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1.  Circadian rhythms in rheumatology - a glucocorticoid perspective 
Arthritis Research & Therapy  2014;16(Suppl 2):S3.
The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in regulating and controlling immune responses. Dysfunction of the HPA axis has been implicated in the pathogenesis of rheumatoid arthritis (RA) and other rheumatic diseases. The impact of glucocorticoid (GC) therapy on HPA axis function also remains a matter of concern, particularly for longer treatment duration. Knowledge of circadian rhythms and the influence of GC in rheumatology is important: on the one hand we aim for optimal treatment of the daily undulating inflammatory symptoms, for example morning stiffness and swelling; on the other, we wish to disturb the HPA axis as little as possible. This review describes circadian rhythms in RA and other chronic inflammatory diseases, dysfunction of the HPA axis in RA and other rheumatic diseases and the recent concept of the hepato-hypothalamic-pituitary-adrenal-renal axis, the problem of adrenal suppression by GC therapy and how it can be avoided, and evidence that chronotherapy with modified release prednisone effective at 02:00 a.m. can inhibit proinflammatory sequelae of nocturnal inflammation better compared with GC administration in the morning but does not increase the risk of HPA axis insufficiency in RA.
doi:10.1186/ar4687
PMCID: PMC4249493  PMID: 25608777
2.  The supplementary therapeutic DMARD role of low-dose glucocorticoids in rheumatoid arthritis 
Arthritis Research & Therapy  2014;16(Suppl 2):S1.
The management of rheumatoid arthritis (RA) is primarily based on the use of disease-modifying antirheumatic drugs (DMARDs), mainly comprising synthetic chemical compounds (that is, methotrexate or leflunomide) and biological agents (tumor necrosis factor inhibitors or abatacept). On the other hand, glucocorticoids (GCs), used for decades in the treatment of RA, are effective in relieving signs and symptoms of the disease, but also interfere with radiographic progression, either as monotherapy or in combination with conventional synthetic DMARDs. GCs exert most of their biological effects through a genomic action, using the cytosolic GC receptor and then interacting with the target genes within target cells that can result in increased expression of regulatory - including anti-inflammatory - proteins (transactivation) or decreased production of proinflammatory proteins (transrepression). An inadequate secretion of GCs from the adrenal gland, in relation to stress and inflammation, seems to play an important role in the pathogenesis and disease progression of RA. At present there is clear evidence that GC therapy, especially long-term low-dose treatment, slows radiographic progression by at least 50% when given to patients with early RA, hence satisfying the conventional definition of a DMARD. In addition, long-term follow-up studies suggest that RA treatment strategies which include GC therapy may favorably alter the disease course even after their discontinuation. Finally, a low-dose, modified night-release formulation of prednisone, although administered in the evening (replacement therapy), has been developed to counteract the circadian (night) rise in proinflammatory cytokine levels that contributes to disease activity, and might represent the way to further optimize the DMARD activity exerted by GCs in RA.
doi:10.1186/ar4685
PMCID: PMC4249490  PMID: 25608624
3.  Hydroxychloroquine in patients with inflammatory and erosive osteoarthritis of the hands (OA TREAT): study protocol for a randomized controlled trial 
Trials  2014;15(1):412.
Background
Osteoarthritis (OA) is a heterogeneous group of conditions with disturbed integrity of articular cartilage and changes in the underlying bone. The pathogenesis of OA is multifactorial and not just a disease of older people. Hydroxychloroquine (HCQ) is a disease-modifying anti-rheumatic drug (DMARD) typically used for the treatment of various rheumatic and dermatologic diseases. Three studies of HCQ in OA, including one abstract and one letter, are available and use a wide variety of outcome measures in small patient populations. Despite initial evidence for good efficacy of HCQ, there has been no randomized, double-blind, and placebo-controlled trial in a larger patient group. In the European League Against Rheumatism (EULAR), evidence-based recommendations for the management of hand OA, HCQ was not included as a therapeutic option because of the current lack of randomized clinical trials.
