with inadequate response to monotherapy with non-biological DMARDs.

Methods. A 48-week comparative, prospective study of patients with active RA [mean 28-joint disease activity score (DAS28): 6.81], despite MTX (n = 48), or LEF (n = 42), or CSA (n = 38) treatment, in whom ANK (100 mg/daily SC) was given with corticosteroid cream topical application.

Results. At 24 and 48 weeks the patient percentages meeting the ACR20 response criteria were 57 and 73%, respectively, 33 and 41% met ACR50, while 15 and 23% met ACR70. Significant improvements in number of swollen and tender joints, HAQ, pain, global disease assessment, CRP and haemoglobin from baseline to 24 and 48 weeks were evident. DAS28 decreased at 24 weeks (– 1.68; 95% CI – 1.46, – 1.90; P < 0.0001), as well as at study end (– 2.24; 95% CI – 2.01, – 2.47; P < 0.0001). Subgroup analysis revealed a significantly weaker response in terms of pain and DAS28 in patients treated with concomitant CSA. The most common ANK-related adverse event was injection-site reaction (29%), being less frequent in male patients, as well as in patients treated with CSA. There were 17 withdrawals, 6 of them due to inefficacy. No opportunistic infections or new safety signals were observed.

Conclusion. Considering the limitations of an open-label study, addition of ANK appears to be an effective and well-tolerated treatment option for many RA patients with inadequate responses to non-biologic DMARDs in clinical practice.

KEY WORDS: Rheumatoid arthritis, Anakinra, Methotrexate, Leflunomide, Cyclosporin-A combination therapy


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Rheumatoid arthritis (RA) is a systemic disease characterized by chronic joint inflammation resulting in bone destruction and severe disability. According to the most recent epidemiological study performed in Greece, the prevalence rate of RA is 0.67% in the adult general population [1]. Clinical practice guidelines for RA recommend initiating treatment with a DMARD within 3 months of diagnosis, aiming to prevent functional disability and retard articular damage [2]. MTX, LEF and CSA are conventional DMARDs that are widely used for the treatment of patients with RA in clinical practice. Important advances in our understanding of RA pathogenesis have contributed to the development of biological therapies that target pro-inflammatory cytokines, such as TNF-{alpha} and IL-1.

Despite recent advances in the treatment options of RA the concept of monotherapy is being reconsidered, because no single drug currently in use, including biological agents, is successful in controlling disease activity and achieving sustained long-term efficacy in many cases [3]. Anakinra (ANK) is a recombinant non-glycosylated form of human IL-1 receptor antagonist, an endogenous natural inhibitor of IL-1 activity [4], which has been approved for RA treatment. In randomized controlled clinical trials, ANK improved the signs and symptoms of RA when used as monotherapy or in combination with MTX [5–7]. In addition, ANK monotherapy slowed the radiographic progression of RA [8, 9] and improved the functional status of patients’ refractory to MTX [10, 11]. The aim of the present prospective study was to assess the efficacy and safety of adjunctive ANK in clinical practice for RA patients in whom active disease persisted despite monotherapy with conventional DMARDs.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Eligibility
Patients aged 18 yrs and older fulfilling the ACR (formerly, the ARA) diagnostic criteria for RA [12] were eligible for this study if they had active disease. Active disease was defined as the presence of at least nine tender or painful joints (of 68 joints evaluated), six swollen joints (of 66 joints evaluated) and at least one of the following: ESR ≥ 28 mm/1st h, CRP ≥ 20 mg/l and morning stiffness lasting at least 45 min. Patients were required to have had RA for at least 6 months but < 12 yrs and should had been treated with maximum tolerated doses of MTX (25 mg/week), or LEF (20 mg/day), or CSA (3.5 mg/kg/day) for a minimum of 6 months, being in stable doses of these drugs for at least 8 weeks before study entry. Concomitant NSAIDs and/or oral corticosteroids (≤ 10 mg prednisolone daily or equivalent) should have been stable for at least 4 weeks prior to study entry.

The standard exclusion criteria used in therapeutic trials in patients with RA were applied. Additionally, patients who had received treatment with TNF antagonists (anti-CD20 therapies or abatacept were not available in Greece at the time of the study), as well as patients who had received IA or systemic corticosteroids injection during the past 8 weeks, were excluded.

