Review

Glucocorticoid treatment in rheumatoid arthritis

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Rolf Rau 1.

Introduction

Irisweg 5, Du¨sseldorf, Germany

2.

Results of clinical trials

3.

Intra-articular GC

4.

Adverse events of low-dose GC

5.

Expert opinion

6.

Expert conclusion

Introduction: In spite of its broad use since 1950 the role of low-dose glucocorticoids (GCs) (up to 7.5 mg/day prednisone) in the treatment of rheumatoid arthritis is still controversial. Areas covered: Publications comparing disease-modifying anti-rheumatic drugs (DMARD) plus prednisolone with DMARD monotherapy were reviewed. Most studies reported greater clinical improvement and greater inhibition of damage progression in the prednisone group. These advantages had vanished after 6 -- 12 months in most studies. Expert opinion: Several limitations of the studies are discussed. Often the advantage of GC treatment was not clinically important. Long-term data are needed to evaluate the real benefit of GC treatment in relation to its toxicity. Knowing the potential toxicity ‘bridging’ GC treatment should be reserved for patients at high risk of damage progression; a reliable method to identify these patients is needed. The toxicity of low-dose GC treatment is often played down. The reporting is incomplete. The increased mortality ratio with GC treatment is rarely mentioned. High cumulative doses are a risk factor. A more comprehensive set of toxicity items is urgently needed. Problems of GC treatment are the ‘drug addiction’ of the patient and the difficulty to reduce or withdraw prednisone. Keywords: corticosteroids, glucocorticoids, review, rheumatoid arthritis, studies, treatment of rheumatoid arthritis, trials Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Rheumatoid arthritis (RA) is a chronic disease and may lead to joint damage, disability and premature death [1]. The major goals of an effective treatment are to relieve symptoms and to prevent future damage. Disease-modifying antirheumatic drugs (DMARDs) are medications that are capable to inhibit radiographic disease progression and typically have a delayed onset of action. Glucocorticoids (GCs) are potent and fast-acting anti-inflammatory agents [2,3]. Although GCs are in broad use since 1950 in treating RA [4], their role as a treatment modality of RA is still controversial. At present, GCs are recommended by many rheumatologists as standard treatment of early RA, whereas others do not see an indication for GC use in any patient with RA. This controversy is reflected by contradictory statements [5-8]. Currently, most rheumatologists appear enthusiastic about the role of GCs in the treatment of RA, which has been confirmed by the results of a cross-sectional study including > 10,000 RA patients [9]: 60% of these RA patients (mean disease duration 11.3 years!) were on GC treatment, 90% of them on low doses (< 7.5 mg prednisone/day). In the great majority (90%), GCs were combined with DMARD treatment. The broad use of GCs demonstrated in this study suggests that recent EULAR recommendations [10] are disregarded. These guidelines recommend using GC only initially, only when indicated and only for a treatment period of maximally 10.1517/14656566.2014.922955 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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R. Rau

Article highlights. .

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Low-dose glucocorticoids (GCs) alone have only a limited disease-modifying effect and should always be combined with a potent sufficiently dosed disease-modifying anti-rheumatic drug (DMARD). The instant ameliorating effect of GCs on clinical symptoms and damage progression is temporary. In combination with DMARD treatment the additional effect of GC is often clinically not important. GCs should be prescribed only in rheumatoid arthritis patients who are at high risk of damage progression; GCs should be tapered rapidly and stopped after up to 6 months. Side-effect reporting is incomplete; toxicity and mortality ratio increase with increasing cumulative dose. The ‘tight control’ strategy is more effective than routine patient care. Inhibition of endogenous cortisol release may contribute to ‘drug addiction’ of the patient.

This box summarises key points contained in the article.

6 months. In contrast to Europe, in North America, patients are more frequently started on limited, short-term therapy, which is explained with the increasing use of the highly effective biologics [7]. In contrast, 90% of patients on biologics are also treated with GC in Germany [9]. This overview will address the rationale for low-dose GCs as a treatment modality for RA and will focus on the results of clinical studies. Due to an unfavourable benefit/risk ratio, medium- and high-dose GC treatment in RA is no longer recommended. 2.