Methods/Design
OA TREAT is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial. A total of 510 subjects with inflammatory and erosive hand OA, according to the classification criteria of the American College of Rheumatology (ACR), with recent X-ray will be recruited across outpatient sites, hospitals and universities in Germany. Patients are randomized 1:1 to active treatment (HCQ 200 to 400 mg per day) or placebo for 52 weeks. Both groups receive standard therapy (non-steroidal anti-inflammatory drugs [NSAID], coxibs) for OA treatment, taken steadily two weeks before enrollment and continued further afterwards. If disease activity increases, the dose of NSAID/coxibs can be increased according to the drug recommendation. The co-primary clinical endpoints are the changes in Australian-Canadian OA Index (AUSCAN, German version) dimensions for pain and hand disability at week 52. The co-primary radiographic endpoint is the radiographic progression from baseline to week 52. A multiple endpoint test and analysis of covariance will be used to compare changes between groups. All analyses will be conducted on an intention-to-treat basis.
Discussion
The OA TREAT trial will examine the clinical and radiological efficacy and safety of HCQ as a treatment option for inflammatory and erosive OA over 12 months. OA TREAT focuses on erosive hand OA in contrast to other current studies on symptomatic hand OA, for example, HERO [Trials 14:64, 2013].
Trial registration
ISRCTN46445413, date of registration: 05-10-2011.
doi:10.1186/1745-6215-15-412
PMCID: PMC4219005  PMID: 25348033
Erosive hand osteoarthritis; Hydroxychloroquine; Double-blind; Hand; Placebo-controlled; Randomized
4.  Autoimmune Rheumatic Diseases 
BioMed Research International  2014;2014:952159.
doi:10.1155/2014/952159
PMCID: PMC4138892  PMID: 25162038
6.  Impact of morning stiffness on working behaviour and performance in people with rheumatoid arthritis 
Rheumatology International  2014;34(12):1751-1758.
Work disability remains a considerable problem for many patients with rheumatoid arthritis (RA). Morning stiffness is a symptom of RA associated with early retirement from work and with impaired functional ability. We aimed to explore the patient’s perception of the impact of morning stiffness on the working life of patients with RA. A survey was conducted in 11 European countries. Patients of working age, with RA for ≥6 months and morning stiffness ≥3 mornings a week, were interviewed by telephone using a structured questionnaire. Responses were assessed in the total sample and in subgroups defined by severity and duration of morning stiffness and by country. A total of 1,061 respondents completed the survey, 534 were working, 224 were retired and the rest were, i.e. homemakers and unemployed. Among the 534 working respondents, RA-related morning stiffness affected work performance (47 %), resulted in late arrival at work (33 %) and required sick leave in the past month (15 %). Of the 224 retired respondents, 159 (71 %) stopped working earlier than their expected retirement age, with 64 % giving RA-related morning stiffness as a reason. There was a differential impact of increasing severity and increasing duration of morning stiffness on the various parameters studied. There were notable inter-country differences in the impact of RA-related morning stiffness on ability to work and on retirement. This large survey showed that from the patient’s perspective, morning stiffness reduces the ability to work in patients with RA and contributes to early retirement.
doi:10.1007/s00296-014-3040-0
PMCID: PMC4237915  PMID: 24871158
Rheumatoid arthritis; Morning stiffness; Work performance; Early retirement
7.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update 
Annals of the Rheumatic Diseases  2013;73(3):492-509.
In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.
doi:10.1136/annrheumdis-2013-204573
PMCID: PMC3933074  PMID: 24161836
Rheumatoid Arthritis; DMARDs (synthetic); DMARDs (biologic); Treatment; Early Rheumatoid Arthritis
8.  Acute murine antigen-induced arthritis is not affected by disruption of osteoblastic glucocorticoid signalling 
Background
The role of endogenous glucocorticoids (GC) in the initiation and maintenance of rheumatoid arthritis (RA) remains unclear. We demonstrated previously that disruption of GC signalling in osteoblasts results in a profound attenuation of K/BxN serum-induced arthritis, a mouse model of RA. To determine whether or not the modulation of the inflammatory response by osteoblasts involves T cells, we studied the effects of disrupted osteoblastic GC-signalling in the T cell-dependent model of antigen-induced arthritis (AIA).
