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2.  mRNA-Expression of ERα, ERβ, and PR in Clonal Stem Cell Cultures Obtained from Human Endometrial Biopsies 
TheScientificWorldJournal  2011;11:1762-1769.
Background. Proliferation and differentiation of the endometrium are regulated by estrogen and progesterone. The enormous regenerative capacity of the endometrium is thought to be based on the activity of adult stem cells. However, information on endocrine regulatory mechanisms in human endometrial stem cells is scarce. In the present study, we investigated the expression of ERα, ERβ, and PR in clonal cultures of human endometrial stem cells derived from transcervical biopsies. Methods. Endometrial tissue of 11 patients was obtained by transcervical biopsy. Stromal cell suspensions were plated at clonal density and incubated for 15 days. Expression of ERα, ERβ and PR was determined by qPCR prior to and after one cloning round, and normalized to 18 S rRNA expression. Results. Expression of ERα and ERβ was downregulated by 64% and 89%, respectively (P = 0.002 and P < 0.001). In contrast, PR was not significantly downregulated, due to a more heterogenous expression pattern. Conclusions. Culture of human endometrial stroma cells results in a downregulation of ERα and ERβ, while expression of PR remained unchanged in our patient collective. These results support the hypothesis that stem cells may not be subject to direct stimulation by sex steroids, but rather by paracrine mechanisms within the stem cell niche.
PMCID: PMC3201690  PMID: 22125434
stem cells; endometrium; estrogen receptor; progesterone receptor;  and endometriosis.
3.  2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis 
Annals of the Rheumatic Diseases  2011;70(6):896-904.
This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made — if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.
PMCID: PMC3086052  PMID: 21540199
4.  Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo-controlled study (SPINE) 
Annals of the Rheumatic Diseases  2011;70(5):799-804.
Patients with advanced ankylosing spondylitis (AS) experience disability because of reduced spinal mobility and pulmonary function impairment. This placebo-controlled study evaluated the effect of etanercept (ETN) in patients with advanced AS.
A multicentre randomised double-blind placebo-controlled trial of 12 weeks' duration was performed. Patients had definite (modified New York criteria), active (Bath AS Disease Activity Index (BASDAI) ≥40), severe (radiological intervertebral bridges) AS refractory to non-steroidal anti-inflammatory drugs and were antitumour necrosis factor naive. They were treated with ETN 50 mg once weekly or identical placebo (PBO).
Of the 95 patients screened, 82 were randomised to receive ETN (n=39) or PBO (n=43). At baseline the disease was active (mean BASDAI 61.0±13.4, C reactive protein (CRP) 20.7±25.5 mg/l) and severe (mean Bath AS Metrology Index (BASMI) 5.7±1.3, mSASSS 36.5±20.5); forced pulmonary vital capacity (FVC) was 3.3±0.7 l. Improvement in BASDAI (normalised net incremental area under the curve between baseline and week 12, primary end point) was significantly greater in the ETN group than in the PBO group (−19.8±16.5 vs −11.0±16.4, p=0.019). Moreover, at week 12, ETN gave better results than PBO for the BASDAI (−26.4±19.7 vs −14.4±19.7; p=0.008), total back pain (−29.2±24.0 vs −14.9±24.0; p=0.010), BASFI (−21.7±17.6 vs −10.1±17.6; p=0.004), BASMI (−0.6±0.6 vs −0.2±0.6; p=0.011), CRP level (−15.7±14.2 vs −1.3±14.2; p<0.001) and FVC (+160±280 ml vs −20±280 ml; p=0.006).
ETN has short-term efficacy for patients with advanced AS, as was previously reported for less advanced disease. The efficacy is observed for the main symptoms (pain) and on markers of inflammation (CRP), as well as disease severity in terms of spinal mobility and pulmonary function.
PMCID: PMC3070274  PMID: 21317434
5.  Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA) 
Annals of the Rheumatic Diseases  2010;70(5):755-759.
To confirm the effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab in patients with rheumatoid arthritis (RA) in a setting close to real-life medical care in Germany.
A multicentre open-label phase IIIb study was undertaken. Patients with active RA with a 28-joint Disease Activity Score (DAS28) >3.2 despite previous disease-modifying antirheumatic drugs (DMARDs) were treated with tocilizumab 8 mg/kg every 4 weeks. The primary end point was the proportion of patients achieving LDAS ≤3.2 at week 24; secondary end points included American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) or Clinical Disease Activity Index (CDAI) responses and decrease in acute phase. Analyses in subgroups such as rheumatoid factor (RF)-positive versus RF-negative patients and patients with an inadequate response to treatment with DMARDs (DMARD-IR) versus those with an inadequate response to tumour necrosis factor (TNF) antagonists (TNF antagonist-IR) were performed. Safety was assessed by adverse event documentation.
