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Improvement thresholds for morning stiffness duration in patients receiving delayed-versus immediate-release prednisone for rheumatoid arthritis.

The patient-reported symptom of morning stiffness is a cause of morbidity and productivity loss for patients with rheumatoid arthritis (RA), including patients with early disease as well as those with low disease activity or in remission. (1-4) As an example, at least some degree of morning stiffness has been reported by approximately 50% of the patients with a disease activity score (DAS28) of less than or equal to 3.2 and 25% of those in DAS28 remission. (3)

Morning stiffness greater than 1 hour in duration has been reported to occur in 24% of patients with long-standing RA (11 years' disease duration) and in 49% with early RA (less than 2 years' disease duration). (3,4) A study that quantified patients' willingness to pay for a reduction in morning stiffness found that complete elimination of morning stiffness was worth 21.74 [euro] or $30.29/day and reducing the duration by 50% was worth 10.63 [euro] or $14.81/day in patients with morning stiffness lasting greater than or equal to 1 hour; willingness to pay for these reductions doubled in patients with severe symptoms. (5) These data demonstrate the ubiquity of morning stiffness in RA patients at all stages and that they ascribe a high value to reducing it.

Furthermore, morning stiffness is a strong predictor of functional disability, and the negative effects of morning stiffness, such as delayed or impaired ability to perform normal morning activities, contribute to a poor quality of life. (4,6,7) In a sample of 750 patients with RA from 11 European countries, 75% reported impaired quality of life associated with morning joint stiffness. (6) Severe morning stiffness also is a strong predictor of early retirement. (8) Morning impairment has been reported to result in 4.5 working days lost per employed person during the previous 6 months. (6) For patients who retired early, were on leave, or were unemployed, 73% cited their RA as the reason they were unable to work. (6) In a time-trade-off validation approach, an United Kingdom population-based study of the relationship between health utility and duration of morning stiffness reported that reductions in morning stiffness from 3 hours to less than 1 hour (66%) were associated with incremental improvements in health-related quality of life. (7)

Disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids are a mainstay of treatment for RA because they exert a combination of anti-inflammatory and immunosuppressive effects, which can result in reducing disease progression, particularly in a treat-to-target approach. (9-13) Evidence from observational data and systematic reviews suggests that patients with RA can be safely and effectively treated with long-term use of low-dose prednisone (5 to 7.5 mg/day) in combination with conventional DMARDs. (14) Systematic reviews and the prospective randomized controlled CAMERA-II (Computer-Assisted Management in Early Rheumatoid Arthritis) study have confirmed the added benefit of low-dose glucocorticoid therapy for limiting pro gressive joint damage. (9,11) In addition, glucocorticoid use for the treatment of RA is currently endorsed by the National Institute for Health and Care Excellence (NICE) and the European League Against Rheumatism (EULAR). (15-18) The most recent EULAR guidelines recommend that low-dose glucocorticoids should be considered as part of the initial treatment strategy (in combination with one or more conventional synthetic DMARDs) for up to 6 months but should be tapered as rapidly as clinically feasible. (17) Given the potential safety concerns with long-term use of high-dose glucocorticoids, it is important to note that doses appear to be declining over time. (11,19,20) Despite the early use of traditional DMARDs and prednisone, as well as biologics, a considerable proportion of patients continue to experience morning symptoms likely indicative of uncontrolled pro-inflammatory cytokine activity. (2)

The early morning symptoms of RA follow a circadian pattern, with the severity correlating with elevated concentrations of pro-inflammatory cytokines, particularly interleukin-6 (IL-6). (21-22) Hypothalamus-pituitary-adrenal (HPA) axis function and endogenous cortisol production in patients with RA is often inadequate to mitigate this nocturnal increase in inflammation resulting in the typical clinical feature of peak joint symptoms in the morning. (22-24) The importance of timing the glucocorticoid dose with respect to the circadian pattern of both the inflammatory mediators and the natural secretion of glucocorticoids has been recognized in EULAR guidelines. (25) Delayed-release (DR) or modified-release prednisone, taken at bedtime, is formulated to enable timed delivery of prednisone during the early morning, which augments endogenous cortisol and thereby aims to target the inflammatory circadian pattern of the disease (Fig. 1). (26) This delivery matches the optimal administration time, which is at the maximal activity of the adrenal cortex (2 a.m. to 8 a.m.), and when the HPA axis is less likely to be disturbed. (24,26) When given at 10 p.m., prednisone from DR-prednisone will be released at approximately 2 a.m. and peak around 4 a.m. (24,26)

The safety and efficacy, including clinically relevant reduction of morning stiffness, of low-dose DR-prednisone in patients with active RA receiving DMARD therapy have been demonstrated versus conventional immediate-release (IR) prednisone in the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) trial (27,28) and versus placebo in the CAPRA-2 trial. (29) Early-morning cytokines were also reduced with DR-prednisone, and treatment with DR-prednisone was not more detrimental to adrenocortical function than treatment with conventional prednisone. (24)

There are no well-established treatment targets for the reduction of morning stiffness in RA patients. Chronic pain threshold models have indicated previously that response rates of 15% to 30% indicate minimally important relief, 40% to 50% indicate substantial pain relief, and greater than 70% indicate extensive pain relief. (30) The objective of the present analysis was to assess differences in the percentages of patients achieving 25% (minimally important change), 50% (substantial change), and 75% (extensive change) thresholds of reduction in the duration of patient-reported morning stiffness between patients receiving DR- and IR-prednisone in the double-blind portion of the CAPRA-1 trial (27) and those switched from IR-prednisone to DR-prednisone in the open-label extension. (28) In addition, we assessed time to achievement of these improvement thresholds.

