Marlies C. van der Goes

The value of glucocorticoid co-therapy in different rheumatic diseases - positive and adverse effects

Glucocorticoids play a pivotal role in the management of many inflammatory rheumatic diseases. The therapeutic effects range from pain relief in arthritides, to disease-modifying effects in early rheumatoid arthritis, and to strong immunosuppressive actions in vasculitides and systemic lupus erythematosus. There are multiple indications that adverse effects are more frequent with the longer use of glucocorticoids and use of higher dosages, but high-quality data on the occurrence of adverse effects are scarce especially for dosages above 10 mg prednisone daily. The underlying rheumatic disease, disease activity, risk factors and individual responsiveness of the patient should guide treatment decisions. Monitoring for adverse effects should also be tailored to the patient. Continuously balancing the benefits and risks of glucocorticoid therapy is recommended. There is an ongoing quest for new drugs with glucocorticoid actions without the potential to cause harmful effects, such as selective glucocorticoid receptor agonists, but the application of a new compound in clinical practice will probably not occur within the next few years. In the meantime, basic research on glucocorticoid effects and detailed reports on therapeutic efficacy and occurrence of adverse effects will be valuable in weighing benefits and risks in clinical practice.

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.

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.

Cortisol during the day in patients with systemic lupus erythematosus or primary Sjogren's syndrome.

Objective. To compare the level and change of cortisol during the day of patients with systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) with low and high erythrocyte sedimentation rate (ESR). Methods. Saliva was collected in the real-life environment of 21 women with SLE, 16 women with pSS, and 30 age-matched healthy women at 9 fixed timepoints during 2 consecutive days. Repeated measures ANOVA was performed to examine whether cortisol levels during the day were different for the patients with low ESR (≤ 20 mm/h) versus those with high ESR (> 20 mm/h). Results. The groups with low and high ESR showed the characteristic change of cortisol during the day (time-of-day effect, F = 124.9, p < 0.001). The cortisol awakening level was lower for patients with high ESR than for patients with low ESR (group*time effect, F = 3.1, p = 0.02). Conclusion. The cortisol awakening level differs for patients with low and high ESR, which indicates the usefulness of further studies of hypothalamic-pituitary-adrenal axis dynamics in patients with SLE and pSS.

Glucocorticoid-targeted therapies for the treatment of rheumatoid arthritis

ABSTRACT Introduction: The beneficial effects of glucocorticoids are highly regarded in the treatment of inflammatory diseases. In rheumatoid arthritis, these drugs are widely used because they effectively reduce signs and symptoms of the disease, and exert disease-modifying effects. However, both patients and physicians frequently associate glucocorticoids with a variety of adverse effects which hamper adherence. Due to this ambivalent nature of these drugs, several new glucocorticoids or glucocorticoid receptor ligands are being developed, aiming at improving their benefit-risk balance. Areas covered: Focussing on rheumatoid arthritis, we discuss current approaches to achieve this goal, including an optimized application of conventional glucocorticoids and the development of novel formulations aiming at minimizing adverse effects while keeping or even enhancing the anti-inflammatory efficacy. Expert opinion: Glucocorticoids – be it conventional or modified/delayed-release formulations – have so far been convincing in clinical practice, and their widespread use will therefore continue. They are not likely to be replaced by novel drugs in the near future although some investigational preparations are promising, and results obtained from currently ongoing clinical trials in humans are eagerly awaited. As a result of these developmental activities, a further improvement of the benefits-risk balance of glucocorticoids or glucocorticoid receptor ligands is expected.

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.