286 patients were treated and 83.6% completed the study. 41.6% had previously been treated with TNF antagonists. 57% of the intention-to-treat patients achieved the primary end point of LDAS, 47.6% achieved DAS remission <2.6 and a EULAR ‘good response’ was achieved by 54.9%; ACR50/70 response rates at week 24 were 50.7% and 33.9%, respectively. The mean±SD decrease in CDAI from baseline to week 24 was 71±29%. C reactive protein levels normalised rapidly within 1 week. Major improvements in fatigue, pain and morning stiffness were observed in the first 4 weeks and further improved until week 24. DAS28, EULAR and ACR responses at week 24 did not differ between RF-positive and RF-negative patients. TNF antagonist-naive patients responded better than patients who had previously failed on TNF antagonists. The safety profile of tocilizumab was comparable to that previously observed in the phase III trial programme. Serious infections were observed in 3.1% of patients.
Tocilizumab is highly effective in a setting close to real-life medical care with a rapid and sustained improvement in signs and symptoms of RA. A manageable safety profile was seen over the 24-week study period.
PMCID: PMC3070275  PMID: 21187298
6.  Progression of radiographic damage in patients with ankylosing spondylitis: defining the central role of syndesmophytes 
Annals of the Rheumatic Diseases  2007;66(7):910-915.
Structural changes such as erosions, syndesmophytes and ankylosis are characteristic of ankylosing spondylitis (AS). These can be quantified by the modified Stokes Anklylosing Spondylitis Spinal Score (mSASSS). It is unknown which radiographic feature is most relevant for the assessment of change and the prediction of future damage in AS.
To analyse radiographic progression in AS by using different assessments to define the most important changes.
Spinal radiographs of 116 patients with AS were scored by the mSASSS at baseline (BL) and after 2 years. Radiographic progression was assessed by differentiating (1) any change; (2) progression to syndesmophytes/ankylosis (definite change); and (3) changes exceeding the smallest detectable change (SDC) as predefined. A growth angle of 45° was used to differentiate syndesmophytes from spondylophytes.
Some radiographic progression after 2 years was detected in 42% of patients, novel syndesmophytes in 31% of patients, and, using the SDC (calculated at 2 mSASSS units) as cut‐off, progression was seen in 28% of patients. Thus, in 74% of the patients changes were because of syndesmophytes and/or ankylosis. Using the predefined cut‐off, only 12% of all syndesmophytes were spondylophytes. Patients with such changes were of older age. Definite radiographic progression was found in 44% of the patients with syndesmophytes/ankylosis at BL (n = 57) versus 19% (p = 0.03) of the patients without such changes (n = 59).
Syndesmophytes and ankylosis are the most relevant structural changes in AS, and also in the mSASSS. Development of just one syndesmophyte within 2 years indicates progression of structural changes in AS; this is relevant for clinical practice. Syndesmophytes are the best predictors of radiographic progression.
PMCID: PMC1955120  PMID: 17329306
7.  S3 guidelines for intensive care in cardiac surgery patients: hemodynamic monitoring and cardiocirculary system 
Hemodynamic monitoring and adequate volume-therapy, as well as the treatment with positive inotropic drugs and vasopressors are the basic principles of the postoperative intensive care treatment of patient after cardiothoracic surgery. The goal of these S3 guidelines is to evaluate the recommendations in regard to evidence based medicine and to define therapy goals for monitoring and therapy. In context with the clinical situation the evaluation of the different hemodynamic parameters allows the development of a therapeutic concept and the definition of goal criteria to evaluate the effect of treatment.
Up to now there are only guidelines for subareas of postoperative treatment of cardiothoracic surgical patients, like the use of a pulmonary artery catheter or the transesophageal echocardiography.
The German Society for Thoracic and Cardiovascular Surgery (Deutsche Gesellschaft für Thorax-, Herz- und Gefäßchirurgie, DGTHG) and the German Society for Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und lntensivmedizin, DGAI) made an approach to ensure and improve the quality of the postoperative intensive care medicine after cardiothoracic surgery by the development of S3 consensus-based treatment guidelines.
Goal of this guideline is to assess the available monitoring methods with regard to indication, procedures, predication, limits, contraindications and risks for use. The differentiated therapy of volume-replacement, positive inotropic support and vasoactive drugs, the therapy with vasodilatators, inodilatators and calcium sensitizers and the use of intra-aortic balloon pumps will also be addressed.
The guideline has been developed following the recommendations for the development of guidelines by the Association of the Scientific Medical Societies in Germany (AWMF). The presented key messages of the guidelines were approved after two consensus meetings under the moderation of the Association of the Scientific Medical Societies in Germany (AWMF).