Materials and Methods

Study Design and Patient Population

The full study design (inclusion and exclusion criteria; blinding procedures; statistical methodology), safety, primary efficacy, and secondary efficacy results of the CAPRA-1 (NCT00146640) trial have been published previously. (27,28) Briefly, CAPRA-1 was a 12-week double-blind, controlled trial in which patients with active RA were randomized to receive either low dose IR-prednisone upon awakening (traditional dosing) or low dose DR-prednisone before bedtime along with established DMARD therapy. (27) During a 9-month open-label extension phase, patients randomized to IR-prednisone were switched to an equivalent dose of DR-prednisone. (28) Eligible patients had morning stiffness of at least 45 minutes duration and were receiving stable low-dose glucocorticoid therapy for greater than or equal to 3 months (2.5 mg to 10 mg prednisone equivalent) and stable DMARD therapy for greater than or equal to 1 month with no biologic therapy in the prior 4 months. The primary outcome was change in duration (in minutes) of morning stiffness from baseline. National and local administrative bodies and ethics committees approved the study protocol; all patients provided written informed consent before initiation of any study procedures.

Daily Diaries

Patients completed daily diary entries throughout both the double-blind and open-label extension phases of the study; patients were asked to complete diary entries on a daily basis and during the double-blind phase and at least 7 days prior to each of the 3-month visits during the open-label extension phase. Patients were asked to record their awakening time, whether they had stiffness (yes/no) upon awakening; and time of resolution of morning stiffness of the joints, and quality of sleep (100 mm VAS: 0 = very good, 100 = very bad). In the evening, they recorded the maximum intensity of pain that they had had during the day, retrospectively summing up any repeated episodes and giving the rating for the most severe one (100 mm VAS: 0 = no pain, 100 = very intensive pain).

Data Analysis

This analysis included all patient recorded diary data and was conducted on a modified intent-to-treat efficacy population defined as patients who entered the open-label extension phase of the study and had at least one diary entry at baseline and at least one morning stiffness measurement during the open-label extension. Using this criteria, this analysis included a higher number of diary entries per patient than the primary dataset used in CAPRA-1. Morning stiffness threshold response categories were defined by 25%, 50%, and 75% improvement in morning stiffness duration from baseline; response categories were not mutually exclusive. Diary entries from 4 weeks prior and after each scheduled visit were analyzed over 1 year for calculation of morning stiffness threshold response rates. P-values were calculated from chi-square tests for treatment differences in the categorical response thresholds during the double-blind phase. Kaplan-Meier estimates were computed using a Cox proportional model for differences in time to achievement of the categorical response thresholds during the open-label extension phase. Statistical significance was set at p < 0.05.


Patient Sample

In the original CAPRA-1 study, 288 patients were enrolled (144 DR-prednisone, 144 IR-prednisone), 249 patients entered the open-label extension phase; 120 continued on DR-prednisone, and 129 switched from IR-prednisone to DR-prednisone. (28) The population for this analysis, which minimally required diary data at baseline and greater than or equal to 1 post-baseline visit (between 9 and 12 months), consisted of 97 patients who received continuous DR-prednisone and 110 who were switched from IR- to DR-prednisone, representing 81% and 85% of the evaluable original population, respectively. Demographics and baseline disease characteristics were well balanced between the analysis groups and the original randomized group, both for the double-blind phase and the open-label extension phase (Table 1).

Percentages of Patients Achieving Morning Stiffness Threshold Improvements

Approximately three-quarters of patients in the DR-prednisone arm achieved at least a 25% reduction in duration of morning stiffness from baseline compared with approximately two-thirds in the IR-prednisone arm (p = 0.05) (Fig. 2A). Significantly more patients who received DR-prednisone achieved the 50% (57% for DR-prednisone versus 41% for IR-prednisone; p = 0.02) and 75% (38% for DR-prednisone versus 26% for IR-prednisone; P < 0.05) response thresholds at week 12 compared with patients who received IR-prednisone (Fig. 2 B and C). For all three response categories, the separation between the DR- and IR-prednisone groups started after 1 week of therapy.

Time to Morning Stiffness Thresholds

Of patients who achieved 25%, 50%, or 75% response in the double-blind phase, it took significantly longer for the IR-prednisone group to achieve the respective level of response compared with the continuous DR-prednisone group (Figs. 3 and 4). The IR-prednisone group, after switching to DR-prednisone, had comparable responses in all categories and significantly shorter time to all response categories when compared with patients already receiving DR-prednisone (all p < 0.008) (Fig. 4 A, B, and C). Within 3 months after switching to DR-prednisone in the open-label extension phase, patients initially treated with IR-prednisone had response rates comparable to patients treated with continuous DR-prednisone for each level of morning stiffness threshold (Fig. 3). The continuous DR-prednisone group had reached the equivalent responses in the double-blind phase and maintained responses in the open-label extension phase; thus, the IR-prednisone patients who switched to DR-prednisone essentially caught up to the continuous DR-prednisone group (Fig. 3). With the beginning of double-blind study as baseline, time to reach the 25%, 50%, and 75% morning stiffness thresholds at the end of the open-label study was equivalent between treatments (Fig. 4). For the IR-prednisone group, the switch to DR-prednisone in the open-label extension phase compensated for the delayed time to reach these thresholds during the double-blind phase.


