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Very recently Durez et al convincingly demonstrated that tumour necrosis factor blockade is, in comparison with glucocorticoid pulse therapy, promising, improving not only clinical measures of disease activity but also biological inflammatory indices in a subset of patients with severe refractory rheumatoid arthritis (RA).1 We would like to comment on the small effect that was seen with intravenous pulse methylprednisolone (MP) in this study.
We recently suggested that glucocorticoid pulse therapy should be defined as treatment with “⩾250 mg prednisone equivalent per day for one or a few days”.2 According to this proposed nomenclature pulse therapy was indeed applied. However, the data obtained for this subset of patients with severe refractory RA show only small, if any, effects on the joint scores, Health Assessment Questionnaire, morning stiffness, or serum C reactive protein (CRP). These results are surprising at first glance. But what can we conclude by trying to interpret these interesting data?
Firstly, a single glucocorticoid application even at a high dose may have a strong but only short lived effect. We assume that 1 g MP produces 100% saturation of cytosolic glucocorticoid receptors with 100% of genomic effects exerted.2,3 This is therapeutically helpful and probably the patient will feel better—but only for a short period because receptor occupation rapidly reverts to the original value unless a new dose is given. The same consideration applies to exerted non-genomic effects, which fade away fairly rapidly unless repeated doses are given.2,3 These may be the reasons why a single application of a high dose does not produce therapeutic effects that are still measurable after 2 or more weeks. Figure 1 shows what we consider to be the duration of effect of MP (and infliximab) for this study.
We further conclude from the presented data that either a very high dose of a glucocorticoid needs to be given for more than just 1 day or monthly repeated infusions are required. Those therapeutic regimens have been successfully established in several different rheumatic diseases.3 Durez et al state in their article (p 1071) that “… the absence of a significant effect of MP pulse therapy contrasts with some previously published studies”. Indeed, reported data show significantly greater effects of pulse therapy than this study demonstrated.
For instance in some of the Utrecht studies on aspects of MP pulse therapy data on efficacy are available,4–6 but in these studies MP was always given three times intravenously at a dosage of 1 g on alternate days (days 1, 3, and 5).
One study compared the efficacy of placebo and MP during the start of oral methotrexate treatment in patients with active RA. All measures evaluated (joint scores, erythrocyte sedimentation rate (ESR), CRP) improved significantly with intravenous pulse therapy compared with placebo at 6 weeks, and after 18 weeks most differences were still significant.4
Another study evaluating the effect of MP also showed that the Ritchie score, ESR, and CRP were significantly decreased after 1 week; these effects were weaker after 3 and 6 weeks.5
In yet another study looking at the short term effects of MP on disease activity and wellbeing in 66 patients with active RA after 1 week, ESR decreased from 68 to 38 mm/1st h, CRP from 57 to 16 mg/l, morning stiffness from 126 to 34 minutes. Grip strength increased from 8 to 15 kPa, while mobility, self care, improvement in pain and depressed mood increased significantly as well.6 These data are in line with published reports, reviewed by Weusten et al.7
Finally, we would like to emphasise that these comments are meant to enhance the work by Durez et al, which was an excellent paper. We would be unable to debate these issues without the availability of the data they obtained from this very carefully conducted study.1 In summary we assume that the glucocorticoid regimen used in the study of Durez et al might have been too weak to reach adequate efficacy and that comparison with tumour necrosis factor α blockade is perhaps limited in this respect.
We sincerely thank Drs Buttgereit, Burmester, and Bijlsma for their stimulating comments on our study.1 They suggest that our decision to administer one intravenous pulse of 1 g of methylprednisolone (MP)—instead of a series of three infusions—explains the tiny effect seen in our patients with rheumatoid arthritis (RA). Although we agree with the pharmacological arguments soundly put forward by Buttgereit, Burmester, and Bijlsma, it should be emphasised that, to the best of our knowledge, a direct comparison of the clinical and biological efficacy of single versus repeated MP pulse therapy in patients with RA is not available. Therefore, we can only speculate on the additional clinical benefit of repeated infusions.
As an alternative (or a complementary) hypothesis for the scanty effects of MP pulse therapy in our patients with RA (at least after 2 weeks of treatment; patients were not evaluated before), we would like to emphasise the severity of the disease in our patients. Despite a median methotrexate (MTX) dose of 12.5 mg/week and a median prednisolone dose of 5 mg/week, our patients had between 7 and 38 swollen joints. By contrast, patients included in the study by van der Veen and Bijlsma2 (quoted by Buttgereit, Burmester, and Bijlsma), were not treated with MTX when MP pulse therapy was prescribed. No data on MTX and glucocorticoid use are available in the two other papers quoted,3,4 thus making it difficult to compare these studies with our data.
Finally, the possibility that we missed the clinical effect of MP pulse therapy by not assessing our patients after 1 week is indeed a possibility. But, in patients with such severe RA, we were obviously aiming at inducing more prolonged responses.