Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis

Boers, Maarten; Verhoeven, A. C.; Markusse, H. M.; Laar, Mart Afj van de; Westhovens, René; Denderen, J.C. van; Zeben, Derkjen van; Dijkmans, Ben A. C.; Peeters, A.J.; Jacobs, Piet; Brink, H. R. Van Den; Schouten, Hubert J. A.; Heijde, Désirée M van der; Boonen, Annelies; Linden, Sjef van der

doi:10.1016/s0140-6736(97)01300-7

Cited by 932 publications

(589 citation statements)

References 24 publications

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“…We evaluated patients in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) study (22,23). The COBRA study was a 56-week multicenter clinical trial in which 155 patients who met the American College of Rheumatology criteria for RA (24) were randomly assigned to 1 of 2 treatment groups: combination therapy with sulfasalazine, methotrexate, and initially, high-dose oral prednisolone (COBRA regimen) or monotherapy with sulfasalazine alone.…”

Section: Methodsmentioning

confidence: 99%

Association of baseline levels of markers of bone and cartilage degradation with long‐term progression of joint damage in patients with early rheumatoid arthritis

Garnero¹,

Landewé²,

Boers³

et al. 2002

Arthritis & Rheumatism

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164

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Objective. The known risk factors for radiologic progression in rheumatoid arthritis (RA) are not optimally discriminative in patients with early disease who do not have evidence of radiologic damage. We sought to determine whether urinary C-terminal crosslinking telopeptide of type I (CTX-I) and type II (CTX-II) collagen (markers of bone and cartilage destruction, respectively) are associated with long-term radiologic progression in patients with early RA.Methods. This was a prospective study of 110 patients with early RA who were participating in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) clinical trial and followup study, a randomized controlled trial comparing the efficacy of oral pulse prednisolone, methotrexate, plus sulfasalazine with sulfasalazine alone. We investigated the relationship between baseline levels of urinary CTX-I and CTX-II and the mean annual progression of joint destruction over a median of 4 years, as measured by changes in the modified Sharp score (average of 2 independent readers).Results. In multivariate logistic regression analysis, baseline urinary CTX-I and CTX-II levels in the highest tertile were the strongest predictors of radiologic progression (Sharp score increase >2 units/year; odds ratio 7.9 and 11.2, respectively), independently of treatment group, erythrocyte sedimentation rate (ESR), Disease Activity Score in 28 joints, rheumatoid factor (RF), and baseline joint damage (Sharp score). The likelihood ratios for a positive test were 3.8 and 8.0 for CTX-I and CTX-II, respectively, which compared favorably with the likelihood ratios for the ESR (3.0), baseline joint damage (1.6), and RF (1.8). When patients were grouped according to the presence (Sharp score >4, n ‫؍‬ 49) and absence (Sharp score <4, n ‫؍‬ 61) of joint damage at baseline, CTX-I and CTX-II levels were predictive only in those without baseline joint damage (odds ratio 14.9 and 25.7, respectively).Conclusion. High baseline levels of urinary CTX-I and CTX-II independently predict an increased risk of radiologic progression over 4 years in patients with early RA, especially those without radiologic joint damage. Urinary CTX-I and CTX-II may be useful for identifying individual RA patients at high risk of progression very early in the disease, before erosions can be detected radiographically. Such patients may be in special need of treatments that inhibit bone and cartilage degradation.

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Section: Methodsmentioning

confidence: 99%

Association of baseline levels of markers of bone and cartilage degradation with long‐term progression of joint damage in patients with early rheumatoid arthritis

Garnero¹,

Landewé²,

Boers³

et al. 2002

Arthritis & Rheumatism

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164

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“…Glucocorticoids can be highly effective in treating joint inflammation, but their systemic application is limited because of a high incidence of serious adverse effects, especially related to long-term treatment (2,3). In addition, it is generally recommended that glucocorticoids should be given in combination with the so-called disease-modifying antiarthritic drugs, because of their limited disease-modifying effects (4,5).…”

Section: Conclusion Targeted Delivery Using Longcirculating Liposomementioning

confidence: 99%

Complete remission of experimental arthritis by joint targeting of glucocorticoids with long‐circulating liposomes

Metselaar¹,

Wauben²,

Wagenaar-Hilbers³

et al. 2003

Arthritis & Rheumatism

276

217

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Objective. To increase the therapeutic activity of glucocorticoids in experimental arthritis by encapsulation in long-circulating polyethylene glycol liposomes, which have shown the ability to preferentially accumulate in inflamed joints after intravenous administration.Methods. Rats with adjuvant-induced arthritis (AIA) were treated intravenously with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of disease. The effect on paw inflammation scores during the weeks after treatment was evaluated. Liposome biodistribution and joint localization were investigated by labeling the preparation with radioactive 111 In-oxine. By studying PLP encapsulated in other types of liposomes, which show a distinctive tissue distribution pattern and reduced accumulation in inflamed joints, the importance of targeted delivery to inflamed joints for achieving an increased therapeutic effect was illustrated.Results. Liposomal PLP proved to be highly effective in the rat AIA model. A single injection of 10 mg/kg resulted in complete remission of the inflammatory response for almost a week. In contrast, the same dose of unencapsulated PLP did not reduce inflammation, and only a slight effect was observed after repeated daily injections. Evidence was found that preferential glucocorticoid delivery to the inflamed joint was the key factor explaining the observed strong therapeutic benefit obtained with the liposomal preparation, while other possible mechanisms, such as splenic accumulation or prolonged release of prednisolone in the circulation, were excluded.Conclusion. Targeted delivery using longcirculating liposomes is a promising, novel means to successfully intervene in arthritis with glucocorticoid therapy.

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“…Although demonstrating that most combinations of DMARDs then in use did not exhibit substantial efficacy (13), notable exceptions included the studies by Tugwell et al (11), who used a step-up strategy with MTX and cyclosporin A (CSA) versus MTX alone; Ferraz et al (14), who used the parallel strategy of hydroxychloroquine (HCQ) plus MTX versus MTX alone; O'Dell et al (15,16), who used the parallel strategy of triple therapy with MTX plus sulfasalazine (SSZ) plus HCQ versus SSZ plus HCQ versus MTX alone; and Boers at al (17), who used a step-down strategy comparing MTX, SSZ, and prednisone with SSZ.…”

Section: Strategies Used In Studies Of Combination Therapies and Revimentioning

confidence: 99%

“…Several DMARDs have been evaluated with the step-down strategy. The classic stepdown therapeutic algorithm is illustrated by the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial conducted by Boers et al (17), who showed that low-dose MTX plus SSZ in combination with high-dose corticosteroids was superior to SSZ alone in reducing joint damage, despite similar reductions in symptoms and signs at the end point (i.e., after steroid withdrawal). Given the low dose of MTX used in the combination arm (7.5 mg/week), it is likely that the short-duration high-dose corticosteroids played the major role in improving both clinical and radiographic outcomes.…”

Section: Study Design Issuesmentioning

confidence: 99%

Superior efficacy of combination therapy for rheumatoid arthritis: Fact or fiction?

Smolen

Aletaha

Keystone

2005

Arthritis & Rheumatism

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Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis

Cited by 932 publications

References 24 publications

Association of baseline levels of markers of bone and cartilage degradation with long‐term progression of joint damage in patients with early rheumatoid arthritis

Association of baseline levels of markers of bone and cartilage degradation with long‐term progression of joint damage in patients with early rheumatoid arthritis

Complete remission of experimental arthritis by joint targeting of glucocorticoids with long‐circulating liposomes

Superior efficacy of combination therapy for rheumatoid arthritis: Fact or fiction?

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