Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review

Figures & data

Figure 1 Circadian rhythm of (A) pain measures in healthy subjects and of (B) stiffness, (C) pain levels, and (D) functional disabilities in rheumatoid arthritis patients.

Notes: Values are expressed as the mean and standard error of mean. Horizontal bars starting at 21.00 (9 pm) indicate sleeping time. Vertical dotted lines show the peak or minimum value for the respective parameter. Republished with permission of John Wiley and Sons Inc, from Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum. 2007;56(2):399–408; permission conveyed through Copyright Clearance Center, Inc.¹⁵

Figure 2 Circadian rhythm of (A) cortisol in healthy subjects (solid lines) and in patients with RA (dotted lines), and (B) in RA patients according to the degree of inflammation (high or low), as determined by ESR; 24-hour serum level variation of (C) TNF-α and (D) IL-6 in healthy donors (solid lines) and in RA patients (dotted lines).

Notes: Values are expressed as the mean and standard error of mean. Horizontal bars starting at 21.00 (9 pm) indicate sleeping time. Republished with permission of John Wiley and Sons Inc, from Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum. 2007;56(2):399–408; permission conveyed through Copyright Clearance Center, Inc.¹⁵
Abbreviations: ESR, erythrocyte sedimentation rate; IL-6, interleukin-6; RA, rheumatoid arthritis; TNF-α, tumor necrosis factor-α.

Table 1 Clinical trials comparing the efficacy of low-dose GCs (5–10 mg/d) in combination with DMARDs vs DMARDs alone, in patients with early RA (disease duration <1–2 years). Outcome measures are ordered based on the study primary and secondary objectives

Reference	Study design (duration)	Intervention	Sample size (disease duration)	Outcome measure	Results in the GC vs ctrl group
Boers et al^Citation24	RCT, MC, DB (80 wks)	• SSZ + MTX + prednisolone (tapered from 60 to 7.5 mg/d in 6 wks) • SSZ alone	N=155 (<2 yrs) • GC arm: 76 • Ctrl arm: 79	• Disease activity and physical function • Radiographic damage	• Rapid improvement, sustained up to wk 28, no longer significant after prednisone withdrawal; at wk 28, higher ACR20 (72% vs 49%, P=0.006) and ACR50 response rate (49% vs 27%, P=0.007) • Significantly slower progression at wk 28, persisting after prednisone withdrawal up to 5 yrs^Citation51
Svensson et al^Citation25	RCT, MC, OL (2 yrs)	• DMARDs + prednisolone (7.5 mg/d) • DMARDs alone	N=250 (≤1 yr) • GC arm: 119 • Ctrl arm: 131	• Radiographic damage • Disease activity and functional disability and impairment • Bone mineral density	• Significantly less change already at 1 yr, lasting up to 2 yrs. Significantly less newly eroded joints at 1 yr and 2 yrs • Significant improvement already at month 3 by DAS28, HAQ, and SOFI, persisting throughout the study period; significantly higher remission rate at 2 yrs (55.5% vs 32.8%, P=0.0005); significantly lower CRP level at 3–6 months • Similar bone loss
Wassenberg et al^Citation26	RCT, MC, DB (2 yrs)	• DMARDs + prednisolone (5 mg/d) • DMARDs + placebo	N=186 (<2 yrs) • GC arm: 80 • Ctrl arm: 86	• Radiographic damage • Clinical and functional outcomes, and remission rate	• Significantly less progression by Ratingen score and SHS already at month 6 and up to month 24; lower % of eroded joints only at 6 months • Trend to higher overall improvement, but without between-group statistical significance
Todoerti et al^Citation27	RCT, SC, OL (2 yrs)	• Step-up DMARDs + prednisone (12.5 mg/d for 2 wks, tapered to 6.25 mg/d) • Step-up DMARDs	N=210 (<1 yr) • GC arm: 105 • Ctrl arm: 105	• Clinical remission	• Significantly higher remission rate after 2 months (25.5% vs 8%, P=0.001); significantly higher probability of being in remission within 1 yr (OR: 1.965, 95% CI: 1.214–3.182, P=0.006) and up to 18 months (OR: 4.48, 95% CI: 1.35–14.82, P=0.014)
Bakker et al^Citation28	RCT, MC, DB (2 yrs)	• MTX-based tight control strategy + prednisone (10 mg/d) • MTX-based tight control strategy + placebo	N=236 (<1 yr) • GC arm: 117 • Ctrl arm: 119	• Erosive joint damage • Disease activity	• Limited and significantly lower at 2 yrs • More rapid improvement (already at month 3) of DAS28, ESR, VAS pain, and HAQ, yet not sustained over time; higher ACR50 response rate at 1 yr (56% vs 43%, P=0.037) and ACR70 at 2 yrs (38% vs 19%, P=0.002); shorter time to sustained remission (6 vs 11 months, P<0.001); reduced need for additional treatments (22% vs 50% of pts, P<0.001) and lower mean maximum MTX dose (19.7±6.1 vs 23.4±4.5 mg/wk, P<0.001)
Montecucco et al^Citation29	RCT, MC, OL (1 yr)	• Step-up MTX + prednisone (6.25 mg/d) • Step-up MTX	N=220 (<1 yr) • GC arm: 110 • Ctrl arm: 110	• Disease activity • Subclinical synovitis	• Significantly higher clinical remission rate at 1 yr (44.8% vs 27.8%, P=0.02); rapid (already at month 2) improvement of pain, DAS28, and number of swollen joints, although not sustained over time; rapid (from month 2) and persistent control of ESR and CRP serum levels • Significantly higher rate of PD negativity (69.8% vs 53.3% of pts, P=0.04)

