Jos N. Hoes

Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis

Glucocorticoids are widely used anti-inflammatory and immunosuppressive drugs for rheumatoid arthritis (RA). The disease-modifying potential of low to medium doses of glucocorticoids has been reconfirmed in the past decade, and co-administration of DMARDs and glucocorticoids has become standard in many treatment protocols, especially those for early disease stages but also for long-standing RA. The glucocorticoid regimens used range from continuous low doses to intermittent high doses. Studies of the rationale for and clinical use of glucocorticoids as co-therapy with DMARDs in RA have shown that this approach has a place in modern (tight control) treatment strategies, and that glucocorticoid co-therapy has disease-modifying effects during the first 2 years of treatment in patients with early RA. Furthermore, medium and high doses of glucocorticoids are useful for bridging the interval between initiation of DMARDs and onset of their therapeutic effect. Intra-articular glucocorticoids give good local control and have been used in tight control strategies. New glucocorticoid compounds are becoming available for clinical use that might have an enhanced risk:benefit ratio. Better monitoring of glucocorticoid use will also improve this ratio, and help to allay both patient and rheumatologist concerns about treatment-related adverse effects.

Glucose tolerance, insulin sensitivity and β-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids

Objectives To compare glucose tolerance and parameters of insulin sensitivity and β-cell function between chronic glucocorticoid (GC)-using and GC-naive patients with rheumatoid arthritis (RA). Methods Frequently sampled 75 g oral glucose tolerance tests were performed in 58 chronic GC-using and 82 GC-naive patients with RA with established disease, with no known type 2 diabetes mellitus (T2DM), and 50 control subjects of comparable age with normal glucose tolerance. The associations between cumulative GC dose and disease characteristics and glucose tolerance state, insulin sensitivity and β-cell function were tested using multivariate linear and logistic regression models, correcting for patient characteristics. Results Glucose tolerance state, insulin sensitivity and β-cell function did not differ between the two RA populations; de novo T2DM was detected in 11% and impaired glucose metabolism in 35% of patients with RA. In patients with RA, cumulative GC dose was associated with T2DM, which seemed mostly driven by the effects of cumulative GC dose on insulin resistance; however, the association decreased when corrected for current disease activity. Patients with RA had decreased insulin sensitivity and impaired β-cell function compared with controls, and multivariate regression analyses showed a negative association between the presence of RA and insulin sensitivity. Conclusions GC-using and GC-naive patients with RA had comparable metabolic parameters, and had decreased insulin sensitivity and β-cell function as compared with healthy controls. Although cumulative GC dose was shown to have a negative impact on glucose tolerance state and insulin sensitivity, confounding by indication remains the main challenge in this cross-sectional analysis.

Are glucocorticoids DMARDs

Abstract:  Disease modifying antirheumatic drugs (DMARDs) are drugs used in rheumatoid arthritis (RA) to control the disease and to limit joint damage and improve long‐term outcome. The last decade evidence has accumulated that suggests that low dosages of glucocorticoids are indeed able to control the disease and limit the destruction. This role is especially present in early disease and in combination with other drugs. The evidence is carefully evaluated and discussed. The ultimate conclusion is that indeed glucocorticoids are DMARDs and are especially useful in early RA.

Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: Balance between diabetogenic effects and inflammation reduction