Prednisone mean dosage remained the same throughout the study and did not differ between any of the comparison groups, before or after the switch (Table 1). Roughly equal number of patients were on less than or equal to 5 mg (55%) and greater than 5 mg (45%) per day of prednisone.

Sensitivity Analysis

A sensitivity analysis was completed to determine if the overall evaluable population in the 9-month double-blind portion of the CAPRA-1 study was similar to the 12-month completer analysis regarding percentage of threshold responders and time to response with DR-prednisone as compared with IR-prednisone. During the 12-week double-blind evaluation of threshold responses, there were significant differences (p < 0.05) from week 1 to week 11 in attainment of minimally important change (25% threshold) and statistically significant differences in all categories of response (25%, 50%, or 75%) at week 10 (p < 0.05). At weeks 11 and 12, DR-prednisone produced either significantly higher or a trend toward higher percentages of patients reaching each threshold response. By week 12, there were 9% (p = 0.13), 13% (p = 0.04), and 10.2% (p = 0.07) higher numbers of patients receiving DR-prednisone reaching the 25%, 50%, and 75% thresholds, respectively. Time to response (Kaplan-Meier analysis) in the 25%, 50%, and 75% threshold categories similarly favored earlier attainment with DR-prednisone as compared with IR-prednisone hazard ratios of 1.34 (p = 0.0638), 1.52 (p = 0.0278), and 1.56 (p = 0.0597), respectively.

Safety and Adverse Events

Patients were exposed for a mean of 256.3 [+ or -] 53.43 days, with a mean of 6.6 mg of prednisone equivalent per day. Adverse events (AEs) were observed in 127/249 (51%) of the patients regardless of causality assessment. Adverse events rated as being possibly related to study medication with a frequency of greater than 7.0% in the total study population were musculoskeletal (N = 27, 10.8%), infections (N = 26, 10.4%), gastrointestinal (N = 18, 7.2%), and RA related (N = 18, 7.2%).

Thirty patients (12%) discontinued treatment during the open-label extension. Twelve patients discontinued for AEs with six (50%) due to reports of RA. Other reasons for discontinuation were infection (N = 5), gastrointestinal (GI) tract disorders (N = 3) and pregnancy (N = 2).

A total of 51 serious AEs were reported by 13% (33/249) of patients in the open-label study regardless of causality assignment. Only 4% (2/51) of serious events (gastric ulcer perforation and gastrointestinal haemorrhage) were judged as possibly related to study drug. Other serious events, not considered related to study therapy, were bone fractures (three patients) and tendon rupture (one patient). (28)

When examining the number of treatment related events reported by dose ([less than or equal to] 5 mg versus > 5 mg), the greater than 5 mg group reported a smaller number of overall AEs (24.8% versus 40.4%).


Because of their anti-inflammatory, immunosuppressive, and disease-modifying effects, glucocorticoids (GCs) are useful in managing the inflammatory processes of RA. However, there are safety concerns about higher doses of GCs ([greater than or equal to] 10 mg/day), especially over the long term (24); data from observational studies and systematic reviews support the use of low-dose prednisone (5.0 mg/day to 7.5 mg/day) with disease-modifying antirheumatic drugs (DMARDs) in patients with RA to reduce disease progression, especially early in diagnosis. (69,11,19)

Our relatively short duration of follow-up (9 months) in patients naive to biologics support the overall safety of low dose prednisone use. Actually, the number of treatment related events were more common in patients with doses less than or equal to 5 mg. This appeared to be related to a higher number of musculoskeletal and connective tissue disorder AEs reported in the less than or equal to 5 mg group (15% versus 6%), which was responsible for 40% of the total related events in the less than or equal to 5 mg group. The total number of RA related events was also higher in the less than or equal to 5 mg group (11% versus 3%). Excluding the musculoskeletal and RA complaints, other treatment emergent adverse events were similar between the two dosage groups. The median doses in both groups were not significantly different (slightly under 5 mg versus slightly under 8 mg) and in alignment with recommended ranges for low dose glucocorticoid use.