Study protocol and evaluation of treatment outcome
The study was a 48-week, open-label prospective study of an add-on, parallel design. Self-administered subcutaneous injections of ANK at the indicated dose (100 mg/daily), in addition to their stable dosage of MTX (n = 48), or LEF (n = 42), or CSA (n = 38) was prescribed in consecutive patients with active RA who were followed up in our clinics and fulfilled the study criteria. Recruitment of patients lasted 10 months. Administration of NSAIDs (52% of patients) and steroids (62% of patients) at doses prior to study entry was not discontinued. All patients were instructed to use triamcinolone cream topical application immediately after ANK injection for at least the first 6 weeks. The study was conducted according to the Declaration of Helsinki and approved by ethical committees according to existing regulations.

Clinical variables were assessed and laboratory evaluations were obtained at baseline, at 2nd and 4th week, every 4 weeks up to 6th month, and every 8 weeks thereafter. Clinical efficacy assessments were performed by rheumatologists who were aware of the patient treatment. The primary efficacy end-point was the rate at which the patient cohort achieved 20, 50 and 70% improvement in ACR criteria at the end of the study [13]. The secondary and tertiary efficacy variables were reductions in 28-joint disease activity score (DAS28) index [14] and HAQ index, respectively [15]. CRP by laser nephelometry and Westergreen ESR were obtained at baseline and every 8 weeks thereafter.

Safety
Safety was assessed on the basis of adverse events (AEs) reported by patients and findings of physical examination and laboratory evaluations. Patients who received at least one injection of ANK were candidates for safety analysis. Treatment was discontinued in patients with leukopenia, neutropenia, thrombocytopenia, persistent elevations of serum creatinine, potassium and liver enzymes (more than double of the upper normal limit on repeated testing, despite dose adjustment). Serious AEs were defined as any adverse reaction resulting in death or life-threatening condition, a significant or permanent disability/incapacity, a malignancy or hospitalization. Patients who were withdrawn because of AE received follow-up care until the drug-related symptoms were resolved.

Statistical analysis
All available data of the intent-to-treat (ITT) population were used in the analysis.

Mixed model analysis by a random coefficient model was employed to evaluate the alteration of ACR components, DAS28, haemoglobin and CRP from baseline to 24 and 48 weeks. Regression curves were fitted for each patient and the regression coefficients were allowed to vary randomly between patients. Time, treatment, treatment x time and sex x time were fitted as fixed factors, whereas patient and patient x time were fitted as random coefficients. Summary statistics adjusted for baseline values are presented as in least square means and the associated 95% CI, as generated by the mixed models. Chi-squared tests were used to assess the distribution of ACR20, ACR50 and ACR70 between the two genders at the end of treatment. Statistical significance was set at 5%.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Baseline characteristics and disposition of patients
Of the 128 patients, 89 (70%) were women, mean age of patients was 47.4 yrs (range 18–79 yrs), median duration of RA at the time of enrolment was 7.1 yrs (range 0.7–12 yrs), while 25.8% of the patients had RA for < 2 yrs. As shown in Table 1, there were no significant differences in disease characteristics among the three treatment groups at study entry. As shown in Fig. 1, 111 patients completed the 48 weeks of ANK treatment. Among patients who dropped out from the study (nine of the MTX group, three of LEF group and five of CSA group), six withdrew because of AEs, six because of inefficacy or disease worsening and three for protocol violation. A 68-yr-old male patient had a fatal acute myocardial infarction at 16 weeks (LEF group) and a 76-yr-old male patient had a lethal stroke at 32 weeks (MTX group). The proportion of total withdrawals was higher during the initial 6 months (13 patients) than the following 6 months (4 patients).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Demographic and disease characteristics of 128 patients with active RA despite MTX, or LEF, or CSA monotherapy (mean ± S.D., percentages)

 

Figure 1
View larger version (15K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		FIG. 1. Disposition of patients during the study period.

