Glucocorticoids in the treatment of early and late RA: a little GC, like a glass of wine, may benefit many people, whereas a high dose of GC, like a bottle of wine, is harmful to all.(Leader)

At the 2003 meeting of the American College of Rheumatology (ACR) a debate on the advantages and disadvantages of glucocorticoids (GCs) in the treatment of early and late rheumatoid arthritis (RA) was held, with some authors putting the case for, and others the case against, such treatment (presentations now available online: http:// www.rheumatology.org). Some new data emerged, and this paper summarises the arguments and the existing and new data.

HISTORY

Hench was awarded the Nobel prize in 1950 for the discovery of GCs and their effect in established RA. However, subsequently disillusionment with GCs set in, caused by the rapid appearance of unacceptable side effects of long term high dose treatment, and loss of efficacy at lower dosing. The dogma became that treatment with systemic GCs caused only temporary symptomatic relief, led to habituation with danger of ever increasing doses necessary to maintain effect, and that chronic treatment universally caused unacceptable side effects. Therefore, such treatment was often only considered as a last resort. An associated idea was that RA was in most cases a benign disease, which, although incurable, caused significant disability in only a minority of cases. The combination of these ideas caused most rheumatologists to limit treatment to traditional schemes that emphasised rest, lifestyle adjustment, non-steroidal anti-inflammatory drugs (NSAIDs), and spa treatment. In unresponsive cases antirheumatic drugs such as intramuscular gold were advised. A paradigm shift was initiated by Wilske and Healey, who argued that the pyramid should be inverted and aggressive treatment should be started early. (1) This was based on the appearance of long term outcome studies that recorded the dismal prognosis of many patients when followed up for a long enough time. With this shift, the door was opened a crack to allow re-examination of the old dogma.

MECHANISMS, USE, AND DOSAGES

To better understand published reports on the effects of GCs in RA, it is important to recognise two different aspects of the disease process. The first aspect is clinical symptoms of inflammation, which may be inhibited by NSAIDs. This process is partly due to infiltration of the synovial tissue by lymphocytes. The second aspect is erosive progression of the disease, which can be inhibited by disease modifying antirheumatic drugs (DMARDs) such as methotrexate and tumour necrosis factor [alpha] blockers. This process is partly due to synovial infiltration by macrophages. Both processes are closely linked, but partially independent and both processes may respond differently to different interventions. GCs seem to influence the inflammatory process especially during the first months of treatment, while effects on erosions become evident after a more prolonged period of time.

GCs have a profound effect on the immune system, interfering with the cytokine network and inflammatory enzymes, and with adhesion molecules, permeability factors, cellular function, and survival. GCs are still the most effective anti-phlogistic and immune suppressive substances known. (2) In early RA, and even in some patients before they develop RA, an insufficiency of the hypothalamic pituitary adrenal (HPA) axis has been documented. Discussion is still continuing as to whether or not this is the "chicken or the egg". In any case it is evident from many studies that cortisol levels found in patients with PA are insufficient to control the continuing inflammatory process. (3 4)

In America up to 75% of patients with PA use glucocorticoids regularly, concomitantly with other drugs. (5 6) In Europe the percentage is around 25%, although the role of GCs was reassessed in Europe during the past decade. (7) In the third world, GC use is very common, as they are one of the only cheap and widely available drugs; they are often sold over the counter. (8) The official views (as expressed in textbooks on both sides of the Atlantic) are similar and consistent in their opposition to GC treatment. The 2002 update of the guidelines for the management of rheumatoid arthritis of the ACR states: "Low dose oral glucocorticoids (10 mg or less of prednisone daily) are highly effective at relieving symptoms in patients with active RA. A patient disabled by active polyarthritis may experience marked and rapid improvement in functional status within days following initiation of glucocorticoids. Frequently, disabling synovitis recurs when glucocorticoids are discontinued, even in patients who are receiving combination therapy with one or more DMARDs. Therefore, many patients with RA are functionally dependent on glucocorticoids and continue them long term". (9)

What is considered to be a low dose of GCs? In patients with active PA participating in most clinical trials, a mean dosage of glucocorticoids of the order of 7 mg/day is found. (5-7) In descriptive cohort studies of patients with longstanding PA many patients have less active disease and the mean dosage of glucocorticoids is of the order of 3-5 mg/day, implying that some patients do very well on even a very low dose of GCs. Recently, a consensus meeting on standardisation of the nomenclature of GCs in rheumatic diseases was held. In the meeting report definitions for the dosage, based …