PMCID: PMC2890209  PMID: 20577643
intensive care medicine; cardiothoracic surgery; monitoring; volume therapy; positive inotropic and vasoactive drugs
8.  An international study on starting tumour necrosis factor‐blocking agents in ankylosing spondylitis 
Annals of the Rheumatic Diseases  2006;65(12):1620-1625.
To determine the type and proportion of patients with ankylosing spondylitis who rheumatologists consider to be candidates for treatment with tumour necrosis factor (TNF)‐blocking agents, and to what extent this is in agreement with the ASsessment in Ankylosing Spondylitis (ASAS) international working group recommendations on initiation of treatment with anti‐TNF agents.
Participants were rheumatologists from 10 different countries, who were considered to be experts in treating patients with ankylosing spondylitis and in the use of anti‐TNF treatment, but were unaware of the ASAS recommendations (unpublished at the time of study in 2003). The first 10 consecutive patients with ankylosing spondylitis seen by the rheumatologist were evaluated as to whether the patient was a candidate for anti‐TNF treatment. Thereafter, a metrologist assessed the patient for disease activity and severity, and collected data on demographics and treatment.
Complete data were available for 1207 of the 1284 patients and were used for analysis. Overall, the rheumatologists indicated that they would initiate TNF‐blocking agents in 49.3% of patients, ranging from 37.2% patients in Canada to 78.3% in Australia. These candidates had higher disease activity, higher levels of acute‐phase reactants, worse spinal mobility, worse function, more often hip involvement and a higher prevalence of sick leave. Of all patients considered to be candidates, 40% did not fulfil ASAS recommendations with respect to previous use of non‐steroidal anti‐inflammatory drugs (NSAIDs; at least two NSAIDs) or Bath Ankylosing Spondylitis Disease Activity Index (⩾4). Conversely, 36% of patients who did not fulfil the NSAID or BASDAI recommendations were still considered to be candidates for TNF‐blocking treatment. Objective variables, such as C reactive protein, erythrocyte sedimentation rate or magnetic resonance activity, were considered less important than disease activity in the decision on starting TNF‐blocking drugs. The only important objective criterion was rapid radiographic progression.
Rheumatologists wanted to initiate TNF‐blocking drugs in roughly half of the patients with ankylosing spondylitis. However, there was a wide variation across countries and doctors. Rheumatologists considered both disease activity and severity to be determinants of starting TNF blockers, but their decision was often in disagreement with ASAS recommendations.
PMCID: PMC1798475  PMID: 16464984
9.  Definition of disease duration in ankylosing spondylitis: reassessing the concept 
Annals of the Rheumatic Diseases  2006;65(11):1518-1520.
The concept and definition of disease duration in patients with ankylosing spondylitis is ambiguous, and often many years pass between the onset of symptoms and diagnosis. Members of the Assessment in Ankylosing Spondylitis (ASAS) International Working Group by consensus recently recommended identifying specific components of the medical history to better define and document the concept of disease duration. These include (1) the time of onset of the first symptoms of axial manifestations (including inflammatory back pain); (2) the time of onset of the first symptoms of each individual manifestation, which may be an extra‐axial sign or symptom of ankylosing spondylitis, such as peripheral arthritis and enthesitis; (3) the time of onset of associated diseases belonging to the spondyloarthritides, in particular acute anterior uveitis, inflammatory bowel disease and psoriasis; and (4) the time since actual diagnosis by a healthcare provider. Such uniformity in data collection will ensure comparability across studies and facilitate future research.
PMCID: PMC1798344  PMID: 16464987
10.  Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: a multicentre randomised controlled trial 
Annals of the Rheumatic Diseases  2006;65(9):1147-1153.
To assess the effect of sulfasalazine (SSZ) on inflammatory back pain (IBP) due to active undifferentiated spondyloarthritis (uSpA) or ankylosing spondylitis in patients with symptom duration <5 years.
Patients with IBP and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >3 from 12 centres were randomly assigned to 24 weeks' treatment with SSZ 2 g/day or placebo. The primary outcome variable was the change in BASDAI over 6 months. Secondary outcomes included measures of spinal pain, physical function and inflammation.
230 patients (50% men, age range 18–64 years, 67% human leucocyte antigen B27 positive) were treated with either SSZ 2×1 g/day or placebo for 6 months. Enthesitis was found in 50%, and peripheral arthritis in 47% of the patients. The mean (SD) BASDAI dropped markedly in both groups: by 3.7 (2.7) and 3.8 (2.4), respectively, as did most secondary outcome measures. No noticeable difference in treatment was observed between groups. Patients with IBP and no peripheral arthritis had significantly (p = 0.03) more benefit with SSZ (BASDAI 5.1 (1.3) to 2.8 (2.3)) than with placebo (5.2 (1.6) to 3.8 (2.4)). Spinal pain (p = 0.03) and morning stiffness (p = 0.05) improved with SSZ in these patients, but other secondary outcomes were not markedly different.