The optimal care of patients with RA includes treatments that improve both disease activity and quality of life. (31) DR prednisone plus DMARD therapy has also shown improvements in many patient reported outcomes. For example, analyses from the 12-week CAPRA-2 study (29) have indicated that when compared with placebo/DMARD treatment, fatigue (FACIT-F), SF-36 vitality, physical component SF36, and general scores with FACT-G were all significantly improved. (32) Furthermore, in addition to significant improvements in morning stiffness, reoccurrence of joint stiffness during the day was significantly reduced as well. (33)

Despite awareness of the impairment associated with morning joint stiffness in RA, current clinical practice indicates that both patients and rheumatologists consider morning stiffness inadequately treated and current pharmacologic options limited. (34-36) Ironically, although morning stiffness is recognized by RA patients as being one of the four most significant symptoms to manage, validated morning stiffness patient-reported outcome (PRO) measures are lacking. (35) Moreover, such data indicate that development of PROs that can be used to assess this treatment benefit in patients with RA are particularly important. (37)

Previously, a health-state study of differing levels of change in the duration of morning stiffness found that a 1-hour improvement was clinically meaningful and would translate into statistically significant improvements in patients' quality of life. (7) In our study, improvements of 50% and 75% with DR-prednisone easily meet the 1-hour improvement criterion in this RA cohort, and the 25% response rate was associated with improvement of at least 40 minutes.

Given that traditional disease measures do not appear to reflect or represent changes in morning stiffness, there remain countervailing incentives to integrate morning stiffness observations or measures into current and future treatment recommendations Treatments that improve the dysfunction associated with morning stiffness have the potential not only to improve patient quality of life and general well-being but also to yield substantial economic benefits in terms of decreased indirect costs associated with greater work productivity and remaining in the workforce longer. (35)

Morning stiffness is a relatively easy-to-assess PRO that can be evaluated in the clinic without laboratory tests or calculation of complicated composite scores. Although it remains an important PRO, measurement of morning stiffness in clinical trials has declined because of variation and lack of standardization. (2,37) However, in a study assessing which variables best predict a change in DMARD therapy for RA in daily clinical practice, morning stiffness was weighted second behind only swollen joint count. (38) Although morning stiffness is a stronger predictor of functional disability in patients with early RA than joint symptoms or standard biomarkers, such as erythrocyte sedimentation rate (4), and is one of the four key PROs in RA, (37) it is not currently a component of the American College of Rheumatology (ACR)/EULAR preliminary remission definition. (2,39-42) It is included in the ACR/EULAR core set of endpoints and the Comprehensive International Classification of Functioning, Disability, and Health (ICF) framework for PROs in clinical trials. (37) Nevertheless, evaluation of clinically relevant morning stiffness threshold response rates, which have not been characterized previously, could complement ACR/ EULAR criteria for determining treatment effectiveness and functional improvement from the patients' perspective, particularly because morning stiffness and disease activity, as currently measured, have not been reported to strongly correlate. (1-4) Recently, a more quantitative electrophysiological way of measuring morning stiffness has been proposed using grip strength as well as premotor response and reaction times, which have demonstrated moderate to good correlations with both duration and severity of morning stiffness, DAS28, and measures of quality of life such as pain VAS and Health Assessment Questionnaire (HAQ). (43)

In the present analysis, more patients who took the DR-formulation achieved threshold reductions in morning stiffness as compared with patients who took a conventional IR-prednisone dose in the morning. These improvements also were achieved more rapidly with the DR-prednisone formulation. Morning stiffness threshold responses for patients who were switched from IR- to DR-prednisone essentially "caught up" and were comparable to those who received continuous DR-prednisone after 3 months. Therefore, DR-prednisone, which targets the pathophysiological circadian chronobiology in RA patients, contributes to clinically meaningful improved morning symptoms associated with RA when given to patients on stable DMARD therapy versus traditionally administered IR-prednisone. (24,27) Furthermore, the changes produced by DR-prednisone have been reported previously to be associated with quality of life improvements, such as a reduction in fatigue, (44,45) significant changes in inflammatory cytokines (IL-6), (27) and may be cost-effective compared with IR-prednisone. (46,47)

Finally, as minimal clinically important differences in morning stiffness threshold response rates have not been defined previously, we propose that 25% (minimally important), 50% (substantial), and 75% (extensive) responses represent important thresholds and that these data provide a foundation for future studies to validate the clinical importance of morning stiffness and identify predictors of objective measures of response. Such validation could justify greater use of this important PRO in clinical trials, as well as inclusion of this endpoint in other composite disease activity and response criteria scores. However, as concluded in a recent article reviewing the effect of therapy from the perspective of patients with RA, a paradox exists between interest in establishing the validity and clinical relevance of key patient-reported measures, such as morning stiffness, and the infrequent use of these measures as outcomes in intervention studies, precisely because they are not validated. (37)

The present study has determined, in a unique design, both the morning stiffness threshold response rate and the time-to-event of two active RA treatment regimens and demonstrated significant differences between them in a double-blind controlled fashion over 12 weeks. Further, we examined the significance and time-to-event of these thresholds in an open-label switch-analysis for an additional 9 months. To our knowledge, the present study is the first to assess time-to-event and percentage threshold responses for the reduction of morning stiffness in patients with RA and propose clinically meaningful response rates.

Limitations of the analysis include that the 9-month observation period following patients' switch from IR- to DR-prednisone was uncontrolled and that the time-to-event analysis population included only completers who entered the open-label extension phase of the study. However, the study design offers a unique opportunity to follow the patients who switched therapies, and an intent-to-treat analysis of the 9-month double-blind portion of the CAPRA-1 study indicated that the results were directionally compatible with the 12-month completer analysis. The population for this analysis was almost exclusively Caucasian and the results may not be applicable to other populations. Strengths of the analysis were the robust collection of patient-reported diary data, in which all morning stiffness diary entries within 4 weeks of the scheduled visits were captured and the real world analysis of switching therapies in the clinical setting.

