Marije F. Bakker, PhD; Johannes W.G. Jacobs, PhD, MD; Paco M.J. Welsing, PhD; Suzanne M.M. Verstappen, PhD; Janneke Tekstra, PhD, MD; Evelien Ton, MD; Monique A.W. Geurts, MD; Jacobine H. van der Werf, MD; Grietje A. van Albada-Kuipers, MD; Zalima N. Jahangier-de Veen, PhD, MD; Maaike J. van der Veen, PhD, MD; Catharina M. Verhoef, PhD, MD; Floris P.J.G. Lafeber, PhD; Johannes W.J. Bijlsma, PhD, MD; on behalf of the Utrecht Rheumatoid Arthritis Cohort Study Group
Bakker MF, Jacobs JW, Welsing PM, Verstappen SM, Tekstra J, Ton E, et al. Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis: A Randomized Trial. Ann Intern Med. 2012;156:329-339. doi: 10.7326/0003-4819-156-5-201203060-00004
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Published: Ann Intern Med. 2012;156(5):329-339.
Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved.
To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)–based treatment strategy for tight control in early RA increases its effectiveness.
A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169)
7 hospitals in the Netherlands.
236 patients with early RA (duration <1 year).
Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission.
The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment.
Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group.
A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible.
Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes.
When methotrexate (MTX) is used as initial therapy for rheumatoid arthritis (RA), additional disease-modifying antirheumatic drugs (DMARDs) must frequently be added to achieve optimal outcomes.
Patients with RA were randomly assigned to receive MTX plus low-dose prednisone or MTX plus placebo. Response was measured frequently, and, if inadequate, another DMARD was added. Patients who received MTX plus prednisone had less erosive joint damage and were more likely to achieve remission and less likely to require additional DMARDS than those who began treatment with MTX plus placebo.
The trial was not powered to compare adverse effects, including infection.
Initial treatment for RA with low-dose prednisone plus MTX may result in improved outcomes.
Appendix Figure. Study flow diagram showing treatment strategy steps and criteria.
The start of the treatment strategy (i.e., MTX, 10 mg/wk, in combination with prednisone, 10 mg/d, or placebo) and all possible subsequent steps of the described treatment strategy are shown. Each visit, if the patient had not improved >20% in swollen joint count and at least 2 of the following: tender joint count, erythrocyte sedimentation rate, and visual analogue scale for general well-being, compared with the previous visit (see the Methods section for details). The next step in the strategy was according to this diagram. MTX = methotrexate.
* Defined as (compared with the previous visit 4 wk ago) >20% improvement of number of swollen joints and of ≥2 out of 3 criteria: number of tender joints, erythrocyte sedimentation rate, and visual analogue scale for general well-being. In case of no >20% improvement: stepwise increment in MTX dosage or add and step up of other medication, according to scheme; in case of >20% improvement at a visit, no change in dose of medication at that visit.
† For subcutaneous MTX, as well as oral MTX, each step was applied for ≥4 wk. The criteria for adding cyclosporine or adalimumab as a subsequent treatment strategy step and for stepping up of cyclosporine were the same as for each subcutaneous MTX step. Shortly after starting the trial (after about 20% of inclusions) a protocol amendment was made replacing cyclosporine by adalimumab as the next step, to be added to the maximum subcutaneous MTX dose. The adalimumab dose was increased to 40 mg/wk if the criteria of response were not met after 12 wk. In case of remission for at least 12 wk, the adalimumab dose was reduced to 40 mg every 2 wk and thereafter if persistent remission, the MTX was stepwise reduced.
Figure 1. Study flow diagram.
MTX = methotrexate.
* Not all patients gave a reason; approximately 80% did not participate because of glucocorticoid use, and 20% found monthly visits too time-consuming.
† One of these patients had been randomly assigned to receive prednisone, and 2 had been randomly assigned to receive placebo.
Figure 2. Individual patients' erosion scores.