Abbreviations: ACR20, ≥20% improvement according to the American College of Rheumatology criteria; ACR50, ≥50% improvement according to the ACR criteria; ACR70, ≥70% improvement according to the ACR criteria; CI, confidence interval; CRP, C-reactive protein; ctrl, control; DAS28, disease activity score in 28 joints; DB, double blind; DMARDs, disease-modifying antirheumatic drugs; ESR, erythrocyte sedimentation rate; GC, glucocorticoid; HAQ, health assessment questionnaire; MC, multicenter; MTX, methotrexate; OL, open label; OR, odds ratio; pts, patients; PD, power Doppler; RCT, randomized controlled trial; SC, single center; SHS, Sharp-van der Heijde score; SOFI, signals of functional impairment; SSZ, sulfasalazine; VAS, visual analog scale; wks, weeks; yrs, years.

Figure 3 Reduction of clinical symptoms and serum interleukin-6 (IL-6) levels after nighttime (2 am) and morning (7.30 am) administration of 5.0–7.5 mg of prednisolone for five consecutive days in two groups of RA patients (n=13 in each group).

Notes: Baseline characteristics of the two groups treated with prednisolone were similar. Values are expressed as the mean and standard error of mean decrease in each variable. Republished with permission of John Wiley and Sons Inc, from Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum. 2007;56(2):399–408; permission conveyed through Copyright Clearance Center, Inc.¹⁵
Abbreviations: RA, rheumatoid arthritis; VAS, visual analog scale.

Figure 4 Pharmacokinetics of conventional and modified-release (MR) prednisone.

Notes: MR-prednisone was measured after a light meal at 17.30 or dinner at 19.30. Alten R. Chronotherapy with modified-release prednisone in patients with rheumatoid arthritis. Expert Review of Clinical Immunology. 2012;8(2):123–133, reprinted by permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com).⁸¹
Abbreviations: IL-6, interleukin-6; MR, modified-release; VAS, visual analog scale.

Table 2 Integrated analysis of adverse events occurring in ≥2% of patients with rheumatoid arthritis, after 12 weeks of therapy with placebo, MR prednisone, or IR prednisone (≤5 mg/d vs >5 mg/d) in the CAPRA studies

Parameter	Placebo	MR prednisone			Conventional IR prednisone
	N=119	≤5 mg/d N=313	>5 mg/d N=62	Total N=375	≤5 mg/d N=76	>5 mg/d N=68	Total N=144
Daily dose, mg (mean ± SD)	NA	4.86±0.37	8.45±1.49	5.46±1.50	4.93±0.34	8.59±1.48	6.66±2.11
Any adverse event, %	48.7	43.1	35.5	41.9	42.1	36.8	39.6
Severity, %
Mild	29.4	20.4	8.1	18.4	18.4	16.2	17.4
Moderate	15.1	20.8	22.6	21.1	19.7	19.1	19.4
Severe	4.2	1.9	4.8	2.4	3.9	1.5	2.8
Preferred term, %
Gastrointestinal disorders
Abdominal pain (upper)	1.7	1.6	1.6	1.6	7.9	2.9	5.6
Diarrhea	0.8	1.3	0	1.1	2.6	2.9	2.8
Nausea	0	2.2	1.6	2.1	2.6	2.9	2.8
Dyspepsia	0	0.6	1.6	0.8	0	4.4	2.1
Infections and infestations
Nasopharyngitis	3.4	4.8	1.6	4.3	6.6	4.4	5.6
Bronchitis	4.2	1.0	3.2	1.3	3.9	2.9	3.5
URTI	0.8	0.6	0	0.5	0	4.4	2.1
Musculoskeletal and connective tissue disorders
Aggravated RA/RA flare	26.1	14.4	4.8	12.8a	11.8	7.4	9.7
Ear and labyrinth disorders
Vertigo	0	1.3	0	1.1	3.9	2.9	3.5
Nervous system disorders
Headache	4.2	4.5	1.6	4.0	3.9	2.0	3.5
General disorders and administration-site conditions
Chest pain	0	0.3	1.6	0.5	2.6	1.5	2.1

Notes:

a P=0.0137 between the placebo and the MR-prednisone groups. All other comparisons are not significant. Republished with permission of John Wiley and Sons Inc, from Buttgereit F, Szechinski J, Doering G, et al. Integrated safety summary of modified-release prednisone and immediate-release prednisone com paring doses <5 mg/day versus >5 mg/day. Arthritis and Rheumatism. 2011;63(1):S475; permission conveyed through Copyright Clearance Center, Inc.⁸²

Abbreviations: CAPRA, circadian administration of prednisone in rheumatoid arthritis; IR, immediate-release; MR, modified-release; NA, not applicable; RA, rheumatoid arthritis; SD, standard deviation; URTI, upper respiratory tract infection.

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