Results of clinical trials

2.1

Early clinical investigations GC versus aspirin

Already in the 1950s, the clinical effects of cortisone were assessed versus aspirin [11,12] demonstrating a slowing of erosive changes at dose levels of 20 -- 40 mg prednisone equivalent/day. However, these doses were associated with unacceptable side effects. Low-dose GC versus DMARD controls In 18 patients, the clinical effects of a much lower dose of prednisone (5 mg/day) were compared with 16 controls on DMARD background over 6 months [13]. No difference regarding clinical efficacy was found. However, fewer patients treated with prednisone had a progression of erosions than in the control group. As a result, a ‘disease-modifying effect’ of prednisone was hypothesised and prednisone recommended as ‘bridging’ treatment when awaiting the DMARD effect. 2.1.2

Placebo-controlled treatment of early RA Another decade later, Kirwan [14] compared 7.5 mg/day prednisone with placebo in patients with early RA (disease 2

Treatment with GC alone The UTRECHT study [15] would hardly pass an Ethics committee today: without concomitant DMARD treatment, 10 mg/day prednisone or placebo was prescribed for 2 years: only sulfasalazine (SAS) as a rescue medication was allowed after 6 months. Initially, the clinical measures of disease activity improved slightly more in the prednisone group with no significant difference after month 6. However, the placebo group had been more active and more erosive at baseline than the prednisone group. At month 24, the radiographic progression rate was significantly lower in the prednisone versus placebo group (3.5 vs 6.0 normalised units, p = 0.007). However, only a minority of patients (around 25%) in both groups remained non-erosive. 2.1.4

Clinical studies of GCs in combination with DMARDs 2.2.1 Scoring radiographic damage 2.2

Scoring radiographic damage is quantified by scoring methods with different maximal scores. That makes it difficult to compare the different scores. For better comparability the ‘normalised score’ will be used, which is the percentage of the maximum possible score. GC with DMARD background In the Kirwan study [14], damage progression was significantly greater with placebo after 2 years: the normalised Larsen score had increased by 0.45 units in the prednisone group and by 3.36 units in the placebo group (p = 0.004). However, the placebo group had a much higher baseline damage score (3.9 vs 1.7 units), suggesting a greater potential for future progression. Moreover, the influence of the uncontrolled DMARD treatment on the progression rate cannot be estimated. After prednisolone treatment was stopped at 24 months radiographic progression was resumed but was still somewhat lower than in the placebo group [16]. 2.2.2

2.1.1

2.1.3

duration < 2 years) over 24 months. Seventy-one percent of the patients were treated with DMARDs in an uncontrolled way. Clinical symptoms improved more with prednisone than with placebo, but this advantage had disappeared in the second year. Acute-phase reactants were not different between groups at any time.

GC with methotrexate or SAS In the open-label BARFOT study [17], 250 patients with early RA (< 1 year) were treated with 7.5 mg/day prednisolone or placebo in addition to methotrexate (MTX) or SAS. A significant improvement in disease activity (DAS28) and in functional disability (health assessment questionnaire) was noted that was slightly greater in the prednisolone group until month 6. Thereafter, the rates of improvement levelled off without further change. At 2 years, 55.5% were in clinical remission in the prednisone group versus 33% of the controls. 2.2.3

Expert Opin. Pharmacother. (2014) 15(11)