Totals of 112 and 110 patients were analyzed for the MTX and prednisone group and the MTX and placebo group, respectively. Arrows with percentages show the proportion of patients within each treatment strategy with no erosions at 2 y. MTX = methotrexate.
Figure 3. Course of disease activity variables during 2 years of treatment, based on pooled results of imputed analyses.
DAS28 = Disease Activity Score assessing 28 joints (range, 0 to 9.3 [highest disease activity]); ESR = erythrocyte sedimentation rate (range, 1 to 140 mm/h); HAQ = Health Assessment Questionnaire (range, 0 to 3 [most physical disability]); MTX = methotrexate; VAS = visual analogue scale (range, 0 to 100 mm [worst status]).
* Significant differences between both treatment strategies at 3 mo, 6 mo, 1 y, 18 mo, or 2 y of treatment.
† P values are based on differences between both treatment strategies evaluated with longitudinal regression analyses.
Figure. No caption available.
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PrasantaPadhan, Consultant in Rheumatology
March 7, 2012
Prednisolone in early RA : Its role in developing nations
Dear Editor, The study by Bakker et al reemphasizes the role of steroids in early RA(1).It will help in developing nations like India to achieve early disease control at a lower cost.However since tuberculosis,both active and latent being rampant in this region of the world,it may be essential to rule out tuberculosis prior to starting prednisolone in patients with early RA.If PPD test is positive then INH prophylaxis may be indicated to prevent reactivation.
1.Bakker MF et al.Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis: A Randomized Trial.Ann Intern Med 2012 156:329-339.
Athanase D.Protogerou, MD, PhD, Evangelia Zampeli, Peter P. Sfikakis
First Department of Propaedeutic and Internal Medicine, Laikon Hospital, Athens University Medical S
March 9, 2012
Low-dose prednisone in rheumatoid arthritis: good for the joints, but what about arteries?
Rheumatoid arthritis (RA) is associated with increased mortality, and the majority of premature deaths are attributable to cardiovascular (CV) disease (1). Both chronic active inflammation, as a result of inadequate disease control, and the increased burden of traditional CV risk factors in these patients contribute to acceleration of atherosclerosis (1, 2, 3). Bakker et al. (4) clearly showed the beneficial effect of a low to moderate dose of prednisone (10 mg/day) on RA tight control when incorporated in the treatment during the first 2 years after disease onset. Their patients' age at baseline was about 53 years and none had serious cardiac disease or inadequately controlled hypertension and diabetes mellitus. Apart for one death due to coronary syndrome in one of 85 patients who completed the study receiving additional prednisone, no serious cardiovascular adverse effects were noted. One could assume that the beneficial effect of prednisone is translated in deceleration of atherosclerosis since inflammatory activity is better controlled. Evidence from retrospective studies suggests differently; the high cumulative dose of prednisone is associated with the later development of acute coronary syndromes in RA (5). As also shown in the first two longitudinal studies, an average cumulative daily dose <2.5 mg at baseline (2), or 2.5-10 mg daily prednisolone (3) were independently associated with the progression of subclinical carotid atherosclerosis over 3 years (intima-media thickening or new plaque formation). Of note, these carotid markers are independent predictors of CV mortality in RA patients (5), implying a significant role of even low dose corticosteroids contributing to the enhanced CV risk in RA. We believe that we all share a common "fear" that needs to be addressed in future studies. The positive outcome of RA patients treated with corticosteroids is difficult to be established. These drugs confidently help in clinical disease control but not on progression of atherosclerosis because they may modulate lipid profile, glucose tolerance, insulin resistance, blood pressure and obesity (1). Therefore, when deciding to chronically use even low to moderate dose corticosteroids in RA patients, it is important to take into account the concomitant traditional CV risk factors. Specifically designed studies are needed in order to establish "safety" criteria for the application of corticosteroid-including treatment strategies. "Bridging therapy" or "the lowest dose for the shortest period possible" might be at the moment the most prudent treatment strategy (1).
1. Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010; 69:325-31.
2. Giles JT, Post WS, Blumenthal RS, Polak J, Petri M, Gelber AC, Szklo M, Bathon JM. Longitudinal predictors of progression of carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum. 2011;11:3216-25.
3. Zampeli E, Protogerou A, Stamatelopoulos K, Fragiadaki K, Katsiari CG, Kyrkou K, et al. Predictors of new atherosclerotic carotid plaque development in patients with rheumatoid arthritis: a longitudinal study. Arthritis Res Ther. 2012;14:R44. [Epub ahead of print]
4. Bakker MF, Jacobs JW, Welsing PM, Verstappen SM, Tekstra J, Ton E, et al; on behalf of the Utrecht Rheumatoid Arthritis Cohort Study Group. Low-Dose Prednisone inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis: A Randomized Trial. Ann Intern Med. 2012;156:329-39.
5. Evans MR, Escalante A, Battafarano DF, Freeman GL, O'Leary DH, del Rinc?n I. Carotid atherosclerosis predicts incident acute coronary syndromes in rheumatoid arthritis. Arthritis Rheum. 2011;63:1211-20.
Alfonse TMasi, Physician, NA
University of Illinois College of Medicine at Peoria
March 23, 2012
One dose of prednisone may not be best for all rheumatoid arthritis patients?
A brief perspective is offered on the article by Bakker et al., "Low- dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial" (1). The report (1) continues a tradition of "elegantly-designed and well-executed Utrecht studies", as commented a decade ago (2), on the predecessor study (3). Starting at initiation of a methotrexate (MTX) tight control strategy, 10 mg/d prednisone clearly had greater efficacy than placebo in reducing disease activity and physical disability in early rheumatoid arthritis (RA), over a 2-years interval (1). As recognized by the Utrecht authors (1) and earlier RA investigators (2, 4), 10 mg/d prednisone might not be described as low-dose, particularly over a 2-year duration.
Almost 30 years ago, a personal editorial (4) had cited and synthesized an almost forgotten review of extensive clinical trial (RCT) data on RA patients which demonstrated that those treated with 10 mg or more prednisolone (mean 11 mg) daily for 4 years had half the number of new erosions (mean 8.5), than those assigned to salicylates only (mean 17.3). Salicylates and glucocorticoids (GCs) were the mainstay therapies in that era (4), before the use of disease modifying anti-inflammatory drugs (DMARDs). In the years following, many RCTs were performed using varied doses of predniso(lo)ne (P) at low (5 mg P/d) to medium levels in RA patients on a diversity of DMARD protocols, as recently reviewed (5). After one or two years duration of prednisone therapy, clinical, functional, and radiographic outcomes were generally improved over the placebo group outcomes (4, S121 - S125).
Of scientific concern, however, clinical research has not yet provided a basis to reliably predict optimal GC therapy in an individual patient having a particular severity of RA (2, 4). In rheumatologic practice, clinical judgment strives to balance expected benefits against adverse effects of GCs in a particular patient's course of disease. Given the 10 mg/d prednisone protocol in the current study (1), future post-hoc analyses hold promise to identify host and disease variables which influence optimal benefits versus adverse consequences in the combined MTX tight control therapy of early RA.
These comments are not intended to detract from the excellent design of the Utrecht report (1). Nonetheless, Annals readers might want to be aware that prednisone doses less than 10 mg/d might enhance efficacy of methotrexate-based tight control strategy with lower likelihood of adverse effects, at least in subsets of early-diagnosed RA patients.
Alfonse T. Masi, MD, DR. P.H. Professor of Medicine and Epidemiology Department of Medicine University of Illinois College of Medicine Peoria, IL 61656, USA Email: firstname.lastname@example.org
(1) Bakker MF, Jacobs JW, Welsing PM, Verstappen SM, Tekstra J, Ton E et al. Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med 2012; 156:329-39.