 
Efficacy
Percentages of patients with active RA despite MTX, or LEF, or CSA monotherapy who achieved 20, 50 and 70% improvement in ACR criteria at 24 and 48 weeks of adjunctive ANK are shown in Fig. 2. Notably, female patients had a better response than male patients in ACR 20 (73/89 vs 22/39, P = 0.005) and in ACR50 (47/89 vs 11/39, P = 0.017). Further analysis of individual components of the ACR response criteria revealed significant improvements from baseline to 24 and 48 weeks (Table 2). A total of 95 patients (74%) achieved the standard clinically meaningful amelioration in HAQ score, i.e. decrease > 0.22, while 20% reached a completely normal physical function status (HAQ = 0).


Figure 2
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		FIG. 2. ACR response rates at 24 weeks and 48 weeks of adjunctive treatment with ANK in 128 patients with active RA despite MTX, or LEF, or CSA monotherapy.

 

View this table:
[in this window]
[in a new window]

  		TABLE 2. Improvement of individual components of the ACR response criteria, DAS28, haemoglobin and CRP in 128 patients with active RA from baseline to 24 and 48 weeks treatment with adjunctive ANK

 
Addition of ANK resulted to an overall significant fall in DAS28 (– 1.68; 95% CI – 1.46, – 1.90; P < 0.0001) during the first 24 weeks, as well as at the end of treatment period (– 2.24; 95% CI – 2.01, – 2.47; P < 0.0001). In total, 27 patients (21%) achieved a DAS28 < 3.2, (cut-off limit for low disease activity), while 18 patients (14%) were found to be under the 2.6 DAS28 value (clinical remission).

Beneficial effects on extra-articular features, including sicca syndrome, pleuritis, interstitial lung disease, leucocytoclastic vasculitis, subcutaneous nodules and episcleritis were observed in some patients of this trial, but no formal analysis was performed due to small patient numbers. Concomitant administration of NSAIDs was discontinued in 9 of 69 patients (13%), while the dose remained unchanged in the remaining patients. Corticosteroid administration was also discontinued in 14 of 79 patients (18%), while dosage was decreased or increased in 24 and 3 patients, respectively. The mean (S.D.) prednisolone dosage at baseline was 6.4 (3.3) mg/day, whereas the dose at the last visit was 3.6 (2.7) mg/day (P < 0.005).

At the end of the study, 65, 81 and 74% of the ANK + MTX, ANK + LEF and ANK + CSA groups, respectively, met the ACR20 response criteria (P = 0.218), whereas 38, 64 and 47% met the ACR50 response criteria (P = 0.039 in favour of ANK + LEF), and 15, 36 and 21% met the ACR70 response criteria (P = 0.057), respectively. Subgroup analysis between patients treated with background MTX, LEF or CSA of the changes in clinical and laboratory parameters revealed non-significant differences in numbers of swollen or tender joints, HAQ, global disease assessment, haemoglobin and CRP (data not shown). A significantly weaker response in terms of pain and DAS28 was noted in patients treated with background CSA (Fig. 3).


Figure 3
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		FIG. 3. Improvement of DAS28 and pain assessed by VAS from baseline to 24 and 48 weeks of adjunctive treatment with ANK in subgroups of patients with active RA despite MTX, or LEF, or CSA monotherapy. P-value denotes the presence of significant difference in subgroup comparison.

 
Adverse events
The overall incidence of clinical AE (84 subjects, 66% total AEs) was not similar among the three treatment groups, albeit not reaching statistical significance (Table 3). In general, AEs were predominantly mild to moderate in severity and intensity. The majority of ANK-related AEs were injection site reactions, which occurred in 37 subjects (29%). The frequency of injection site reactions was lower in subjects who used concomitant corticosteroids (18% vs 41%, P = 0.003), as well as in men compared with women (18% vs 34%, P = 0.014), and in patients under CSA compared with those treated with MTX (19% vs 42%, P = 0.04).