Glucocorticoid treatment in RA

At month 24, the increase in the total normalised Sharp score was very small in both groups but slightly smaller under prednisolone treatment (0.2 vs 0.4%; p = 0.019). Prednisolone-treated patients had fewer newly eroded joints (0.5 after 2 years vs 1.25; p = 0.007). A progression beyond the smallest detectable change was seen in 25.9 versus 39.8% of patients. GC with IM gold or IM MTX The low dose prednisone treatment (LDPT) study [18] included 192 patients with early active RA in whom treatment with parenteral gold (50 mg gold sodium thiomalate weekly) or parenteral MTX (15 mg weekly) was started. Both DMARDs had been shown previously to be similarly effective in the treatment of RA [19]. Patients were matched to receive 5 mg prednisone/day or placebo over 2 years. Clinical measures of disease activity improved impressively already during the first 6 months and continued to improve further, with a trend to better improvement in the prednisone group [18]. During the first 6 months, the Ratingen score [20] increased by 0.4 normalised units in the prednisone group versus 1.3 units in the placebo group (p < 0.0001). During the second 6-month period, the progression rates were reduced to 0.05 vs 0.4 units. Within the second year, the progression was still less pronounced in the prednisone group than in the placebo group (0.15 vs 0.5); but this difference appeared not to be clinically relevant. A progression above the maximal detectable change was seen only in ~ 25 vs ~ 10% of patients of the placebo versus the prednisone group. The results of the LDPT study suggest that treatment with parenteral gold or parenteral MTX is capable to retard damage progression impressively and very quickly. Five milligrams of prednisone/day reduced the progression rate further significantly, but no longer clinically relevant during the second year. The clinical effect of prednisone was only marginal. Of note, the Ratingen score [20] evaluates only the amount of erosive destruction of the joints, which is more relevant to assess treatment effects than joint space narrowing as used in the Sharp--van der Heijde score.

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2.2.4

GC with SAS The WOSERACT study [21] compared SAS + 7 mg prednisone/day with SAS + placebo over 2 years. Some initial clinical advantage after 1 year had vanished after 2 years. The method of radiographic evaluation has been questioned. However, both ratings showed a non-significantly greater progression in the prednisone group. This is the only known study showing that GC was inferior placebo. 2.2.5

received concomitant SAS, and patients of the prednisone group received 7.5 mg MTX/week in addition from baseline to week 40. The combination group (prednisone, SAS, MTX) improved almost immediately in all disease activity measures up to week 28. However, after 1 year, the differences in clinical efficacy between both groups had nearly completely disappeared. During the first 28 weeks, the combination group had significantly less progression than the SAS + placebo group (median 1 vs 4; p < 0.0001), and damage progression was still less pronounced during weeks 28 -- 56 (1 vs 2.5; p = 0.04), whereas no difference was noted during weeks 56 -- 80 [23]. CARDERA study In the CARDERA study [24], 231 patients received 60 mg prednisolone/day, which was tapered to 0 mg over a period of 34 weeks together with MTX or MTX + cyclosporine. At 2 years, the mean change in the GC group was significantly lower than in the control group (2.4 vs 3.7 normalised Larsen units). Cyclosporine had no additional effect. Both the COBRA [22] and the CARDERA study can also be classified as bridging therapy. 2.3.2

Established disease In 102 patients with active established disease, a new DMARD treatment was initiated [25]. They were randomised to be treated with placebo or prednisolone in addition over 1 year. The initial prednisone dose of 30 mg/day was gradually reduced to 15 mg at day 15. Thereafter, the patients were free to choose a dose between 15 and 2.5 mg/day depending on their feeling about a sufficient control of their disease. Swollen joint count and C-reactive protein (CRP) decreased faster in the prednisone group but at 6 and 12 months there was no difference between the groups. The normalised Larsen score was already 20 (placebo) and 18 (prednisone) at baseline and increased significantly less in the prednisone group (1.1 vs 2.1 normalised units). The study demonstrates that radiographic progression and treatment effects will be similar in patients with established and early disease in case they present with similar disease activity. 2.3.3

Studies with a ‘tight control’ design Studies aiming for tight control of disease activity have a clear treatment goal and change the medication if this is not achieved. 2.4

