Efficacy and safety of modified-release prednisone in patients with rheumatoid arthritis

Figures & data

Figure 1 Chart showing the circadian rhythm of cortisol production as well as levels of IL-6 in RA patients.

Notes: Chart showing the circadian rhythm of cortisol production as well as levels of IL-6 in RA patients. The optimal time frame for prednisone application is indicated by the two arrows. Since this nocturnal medication is impractical, the formulation of MR-prednisone with a time-delayed release of the acting agent was developed. Adapted with permission from © 2007 by the American College of Rheumatology. Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum. 2007;56(2):399–408.²²
Abbreviations: IL-6, interleukin 6; MR, modified-release; RA, rheumatoid arthritis.

Figure 2 Simplified diagram showing ingestion, liberation, and way of action of modified-release prednisone.

Notes: Shown are ingestion, liberation, and way of action of modified-release prednisone in a simplified manner. The coating (1), displayed here in light gray, bursts approximately 4 hours after ingestion due to water penetration³⁶ and releases the acting prednisone (blue) (2). As a lipophilic hormone, it is able to freely pass the plasma membrane. When reaching the cytosol, it binds (3) to the cytosolic glucocorticoid receptor (cGCR; orange), forming a complex and translocates into the nucleus. Within the nucleus, the complex either binds (4) to glucocorticoid response elements (GREs; yellow) as a dimer which in turn leads to increased production (green) of anti-inflammatory proteins, such as Annexin A1 (right side), or interferes negatively with transcription factors (TF; gray), resulting in a suppression (red) of pro-inflammatory proteins, such as interleukin 6 (IL-6) (left side). The also proposed nongenomic effects are not shown for reasons of clarity and comprehensibility.

Table 1 Details of the most important clinical trials or evaluations of trial data on MR prednisone so far

	CAPRA-1^Citation36	CAPRA-1 OLE^Citation39	CAPRA-2^Citation38	Observational study^Citation40	IR-MR CAPRA-1^Citation57
Investigator Year	Buttgereit et al 2008	Buttgereit et al 2010	Buttgereit et al 2012	Cutolo et al 2013	Alten et al 2015
Study design	Double-dummy placebo-controlled, randomized, multicenter study	Open-label	Double-blind, placebo-controlled, multicenter study	Open-label, multicenter, longitudinal observational study	Secondary analysis of CAPRA-1 data
Primary endpoint	Relative change in morning stiffness duration (MR vs IR)	See CAPRA-1; OLE was designed to prove sustained effectiveness of MR prednisone	Percentage of patients achieving an ACR20 response (MR vs placebo)	Reduction of morning stiffness duration after switching from IR or 6M-prednisolone to MR prednisone	Absolute and relative duration of morning stiffness in patients who switched to MR after an ineffective course of IR within CAPRA-1
Study duration	12 weeks^Citation36 +9 months OLE^Citation39,Citation57	9 months after CAPRA-1	12 weeks	16 weeks	9 months after CAPRA-1
n	144 MR vs 144 IR	249 with n=129 switching from IR	231 MR vs 119 placebo	437 6M-prednisolone → MR and 513 IR → MR	110 IR → MR
RA diagnosis	ACR 1987	ACR 1987	Not further specified	Not further specified	ACR 1987
Prednisone dose	3–10 mg/day; 84% 5 mg or less	6.4 mg/day	5 mg/day	6.7 mg (6M-prednisolone) and 9.4 (IR)/day	3–10 mg/day, stable
Existing treatment	DMARDs $3 months, no biologics within 4 months prior to inclusion, all patients already using IR prednisone	See CAPRA-1	DMARDs $6 months, no IR prednisone at BL	Any DMARDs allowed, no time frames defined	Stable DMARD treatment
Morning stiffness	−22.7% vs −0.4% relative change; P=0.045a	3 months: −56 (MR/MR) vs −54% (IR/MR) 6 months: −61 (MR/MR) vs −49% (IR/MR) 9 months: −55 (MR/MR) vs −45% (IR/MR)	−55% vs −35% median relative change; P<0.004	6M-prednisolone: 67 (BL) vs 37 minutes (w16); P<0.001 IR: 50 (BL) vs 27 minutes (w16); P<0.001 All patients: 58 (BL) vs 32 minutes (w16); P<0.001a	50 minutes absolute reduction after 3 months, >40% relative reduction at each visit (3, 6, 9 months); P<0.001
IL-6 levels	−28.6% vs 0.0% relative change (median); P=0.0322	NA	NS	NA	−53% relative change (median) from BL to 9 months
DAS28	−0.53 vs −0.75; NS (ΔDAS28)	5.8 vs 4.8 (MR/MR), P<0.05 5.9 vs 4.9 (IR/MR), P<0.05	−1.15 vs −0.63; P<0.001 (ΔDAS28)	6M-prednisolone: 4.1 (BL) vs 3.2 (w16); NS IR: 4.2 (BL) vs 3.3 (w16); NS all patients: 4.2 (BL) vs 3.3 (w16); P<0.001	No significant change
HAQ-DI	−0.07 vs −0.09; NS	NA	−0.238 vs −0.079; P<0.001	NA	NA
SF36
– Physical	19.43% vs 21%; NS	NA	3.6 vs 1.3; P<0.001	NA	NA
– Mental	10.63% vs 18.08%; NS	NA	2.0 vs 0.9; NS	NA	NA
FACIT-F	NA	NA	3.8 vs 1.6; P=0.003	NA	NA
ACR20 response (week 12)	NA	NA	48% vs 29%; P<0.001a	NA	NA
ACR50 response (week 12)	NA	NA	22% vs 10%; P<0.006	NA	NA
ACR70 response (week 12)	NA	NA	7% vs 3%; NS	NA	NA
Any AEs	41% vs 41%	51% (all patients in OLE)	42.9% vs 48.7%	NA	See CAPRA-1
Treatment-related AEs	13% vs 11%	5.2% (all patients in OLE)	7.8% vs 8.4%	NA	See CAPRA-1
SAEs	3% vs 2%	NA	0.4% vs 1.7%	NA	See CAPRA-1