View this table:
[in this window]
[in a new window]

  		TABLE 3. Adverse events

 
Serious AEs occurred in four patients (Table 3). An LEF-treated man developed a Staphylococcus aureus ocular infection at the 10th month, requiring hospitalization for intravenous antibiotics administration; he resumed ANK monotherapy once the infection resolved. An MTX-treated woman developed severe thrombocytopenia at fifth month of therapy, which partially improved after ANK cessation, but close monitoring revealed normal platelet count upon MTX discontinuation. In a young CSA-treated woman with no concomitant NSAIDs use, gastroduodenal bleeding requiring hospitalization occurred at the fourth month and ANK was resumed with no further problems. Finally, ovarian cancer was diagnosed in one MTX-treated patient, at the ninth month. Unusual or opportunistic infections, as well as skin rashes or mucosal events were not observed in this trial. No evidence of severe hepatotoxicity, renal toxicity, leukopenia or other drug-related laboratory abnormalities, requiring cessation of treatment were observed.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
The present study was designed to expand the available information on the efficacy, safety and tolerance of introducing an IL-1 antagonist in patients with severe, active RA, treated in clinical practice with traditional DMARDs. Although the patients enrolled in the present study had high disease activity (DAS28 = 6.81), almost 75% achieved an ACR20 response. Whether the observed high response rate in ACR20 can be attributed to the effectiveness of the combined therapy or to the low sensitivity of the ACR20 index (high response in placebo groups in randomized trials) is uncertain and should be interpreted with caution due to the open study design. However, the significant percentages of patients meeting the more stringent ACR50 and ACR70 indices, as well as that 14% of patients achieved remission (DAS28 < 2.6), suggest a robust clinical efficacy resulting from the combined treatment. Moreover, significant reductions of acute-phase reactants were noted and haemoglobin concentration increased substantially, suggesting a role for IL-1 in the anaemia of chronic disease. The reduction of the concomitant steroid dose in all treatment groups by almost 50% also pointed to the effectiveness of the combined regimen.

According to a recent 2-yr prospective, partly retrospective, Dutch trial, the drug survival after 12 months of ANK administration was 32% in patients with RA, with a lack in efficacy being the main reason for discontinuation [16]. The fact that only 52% of these patients were receiving concomitant DMARDs may explain these results [16]. In our study, disease activity was further reduced at the second semester (DAS28 change of – 1.68 at 24 weeks and – 2.24 at 48 weeks) and only one patient had disease exacerbation after the first 6 months, further implying a stable efficacy of ANK treatment when combined with conventional DMARDs.

Several recent studies have demonstrated that patient-reported outcomes, including patient global assessment of disease activity, pain and HAQ, better discriminate between placebo and active medication, than physician-reported outcomes [17]. Furthermore, previous reports have confirmed that greater disability or reduced functional status in RA patients is associated with increased mortality [18]. Along these lines, the significant improvement of HAQ observed in our patients is of clinical importance. Indeed, HAQ score improved in 95 of 128 patients, regardless of DMARD background, while >20% of patients improved to the point that no impairment in any area of functioning was evident (HAQ = 0). Similar results have been obtained in patients treated with anti-TNF agents in combination with MTX [19, 20].

The major limitation of this study is the lack of a placebo-treated group. On the other hand, although the subgroups for comparison were not formed on the basis of randomized assignment, subgroups of patients treated with either DMARD had almost similar baseline characteristics (Table 1). Subgroup analysis suggested a modestly better ACR50 response to adjunctive ANK in patients under LEF treatment, the reasons for which remain unclear due to the study design. Prospective trials have stressed the potential for synergy between LEF and conventional or anti-cytokine drugs [21–24]. The only report on the combination of ANK with LEF is by Tesser et al. [25] in roughly 70 RA patients, but only the regimen's safety profile was assessed. To the best of our knowledge, no published data about the combination of ANK with CSA are available.

The incidence of serious infections was 0.7%, a rate lower than that reported earlier (2.1%) [5], and similar with the rate found in the Dutch study of ANK [16]. Although the sample size was relatively small for definitive conclusions, unusual or opportunistic infections were not observed. The types and rates of malignancies found in the present study are consisted with those reported previously for ANK [5], TNF-antagonists and in the general population of RA patients [26].

Injection site reactions were the most commonly reported AEs occurring in 29% of the patients. The incidence of injection site reactions related to ANK decreased from 73% in the initial studies to 36% of the patients in more recent studies [16]. The relatively low frequency of this side-effect in our study may be due to the systematic corticosteroid cream application. Notably, the frequency of injection site reactions was significantly lower in patients who used concomitant oral steroids and was associated with DMARD background. Additionally, the rate of injection site reactions was higher among female than among male subjects, as also reported in the large, international, controlled trial of Fleischmann et al. [5].