In conclusion, DR-prednisone produced significantly higher morning stiffness response rates as defined by 25%, 50%, or 75% improvement thresholds compared with IR-prednisone in patients with RA. Moreover, patients who received DR-prednisone reached these thresholds sooner than those who received IR-prednisone. Patients who switched from IR-prednisone to DR-prednisone in the open-label extension achieved response thresholds quickly, and rates were comparable to those who received continuous DR-prednisone after 3 months. Patients treated with DR-prednisone maintained their morning stiffness responses with no evidence of tachyphylaxis for up to 1 year.

Disclosure Statement

This research was supported by Horizon Pharma, USA. Medical writing services were provided by Cathryn M. Carter, M.S., of Arbor Communications, Inc. Frank Buttgereit, M.D., received consultancy fees, honoraria, and travel expenses from Merck Serono, Horizon Pharma (formerly Nitec Pharma), and Mundipharma International Ltd, and grant support from Merck Serono and Horizon Pharma. Jeffrey D. Kent, M.D., and Amy Y. Grahn, M.S., are employed by Horizon Pharma, Inc., Deerfield, Illinois. Robert J. Holt, Pharm.D., M.B.A., has received consulting fees from Horizon Pharma, Inc. Patricia Rice, M.S., has received payment from Horizon Pharma for statistical assessments. Rieke Alten, M.D., received consultancy fees, honoraria, and travel expenses from Merck Serono, Horizon Pharma (formerly Nitec Pharma), and Mundipharma International Ltd, and grant support from Merck Serono and Horizon Pharma. Yusuf Yazici, M.D., has received consulting fees from AbbVie, BMS, Celgene, Genentech, Janssen, and UCB. He has also received research support from AbbVie, Celgene, BMS, and Genentech.

Frank Buttgereit, M.D., Charite University Medicine, Berlin, Germany. Jeffrey D. Kent, M.D., and Amy Y Grahn, M.S., Horizon Pharma, Deerfield, Illinois. Robert J. Holt, Pharm.D., M.B.A., University of Illinois-Chicago, Vernon Hills, Illinois. Patricia Rice, M.S., Premier Research, Naperville, Illinois. Rieke Alten, M.D., Schlosspark-Klinik, Charite University Medicine, Berlin, Germany. Yusuf Yazici, M.D., New York University Hospital for Joint Diseases, New York, New York.

Correspondence: Robert J. Holt, PharmD, Adjunct Pro fessor, College of Pharmacy, University of Illinois-Chicago, 1721 North Woods Way, Vernon Hills, IL 60025;


(1.) van Tuyl LH, Lems WF, Boers M. Measurement of stiffness in patients with rheumatoid arthritis in low disease activity or remission: a systematic review. BMC Musculoskelet Disord. 2014 Jan 29; 15:28. doi: 10.1186/1471-2474-15-28.

(2.) Sierakowski S, Cutolo M. Morning symptoms in rheumatoid arthritis: a defining characteristic and marker of active disease. Scand J Rheumatol Suppl. 2011; 125:1-5.

(3.) Khan NA, Yazici Y, Calvo-Alen J, et al. Reevaluation of the role of duration of morning stiffness in the assessment of rheumatoid arthritis activity. J Rheumatol. 2009 Nov; 36(11):243542.

(4.) Yazici Y, Pincus T, Kautiainen H, Sokka T. Morning stiffness in patients with early rheumatoid arthritis is associated more strongly with functional disability than with joint swelling and erythrocyte sedimentation rate. J Rheumatol. 2004 Sept; 31(9):1723-6.

(5.) Tuominen R, Tuominen S, Mottonen T. How much is a reduction in morning stiffness worth to patients with rheumatoid arthritis? Scand J Rheumatol Suppl. 2011; 125:12-6.

(6.) da Silva JA, Phillips S, Buttgereit F. Impact of impaired morning function on the lives and well-being of patients with rheumatoid arthritis. Scand J Rheumatol Suppl. 2011; 125:6-11.

(7.) Iqbal I, Dasgupta B, Taylor P, et al. Elicitation of health state utilities associated with differing durations of morning stiffness in rheumatoid arthritis. J Med Econ. 2012 Aug; 15(6):1192-200.

(8.) Westhoff G, Buttgereit F, Gromnica-Ihle E, et al. Morning stiffness and its influence on early retirement in patients with recent onset rheumatoid arthritis. Rheumatology (Oxford). 2008 Jul; 47(7):980-4.

(9.) Bakker MF, Jacobs JW, Welsing PM, et al; Utrecht Rheumatoid Arthritis Cohort Study Group. Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2012 Mar; 156(5):329-39.

(10.) Buttgereit F. A fresh look at glucocorticoids how to use an old ally more effectively. Bull NYU Hosp Jt Dis. 2012; 70 Suppl 1:26-9.

(11.) Kirwan JR, Bijlsma JW, Boers M, Shea BJ. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev. 2007 Jan 24; (1):CD006356.

(12.) Yazici Y Corticosteroids as disease modifying drugs in rheumatoid arthritis treatment. Bull NYU Hosp Jt Dis. 2012; 70 Suppl 1:11-3.