Methods
Acute arthritis was induced in pre-immunised 11-week-old male 11β-hydroxysteroid dehydrogenase type 2 transgenic (tg) mice and their wild-type (WT) littermates by intra-articular injection of methylated bovine serum albumine (mBSA) into one knee joint. Knee diameter was measured every 1–2 days until euthanasia on day 14 post injection. In a separate experiment, arthritis was maintained for 28 days by weekly reinjections of mBSA. Tissues were analysed by histology, histomorphometry and microfocal-computed tomography. Serum cytokines levels were determined by multiplex suspension array.
Results
In both short and long term experiments, arthritis developed in tg and WT mice with no significant difference between both groups. Histological indices of inflammation, cartilage damage and bone erosion were similar in tg and WT mice. Bone volume and turnover at the contralateral tibia and systemic cytokine levels were not different.
Conclusions
Acute murine AIA is not affected by a disruption in osteoblastic GC signalling. These data indicate that osteoblasts do not modulate the T cell-mediated inflammatory response via a GC-dependent pathway.
doi:10.1186/1471-2474-15-31
PMCID: PMC3922092  PMID: 24491163
11-beta-hydroxysteroid dehydrogenase type 2; Disease models; Animal; Arthritis; Glucocorticoids; Osteoblasts
9.  Osteoarthritis synovial fluid activates pro-inflammatory cytokines in primary human chondrocytes 
International Orthopaedics  2012;37(1):145-151.
Purpose
Two of the most common joint diseases are rheumatoid arthritis (RA) and osteoarthritis (OA). Cartilage degradation and erosions are important pathogenetic mechanisms in both joint diseases and have presently gained increasing interest. The aim of the present study was to investigate the effects of the synovial fluid environment of OA patients in comparison with synovial fluids of RA patients on human chondrocytes in vitro.
Methods
Primary human chondrocytes were incubated in synovial fluids gained from patients with OA or RA. The detection of vital cell numbers was determined by histology and by using the Casy Cell Counter System. Cytokine and chemokine secretion was determined by a multiplex suspension array.
Results
Microscopic analysis showed altered cell morphology and cell shrinkage following incubation with synovial fluid of RA patients. Detection of vital cells showed a highly significant decrease of vital chondrocyte when treated with RA synovial fluids in comparison with OA synovial fluids. An active secretion of cytokines such as vascular endothelial growth factor (VEGF) of chondrocytes treated with OA synovial fluids was observed.
Conclusions
Significantly increased levels of various cytokines in synovial fluids of RA, and surprisingly of OA, patients were shown. Activation of pro-inflammatory cytokines of human chondrocytes by synovial fluids of OA patient supports a pro-inflammatory process in the pathogenesis of OA.
doi:10.1007/s00264-012-1724-1
PMCID: PMC3532646  PMID: 23212731
10.  Human immune cells' behavior and survival under bioenergetically restricted conditions in an in vitro fracture hematoma model 
Cellular and Molecular Immunology  2013;10(2):151-158.
The initial inflammatory phase of bone fracture healing represents a critical step for the outcome of the healing process. However, both the mechanisms initiating this inflammatory phase and the function of immune cells present at the fracture site are poorly understood. In order to study the early events within a fracture hematoma, we established an in vitro fracture hematoma model: we cultured hematomas forming during an osteotomy (artificial bone fracture) of the femur during total hip arthroplasty (THA) in vitro under bioenergetically controlled conditions. This model allowed us to monitor immune cell populations, cell survival and cytokine expression during the early phase following a fracture. Moreover, this model enabled us to change the bioenergetical conditions in order to mimic the in vivo situation, which is assumed to be characterized by hypoxia and restricted amounts of nutrients. Using this model, we found that immune cells adapt to hypoxia via the expression of angiogenic factors, chemoattractants and pro-inflammatory molecules. In addition, combined restriction of oxygen and nutrient supply enhanced the selective survival of lymphocytes in comparison with that of myeloid derived cells (i.e., neutrophils). Of note, non-restricted bioenergetical conditions did not show any similar effects regarding cytokine expression and/or different survival rates of immune cell subsets. In conclusion, we found that the bioenergetical conditions are among the crucial factors inducing the initial inflammatory phase of fracture healing and are thus a critical step for influencing survival and function of immune cells in the early fracture hematoma.
