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Re: Corticosteroid side effects

Dear Editor,

The excellent review by da Silva and colleagues (1) comprehensively covers the range of glucocorticoid side effects and points out that more research in this area is sorely needed. One area they don�t review and which we have previously suggested should be considered as an adverse effect (2) is that the use of steroids by both primary doctors and rheumatologists so frequently preempts the use of DMARDs in patients with rheumatoid arthritis. Thus steroids are given, there is a rapid symptomatic response and the patient is more comfortable. Whether they then decline further treatment or whether the doctor fails to recommend it is unclear to me. However there are numerous studies where rheumatoid patients are receiving oral glucocorticoids but are not on DMARDs. (3 4 5) In one of the Leflunomide studies this was true of enrolled patients even with a disease duration of eight years (4). I realize that may not be what most would recommend but it happens.

The other issue, and here I suspect I do disagree with some of the authors, is efficacy. While the articles by Kirwan at al (6) and Van Everdingen et al (7) did suggest that when given with DMARDs there is a small disease modifying effect, Capell et al (8) didn�t find this. All of the manuscripts however, were convincing that at 2 years there was no persistent symptomatic benefit in the steroid group. Thus, if it is to be used for such symptomatic reasons, - and I believe this still is the principle reason it�s prescribed, - then surely only short term use can be justified (9).

References

1. JAP Da Silva, JWG Jacobs, JR Kowan, M Boers, KG Saag, LBS Ines et al. Safety of low dose glucocorticoid treatment in rheumatoid arthritis; published evidence of prospective trial data. AnnRheumDis 2006;65:285-293.

2. L Caplan, AS Russell, F Wolfe. Steroids for rheumatoid arthritis: The honeymoon revisited (once again). J Rheumatol 2005;32:1863-5.

3. D. Lacaille, AH Anis, DP Buk, JM Esdaile. Gaps in care for rheumatoid arthritis: a population study. Arthritis Care and Research 2004;53:241-248.

4. V Strand, S Cohen, M Schiff, A Weaver, R Fleischman, G Cannon et al. Treatment of active rheumatoid arthritis with Leflunamide compared with placebo and Methotrexate. Arch Int Med 1999;159:2542-2550.

5. LS Simon, AL Weaver, DY Graham, AJ Kivitz, PE Lipsky, RC Hubbard et al. Anti-inflammatory upper grastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. J.AMA 1999;282:1921-8.

6. JR Kirwan, M Byron, P Dieppe, C Eastmond, J Halsey, P Hickling et al. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The arthritis and rheumatism council low dose glucocorticoid study group. N.Engl.J.Med 1995;333:142-146.

7. AA Van Everdingen, JWG Jacobs, DRS van Reesema, WJ Bijlsma. Low dose prednisone therapy for patients with early rheum arthritis, clinical efficacy disease modifying properties and side effects. A randomized double blind placebo controlled clinical trial. Ann Int Med 2002;136:1-12.

8. HA Capell, R Madhok, JA Hunter, D Porter, E Morrison, J Larkin et al. Lack of radiological and clinical benefit over two years of low dose Prednisone for rheumatoid arthritis: results of a randomized controlled trial. Ann Rheum Dis 2004;63:797-803.

Send letter to journal:
Re: Low-dose glucocorticoid treatment in Rheumatoid Arthritis: Is it safe? Is it effective?

Dear Editor,

A recent review was published in Annals (1) which assessed the safety of low dose glucocorticoid (GC) treatment in rheumatoid arthritis (RA), relying heavily on the results of four small randomized controlled trials. The summary of this review stated “Safety data from recent randomized controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo”.

This review gives the impression to the reader that the addition of low dose GC to the RA treatment regime is both effective and relatively harmless, but do the published data really support such a position? In any decision about drug treatment, there must be a balance between the effectiveness on the treatment and the potential side effects with an excess of effectiveness over side effects, otherwise it is not in the patients’ best interest to receive that treatment, especially when this is a potentially long term treatment.

There were four pivotal randomized clinical trials on which this review relied on to come to the final conclusion (2-6). It should be immediately acknowledged that all of these trials contained small numbers of patients (the largest patient number in the GC arm was 84 (6)), were heterogeneous in relation to dose of GC used and additional treatment (including disease modifying anti-rheumatic drugs (DMARDs) allowed), were of limited duration (2 years) and were certainly not of sufficient power or duration to confidently assess long term safety of GC treatment in RA.

As stated in one paper (3) in relation to the effect of GC use on bone density in RA, “a sample size in excess of 200 would be required to demonstrate a significant difference between the groups at year 1 with 80% power given the variance in measurements”. These four randomized trials (2-6) were actually designed to assess efficacy of low dose GC in RA, not safety, although they did collect safety data. The results of these studies are quite variable, as are the dose of GC used and the concomitant use of DMARDs. The ARC study (2, 3) used 7.5 mg Prednisolone a day for 2 years with the primary outcome measure of change in Larsen score of hand x-rays only over two years. The use of DMARDs, while allowed, was not standardized and the two treatment groups were not balanced for joint damage at study entry, which is important as patients who have joint damage at study entry are more likely to have progression of damage with time, irrespective of treatment. In addition, although there was a difference between treatment groups in progression of radiological damage in favour of the GC treated group, the mean change in Larsen score of 5.4 units over two years was less than the clinically significant minimal detectable difference. Cessation of GCs after two years (3) lead to an increase in radiological damage in this group of patients.