Although no head-to head studies are available, many authorities suggest that the clinical efficacy of ANK is not as robust as TNF antagonists [27]. Explicit reproaches address the low drug survival [16, 28], as well as the fact that the latest large trial included only safety data, raising doubt about the effectiveness of ANK in the treatment of difficult RA [29]. The current trend for patients who failed TNF antagonists is switching to novel therapy approaches, including B-cell depletion agents [30] and selective T-cell co-stimulation modulators [31]. Although patients using anti-TNF agents were excluded from this study, our data may imply that ANK should not be considered an obsolete biological agent, but it could also be tried in TNF blockade failure, particularly when the question of safety dominates. In a recent study from Finland, about one-third of patients with poor response to TNF blockade clearly benefited when switched to ANK [32].

To conclude, considering the limitations of an uncontrolled open-label study, the combination of ANK with traditional DMARDs in clinical practice may control signs and symptoms of RA with fair compliance and low withdrawal rate. To acquire more creditable and longer term information about drug effectiveness and absence of delayed toxicity, controlled studies and extensive follow-up are needed.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
We are grateful to the following physicians who participated in the study: Dr A. Akkizidou (Athens); Dr P. Alexiou (Thessaloniki); Dr C. Antoniades (Athens); Dr M. Avgoustinaki (Athens); Dr S. Gazi (Athens); Dr B. Hatzilouloudes (Athens); Dr E. Karlou (Athens); Dr E. Koukli (Athens); Dr A. Lagoudakis (Thessaloniki); Dr A. Lambropoulos (Kozani); Dr S. Mitakides (Athens); Dr C. Morsikas (Athens); Dr J. Papachronis (Athens); Dr M. Papadopoulou (Athens); Dr A. Sfiroera (Athens); Dr E. Stavropoulos (Athens); Dr E. Tsiakou (Patra); and Dr K. Zervas (Larisa).