Tight control study A recent tight control study [26] aimed to achieve a DAS of £ 2.4 reflecting low disease activity. The initial MTX dose of 10 mg weekly could be gradually increased to 20 mg per week and finally combined with a TNF inhibitor. Patients were randomised to prednisone (12.5 mg/day for 2 weeks, then tapered to 6.25 mg per day) or placebo. Patients on GC achieved higher rates of clinical remission during the first 2.4.1

Initial high doses combined with DMARDs 2.3.1 The COBRA study 2.3

The COBRA study [22] included patients with early RA and high disease activity. Assuming an increased corticosteroid effect by means of a higher initial dose, patients were treated with 60 mg/day prednisone initially for 1 week, tapered weekly to reach 10 mg/day at week 6 and 0 mg at week 28. All patients

Expert Opin. Pharmacother. (2014) 15(11)

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R. Rau

year and a higher probability of sustained remission (40 vs 30%; p = 0.01) during the second year.

was seen between week 20 and week 24. Radiographic progression was not different between both groups [30].

TICORA study In the TICORA study [27], patients started a new DMARD. A tight control group was treated in addition with 120 mg of depot triamcinolone every 4 weeks via the intramuscular or intra-articular route over the first 3 months. The routine care group had visits at the discretion of the treating rheumatologist with no concomitant steroid injections. At 18 months, the DAS44 had improved by -3.5 versus -1.9, and 65% versus 60% of patients were in clinical remission. The median total normalised Sharp score increased more in the control group (1.0 vs 1.9).

2.7

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2.4.2

CAMERA II CAMERA II, another MTX-based tight control study [28], where 10 mg prednisone per day over 2 years was prescribed, demonstrated an improvement of clinical efficacy compared to placebo. After 2 years, 72 versus 61% were in sustained remission and only 14 versus 36% needed biological treatment. Seventy-eight percent of patients in the MTX + prednisolone group remained erosion free after 2 years versus 67% in the MTX + placebo group. However, the difference in the progression rate was only minimally smaller (0.3 normalised units) in the prednisone group. 2.4.3

Intra-muscular GC administration Monthly IM injections of 120 mg depomedrone were compared with placebo injections over 2 years. Patients had established RA and used DMARD treatment but nevertheless had active disease [29]. The DAS28 improved more rapidly in the GC-treated patients only during the first 6 months, and a smaller reduction in damage progression was noted with GC treatment than under placebo. More severe adverse reactions occurred in the steroid group including vertebral fractures, diabetes and myocardial infarction. Hip bone density decreased significantly in steroid-treated but not placebo patients. 2.5

Bridging therapy Typically, it takes 2 -- 6 months to establish a significant clinical response after initiation of a DMARD treatment. As in the small group of patients with very active disease damage may start to progress during that period, it became clinical practice to bridge the time with GC in all patients. This ‘bridging therapy’ has been investigated in 40 patients starting parenteral gold treatment. They were randomised to receive either prednisone or placebo. The prednisone dose was 10 mg/day in the first 12 weeks and was gradually reduced to 0 at the end of week 18. Both groups improved almost in all variables from week 4 onwards, a little more pronounced in the prednisone group until week 12, but with no difference thereafter. A response to prednisone treatment was noticed in only 60% of patients. In 58% of them, rebound deterioration 2.6

4

Withdrawal rate as a measure of clinical efficacy? In 31 RA patients who had been on long-term treatment with 1 -- 4 mg/day of prednisone and had stable disease, the dose was reduced by 1 mg prednisone or placebo tablets every 4 weeks over 12 weeks. The primary outcome was withdrawal from the study due to patient-reported lack of efficacy. Three of fifteen prednisone and 11/16 placebo patients withdrew (p < 0.03) [31]. Some limitations of the studies Homogeneity in the erosive joint status between study groups at study entry is important as it is a good predictor of future progression. In the Kirwan study [14], the patients in the placebo arm had much higher radiographic scores at study entry than patient in the GC arm, thus predisposing them to a more progressive disease course. The Utrecht study [15] encountered the same problem. In the COBRA trial [22], it is not clear how much of the success of the GC group in preventing damage progression is due to the addition of a very potent second DMARD -MTX. A combination group SAS/MTX without GC that could have answered this question is lacking. Choy [29] recommends that patients with suboptimal response to a DMARD should try an alternative or additional DMARD instead of prescribing GC. 2.8

3.

