The 70th Anniversary of Glucocorticoids in Rheumatic Diseases

The Second Youth of an Old Friend

Yannick Palmowski; Thomas Buttgereit; Frank Buttgereit


Rheumatology. 2019;58(4):580-587. 

In This Article

GCs in 2018: What we Know and What we do not Know

More than 70 years after their discovery, GCs remain a central element in the treatment of a wide range of inflammatory diseases. They are still indispensable for the treatment of several rheumatic diseases (e.g. GCA)[31] and have recently regained importance in the management of others (RA). Moreover, they have been unchallenged since their discovery as being among the number one choices in any situation where a rapid reduction of inflammation is especially urgent (e.g. anaphylaxis).

All the same, even after all this time, the use of GCs is still controversially discussed and often fiercely debated among experts, particularly in RA.[5] An extensive systematic review of international guidelines was recently conducted in an attempt to clarify their current status in the management of RA.[3] It was confirmed that there is an overall consensus about the general appropriateness of GCs as an option for the treatment of RA, especially if given at low doses and for short durations. However, most guidelines failed to provide exact and detailed recommendations, as reliable evidence concerning virtually all aspects of GC therapy is still scarce, particularly regarding the optimal tapering strategy, long-term safety and efficacy and the optimal duration of GC therapy. When exact numbers were provided, the dosages most frequently recommended were prednisone doses of no more than 10 mg/day for a maximum duration of up to 6 months, with tapering as quickly as clinically feasible. Concerning the situations in which GCs should be used, most recommendations see the main purpose of GCs as that of a bridging therapy for initial treatment until DMARDs take effect. Strikingly, the long-term use of GCs is hardly addressed by the guidelines examined in that review.[3] This might be far from actual clinical practice, where 13.6% of patients with RA in the UK were reported to receive long-term GC treatment (defined as ≥3 months).[32]

Valuable new evidence to allow for respective recommendations might soon arise from the currently ongoing Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis Study (GLORIA), which is under way to evaluate the safety and efficacy of an additional long-term low-dose co-medication with GCs (5 mg/day of prednisone vsplacebo over 2 years; identifier NCT02585258).

For the time being, the results of a EULAR task force that recently tried to define the conditions where long-term GC treatment has an acceptably low level of harm provides guidance.[33] The multidisciplinary experts critically appraised existing literature on adverse effects and concluded that the risk of harm of a long-term treatment with predniso(lo)ne is acceptably low for doses of up to 5 mg/day in most patients, whereas it is increased for doses >10 mg. For doses between 5 and 10 mg of prednisone, patient-specific factors like age, gender, genetic predisposition, comorbidities and individual lifestyle (smoking, alcohol consumption, nutrition, physical exercise) need to be taken into account and regularly re-evaluated as long as the treatment is continued. This emphasis on the importance of patient-specific factors is particularly remarkable since they are hardly addressed in current guidelines.[3]

The hypothesis that the widespread idea of unacceptable adverse effects of GCs is obsolete has recently been supported by the results of a 7 year prospective multicentre observational cohort study of patients with early RA, which showed no significant difference in the real-life tolerability outcomes among patients with RA with and without low-dose prednisone treatment [mean 3.1 (SD 2.9) mg/day].[34] Clear proof of the recently (re-)increasing importance of GCs is the comparison of RA guidelines over time. While the ACR RA treatment guidelines still completely omitted GCs in the 2012 version, they specifically address them in several recommendations of the current 2015 version (Figure 1).[35–37] The EULAR guidelines have adapted to the ongoing re-evaluation of GCs, too. This is particularly well demonstrated by the changes that were made to the treatment algorithm flow chart. While initially depicting a '±' for GCs as part of the initial treatment strategy, the algorithm has been gradually adapted and only shows a '+' for GCs in the latest version of the guideline, providing a demonstrative example of the changing opinion regarding GCs.[4,5,38] In addition, the current EULAR guidelines now recommend the consideration of GCs in all situations where conventional synthetic DMARDs are initiated or changed, no longer restricting them to the initial treatment strategy, and also introduces flexible treatment schemes including higher starting doses. Concerning the duration of treatment, the current EULAR guidelines recommend a gradual tapering and stopping within 3 but up to 6 months from treatment start. The choice of the route of administration is left to the treating rheumatologist.[4]

Figure 1.

Milestones and perception of glucocorticoids in RA Data from 17, 33, 36, 37, 47, 51, 62–75.