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Andrianakos A, Trontzas P, Christoyannis F, et al. Prevalence of rheumatic diseases in Greece: a cross-sectional population based epidemiological study. The ESORDIG study. J Rheumatol (2003) 30:1589–01.[Abstract/Free Full Text]
  2. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum (2002) 46:328–46.[CrossRef][Web of Science][Medline]
  3. Irvine S, Cappel HC. Great expectations of modern RA treatment. Ann Rheum Dis (2005) 64:1249–51.[Free Full Text]
  4. Arend WP. Cytokine imbalance in the pathogenesis of rheumatoid arthritis: the role of interleukin-1 receptor antagonist. Semin Arthritis Rheum (2001) 30(Suppl. 2):1–6.[CrossRef][Web of Science][Medline]
  5. Fleischmann RM, Schechtsman J, Bennett R, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist, in patients with rheumatoid arthritis. Arthritis Rheum (2003) 48:927–34.[CrossRef][Web of Science][Medline]
  6. Cohen SB, Hurd E, Cush JJ, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum (2002) 46:614–24.[CrossRef][Web of Science][Medline]
  7. Cohen SB, Moreland LW, Cush JJ, et al. A multicentre, double blind, randomized, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis (2004) 63:1062–68.[Abstract/Free Full Text]
  8. Jiang Y, Genant HK, Watt I, et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum (2000) 43:1001–09.[CrossRef][Web of Science][Medline]
  9. Bresnihan B, Newmark R, Robbins S, Genant HK. Effects of anakinra monotherapy on joint damage in patients with rheumatoid arthritis. Extension of a 24-week randomized, placebo-controlled trial. J Rheumatol (2004) 31:1103–11.[Abstract/Free Full Text]
  10. Cohen S, Wooley M, Chan WW. Interleukin-1 receptor antagonist anakinra improves functional status in patients with rheumatoid arthritis. J Rheumatol (2003) 30:225–31.[Abstract/Free Full Text]
  11. Kavanaugh A. Anakinra (interleukin-1 receptor antagonist) has positive effects on function and quality of life in patients with rheumatoid arthritis. Advances Ther (2006) 23:208–17.[CrossRef]
  12. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum (1988) 31:315–24.[Web of Science][Medline]
  13. Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum (1993) 36:729–40.[Web of Science][Medline]
  14. Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum (1995) 38:44–8.[Web of Science][Medline]
  15. Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: a review of its history, issues, progress, and documentation. J Rheumatol (2003) 30:167–78.[Abstract/Free Full Text]
  16. den Broeder AA, de Jong E, Franssen MJAM, Jeurissen MEC, Flendrie M, van den Hoogen FHJ. Observational study on efficacy, safety, and drug survival of anakinra in rheumatoid arthritis patients in clinical practice. Ann Rheum Dis (2006) 65:760–2.[Abstract/Free Full Text]
  17. Strand V, Cohen S, Crawford B, Smolen JS. Patient-reported outcomes better discriminate active treatment from placebo in randomized controlled trials in rheumatoid arthritis. Rheumatology (2004) 43:640–7.[Abstract/Free Full Text]
  18. Pincus T, Sokka T, Wolf F. Premature mortality in patients with rheumatoid arthritis: evolving concepts. Arthritis Rheum (2001) 44:1234–6.[CrossRef][Web of Science][Medline]
  19. Maini R, St Clair EW, Breedveld F, et al. The ATTRACT Study Group. Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet (1999) 354:1932–9.[CrossRef][Web of Science][Medline]
  20. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med (1999) 340:253–9.[Abstract/Free Full Text]
  21. Kremer J, Genovese M, Cannon GW, et al. Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial. J Rheumatol (2004) 31:1521–31.[Abstract/Free Full Text]
  22. Karanikolas G, Charalambopoulos D, Andrianakos A, Antoniades C, Katsilambros N. Combination of cyclosporine and leflunomide versus single therapy in severe rheumatoid arthritis. J Rheumatol (2006) 33:486–90.[Abstract/Free Full Text]
  23. Flendrie M, Creemers MC, Welsing PM, van Riel PL. The influence of previous and concomitant leflunomide on the efficacy and safety of infliximab therapy in patients with rheumatoid arthritis; a longitudinal observational study. Rheumatology (2005) 44:472–8.[Abstract/Free Full Text]
  24. Kalden J, Antoni C, Alvaro-Gracia JM, et al. Use of combination of leflunomide with biological agents in treatment of rheumatoid arthritis. J Rheumatol (2005) 32:1620–31.[Abstract/Free Full Text]
  25. Tesser J, Fleischmann R, Dore R, et al. Concomitant medication use in a large, international, multicenter, placebo controlled trial of anakinra, a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis. J Rheumatol (2004) 31:649–54.[Abstract/Free Full Text]
  26. Geborek P, Bladstrom A, Turesson C, et al. TNF blockers do not increase overall tumor risk in patients with rheumatoid arthritis, but may be associated with increased risk of lymphomas. Ann Rheum Dis (2005) 64:699–703.[Abstract/Free Full Text]
  27. Fleischmann R, Stern R, Iqbai I. Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis. Expert Opin Biol Ther (2004) 4:1333–44.[CrossRef][Web of Science][Medline]
  28. Burls A, Jobanputra P. The trials of anakinra. Lancet (2004) 364:827–8.[CrossRef][Web of Science][Medline]
  29. Fleischmann R, Tesser J, Schiff M, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis (2006) 65:1006–12.[Abstract/Free Full Text]
  30. Emery P, Fleischmann R, Filipowitz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment. Arthritis Rheum (2006) 54:1390–400.[CrossRef][Web of Science][Medline]
  31. Nogid A, David Q. Role of abatacept in the management of rheumatoid arthritis. Clin Ther (2006) 28:1764–78.[CrossRef][Web of Science][Medline]
  32. Konttinen L, Kankaanpaa E, Luosujarvi R, et al. Effectiveness of anakinra in rheumatic disease in patients naïve to biological drugs or previously on TNF blocking drugs: an observational study. Clin Rheumatol (2006) 25:882–4.[CrossRef][Web of Science][Medline]
Submitted 18 September 2007; revised version accepted 15 May 2008.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
47/9/1384    most recent
ken223v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Karanikolas, G.
Right arrow Articles by Sfikakis, P. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Karanikolas, G.
Right arrow Articles by Sfikakis, P. P.
Related Collections
Right arrow Pharmacology
Right arrow Rheumatoid Arthritis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?