Intra-articular GC

If the arthritis is limited to or particularly active in only a few joints, the injection of a GC-crystal suspension into the joint space is an excellent measure for temporary local palliation of inflammation [32]. The effect size and effect duration depend on the nature of the GC formulation. Single triamcinoloneacetate injections have shown beneficial effects for 2 -- 3 weeks and triamcinolone-hexacetonide injections were effective for 4 -- 5 weeks [33]. Unfortunately, the GC formulation is rarely disclosed in publications. The hormone is taken up by the synovial membrane within a few hours and there it is hydrolysed only very slowly. An excess over the amount the synovial membrane can retain will be hydrolysed very quickly by the enzymes of the synovial fluid and will be released into the systemic circulation [32]. Therefore, the steroid dose has to be adapted to the size of the joint. Trials incorporating intra-articular GC injections Trials incorporating intra-articular GC injections in addition to DMARDs have successfully been used and resulted in long-term benefits. In the CIMESTRA trial [34], 160 patients with early RA (< 6 months) were randomised to receive intraarticular betamethasone (which formulation?) up to a dose of 28 mg, corresponding to > 180 mg of prednisone, in any swollen joint in combination with step-up treatment comprising 3.1

Expert Opin. Pharmacother. (2014) 15(11)

Glucocorticoid treatment in RA

MTX + either placebo or cyclosporine for 24 months. A good disease control was reported with an ACR50 response in around 57% of patients and minimal radiological progression. Cyclosporine did not improve the results.

was observed [44]. A UK database stated an increase of clinical vertebral fractures by 55% for a prednisone dose of < 2.5 mg/ day and by > 400% if the dose exceeded 7.5 mg/day [45]. Peptic ulcer With concomitant use of NSAID and GC, the risk for that disease is up to 15 times greater than with GC alone [46]. 4.3

4.

Adverse events of low-dose GC

General toxicity profile The dose-dependent toxicity profile is defined in drug monographs. Doses of < 7.5 mg prednisone equivalent/day are considered to be safe in case of short- and medium-term use. Therefore, in daily practice, standard monitoring with corticosteroid treatment is not necessary [35]. That statement of the task force is based on consensus since literature data on monitoring are scarce and incomplete [35]. For clinical trials they recommend a higher frequency of monitoring, a more comprehensive set of items to monitor and a standardised reporting of adverse events (AEs) [35]. Currently, many patients are on long-term GC treatment [9] and toxicity also depends on cumulative doses. Recently, the threshold for increased mortality was set at 8 mg/day and a total cumulative dose of 40 g. That corresponds to 5 mg/day over 21 years or 7.5 mg/day over 14.5 years [36]. Such time periods can easily be reached in the treatment of RA. So far we have no valuable information of the risks of longer treatment periods since most randomised trials are too short. However, the retrospective analysis of patients on low-dose GC treatment for over 5 years demonstrated that these patients were prone to a significantly higher and frightening prevalence of fragility fractures, arterial hypertension and myocardial infarctions, increasing with the duration of treatment [37]. Most publications are primarily focussed on treatment effects, while reporting on the occurrence of AES is often limited [38]. The doctor may not be interested in and the patient hesitates to mention ‘minor’ complaints such as tachycardia, weight gain and beginning moon face. Patient´s fears and experiences are often discredited as ‘unfounded worries’ [39] or as prejudices. Patients who were interviewed about their psychiatric problems during intermittent GC therapy for asthma over 5 years complained of initial euphoria, insomnia, depression, confusion, memory problems and tendency to suicide. Five of eight had not informed their doctor [40]. Some patients experience mood disturbances already with prednisone doses < 3 mg/day [41]. The patients’ fears are reflected by the high percentage of candidates refusing to participate in studies with GC treatment [15,28]. In the BeSt trial, more patients disliked taking oral GC therapy than receiving intravenous infusions of TNF inhibitors at hospital [42]. Many Dutch rheumatologists are reluctant to use the COBRA treatment strategy (with high initial doses) in early RA [43].

