A systematic review «Gaujoux-Viala C, Nam J, Ramiro S, et al. Efficacy ...»1 of the literature was performed from 2009 until January 2013 about the efficacy of glucocorticoids in early RA. Of 222 hits, five publications relating to four new trials were analysed for efficacy.
In one trial, a single IM 120 mg methylprednisolone injection was given in the study group vs. the control group with similar outcomes in both groups over one year «Machold KP, Landewé R, Smolen JS, et al. The Stop ...»2.
One trial appeared only as an abstract and has not been published «Fedorenko E, Lukina GV, Sigidin YA, et al. Remissi...»3.
In an Italian trial «Montecucco C, Todoerti M, Sakellariou G, et al. Lo...»4, «Todoerti M, Scirè CA, Boffini N, et al. Early dise...»5, Prednisolone was started with a dose of 12.5 mg and continued with a dose of 6,25 mg for the follow up period of two years. The DAS28 remission rate at 52 wk was better among those who received Prednisolone although there was no significant difference between the groups, for the proportion of low disease activity.
In the Computer Assisted Management in Early Rheumatoid Arthritis trial-II «Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose ...»6 (CAMERA II), patients were randomized to receive MTX plus prednisone (10 mg/day) vs MTX plus placebo for two years. Those who received Prednisolone, had higher rates for sustained remission and the need for additional treatment (subcutaneous MTX, ciclosporin or adalimumab) was significantly lower than in the MTX monotherapy group.
The authors concluded that initial treatment of RA with low-dose prednisone plus methotrexate (MTX) results in better clinical and structural outcomes at 1 and 2 years than treatment with MTX alone.
In a randomized controlled trial «Hafström I, Albertsson K, Boonen A, et al. Remissi...»7 in Sweden 211 patients with RA had been randomised to the 7.5 mg prednisolone group (P) or no prednisolone group (NoP) in addition to the initial disease-modifying antirheumatic drugs. A total of 150 could be included in analysis. Radiographs of hands and feet were scored using the Sharp-van der Heijde scoring method. A patient was considered to be in remission if the 28-joint count disease activity score was < 2.6.
At 2 years the proportion of patients in remission in the P and NoP groups was 55 vs 30 %, p = 0.003. Longitudinal analysis showed that over the entire course of the disease, patients on prednisolone had a higher probability of being in remission. Patients in remission at 2 years, compared with those not in remission, had significantly lower total Sharp score, erosion score and joint space narrowing score at 2 and 4 years.
In a German study 192 patients with active early RA (disease duration less than two years.) received either prednisolone 5 mg/day or placebo on concomitant DMARD therapy with parenteral gold or methotrexate for two years «Wassenberg S, Rau R, Zeidler H, et al. A dose of o...»8. 166 were available for intention to treat analysis (ITT), and 76 completed the study per protocol.
Radiographs of hands and feet were taken at baseline, and at 6, 12 and 24 months. Structural damage was assessed using change in the Ratingen score (0–190 scale) as the primary outcome, and change in the Sharp/van der Heijde score (0–448 scale). Progression of the Ratingen score was significantly less at all consecutive time points in the prednisolone group compared to the control group, with the greatest difference after 6 months. At 24 months the increase in score in the prednisolone group was 1.2 + 3.5, (95 % CI 0.4–2.1) and in the placebo group 4.3 + 6.8 (95 % CI 2.7–5.9) (p = 0.006, ITT-analysis). This was confirmed by the results of the Sharp/van der Heijde erosion and total score with an increase of the total score of 5.3 + 10.7 units in the prednisolone compared to 11.4 + 19.1 in the placebo group (p = 0.022) at 24 months.
In the NORD-STAR study «Østergaard M, van Vollenhoven RF, Rudin A, et al. ...»9, the best conventional therapy was compared with three biological agents. This was a Nordic, investigator-initiated, blinded, multicentre study in which 812 patients with early rheumatoid arthritis were randomized between December 2012 and December 2018. The primary clinical endpoint was CDAI remission at week 48, and the co-primary endpoint was radiographic progression assessed by the van der Heijde–Sharp score (vdHSS) at week 48.