OBJECTIVE To investigate the dose-related effects of glucocorticoid treatment on glucose tolerance, beta cell function, and insulin sensitivity in patients with early active rheumatoid arthritis (RA). METHODS A randomized, controlled, single-blind trial was conducted in 41 patients with early active RA. At the beginning of the trial patients had not been treated for their RA, and were randomized to begin treatment with prednisolone at 60 mg/day or 30 mg/day. Before and at the end of 1 week of treatment, a frequently sampled oral glucose tolerance test was performed. The glucose area under the curve (AUC(G) ) was calculated. In addition, beta cell function and insulin sensitivity parameters were computed. RESULTS Patients (mean ± SD age 55.5 ± 14.8 years and 54.2 ± 12.6 years in the prednisone 60 mg/day and prednisone 30 mg/day groups, respectively; body mass index 24.5 ± 4.1 kg/m(2) and 25.4 ± 4.2 kg/m(2) , respectively) had active disease at baseline (mean ± SD Disease Activity Score in 44 joints 4.1 ± 0.7 and 4.0 ± 0.8, respectively; median C-reactive protein [CRP] level 14 mg/liter [interquartile range 6-34] and 19 mg/liter [interquartile range 3-39], respectively). In addition, 56% of the patients had impaired glucose tolerance at baseline, and 7% were found to have previously unrecognized type 2 diabetes mellitus (DM). Associations of the AUC(G) with erythrocyte sedimentation rate (β = 2.430 [95% confidence interval 0.179-4.681], P = 0.04) and with CRP level (β = 2.358 [95% confidence interval 0.210-4.506], P = 0.03) were demonstrated. Treatment with prednisolone at both dosages reduced CRP levels significantly. The incidence of type 2 DM increased to 24% (P < 0.001) (evenly distributed across the groups). The mean AUC(G) did not change in either treatment arm. Beta cell function improved during prednisone treatment at 60 mg/day (P = 0.02) and at 30 mg/day (P = 0.04). Disease duration was associated with changes in the AUC(G) (β = 3.626 [95% confidence interval 1.077-6.174], P = 0.007) and with deterioration of the glucose state (odds ratio 1.068 [95% confidence interval 1.017-1.122], P = 0.009). CONCLUSION In this study, short-term treatment with prednisolone 60 mg or 30 mg per day improved disease activity without deterioration of glucose tolerance in patients with active RA. However, due to individual differences, monitoring is recommended.

Low‐dose glucocorticoid therapy in rheumatoid arthritis: an obligatory therapy

Glucocorticoids (GCs) are used extensively in patients with rheumatoid arthritis (RA). Recent data on the efficacy of these drugs in alleviating symptoms of inflammation, but also in retarding erosive damage, are presented. In addition, a critical review of the rather limited literature on adverse effects of chronic use of low dose GCs is given. It becomes clear that the net effect of low‐dose GCs in the treatment of rheumatoid arthritis favors the beneficial aspects of these drugs above the negative aspects. Prudent use of GCs can be recommended.

Management of osteoporosis in rheumatoid arthritis patients

Introduction: In rheumatoid arthritis (RA) patients, the risk of both vertebral and non-vertebral fractures is roughly doubled, which is for an important part caused by inflammation-mediated amplification of bone loss and by immobilization. New treatments have become available in the last two decades to treat both RA and osteoporosis. Areas covered: Epidemiology and assessment of osteoporosis and fracture risk (including the influence of RA disease activity and bone-influencing medications such as glucocorticoids), the importance of vertebral fracture assessment in addition to bone density measurement in patients with RA, the use of disease-modifying antirheumatic drugs and their effects on generalized bone loss, and current and possible future anti-osteoporotic pharmacotherapeutic options are discussed with special focus on RA. Expert opinion: Assessment of osteoporosis in RA patients should include evaluation of the effects of disease activity and bone-influencing medications such as (the dose of) glucocorticoids, above standard risk factors for fractures or osteoporosis as defined by the FRAX instrument. Disease-modifying antirheumatic drugs are now well able to control disease activity using treat to target strategies. This lowering of disease activity by antirheumatic medications such as anti-TNF-α results in hampering of generalized bone loss; however, no fracture data are currently available. When treating osteoporosis in RA patients, additional focus should be on calcium supplementation, particularly in glucocorticoid users, and also on sufficient vitamin D use. Several anti-osteoporotic medications are now on the market; oral bisphosphonates are most commonly used, but in recent years, more agents have entered the market such as the parenteral antiresorptives denosumab (twice yearly) and zoledronic acid (once yearly), and the anabolic agent parathyroid hormone analogues. New agents, such as odanacatib and monoclonal antibodies against sclerostin, are now being tested and will most likely enlarge the possibilities of osteoporosis treatment in RA patients.