(13.) Sokka T, Kautiainen H, Toloza S, et al. QUEST-RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries. Ann Rheum Dis. 2007 Nov; 66(11):1491-6.

(14.) Kavanaugh A, Wells AF. Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis. Rheumatology (Oxford). 2014 Oct; 53(10):1742-51.

(15.) Gaujoux-Viala C, Nam J, Ramiro S, et al. Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2014 Mar; 73(3):510-5.

(16.) Smolen JS, Landewe R, Breedveld FC, et al (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010 June; 69(6):964-75.

(17.) Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014 Mar; 73(3):492509.

(18.) National Institute for Health and Care Excellence. NICE Clinical Guideline 79, 2013. Rheumatoid arthritis. The management of rheumatoid arthritis in adults. http://www.nice. Accessed 2 April 2014

(19.) Pincus T, Sokka T, Castrejon I, Cutolo M. Decline of mean initial prednisone dosage from 10.3 to 3.6 mg/day to treat rheumatoid arthritis between 1980 and 2004 in one clinical setting, with long-term effectiveness of dosages less than 5 mg/day. Arthritis Care Res (Hoboken). 2013 May; 65(5):72936.

(20.) da Silva JA, Jacobs JW, Kirwan JR, et al (2006) Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis. 2006 Mar; 65(3):285-93.

(21.) Kirwan JR, Clarke L, Hunt LP, et al. Effect of novel therapeutic glucocorticoids on circadian rhythms of hormones and cytokines in rheumatoid arthritis. Ann N Y Acad Sci. 2010 Apr; 1193:127-33.

(22.) Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum. 2007 Feb; 56(2):399-408.

(23.) Olsen NJ, Brooks RH, Furst D. Variability of immunologic and clinical features in patients with rheumatoid arthritis studied over 24 hours. J Rheumatol. 1993 June; 20(6):940-3.

(24.) Alten R, Doring G, Cutolo M, et al. Hypothalamus-pituitary-adrenal axis function in patients with rheumatoid arthritis treated with nighttime-release prednisone. J Rheumatol. 2010 Oct; 37(10):2025-31.

(25.) Hoes JN, Jacobs JW, Boers M, et al. EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis. 2007 Dec; 66(12):1560-7.

(26.) RAYOS (prednisone) delayed-release tablets, prescribing information. Horizon Pharma USA, Inc. Deerfield, IL. Available at: Accessed 23 April 2104.

(27.) Buttgereit F, Doering G, Schaeffler A, et al. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet. 2008 Jan; 371(9608):205-14.

(28.) Buttgereit F, Doering G, Schaeffler A, et al. Targeting patho-physiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis. Ann Rheum Dis. 2010 Jul; 69(7):1275-80.

(29.) Buttgereit F, Mehta D, Kirwan J, et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis. 2013 Feb; 72(2):204-10.

(30.) Moore RA, Moore OA, Derry S, et al. Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice. Ann Rheum Dis. 2010 Feb; 69(2):374-9.

(31.) Smolen JS, Aletaha D. The assessment of disease activity in rheumatoid arthritis. Clin Exp Rheumatol. 2010 May-Jun; 28(3 Suppl 59):S18-27.

(32.) Alten R, Grahn A, Rice P, Buttgereit F. Improved fatigue-related quality of life in CAPRA-2, a 12 week study of 5-mg modified (delayed) release prednisone in rheumatoid arthritis. Arthritis Rheum. 2012; 64(10):S159-60.

(33.) Alten R, Grahn A, Rice P, Holt R, Buttgereit F. Response of patient reported symptoms of stiffness and pain during the day from adding low-dose delayed-release (DR) prednisone to stable DMARD therapy over 12 weeks in patients with moderate rheumatoid arthritis (RA). Arthritis Rheum. 2014; 66(11):S651.

(34.) Buttgereit F. How should impaired morning function in rheumatoid arthritis be treated? Scand J Rheumatol Suppl. 2011; 125:28-39.

(35.) Mattila K, Buttgereit F, Tuominen R. Impact of morning stiffness on working behaviour and performance in people with rheumatoid arthritis. Rheumatol Int. 2014 Dec; 34(12):1751-8.

(36.) Orbai A-M, Smith KC, Bartlett SJ, et al. "Stiffness has different meanings, I think to everyone". Examining stiffness from the perspective of people living with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014 Nov; 66(11):1662-72.

(37.) Rendas-Baum R, Bayliss M, Kosinski M, et al. Measuring the effect of therapy in rheumatoid arthritis clinical trials from the patient's perspective. Curr Med Res Opin. 2014 Jul; 30(7):1391-403.

(38.) Soubrier M, Zerkak D, Gossec L, et al. Which variables best predict change in rheumatoid arthritis therapy in daily clinical practice? J Rheumatol. 2006 Jul; 33(7):1243-6.

(39.) Felson DT, Smolen JS, Wells G, et al; American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011 Mar; 63(3):573-86.

(40.) Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010 Sept; 69(9):1580-8.

(41.) Funovits J, Aletaha D, Bykerk V, et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: methodological report phase I. Ann Rheum Dis. 2010 Sept; 69(9):1589-95.