Intra-articular glucocorticoid injections decrease the number of steroid hormone receptor positive cells in synovial tissue of patients with persistent knee arthritis

Objectives To explore changes in the number of steroid hormone receptor positive cells in synovial tissue (ST) after intra-articular glucocorticoid injection, to correlate these changes with changes in clinical variables, and to evaluate whether the number of steroid hormone receptor positive cells predicted the clinical response to glucocorticoid injection. Methods Fourteen patients with persistent knee arthritis despite at least two previous injections in an outpatient setting received an intra-articular injection with glucocorticoids, followed by 3 days of admission with bed rest. Clinical efficacy was assessed at 6 and 12 weeks. ST biopsies were performed 2 weeks before and 12 weeks after the injection. The presence of different cell types (T cells, macrophages, fibroblast-like synoviocytes) and numbers of glucocorticoid, androgen and oestrogen α and β receptor positive cells were evaluated by histochemistry. Results Patients showed, despite previous failures, good clinical response to glucocorticoid injection, with significant improvement in erythrocyte sedimentation rate, visual analogue scale (VAS) for pain, and joint disability score. The number of steroid hormone receptor positive cells decreased markedly (p<0.05 for all four receptors). The decrease in oestrogen receptor α positive cells correlated significantly with the improvement in VAS for pain and joint disability score. The number of glucocorticoid, androgen and oestrogen α and β receptor positive cells before injection did not predict the effect of treatment. Conclusions Intra-articular glucocorticoid injections followed by bed rest for persistent arthritis are clinically effective and significantly decrease the number of steroid hormone receptor positive cells in ST. The relevance of the latter needs further study.

Predicting Flare Probability in Rheumatoid Arthritis using Machine Learning Methods.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease that mostly affects joints. It requires life-long treatment aiming at suppression of disease activity. RA is characterized by periods of low or even absent activity of the disease (“remission”) alternated with exacerbations of the disease (“flares”) leading to pain, functional limitations and decreased quality of life. Flares and periods of high disease activity can lead to joint damage and permanent disability. Over the last decades treatment of RA patients has improved, especially with the new “biological” drugs. This expensive medication also carries a risk of serious adverse events such as severe infections. Therefore patients and physicians often wish to taper the dose or even stop the drug, once stable remission is reached. Unfortunately, drug tapering is associated with the increased risk of flares. In this paper we applied machine learning methods on the Utrecht Patient Oriented Database (UPOD) to predict flare probability within a time horizon of three months. Providing information about flare probability for different dose reduction scenarios would enable clinicians to perform informed tapering which may prevent flares, reduce adverse events and save drug costs. Our best models can predict flares with AUC values of about 80%.

Response to viewpoint ‘Defining refractory rheumatoid arthritis’ by Buch

With great interest, we read the clinically highly relevant viewpoint on ‘Defining refractory rheumatoid arthritis’ by Professor Maya H. Buch.1 The author classifies refractory rheumatoid arthritis (RA) into ‘intrinsic refractory’ (persistent inflammation, no antidrug antibodies (ADA)), ‘pharmacokinetic refractory’ (persistent inflammation, presence of ADA) or ‘false positive refractory’ (no persistent inflammation, no ADA). Professor Buch highlights the gap of knowledge in the understanding of refractory RA and states that consistent definitions and criteria are required for future research. We fully agree with the author that this subpopulation of patients with RA is facing unmet needs, …

Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey

Objectives Patients with difficult-to-treat rheumatoid arthritis (RA) remain symptomatic despite treatment according to current European League Against Rheumatism (EULAR) management recommendations. These focus on early phases of the disease and pharmacological management. We aimed to identify characteristics of difficult-to-treat RA and issues to be addressed in its workup and management that are not covered by current management recommendations. Methods An international survey was conducted among rheumatologists with multiple-choice questions on disease characteristics of difficult-to-treat RA. Using open questions, additional items to be addressed and items missing in current management recommendations were identified. Results 410 respondents completed the survey: 50% selected disease activity score assessing 28 joints >3.2 OR presence of signs suggestive of active disease as characteristics of difficult-to-treat RA; 42% selected fatigue; 48% selected failure to ≥2 conventional synthetic disease-modifying antirheumatic drugs (DMARDs) AND ≥2 biological/targeted synthetic DMARDs; 89% selected inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily. Interfering comorbidities, extra-articular manifestations and polypharmacy were identified as important issues missing in current management recommendations. Conclusions There is wide variation in concepts of difficult-to-treat RA. Several important issues regarding these patients are not addressed by current EULAR recommendations.