Low-dose glucocorticoid therapy in rheumatoid arthritis: An obligatory therapy: Annals of the New York Academy of Sciences

Glucocorticoids (GCs) are used extensively in patients with rheumatoid arthritis (RA). Recent data on the efficacy of these drugs in alleviating symptoms of inflammation, but also in retarding erosive damage, are presented. In addition, a critical review of the rather limited literature on adverse effects of chronic use of low dose GCs is given. It becomes clear that the net effect of low‐dose GCs in the treatment of rheumatoid arthritis favors the beneficial aspects of these drugs above the negative aspects. Prudent use of GCs can be recommended.

Changes in macrophage inhibitory factor correlate with changes in bone mineral density in glucocorticoid-treated patients with rheumatoid arthritis

OBJECTIVES To investigate whether changes in bone density and turnover are associated with changes in inflammatory mediators in RA patients treated with glucocorticoids (GCs) upon vitamin D treatment in comparison with alendronate treatment. METHODS RA patients (n = 40) on long-term oral GC treatment received either alfacalcidol or alendronate. At baseline and after 18 months, we measured cytokines capable of antagonizing GCs [macrophage migration inhibitory factor (MIF), IL-13 and IL-7], cytokines causing T-cell differentiation (IL-6, IL-7, IL-12, IL-10 and IL-23) and cytokines produced by effector T cells (IFN-γ, IL-4, IL-17, IL-22). Associations of cytokine profiles with bone markers and BMD changes of the lumbar spine were explored using multiple regression analyses that corrected for study medication and risk factors of osteoporosis (gender, age, cumulative/change in GC dose). RESULTS Alendronate, unlike alfacalcidol, increased BMD changes in the lumbar spine. Most cytokines were below detection limits. MIF and IL-23 were detectable in almost all samples; neither alfacalcidol nor alendronate significantly influenced serum concentrations of these cytokines. Interestingly, changes in MIF correlated positively with changes in BMD of the lumber spine (Pearsons correlation = 0.31), and in multivariate analysis adjusting for treatment, age and change in GC dose (P = 0.022). CONCLUSION During GC treatment, changes in the GC-antagonist MIF were positively correlated with changes in BMD, which could mean MIF has bone-protecting capacities in patients suffering from GC-induced bone destruction. Further studies need to validate the importance of these findings.

Glucocorticoids, Inflammation and Bone

AbstractThe current review on glucocorticoids (GCs), inflammation and bone is focused on three aspects: (1) the mutual effects between GCs, inflammation and bone in inflammatory rheumatic diseases, (2) current views on fracture risk assessment in patients using GCs and (3) non-pharmacological and pharmacological treatment to prevent fractures in GC-using patients with inflammatory rheumatic diseases. The use of GCs results in increased risk for fractures due to both direct and indirect negative effects of GCs on bone mass, and on bone and muscle strength. However, also the underlying inflammatory rheumatic disease is associated with the increased bone loss and fracture risk due to the chronic inflammation itself, and due to disability/immobility caused by active disease or joint destruction. The rapid and strong anti-inflammatory effect of GCs in patients with rheumatoid arthritis seems to balance the negative effects of GCs on bone in the early, active phase of the disease. Recently, an update of the American College of Rheumatology guidelines for prevention and treatment of GC-induced osteoporosis was published with renewed recommendations. To prevent fractures, general measures, including treatment of the underlying inflammatory disease adequately (even with GCs when indicated), a healthy lifestyle, including adequate calcium and vitamin D supplementation, and regular weight bearing exercises are important. In rheumatic patients with high fracture risk using GCs, especially when the cumulative dose is high and/or the underlying inflammatory disease is active, treatment with anti-osteoporotic drugs, usually an oral bisphosphonate, is indicated.