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4.1

Osteoporosis In patients exposed to 7.5 mg of prednisolone/day over only 20 weeks, an average loss of 9.5% from spinal trabecular bone 4.2

Cardiovascular risks The incidence rate of cardiovascular events (coronary disease, cerebral artery disease) in patients with RA is twice as high as in the general population [47]. GC may enhance cardiovascular risk by their negative effects on lipid profiles, glucose tolerance, blood pressure and obesity [48], although low doses may compensate these effects by inhibiting the local inflammatory response in the artery wall [49]. 4.4

Infections The risk of systemic infections including tuberculosis is significantly increased with GC treatment and is considered to be dose dependent. The relative risk increased from 1.3 to 5.5 when compared to MTX as the dose of prednisoneequivalent increased from £ 5 mg/day to > 20 mg/day [50]. 4.5

Increased mortality The mortality ratio in RA patients is increased in correlation with disease activity and functional impairment [51,52]. In a recent study, the standard mortality ratio was 0.86 for patients with a mean DAS of < 3.2 and increased to 3.33 for a mean DAS of > 5.1 [53]. GC treatment has been identified as an additional independent factor for a shortened life expectancy, which is rarely mentioned in overviews over GC toxicity. In a recent study, patients on mean doses of > 5 -- 10 mg/day had a hazard ratio of 2.22 for premature death, which increased to 6.68 in patients on > 15 mg/day [53]. In 1983, Scott suspected that some of the deaths observed in a 20-year follow-up were steroid related [54]. In 1984, Pincus (1) observed a severe functional decline and premature death in 75 RA patients followed for 9 years; the increased death rate is rarely mentioned when citing his paper. In early RA, when patients were followed for 15 years, 39% of those who died had been on steroids, but only 3% of those who were still alive [55]. The ARAMIS database demonstrated that steroids were associated with increased mortality, whereas azathioprine, at that time reserved for more severe disease, was not [56]. 4.6

Hormone-induced ‘drug addiction’ High and medium GC doses have been shown to inhibit the hypothalamic -- pituitary -- adrenal (HPA) axis. However, even low doses of GC resulted in a depression of baseline and adreno-cortico-trophic hormone (ACTH)-stimulated cortisol levels [57]. With time, exogenous GC may become only a substitute for the reduced endogenous cortisol production. 4.7

Expert Opin. Pharmacother. (2014) 15(11)

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R. Rau

This could explain in part the ‘drug addiction’ of the patient. Independent of disease activity, it is difficult to reduce the dose or withdraw the drug because the patient comes into a state of hormonal deficiency with tiredness, hypotension, hypoglycaemia, etc. Even in patients who were treated with prednisone doses around 3 mg/day, it was rarely possible to withdraw the drug [31]. After prolonged therapy it may last a year before HPA responses return to normal [58]. After stopping the UTRECHT study [15], 35% of patients of the original prednisone group had resumed to take prednisone compared to 3% of the placebo group. Prednisone doses must always be reduced very slowly; when patients are taking 7.5 mg/day prednisone or less, the best practice is to taper it in 1-mg decrements each month [41]. Doses above 7.5 mg prednisone/day are contraindicated in most RA patients. 5.