The next study (4) actually used quite a high dose of GC (10mg a day of Prednisone) and DMARDs (in this study Sulphasalazine) were not allowed except as rescue medication after 6 months based on clinical grounds). The numbers in this study were small (35 2 year completers in the GC group versus 36 in the placebo group), but there was significantly reduced radiological progression in hand and feet x-rays as assessed by the van der Heijde modification of Sharp scoring system. Most of the progression occurred in the patients who already had erosions at baseline, with a 14 unit difference between the two groups in the erosion score at 24 months.

A third study (5) used very low dose (5mg a day prednisolone) in combination with either intramuscular Gold injections or Methotrexate, with more patients starting on Gold than Methotrexate. The numbers randomized to each group were reasonable (94 GC group, 98 placebo) but the number of patients with fully evaluable x-rays at all time points was much less (34 GC, 42 placebo). This study evaluated hand and feet x-rays using both a Ratingen scoring system and the van der Heijde modification of Sharp scoring system. While there was more radiological progression in the placebo versus the GC treatment group, the change in both scoring systems was less than the minimal detectable change as assessed by the authors of this paper, so it is difficult to assess how clinically relevant the difference between the treatment groups actually was.

The fourth study (6) was the largest of these studies with evaluable radiology in 64 GC and 66 placebo treated patients. This study used a modest (7mg prednisolone a day) GC dose with initiation of DMARD (Sulphasalazine) treatment at the same time. While there are some concerns about the differences in scores between the two assessors, there was no significant difference between the two treatment groups for radiological progression over two years. This prompted the authors to conclude “Low dose corticosteroids have no role in the routine management of rheumatoid arthritis treated with conventional disease modifying drugs”. As indicated above, these studies (2-6) were not of sufficient power or duration to assess the long term safety of GC treatment in RA. In addition, many of the safety evaluations were not standardized or of sufficient sensitivity (plain x-rays versus bone densitometry to assess osteoporosis) to reliably detect significant side effects of GC treatment.

Age has a significant effect on the incidence of osteoporosis yet most of these studies excluded older patients (2, 3, 5, 6) and the mean age of patients included was relatively low (49.2 years (2, 3), 60 years (4), 53.4 years (5) and 56 years (6)). Despite these caveats, there is evidence from these trials that low dose GC treatment in RA will at least lead to significant weight gain (2-6) and bone loss (3, 5). In addition, there are studies in the literature which also suggest that even low dose GC treatment will lead to increased bone loss (7, 8). While prophylaxis for GC related bone loss can be initiated with bisphosphonates, the long term efficacy and safety (9) of bisphosphonate treatment is becoming increasingly uncertain.

Those of us who have practiced in Rheumatology for long enough can remember the days when the use of GC treatment in RA was very common (admittedly often in higher doses) and the wards were full of RA patients with health problems related to the side effects of GC treatment. We still see RA patients with such GC related side effects despite the trend to using lower doses of GC in the treatment of RA. Before we enthusiastically and confidently retrace our steps down this path, we need to reflect on what previous generations of patients have shown us and re-assess whether the benefits of low dose GC treatment outweigh the modest side effects, as this recent review (1) would have rheumatologists believe. I contend that the case is not proven and we still do not have a reliable estimate of the cost to patients’ long term health of long term low dose GC treatment.

References

1. Da Silva JAP, Jacobs JWG, Kirwan JR, Boers M, Sag KG, Ines LBS, de Koning EJP, Buttgereit F, Cutolo M, Capell H, Rau R, Bijlsma JWJ. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann. Rheum. Dis. 2006; 65: 285-293

2. Kirwan JR and the Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. New Engl. J. Med. 1995; 333: 142-6

3. Hickling P, Jacoby RK, Kirwan JR and the Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. Br. J. Rheumatol. 1998; 37: 930-6

4. van Everdingen AA, Jacobs JWJ, van Reesma DRS, Bijlsma JWJ. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: Clinical efficacy, disease-modifying properties, and side effects. Ann. Intern. Med. 2002; 136: 1-12

5. Wassenberg S, Rau R, Steinfeld P, Zeidler H for the Low-Dose Prednisolone Therapy Study Group. Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years. Arthritis Rheum. 2005; 32: 3371-80

6. Capell H, Madhok R, Hunter JA, Porter D, Morrison E, Larkin J, Thomson EA, Hampson R, Poon FW on behalf of the WOSERACT Group. Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomized controlled trial. Ann. Rheum. Dis. 2004; 63: 797-803

7. de Nijs RNJ, Jacobs JWG, Bijlsma JWJ, Lems WF, Laan RFJM, Houben HHM, ter Borg EJ, Huisman AM, Bruyn GAW, van Oijen PLM, Westgeest AAA, Algra A, Hofman DM on behalf of the Osteoporosis Working Group of the Dutch Society for Rheumatology. Prevalence of vertebral deformities and symptomatic vertebral fractures in corticosteroid treated patients with rheumatoid arthritis. Rheumatol. 2001; 40: 1375-83

8. Laan RF, van Riel PL, van de Putte LB, van Erning LJ, van’t Hof MA, Lemmens JA. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. A randomized controlled study. Ann. Intern. Med. 1993; 119: 963-8