Supplementary data

Supplementary table S1. Clinical Efficacy and Safety of Low-dose GCs in RA Patients

Reference / Patients / Duration, Design, and Treatment / Primary Efficacy/Safety Endpoint / Efficacy for Primary Endpoint / Safety
Allaart
[78] / 508 patients, active RA <2 years
(BeST) / ·  2-year results from randomized trial of 4 treatment strategies
·  Group 1: sequential monotherapy, starting with MTX
·  Group 2: step up combination therapy, starting with MTX
·  Group 3: initial combination therapy with MTX, SSZ, and tapered high dose prednisone
·  Group 4: initial combination therapy with MTX and IFX
·  3-monthly therapy adjustments based on DAS, with goal of DAS ≤2.4
·  HAQ every 3 months
·  Radiographs of hands/feet assessed yearly, blinded for patient identity and treatment and in random order (Sharp van der Heijde score) / Functional ability as measured by HAQ (every 3 months)
Radiographic progression (12 months/24 months)
Disease activity as measured by DAS44 / ·  After 3 months, functional ability significantly improved (from 1.4 to 0.6) in Group 3(MTX +SSZ + prednisone) and Group 4 (MTX + IFX) compared to Groups 1 and 2 (initial MTX monotherapy), from 1.4 to 1.0. After 6 and 9 months, HAQ further improved in all groups, remaining lower in groups 3 and 4 vs. groups 1 and 2; After 12 months, lower in groups 3 and 4 vs. group 1; between 12-24 months, no further improvement seen and no significant differences between treatment groups.
·  After year 1, less radiographic progression in groups 3 and 4 vs. groups 1 and 2; median increase in total SHS, 2.0 group 1, 2.5 group 2, 1.0 group 3, 0.5 group 4 (p=0.003 for group 1 vs. group 3; p<0.001 for group 1 vs. group 4; p=0.007, group 2 vs. group 3. After 2 years, median SHS remained the same
·  After 2 years, goal of a DAS44 ≤2.4 reached by 75% of patients in group 1, 81% in group 2, 78% in group 3, 82% group 4 (p = NS); More patients in groups 1 and 2 than 3 and 4 changed from the initial treatment step to subsequent therapy adjustments; more patients in groups 3 and 4 able to taper and discontinue drugs of initial combination therapy. Number of patients achieving DAS <1.6 initially higher in groups 3 and 4, but after 2 years, no statistically significant differences were seen in percentages of patients in clinical remission: 46% group 1, 38% group 2, 41% group 3, 42% group 4 / ·  No significant differences in number of AEs or SAEs between 4 treatment arms during 2 years of treatment
Allaart
[79] / 508 patients active RA, ≤2 years (BeST) / ·  3 year results randomized trial with 4 treatment arms:
·  Group 1: sequential monotherapy, starting with MTX
·  Group 2: step up combination therapy, starting with MTX
·  Group 3: initial combination therapy with MTX, SSZ, and tapered high dose prednisone
·  Group 4: initial combination therapy with MTX and IFX
·  Treatment adjustments based on 3-mnthly calculates of DAS (target ≤2.4
·  Yearly anonymized radiographs of hands/feet
·  Protocol adapted in year 3, possibility of discontinuing all drugs if patient in clinical remission, DAS <1.6, for 6 months after tapering to monotherapy in maintenance dose; if DAS increased to ≥ 1.6, last discontinued drug restarted; if DAS >2.4, dose increased, and if necessary n next drug or combination of drug reintroduced; in the case of repeated remission for ≥6 months, all medication tapered and stopped with exception of IFX which is kept at maintenance dose / Functional ability as measured by HAQ (every 3 months)
Radiographic progression (yearly)
Disease activity as measured by DAS44 / ·  After 12 months, no significant differences between the groups most likely due to therapy adjustments in case of insufficient clinical response; at the end of year 2, 68% of patients in Group 1 and 2 had discontinued first treatment (MTX) and moved on to next treatment
·  Once DAS ≤2.4 achieved (and medication remained unchanged) likelihood of the next DAS being ≤2.4 was 74% regardless of treatment group
·  Adaptation of protocol results in patients in clinical remission without therapy: group 1, 11% of patients discontinued all medication and still in remission at 3 years; group 2, 6%; Group 3, 7%; Group 4, 16% (p<0.005 for group 4 vs. groups 2 and 3). Group 4, 14 patients restarted IFX due to increase in DAS > 2.4
·  Radiographic progression remained low in all groups; median increase in total SHS score was 3.8, 3.0, 1.8 and 1.5 in groups 1-4 respectively (Group 1 vs. 2, p=0.518; group 1 vs. 3, p=0.007; group 1 vs. 4, p<0.001; group 2 vs.4, p=0.004; other comparisons, p>0.05) / ·  3 year safety not reported