doi:10.1038/cmi.2012.56
PMCID: PMC4003042  PMID: 23396474
apoptosis; fracture hematoma model; hypoxia; immune cells; inflammation
11.  Energy metabolism and rheumatic diseases: from cell to organism 
In rheumatic and other chronic inflammatory diseases, high amounts of energy for the activated immune system have to be provided and allocated by energy metabolism. In recent time many new insights have been gained into the control of the immune response through metabolic signals. Activation of immune cells as well as reduced nutrient supply and hypoxia in inflamed tissues cause stimulation of glycolysis and other cellular metabolic pathways. However, persistent cellular metabolic signals can promote ongoing chronic inflammation and loss of immune tolerance. On the organism level, the neuroendocrine immune response of the hypothalamic-pituitary adrenal axis and sympathetic nervous system, which is meant to overcome a transient inflammatory episode, can lead to metabolic disease sequelae if chronically activated. We conclude that, on cellular and organism levels, a prolonged energy appeal reaction is an important factor of chronic inflammatory disease etiology.
doi:10.1186/ar3885
PMCID: PMC3446535  PMID: 22747923
12.  Human Early Fracture Hematoma Is Characterized by Inflammation and Hypoxia 
Background
An effective immune system, especially during the inflammatory phase, putatively influences the quality and likelihood of bone healing. If and how this is reflected within the initial fracture hematoma is unclear.
Questions/purposes
We therefore asked the following questions: (1) Does the local expression in fracture hematoma of genes involved in adaptation to hypoxia, migration, angiogenesis, and osteogenesis vary as compared to the peripheral blood? (2) Do these changes occur time dependently? (3) Is the gene expression during fracture hematoma formation altered by irradiation?
Methods
Cells from fracture hematoma of 20 patients and hematomas formed in 40 patients after THA (20 without and 20 with preoperative radiation) were isolated and RNA was extracted to analyze the influence of oxygen deprivation during fracture healing on mRNA expression of genes (HIF1A, LDHA, and PGK1) involved in immunoregulation (IL6, IL8, CXCR4), angiogenesis (VEGF, IL8), and osteogenesis (SPP1, RUNX2) by quantitative PCR.
Results
We observed locally increased LDHA gene expression in fracture hematoma cells (6–72 h post fracture) reflecting the adaptation to hypoxia. IL6, IL8, and VEGF upregulation indicated hypoxia-mediated inflammation and angiogenesis; increased CXCR4 expression reflected immigration of immune cells. Osteogenic differentiation was reflected in the increased expression of the SPP1 and RUNX2 genes. The increased expression of the LDHA, VEGF, IL8, SPP1 and RUNX2 genes occurred time dependently. Irradiation suppressed HIF1A, IL6, IL8, CXCR4, and RUNX2 gene expression.
Conclusions
Our data suggest cells in the fracture hematoma (1) adapt to hypoxia and (2) promote inflammation in fracture healing at the mRNA level, indicating early involvement of the immune system.
Clinical Relevance
The initial fracture hematoma is important for the onset of angiogenesis, chemotaxis, and osteogenesis.
doi:10.1007/s11999-011-1865-3
PMCID: PMC3183184  PMID: 21409457
13.  Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism 
The Journal of Clinical Investigation  2012;122(11):4172-4189.
Long-term glucocorticoid treatment is associated with numerous adverse outcomes, including weight gain, insulin resistance, and diabetes; however, the pathogenesis of these side effects remains obscure. Glucocorticoids also suppress osteoblast function, including osteocalcin synthesis. Osteocalcin is an osteoblast-specific peptide that is reported to be involved in normal murine fuel metabolism. We now demonstrate that osteoblasts play a pivotal role in the pathogenesis of glucocorticoid-induced dysmetabolism. Osteoblast-targeted disruption of glucocorticoid signaling significantly attenuated the suppression of osteocalcin synthesis and prevented the development of insulin resistance, glucose intolerance, and abnormal weight gain in corticosterone-treated mice. Nearly identical effects were observed in glucocorticoid-treated animals following heterotopic (hepatic) expression of both carboxylated and uncarboxylated osteocalcin through gene therapy, which additionally led to a reduction in hepatic lipid deposition and improved phosphorylation of the insulin receptor. These data suggest that the effects of exogenous high-dose glucocorticoids on insulin target tissues and systemic energy metabolism are mediated, at least in part, through the skeleton.
doi:10.1172/JCI63377
PMCID: PMC3484445  PMID: 23093779
14.  Hypoxia Promotes Osteogenesis but Suppresses Adipogenesis of Human Mesenchymal Stromal Cells in a Hypoxia-Inducible Factor-1 Dependent Manner 
PLoS ONE  2012;7(9):e46483.