Notes: All values given are mean values unless stated otherwise. The first mentioned value always refers to the MR prednisone group, if applicable. Significance levels as indicated – missing values mean there was no significance given from the authors.

a Primary endpoint.

Abbreviations: 6M-prednisolone, 6-methyl-prednisolone; ACR, American College of Rheumatology; AE, adverse event; BL, baseline; CAPRA, Circadian Administration of Prednisone in Rheumatoid Arthritis; DAS28, Disease Activity Score 28 joints; DMARD, disease-modifying antirheumatic drugs; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI, Health Assessment Questionnaire Disability Index; IL, interleukin; IR, immediate-release prednisone; MR, modified-release prednisone; NA, not applicable; NS, not significant; OLE, open-label extension; RA, rheumatoid arthritis; SAE, serious adverse event; SF36, Short-Form 36; w16, week 16.

Table 2 AEs reported in the clinical trials comparing MR prednisone with IR prednisone and placebo, respectively^36,38,39

AE	MR (%)	IR (%)*	Placebo (%)‡
Arthralgia	1*−10.4‡	2	20.2
RA flare	6.5‡−8*	9	9.2
Abdominal pain	4*	6	–
Nasopharyngitis	3*−4.8‡	6	3.4
Headache	3.9‡−4*	3	4.2
Flush	3*	4	–
Weight increase	2.4^≤	–	–
Hypertension	2*−2.2‡	2	0.8
Chest pain	2*	2	–
Nausea/vomiting	1.3‡−4*	3	0.8
Diarrhea	1.7‡	–	0.8
Rash	1.7‡	–	0.8
Gastritis	1.6^≤	–	–
Back pain	1.3‡	–	0.8
Bronchitis	1*−1.3‡	4	4.2
Vertigo	1*	3	–
Dyspepsia	1*	2	–
Upper respiratory tract infection	1*	2	–
Peripheral edema	0.9‡	–	1.7
Hematuria	0.4‡	–	2.5

Notes: All values represent percentage of patients in the distinct group experiencing the named AEs. Missing values indicate that the named AE did not occur. The according clinical trial is marked as follows:

* CAPRA-1;

‡ CAPRA-2;

# CAPRA-1 OLE.

Abbreviations: AE, adverse event; CAPRA, Circadian Administration of Prednisone in Rheumatoid Arthritis; IR, immediate-release prednisone; MR, modified-release prednisone; OLE, open-label extension; RA, rheumatoid arthritis.

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