(2) Pincus T, Sokka T, Stein CM. Are long-term very low doses of prednisone for patients with rheumatoid arthritis as helpful as high doses are harmful? Ann Intern Med 2002; 136:76-8.
(3) van Everdingen AA, Jacobs JW, Siewertsz van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med 2002; 136:1-12.
(4) Masi AT. Low dose glucocorticoid therapy in rheumatoid arthritis (RA): transitional or selected add-on therapy? J Rheumatol 1983; 10:675-8.
(5) Bijlsma JWJ, Braun J, Buttgereit F, Cutolo M, Pincus T. Low- dose glucocorticoids in rheumatic diseases. Clin Exp Rheumatol. 2011;29(Suppl. 68): S1-S152.
TheodorePincus, Director of Outcomes Research, Isabel Castrejon, Yusuf Yazici
NYU Hospital for Joint Diseases
March 26, 2012
3-5mg prednisone may be preferable to 10mg/day in most patients with rheumatoid arthritis
The report of Bakker et al  presents impressive control of disease activity in patients with rheumatoid arthritis, which ironically may have attenuated the apparent treatment effect of prednisone. Overall, 67% of patients who received no prednisone experienced no erosions, only 11% less than the 78% treated with 10mg/ a day prednisone for 2 years, albeit a statistically significant difference. The strongest treatment effects, maintained over 2 years, involved patient functional status, which generally is more significant than laboratory and radiographic data to predict work disability and mortality in rheumatoid arthritis.
While unequivocal advantages are documented for 10 mg/day prednisone added to tight control with methotrexate (and adalimumab if indicated by DAS28), 10 mg/day prednisone may not necessarily be "low-dose," as noted in the report . No statistically significant differences in adverse events were seen over 2-years . However, over long periods, 10mg/day prednisone is associated with increased osteoporosis, atherosclerosis, infection, adrenal suppression, and higher mortality rates, even when discontinued after 2 years .
Randomized trials reported after initiation of CAMERAII have documented clinical and radiographic efficacy of 5 mg/day prednisone  and clinical efficacy of 3 mg/day . Clinical effectiveness of long- term 3 mg/day prednisone was found in more than 90% of patients treated after 1990, when almost all patients received concomitant methotrexate. Patients could titrate their dose and discontinue prednisone, but most chose to continue doses of 1-4 mg/day over long periods, despite bruising and skin-thinning in some patients. Hypertension, diabetes and cataracts were not increased over expected numbers , consistent with CAMERAII and population-based evidence comparing moderate (7.5mg/day) to high doses . Doses of <5 mg/day prednisone do not result in suppression of the hypothalamic-adrenal-pituitary axis .
These comments in no way detract from the excellently-executed Utrecht study. Nonetheless, readers of the Annals might be made aware that, while not documented as elegantly, initial and long-term prednisone 3-5 mg/day might also enhance methotrexate therapy clinically and structurally, with considerably lower likelihood of adverse effects. Furthermore, while costs are higher, biological agents may be safer than 10mg/day prednisone over long periods (as <5 mg/day prednisone may be safer than non-steroidal anti- inflammatory drugs). As noted a decade ago, "long-term very low doses of prednisone for patients with rheumatoid arthritis may be as helpful as high doses are harmful", and 10mg/day may not be "low-dose" or needed for most patients.
1. Bakker MF, Jacobs JW, Welsing PM, Verstappen SM, Tekstra J, Ton E, et al. Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis: A Randomized Trial. Ann Intern Med. 2012 Mar 6; 156(5):329-339.
2. Bijlsma JW, Braun J, Buttgereit F, Cutolo M, Pincus, T. Low-dose glucocorticoids in rheumatic diseases. Clin Exp Rheumatol. 2011 Sep-Oct; 29(5 Suppl 68).