Background
Bone fracture initiates a series of cellular and molecular events including the expression of hypoxia-inducible factor (HIF)-1. HIF-1 is known to facilitate recruitment and differentiation of multipotent human mesenchymal stromal cells (hMSC). Therefore, we analyzed the impact of hypoxia and HIF-1 on the competitive differentiation potential of hMSCs towards adipogenic and osteogenic lineages.
Methodology/Principal Findings
Bone marrow derived primary hMSCs cultured for 2 weeks either under normoxic (app. 18% O2) or hypoxic (less than 2% O2) conditions were analyzed for the expression of MSC surface markers and for expression of the genes HIF1A, VEGFA, LDHA, PGK1, and GLUT1. Using conditioned medium, adipogenic or osteogenic differentiation as verified by Oil-Red-O or von-Kossa staining was induced in hMSCs under either normoxic or hypoxic conditions. The expression of HIF1A and VEGFA was measured by qPCR. A knockdown of HIF-1α by lentiviral transduction was performed, and the ability of the transduced hMSCs to differentiate into adipogenic and osteogenic lineages was analyzed. Hypoxia induced HIF-1α and HIF-1 target gene expression, but did not alter MSC phenotype or surface marker expression. Hypoxia (i) suppressed adipogenesis and associated HIF1A and PPARG gene expression in hMSCs and (ii) enhanced osteogenesis and associated HIF1A and RUNX2 gene expression. shRNA-mediated knockdown of HIF-1α enhanced adipogenesis under both normoxia and hypoxia, and suppressed hypoxia-induced osteogenesis.
Conclusions/Significance
Hypoxia promotes osteogenesis but suppresses adipogenesis of human MSCs in a competitive and HIF-1-dependent manner. We therefore conclude that the effects of hypoxia are crucial for effective bone healing, which may potentially lead to the development of novel therapeutic approaches.
doi:10.1371/journal.pone.0046483
PMCID: PMC3459928  PMID: 23029528
15.  Human monocytes and macrophages differ in their mechanisms of adaptation to hypoxia 
Arthritis Research & Therapy  2012;14(4):R181.
Introduction
Inflammatory arthritis is a progressive disease with chronic inflammation of joints, which is mainly characterized by the infiltration of immune cells and synovial hyperproliferation. Monocytes migrate towards inflamed areas and differentiate into macrophages. In inflamed tissues, much lower oxygen levels (hypoxia) are present in comparison to the peripheral blood. Hence, a metabolic adaptation process must take place. Other studies suggest that Hypoxia Inducible Factor 1-alpha (HIF-1α) may regulate this process, but the mechanism involved for human monocytes is not yet clear. To address this issue, we analyzed the expression and function of HIF-1α in monocytes and macrophages, but also considered alternative pathways involving nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB).
Methods
Isolated human CD14+ monocytes were incubated under normoxia and hypoxia conditions with or without phorbol 12-myristate 13-acetate (PMA) stimulation, respectively. Nuclear and cytosolic fractions were prepared in order to detect HIF-1α and NFκB by immunoblot. For the experiments with macrophages, primary human monocytes were differentiated into human monocyte derived macrophages (hMDM) using human macrophage colony-stimulating factor (hM-CSF). The effects of normoxia and hypoxia on gene expression were compared between monocytes and hMDMs using quantitative PCR (quantitative polymerase chain reaction).
Results
We demonstrate, using primary human monocytes and hMDM, that the localization of transcription factor HIF-1α during the differentiation process is shifted from the cytosol (in monocytes) into the nucleus (in macrophages), apparently as an adaptation to a low oxygen environment. For this localization change, protein kinase C alpha/beta 1 (PKC-α/β1 ) plays an important role. In monocytes, it is NFκB1, and not HIF-1α, which is of central importance for the expression of hypoxia-adjusted genes.