(42.) Neogi T, Aletaha D, Silman AJ, et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: phase 2 methodological report. Arthritis Rheum. 2010 Sept; 62(9):2582-91.

(43.) Mengi G, Gogus F, Beyazova M. Is it possible to quantify morning stiffness objectively? Ann Rheum Dis. 2014 Jun; 73(Suppl 2):643-4.

(44.) Buttgereit F, Kirwan J, Saag K, et al. Relationship between morning stiffness duration and severity, pain intensity, and measures of disease activity in a 12-week efficacy study of a modified (delayed-release) prednisone plus disease-modifying antirheumatic drugs in rheumatoid arthritis (RA). Arthritis Rheum. 2012 Oct; 64(10 Suppl):s544-5.

(45.) Alten R, Grahn A, Rice P, et al. Improved fatigue-related quality of life in CAPRA-2, a 12 week study of 5-mg modified (delayed) release prednisone in rheumatoid arthritis. Arthritis Rheum. 2012 Oct; 64(10 Suppl):s159-60.

(46.) Dunlop W, Iqbal I, Khan I, et al. Cost-effectiveness of modified-release prednisone in the treatment of moderate to severe rheumatoid arthritis with morning stiffness based on directly elicited public preference values. Clinicoecon Outcomes Res. 2013 Oct 30; 5:555-64.

(47.) Boers M, Buttgereit F. A simple model that suggests possible cost savings when modified-release prednisone 5 mg/day is added to current treatment in patients with active rheumatoid arthritis. Rheumatology (Oxford). 2013 Aug; 52(8):1435-37.

Caption: Figure 1 Levels of cytokines and symptoms in patients with RA: Effect of DR-prednisone versus IR-prednisone. DR, delayed-release; IR, immediate-release; RA, rheumatoid arthritis.

Caption: Figure 3 Threshold improvement in morning stiffness duration for continuous DR-prednisone versus after switch from IR-prednisone to DR-prednisone in the open-label extension phase. Threshold for improvement represents percentage of patients achieving 25%, 50%, or 75% improvement in duration of morning stiffness from baseline. There were no significant differences between treatment groups at months 6, 9, or 12 (chi-square tests). DR, delayed-release; IR, immediate-release; MS 25, 25% improvement in morning stiffness; MS 50, 50% improvement in morning stiffness; MS 75, 75% improvement in morning stiffness.

Table 1 Patient Characteristics: Double-Blind Baseline
and Open-Label Extension Analysis Population

                         Baseline (Week 0/Visit 2)

Characteristic           DR-Prednisone   IR-Prednisone
                           (N = 144)       (N = 144)

Age (years), mean (SD)    54.6 (11.2)     55.4 (11.4)
Women, n (%)              125 (86.8)      122 (84.7)
Caucasian/white           143 (99.3)       144 (100)
Duration of morning      164.1 (101.4)   182.5 (125.0)
  stiffness (min),
  mean (SD)
VAS pain score (mm),      57.9 (14.8)     59.7 (15.8)
  mean (SD)
HAQ-DI, mean (SD)          1.5 (0.6)       1.5 (0.5)
DAS28, mean (SD)           5.8 (0.8)       5.9 (0.9)
Stable predniso(lo)ne     6.5 (2-10)      6.7 (3-10)
  daily dose or
  equivalent (mg),
  mean (range)

                         Open-Label Analysis Population
                         Baseline (Week 12/Visit 5)

Characteristic           DR-Prednisone   Switch From IR- to
                           Continued       DR-Prednisone
                           (N = 97)          (N = 110)

Age (years), mean (SD)    54.8 (10.5)       55.1 (11.8)
Women, n (%)               85 (87.6)         96 (87.3)
Caucasian/white            96 (99.0)         110 (100)
Duration of morning      99.8 (101.7)      143.5 (116.7)
  stiffness (min),
  mean (SD)
VAS pain score (mm),      44.3 (24.1)       44.1 (24.0)
  mean (SD)
HAQ-DI, mean (SD)          1.5 (0.5)         1.4 (0.5)
DAS28, mean (SD)           5.2 (1.2)         5.0 (1.1)
Stable predniso(lo)ne     6.2 (2-10)         6.8 (3-15)
  daily dose or
  equivalent (mg),
  mean (range)

DAS28, 28-joint disease activity score; DR,
delayed-release; HAQ-DI, Health Assessment Questionnaire
Disability Index; IR, immediate-release; min, minutes;
SD, standard deviation; VAS, visual analog scale.

Figure 2 percentages of patients reaching morning stiffness
thresholds of improvement from baseline (visit 2/Week 0):
DR-prednisone (N = 97) versus IR-prednisone (N = 110). A, 25%
improvement in morning stiffness. B, 50% improvement in morning
stiffness. C, 75% improvement in morning stiffness. Frequencies
and percentages are cumulative across weeks. Improvement categories
were not exclusive (i.e., a patient who achieved the 50%
response level was also counted in the 25% category). P-values for
treatment differences at week 12 were from chi-square tests. DR,
delayed-release; IR, immediate-release; MS 25, 25% improvement
in morning stiffness; MS 50, 50% improvement in morning stiffness;
MS 75, 75% improvement in morning stiffness.