3. Wassenberg S, Rau R, Steinfeld P, Zeidler H. Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2005 Nov; 52(11):3371-3380.
4. Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med. 2004 Nov 16; 141(10):764-770.
5. Pincus T, Sokka T, Stein CM. Are long-term very low doses of prednisone for patients with rheumatoid arthritis as helpful as high doses are harmful? Ann Intern Med. 2002 Jan 1; 136(1):76-78.
Marije F.Bakker, PhD, Johannes W.G. Jacobs, PhD, MD, Johannes W.J. Bijlsma, PhD, MD
Utrecht Rheumatoid Arthritis Cohort Study Group
May 24, 2012
We appreciate the interest in our Computer Assisted Management in Early Rheumatoid Arthritis trial-II (CAMERA-II). Based on the results of our previous CAMERA study, we anticipated good disease control,1 which leaves less room for a specific glucocorticoid treatment effect. Therefore, we chose a daily dose of prednisone which indeed can be described as low-to medium. Lower doses which have been proved effective in not-tightly controlled or observational studies are not necessarily also effective in a tight control study. Up to date, CAMERA-II is the only tight control study with systematic evaluation of the effect of additional glucocorticoid therapy. Data indicating an association between glucocorticoids and cardiovascular adverse effects are derived from observational studies, which tend to overestimate adverse effects. First, in these studies there is bias by indication, i.e. patients with more severe disease are more frequently prescribed glucocorticoids. In these patients the risk of adverse effects is higher based on their higher disease activity and their often more frequent comorbidities. It is very hard in observational studies to statistically correct for possible bias by indication. Second, not all negative events are adverse effects of glucocorticoids; they could be complications of the disease itself, and several negative effects on lipids, endothelium, bone mass, glucose metabolism and infection risk are associated both with the disease treated and with glucocorticoids, especially at medium and high doses.2-5 The use of glucocorticoid in lower doses inhibiting the inflammatory process might counteract these negative effects of the disease. Effects on joint damage of glucocorticoid use beyond the first 2 years of RA have not been investigated. We do not advocate long-term glucocorticoid use; a low to medium dose for the first 2 years results in a cumulative dose very well below that found to be predictive of cardiovascular adverse effects in the study of Evans et al.
Only in a large controlled trial randomizing RA-patients on disease modifying drugs for glucocorticoid therapy or placebo with predefined standardized assessments of adverse effects, the real risk of adverse effects of glucocorticoids can be estimated reliably. Although we agree that now the time has come to investigate whether lower doses of glucocorticoids or shorter duration of glucocorticoid treatment than we used in CAMERA-II would also be beneficial in a tight control strategy, we would not advocate the lowest dose for the shortest period possible, if the treatment goal goes beyond a short-term symptomatic effect only.
Utrecht; JWG Jacobs, MF Bakker, JWJ Bijlsma
1. Verstappen SM, Jacobs JW, van der Veen MJ, Heurkens AH, Schenk Y, ter Borg EJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis 2007; 66:1443-9.
2. Au K, Reed G, Curtis JR, Kremer JM, Greenberg JD, Strand V, et al. Extended report: high disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. Ann Rheum Dis 2011; 70:785-91.
3. Wasko MC, Kay J, Hsia EC, Rahman MU. Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: risk reduction in a chronic inflammatory disease. Arthritis Care Res (Hoboken ) 2011; 63:512- 21.
4. Klarenbeek NB, van der Kooij SM, Huizinga TJ, Goekoop-Ruiterman YP, Hulsmans HM, van Krugten MV, et al. Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc analysis from the BeSt trial. Ann Rheum Dis 2010; 69:1342-5.
5. Peters MJ, Vis M, van Halm VP, Wolbink GJ, Voskuyl AE, Lems WF, et al. Changes in lipid profile during infliximab and corticosteroid treatment in rheumatoid arthritis. Ann Rheum Dis 2007; 66:958-61.
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