Bakker
[18] / 236 patients with early RA (< 1 year); glucocorticoid, DMARD naïve
(CAMERA-II) / ·  2-year prospective, randomized, placebo-controlled, double-blind multicenter, tight control strategy trial
·  Patients randomly assigned to MTX + prednisone or MTX + placebo
·  Initial dose of oral MTX, 10 mg/week
·  Monthly visits: assessment of SJC, TJC, ESR, VAS (0-100mm)
·  Criteria of response: >20% improvement compared to previous visit in SJC and in ≥2 of following factors: TJC, ESR, VAS
·  If criteria of response not met, dose of MTX increased by 5 mg/week until remission (defined as SJC of 0 and at least 2 of the following: TJC ≤3, VAS score ≤20 mm, ESR ≤20 mm/h) or the maximum dosage of MTX 30 mg/week or maximum tolerable MTX dose
·  If remission not reached by 4 weeks after reaching maximum tolerable dose, MTX administered SC (at same dose) and, as next step cyclosporine added
·  Protocol amended after 20% patients recruited; ADA replaced cyclosporine as next step to be added to maximum dosage of SC MTX; starting dose of ADA 40 mg SC every 2 weeks; if criteria of response unmet after 12 weeks, dosage increased to 40 mg/week. In case of remission, ADA dosage reduced to 40 mg every 2 weeks. MTX dose reduced stepwise by 2.5 mg/week each month as long as remission present / Primary Endpoint: Radiographic erosive joint damage after 2 years
Secondary: response criteria, remission, need to add cyclosporine or biologic agent to treatment / ·  Primary Endpoint: Erosive joint damage less in MTX + prednisone group (median, 0 [IQR, 0 to0]) than MTX + placebo (median, 0 [IQR, 0 to 2]) (p=0.022). Cumulative probability plot on erosion scores, 78% of patients in MTX + prednisone group vs. 67% in MTX + placebo group were erosion-free. JSN and total SHS were not different.
·  Secondary Endpoint: Longitudinal regression analyses, patients in MTX + prednisone group had lower disease activity for all disease activity variables than patients in MTX + placebo group (p<0.001 for all) / ·  Patients in the MTX + prednisone group had less nausea (p=0.006) and alanine and aspartate aminotransferase levels above the upper limit of normal (p=0.006 and 0.016 respectively) than did patients in the MTX + placebo group. No differences between the groups in numbers of patients having other adverse events.
Buckley
[34] / 96 patients with RA, 65 of whom were receiving treatment with corticosteroids (mean dosage, 5.6 mg/day) / ·  2-year randomized, double-blind, placebo-controlled trial.
·  Patients received either calcium carbonate (1000 mg/day) and vitamin D3 (500 IU/day) or placebo
·  BMD of the femur and lumbar spine measured at beginning of study and at yearly follow-up visits
·  Patients seen every 6 months to assess compliance / Assess effects of supplemental calcium and vitamin D3 on BMD of patients with RA
Assess relation between effects of supplementation and corticosteroid use / ·  Patients in calcium + vitamin D3 group, average increase in BMD in lumbar spine of 0.63% per year vs. a decrease of 1.31% in placebo group (p=0.015); BMD in the femur increased by 0.85% per year in the calcium vitamin D3 group and decreased by 0.90% per year in the placebo group (p=0.024)
·  Dietary supplementation with calcium and vitamin D3 stabilized BMD in lumbar spine and trochanter during 2 years of treatment in RA patients receiving long-term, low-dose prednisone therapy (mean dosage, 5.6 mg/day); in patients not treated with corticosteroids, not receiving calcium and vitamin D3, BMD of lumbar spine and trochanter decreased by 2.0% and 0.9% per year respectively / ·  Not evaluated
Buckley
[35] / 133 RA patients / ·  3-year prospective, randomized, placebo controlled study
·  MTX users, taking MTX at time of enrollment; non-MTX users defined as patients who had not taken MTX for 1 year before enrollment and had not received more than 90mg total dose in the past
·  Mean duration of MTX use at baseline, 3.5 years (1-10 years), mean dose 10.6 mg/week, mean cumulative dose 1537 mg / Effects of calcium and vitamin D3 supplementation on BMD / ·  Change in BMD, adjusted for age, sex, HAQ and prednisone use, similar in MTX and non-MTX treated patients (difference -2%, p=0.359, in lumbar spine, and 0.85%, p=0.58 in femoral neck)