Expert opinion

Effects of GCs on disease activity Since damage progression is correlated to disease activity and may occur quickly, treatment guide lines recommend the prescription of GC in combination with DMARDs as part of the initial treatment in (all) patients with early RA [6]. However, the immediate effects of low-dose GCs on clinical and laboratory measures of disease activity in patients with RA are limited in their magnitude and are typically not maintained for longer than 6 months in the majority of cases [15,17,18,30]. In some studies, no or only tiny differences in the acute reactants were seen [14,18]. 5.1

Effects on radiographic disease progression GC effects on radiographic disease progression have been extensively investigated with different GC dosing schedules in combination with DMARDs. As the inhibition of damage progression with 10 mg/day prednisone monotherapy was disappointing when compared with placebo [15], it was concluded that prednisone should only be used in combination with a DMARD. The effct of that combination was more pronounced than DMARD monotherapy in the majority of studies. But this beneficial effect did not persist beyond 6 -- 12 months. Moreover, with DMARD monotherapy, inhibition of erosion progression can start quickly and be very effective [17,18,30,59]. The contribution of GC added is often small and may not be of clinical relevance. IM gold monotherapy was as effective from the beginning as gold in combination with GC [30]. The WOSERACT trial [21] even found a worse outcome in the prednisone-treated patients. A Cochrane systematic review stated that the mean advantage of prednisone added to a DMARD of all studies was only 0.39% of the maximum possible score [60]. Little advantage with prednisone occurred with a tight control strategy [28]. The long-term effect of corticosteroids on joint destruction is still unknown. Out of patients initially matched for severity, those who were treated with GC showed a significantly worse outcome at the 5-year follow-up [61]. A steroid-osteoporosis 5.2

6

with reduced bone resistance against damage may have played a role for this unfavourable outcome. Problem of predicting damage progression There is no proven indicator or biomarker predicting the risk of joint erosion and/or its progression. Certainly the risk is correlated with swollen joint count, erythrocyte sedimentation rate or CRP, rheumatoid factor or anti-CCP-antibody titres and, importantly, the erosion score at baseline. A more reliable method to predict the risk of damage progression is needed. 5.3

Can study results be generalised? Study results are generally presented as mean values. However, not all patients respond similarly to a GC treatment: in one study, 40% of patients on steroids failed to respond, and after stopping GC a rebound deterioration of clinical symptoms was noticed in 58% of responders [30]. Damage progression above the minimal detectable change of the scoring method occurs only in 10 -- 40% of individuals even in the placebo group of a trial. Patients in general practice may be less active and consequently have a smaller risk of deteriorating. Knowing the potential side effects, GC treatment should be reserved for patients at high risk of damage progression. 5.4

The necessity to ‘fill the gap’ A rationale for early GC application is the management of the therapeutic gap between the initiation of a DMARD and the evidence of onset of clinical efficacy. This time period is difficult to determine since the first outcome measurements are made only after 6 months in most studies. In two studies with earlier follow-up examinations, a significant DMARD effect could be documented already at 4 and 12 weeks, respectively [19,30]. In our experience, the gap can be filled with educating the patient about the disease and its treatment and by starting physiotherapy. This may be much more effective in the long run than suppressing clinical symptoms with GC prescription. 5.5

‘Tight control’ design Several studies [26-28] have demonstrated that ‘tight control’ can improve the results of treatment, which could only moderately be improved by adding 10 mg prednisone/day to the treatment protocol [28]. Sometimes it is not clear if the better outcome is related to the GC injections or to the tight control [27]. 5.6

Intra-articular injections Intra-articular injections of depot-steroids intend to induce a long-lasting suppression of inflammation only in the injected joint. The steroid dose has to be adapted to the size of the joint. For a knee joint the optimal dose is 20 mg of triamcinolone-hexacetonide. In case of overdosing [34] most of the injected GC will quickly be released into the circulation and 5.7

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Glucocorticoid treatment in RA

will induce a systemic reaction for 1 -- 3 days without giving a lasting advantage for the patient. Risks of GC treatment The risks of GC treatment in RA with doses up to 7.5 mg/day are often played down, for example, in an overview [62] relying on results of prospective trials. However, the side effect reporting in these trials was incomplete [35,38] and ‘minor’ AEs have been disregarded (see Chapter 4.1). An extended drug application resulting in high cumulative doses is an important factor for increasing toxicity. A EULAR task force [38] recommends developing a more comprehensive set of items to monitor AES, hopefully including a questionnaire for the patient.