             % of Patients With 25% Improvement

          DR-Prednisone MS 25   IR-Prednisone MS 25

Week 1            30                    20
Week 2            50                    33
Week 3            56                    41
Week 4            59                    45
Week 5            61                    45
Week 6            66                    46
Week 7            71                    52
Week 8            74                    54
Week 9            74                    56
Week 10           74                    58
Week 11           75                    59
Week 12           75                    63

P = 0.05

           % of Patients With 50% Improvement

          DR-Prednisone MS 50   IR-Prednisone MS 50

Week 1            13                    8
Week 2            24                    16
Week 3            30                    23
Week 4            36                    26
Week 5            40                    27
Week 6            41                    30
Week 7            46                    34
Week 8            50                    36
Week 9            53                    36
Week 10           55                    40
Week 11           55                    41
Week 12           57                    41

P = 0.02


            % of Patients Within 75% Improvement

          DR-Prednisone MS 75   IR-Prednisone MS 75

Week 1            4                     4
Week 2            10                    6
Week 3            16                    12
Week 4            19                    15
Week 5            20                    16
Week 6            25                    18
Week 7            29                    21
Week 8            31                    21
Week 9            33                    22
Week 10           36                    22
Week 11           37                    23
Week 12           38                    26

P < 0.05

Note: Table made from line graph.

Figure 4 Time to morning stiffness improvement. A, 25%
improvement with open-label as baseline. B, 50% improvement with

open-label as baseline. C, 75% improvement with open-label as
baseline. D, 25% improvement with double-blind as baseline. E, 50%
improvement with double-blind as baseline. F, 75% improvement with
double-blind as baseline. All summary statistics were computed
using Kaplan-Meier methods. HRs, 95% CIs, and p-values were from
a Cox proportional hazards model. CI, confidence interval; DR,
delayed-release; HR, hazard ratio; IR, immediate-release; NE,
not estimable; SE, standard error.


% of Patients Free of Event (25% Improvement
in Morning Stiffness Threshold/V5 Baseline)

                        DR-Prednisone         Switch From
                         Continued               IR-to
                         (N = 97)            DR-Prednisone
                                               (N = 110)

Number of events          60 (37)               90 (20)
Mean [+ or -] SE   243.8 [+ or -] 8.10   210.4 [+ or -] 6.45
Median                     252                   168
HR (95% CI)                   0.64 (0.46, 0.89)
P-value                             0.0083


% of Patients Free of Event (25% Improvement
in Morning Stiffness Threshold/V2 Baseline)

                        DR-Prednisone         Switch From
                         Continued               IR-to
                         (N = 97)            DR-Prednisone
                                               (N = 110)

Number of events          88 (9)                101 (9)
Mean [+ or -] SE    78.2 [+ or -] 11.22    96.6 [+ or -] 9.78
Median                     21                    49
HR (95% CI)                   1.18 (0.88, 1.57)
P-value                             0.2691


% of Patients Free of Event (50% Improvement
in Morning Stiffness Threshold/V5 Baseline)

                        DR-Prednisone         Switch From
                         Continued               IR-to
                         (N = 97)            DR-Prednisone
                                               (N = 110)

Number of events          46 (51)               72 (38)
Mean [+ or -] SE   273.3 [+ or -] 7.77    246.5 [+ or -] 7.25
Median                     NE                    252
HR (95% CI)                   0.57 (0.39, 0.84)
P-value                             0.0043


% of Patients Free of Event (50% Improvement
in Morning Stiffness Threshold/V2 Baseline)

                        DR-Prednisone         Switch From
                         Continued               IR-to
                         (N = 97)            DR-Prednisone
                                               (N = 110)

Number of events          75 (22)               87 (23)
Mean [+ or -] SE   131.0 [+ or -] 13.18   151.7 [+ or -] 11.39
Median                     63                    168
HR (95% CI)                   1.12 (0.82, 1.53)
P-value                             0.4777


% of Patients Free of Event (75% Improvement
in Morning Stiffness Threshold/V5 Baseline)

                        DR-Prednisone         Switch From
                         Continued               IR-to
                         (N = 97)            DR-Prednisone
                                               (N = 110)

Number of events          33 (64)               51 (59)
Mean [+ or -] SE   297.6 [+ or -] 6.48    275.0 [+ or -] 7.21
Median                     NE                    336
HR (95% CI)                   0.53 (0.33, 0.85)
P-value                             0.0078


% of Patients Free of Event (75% Improvement
in Morning Stiffness Threshold/V2 Baseline)

                        DR-Prednisone         Switch From
                         Continued               IR-to
                         (N = 97)            DR-Prednisone
                                               (N = 110)

Number of events          59 (38)               71 (39)
Mean [+ or -] SE   194.1 [+ or -] 13.86   207.7 [+ or -] 11.72
Median                     168                    168
HR (95% CI)                   0.93 (0.65, 1.32)
P-value                             0.6660


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Article Details
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Author:Buttgereit, Frank; Kent, Jeffrey D.; Holt, Robert J.; Grahn, Amy Y.; Rice, Patricia; Alten, Rieke; Y
Publication:Bulletin of the NYU Hospital for Joint Diseases
Article Type:Report
Date:Jul 1, 2015
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