·  Multiple linear regression showed a significant interaction between the effects of prednisone and MTX on change in lumbar spine BMD (p=0.004)
·  Among patients not treated with corticosteroids (n=27), no difference in adjusted change in lumbar spine BMD between MTX and non-MTX patients
·  Adjusted change in lumbar spine BMD not significantly different between MTX and non-MTX patients receiving low dose corticosteroids (prednisone dose <5 mg/day); among patients taking ≥5 mg prednisone per day, MTX users lost significantly more BMD in the lumbar spine than non-MTX users
·  At 3 years, effects of low and high dose MTX not statistically significantly different (p=0.54) / ·  Not evaluated
Capell
[13] / 167 patients with RA <3 years / ·  2-year double-blind placebo controlled trial
·  Patients initiated on SSZ 500 mg/day (increased weekly by 500 mg/day to target dose of 40 mg/kg) and randomized to prednisolone 7 mg/day or placebo
·  Patients discontinuing SSZ offered an alternative DMARD / Primary Outcome: Radiographic damage assess by mTSS
Secondary Outcome: clinical benefit / ·  Radiology available in 64/83 patients on active prednisolone and 66/84 on placebo
·  Comparison of initial and 2-year mTSS in both placebo and prednisolone groups showed significant deterioration; no difference between the groups in total scores or in any other radiological variable examined
·  Improvement in clinical measures in both groups; year 1, 53% prednisolone treated patients showed a modified ACR20 response vs. 39% on placebo (p=0.07); year 2, 41% on prednisolone and 43% on placebo showed a modified ACR20 response
·  No significant difference between prednisolone or placebo groups in femoral neck and lumbar spine DEXA scores (p=0.315 and 0.215 respectively) / ·  Trend towards higher DBP in prednisolone group
·  Significant weight gain in prednisolone group in years 1 & 2 with associated increase in BMI; borderline weight change in placebo group at year 2
Choy
[33] / 467 RA Patients <2yr duration / ·  2-year randomized, double-blind, multi-center factorial trial
·  Group 1: open-label MTX (starting 7.5 mg/weekly, increasing incrementally to target dose of 15 mg/week)
·  Group 2: step-down prednisolone started with MTX (60 mg/day initially, reduced to 7.5 mg at 6 weeks, 7.5 mg daily from 6 to 28 weeks, stopped by 34 weeks)
·  Group 3: ciclosporin started 3 months after MTX (initial dose 100 mg/day, increased gradually to target dose of 3 mg/kg daily) / Primary outcome: Development of new erosions in x-rays of hands/feet
Secondary outcome: Changes in total Larsen score for x-ray damage, HAQ, SF36 (physical/mental) DAS28, AEs / ·  With MTX monotherapy, 29% developed new erosions
·  Logistic regression analysis showed reductions with prednisolone (OR 0.59 [95% CI 0.36,0.96] p=0.03) and ciclosporin (OR 0.54 [95% CI, 0.33,0.88] p=0.01)
·  Least new erosions seen with triple therapy (15 of 116, 13%)
·  Combining step-down prednisolone or ciclosporin with MTX reduced erosive damage in active early RA patients
·  Larsen scores increased most with MTX monotherapy; rate of increase declined with time; ciclosporin reduced progression throughout 2 year period; prednisolone showed rapid initial effect without a rebound increase after stopping steroid therapy
·  HAQ scores decreased with all treatments; SF-36 showed similar changes; disease activity fell in all groups / ·  Prednisolone resulted in hypertension (OR 2.16 [95% ci 1.07, 4.36]) and larger falls in hip DEXA scores (p=0.03)
·  Ciclosporin also resulted in hypertension (3.35; 1.57, 7.12)
Coluccia
[38] / 24 patients with RA / ·  Placebo controlled, double-blind crossover design clinical trial
·  Two groups: patients treated chronically (5.3 ± 1.0 years) with low to moderate doses of prednisone (7.5 ± 0.8 mg) or patients treated without glucocorticoids
·  Day 1, steroid group took daily prednisone dose and the nonsteroid group received 5 mg of prednisone; 1 hour later, patients presented a list of 60 words; tested for retention after 24 hours followed by an immediate recall test of 20 words / Memory function and hippocampal volume in patients treated chronically with low to moderate doses of prednisone or being treated without glucocorticoids / ·  Significant effect for delayed recall of acute prednisone administration but not chronic treatment; in the steroid group, no significant correlations of dose or duration of chronic prednisone treatment with memory performance under acute prednisone or placebo medication