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5.8

GC prescription in clinical practice Too many patients are treated too long with GC. The EULAR recommends the introduction of GC treatment only in early RA when indicated and only up to a period of 6 months [10]. However, most patients seem to be treated much longer [9]. The prescription of GC appears to be based more on the personality of the physician than on the severity of the patient‘s disease. ‘It emanates in part from a simple desire to rapidly alleviate patients ‘symptoms’ and thereby to impress the patient [62]. ‘A rapid alleviation with GC treatment may delay or even prevent referral to better treatment’ [7]. ‘If rheumatologists are seen to regularly prescribe oral steroids, this may provide cover for the primary care physician to do the same’. 5.9

‘Drug addiction’ Even low-dose GC treatment may suppress endogenous cortisol release [57] (see Chapter 4.5). This may be a major reason 5.10

Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

Pincus T, Callahan LF, Sale WG, et al. Severe functional decline, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 1984;27:864-72 Gotzsche PC, Johansen HK. Meta-analysis of short-term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis. BMJ 1998;316:811-18 Saag KG, Criswell LA, Sems KM, et al. Low-dose corticosteroids in rheumatoid arthritis: a meta-analysis of their moderate-term effectiveness. Arthritis Rheum 1996;39:1818-25

for the ‘drug addiction’ of the patient. Clinical experience and several studies [15,31] have documented the difficulty to reduce the GC dose or withdraw it. This can be a starting point for chronic GC prescription with all its risks. If the vanishing efficacy of GCs is related to the inhibition of the HPA axis is a subject of future research. 6.

Expert conclusion

We have still no proven knowledge concerning the long-term effect of GC on joint destruction and what price we will have to pay for the temporary improvement of the disease we can achieve. A prolonged follow-up of patients after undergoing ‘bridging’ therapy should clarify if the temporary symptomatic and radiographic benefit will affect long-term outcome or if negative effects prevail. Future randomised studies over at least 5 years are needed to determine the long-term outcome in patients with or without GCs in addition to DMARDs. To determine the real long-term toxicity of low-dose GC treatment in extended studies, more frequent monitoring should be done using a comprehensive set of items including a patient questionnaire and standardised reporting of AEs.

Declaration of interest The author has no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

4.

Hench P. Effects of cortisone in the rheumatic diseases. Lancet 1950;2:483-4

5.

Saag KG. Resolved: low-dose glucocorticosteroids are neither safe nor effective for the long-term treatment of rheumatoid arthritis. Arthritis Rheum 2001;45:468-71

6.

Conn DL. Resolved: low-dose prednisone is indicated as a standard treatment in patients with rheumatoid arthritis. Arthritis Rheum 2001;45:462-7

7.

Russell AS. Oral corticosteroids should not be used in rheumatoid arthritis. Rheumatologist 2013;7:29-30 Explains why oral glucocorticoids (GCS) should not be prescribed in rheumatoid arthritis (RA).

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Kirwan JR. The Arthritis and Rheumatism Council and Low Dose Glucocorticoid Study Group: the effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995;333:1442-6 First randomized double-blind trial comparing DMARD + prednisone with DMARD +placebo. Van Everdingen AA, Jacobs JWG, Van Reesema DR, 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 Indicates that prednisone monotherapy has limited disease-modifying qualities. Hickling P, Jacoby RK, Kirwan JR. Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. Br J Rheumatol 1998;37:930-6 Svensson B, Boonen A, Albertsson K, et al. for the BARFOT Study Group. Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Arthritis Rheum 2005;52:3360-70 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: a multicentre, double-blind, placebo-controlled trial. Arthritis Rheum 2005;52:3371-80 Documents a significantly increased inhibition of damage progression with only 5 mg/day prednisolone but also quick and profound effect of potent

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Affiliation Rolf Rau Professor, Irisweg 5, D - 40489 Du¨sseldorf, Germany Tel: +49 203 740441; Fax: +49 203 7384800; E-mail: [email protected]

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