Conclusions
These data demonstrate that during differentiation of monocytes into macrophages, crucial cellular adaptation mechanisms are decisively changed.
doi:10.1186/ar4011
PMCID: PMC3580576  PMID: 22870988
16.  The association between rheumatoid arthritis and periodontal disease 
Chronic, plaque-associated inflammation of the gingiva and the periodontium are among the most common oral diseases. Periodontitis (PD) is characterized by the inflammatory destruction of the periodontal attachment and alveolar bone, and its clinical appearance can be influenced by congenital as well as acquired factors. The existence of a rheumatic or other inflammatory systemic disease may promote PD in both its emergence and progress. However, there is evidence that PD maintains systemic diseases. Nevertheless, many mechanisms in the pathogenesis have not yet been examined sufficiently, so that a final explanatory model is still under discussion, and we hereby present arguments in favor of this. In this review, we also discuss in detail the fact that oral bacterial infections and inflammation seem to be linked directly to the etiopathogenesis of rheumatoid arthritis (RA). There are findings that support the hypothesis that oral infections play a role in RA pathogenesis. Of special importance are the impact of periodontal pathogens, such as Porphyromonas gingivalis on citrullination, and the association of PD in RA patients with seropositivity toward rheumatoid factor and the anti-cyclic citrullinated peptide antibody.
doi:10.1186/ar3106
PMCID: PMC2990988  PMID: 21062513
17.  Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2010;69(7):1275-1280.
Objective
This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study (CAPRA 1) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release (MR) prednisone for up to 12 months.
Methods
Of 288 patients with rheumatoid arthritis originally randomised to MR or immediate-release (IR) prednisone, 249 continued with prednisone chronotherapy (2–10 mg/day) in the 9-month open-label extension. Duration of morning stiffness of the joints (MS), disease activity scores (DAS28), American College of Rheumatology (ACR20) responses and plasma levels of interleukin 6 (IL-6) were assessed. Safety was analysed from adverse event reports and laboratory investigations.
Results
During the 3-month double-blind phase, patients in the MR group achieved a reduction in MS of 33.1% while no change was observed in the IR group. After 6 months of treatment, MS was reduced in the IR/MR group by 54% and in the MR/MR group by 56%. MS reduction after 12 months was 45% (IR/MR group) and 55% (MR/MR group). Plasma levels of IL-6 declined on MR treatment. DAS28 was reduced from 5.8 to 4.8 (MR/MR group) and 4.9 (IR/MR group), respectively. 37% of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria. Adverse events did not differ from the known profile of low-dose prednisone.
Conclusions
Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which resulted in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months.
doi:10.1136/ard.2009.126888
PMCID: PMC2946119  PMID: 20542963
18.  Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2) 
Annals of the Rheumatic Diseases  2012;72(2):204-210.
Objective
To assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of rheumatoid arthritis (RA).
Methods
In this 12-week, double-blind, placebo-controlled study, patients with active RA (n=350) were randomised 2:1 to receive MR prednisone 5 mg or placebo once daily in the evening in addition to their existing RA disease-modifying antirheumatic drug (DMARD) treatment. The primary end point was the percentage of patients achieving a 20% improvement in RA signs and symptoms according to American College of Rheumatology criteria (ie, an ACR20 response) at week 12. Changes in morning pain, duration of morning stiffness, 28-joint Disease Activity Score and health-related quality of life were also assessed.
Results
MR prednisone plus DMARD treatment produced higher response rates for ACR20 (48% vs 29%, p<0.001) and ACR50 (22% vs 10%, p<0.006) and a greater median relative reduction from baseline in morning stiffness (55% vs 35%, p<0.002) at week 12 than placebo plus DMARD treatment. Significantly greater reductions in severity of RA (Disease Activity Score 28) (p<0.001) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score) (p=0.003) as well as a greater improvement in physical function (36-item Short-Form Health Survey score) (p<0.001) were seen at week 12 for MR prednisone versus placebo. The incidence of adverse events was similar for MR prednisone (43%) and placebo (49%).
Conclusion
Low-dose MR prednisone added to existing DMARD treatment produced rapid and relevant improvements in RA signs and symptoms.
ClinicalTrials.gov, number
NCT00650078
doi:10.1136/annrheumdis-2011-201067
PMCID: PMC3553491  PMID: 22562974

Results 1-18 (18)