Patients were randomized into four treatment arms:
1: Best conventional therapy
1A: Methotrexate (MTX) plus prednisolone, with a starting dose of 20 mg/day, tapered to 5 mg/day by week 9 and discontinued at 9 months. This regimen was used in Sweden, Norway, Iceland, and the Netherlands.
1B: MTX plus sulfasalazine 2 g/day plus hydroxychloroquine 35 mg/kg/week or 200 mg/day, combined with intra-articular treatment of swollen joints using long-acting glucocorticoids (triamcinolone hexacetonide) at each visit (maximum of four joints and 80 mg per visit). This regimen was used in Finland and Denmark.
Three arms including a biological DMARD (bDMARD):
2: MTX plus certolizumab pegol 200 mg subcutaneously every other week (400 mg at weeks 0, 2, and 4)
3: MTX plus abatacept 125 mg subcutaneously once weekly
4: MTX plus tocilizumab 8 mg/kg intravenously every four weeks or 162 mg subcutaneously weekly
The target and maximum MTX dose was 25 mg by week 4. Dose adjustments were permitted, as was subcutaneous administration of MTX. Folic acid supplementation was at least 5 mg per week.
Intra-articular joint injections were permitted in treatment arms 2–4. However, no local treatments were allowed between weeks 20–24 and 44–48 in order to avoid interference with treatment outcomes at weeks 24 and 48.
Oral prednisolone was not permitted in any group other than arm 1A.
Of the patients, 69% were women, 82% were anti‑CCP positive, the mean age was 54 years, and the mean symptom duration was 204 days.
The numbers of patients who initiated and discontinued treatment during the 48-week study period were as follows:
1: 200 / 38; 2: 203 / 35; 3: 204 / 20; 4: 188 / 35.
In the best conventional therapy group, discontinuations were mainly due to lack of efficacy, whereas in the tocilizumab group they were mainly due to adverse events.
Treatment efficacy assessed by different outcome measures was similar among patients receiving bDMARDs at week 48, but numerically slightly lower in those receiving best conventional therapy.
CDAI remission rates were similar across all treatment arms until prednisolone was withdrawn in group 1A at 9 months.
Follow-up analysis of the study: Comparison of the conventional treatment arms
In a follow-up analysis of the study, the groups receiving best conventional therapy were compared with each other «Hetland ML, Heiberg MS, Sokka-Isler T, et al. Trea...»10.
Group 1A included 137 patients and group 1B 80 patients; 78% of patients in group 1A and 89% in group 1B remained in the study until week 48. Treatment response at weeks 4 and 8 was better in group 1A, as patients received a moderate dose of prednisolone. At three months (week 12), CDAI and DAS28 scores were similar in groups 1A and 1B.
At week 48, treatment response assessed by various outcome measures was better in patients receiving combination therapy than in those treated with MTX plus prednisolone. Fewer adverse events were observed in the combination therapy group, and the cumulative glucocorticoid dose was lower compared with group 1A. Radiographic progression was low in both groups but numerically slightly lower in group 1A, in which prednisolone was used for nine months.
Among patients receiving combination therapy (group 1B), 55% were in CDAI remission at week 48 compared with 36% in group 1A. Among patients receiving biological therapies, CDAI remission rates were 52% in the certolizumab and tocilizumab arms and 59% in the abatacept arm.
Comment: The effect of prednisolone on symptoms and disease activity measures of rheumatoid arthritis persisted only for as long as the drug was administered. Prednisolone had a modest positive effect on the radiographic endpoint.
General comment:
Systemic glucocorticoid therapy rapidly alleviates the symptoms of rheumatoid arthritis and has a modest effect on preventing erosive progression.
However, it may mask disease activity, potentially delaying the initiation or modification of disease-modifying antirheumatic drug therapy.
The adverse effects associated with long-term glucocorticoid use must be taken into account when initiating systemic glucocorticoid therapy in patients with rheumatoid arthritis.
In the 2022 EULAR recommendations, the guidance on glucocorticoid therapy was revised compared with previous recommendations, placing stronger emphasis on discontinuing systemic glucocorticoids as soon as possible. Short-term treatment was defined as a maximum of three months; treatment longer than this is considered long-term therapy and is not recommended «Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR ...»11.
Parts of the text were translated from Finnish into English using artificial intelligence. The translation was reviewed by an expert.