SSZ was no better than placebo for the treatment of the signs and symptoms of uSpA; however, SSZ was more effective than placebo in the subgroup of patients with IBP and no peripheral arthritis.
PMCID: PMC1798286  PMID: 16606646
11.  The process of producing recommendations for rheumatic diseases: what is evidence? 
PMCID: PMC1798197  PMID: 16308340
ankylosing spondylitis; evidence; recommendations
12.  Immunohistological examination of open sacroiliac biopsies of patients with ankylosing spondylitis: detection of tumour necrosis factor α in two patients with early disease and transforming growth factor β in three more advanced cases 
Annals of the Rheumatic Diseases  2005;65(6):713-720.
To characterise the immunohistological features of sacroiliitis in ankylosing spondylitis (AS) at different disease stages.
Biopsy samples from sacroiliac joints (SIJs) of five patients with AS, two with early, three with advanced changes and samples from age matched controls from one necropsy SIJ and two iliac bone marrow (BM) biopsies were studied. Paraffin sections were immunostained in triplicate for T cells (CD3, CD8), macrophages (CD68), and the cytokines tumour necrosis factor α (TNFα), interferon γ, interleukin (IL) 1β, IL6, IL10, and transforming growth factor β1 (TGFβ1). Stained cells were counted over one entire high power field (×400) per section in BM, cartilage, and other connective tissue (CT). Results are the mean of three sections.
CD3+ T cells were numerous in the BM of early AS, and in the CT of one patient with early and one with late AS, with variable proportions of CD8+ T cells. All patients with AS had more CD68+ macrophages than controls in BM and CT; in cartilage, one patient with early and one with late AS had increased CD68+ cells, some being osteoclasts. The patient with very early AS had large numbers of TNFα cells in the three tissular areas; for the other patient with early disease they were found only in CT and cartilage. IL6 was seen in 4/4 patients with AS in most areas. Patients with early disease had more T cells, TNFα, and IL6, and patients with advanced AS more TGFβ1.
The immunohistological findings of a limited sample suggest a role for BM in sacroiliitis, for TNFα and IL6 in early, active lesions, and for TGFβ1 at the time of secondary cartilage and bone proliferation.
PMCID: PMC1798185  PMID: 16249231
ankylosing spondylitis; sacroiliitis; immunohistology; tumour necrosis factor α; transforming growth factor β
13.  ASAS/EULAR recommendations for the management of ankylosing spondylitis 
Annals of the Rheumatic Diseases  2005;65(4):442-452.
To develop evidence based recommendations for the management of ankylosing spondylitis (AS) as a combined effort of the ‘ASsessment in AS' international working group and the European League Against Rheumatism.
Each of the 22 participants was asked to contribute up to 15 propositions describing key clinical aspects of AS management. A Delphi process was used to select 10 final propositions. A systematic literature search was then performed to obtain scientific evidence for each proposition. Outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, relative risk, number needed to treat, and incremental cost effectiveness ratio were calculated. On the basis of the search results, 10 major recommendations for the management of AS were constructed. The strength of recommendation was assessed based on the strength of the literature evidence, risk‐benefit trade‐off, and clinical expertise.
The final recommendations considered the use of non‐steroidal anti‐inflammatory drugs (NSAIDs) (conventional NSAIDs, coxibs, and co‐prescription of gastroprotective agents), disease modifying antirheumatic drugs, treatments with biological agents, simple analgesics, local and systemic steroids, non‐pharmacological treatment (including education, exercise, and physiotherapy), and surgical interventions. Three general recommendations were also included. Research evidence (categories I–IV) supported 11 interventions in the treatment of AS. Strength of recommendation varied, depending on the category of evidence and expert opinion.
Ten key recommendations for the treatment of AS were developed and assessed using a combination of research based evidence and expert consensus. Regular updating will be carried out to keep abreast of new developments in the management of AS.
PMCID: PMC1798102  PMID: 16126791
ankylosing spondylitis; management; recommendations; evidence based medicine; spondyloarthropathies; ASAS; EULAR
14.  Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis 
Annals of the Rheumatic Diseases  2005;65(4):423-432.
To assess available management strategies in ankylosing spondylitis (AS) using a systematic approach, as a part of the development of evidence based recommendations for the management of AS.
A systematic search of Medline, Embase, CINAHL, PEDro, and the Cochrane Library was performed to identify relevant interventions for the management of AS. Evidence for each intervention was categorised by study type, and outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, rate ratio, number needed to treat, and incremental cost effectiveness ratio were calculated for each intervention where possible. Results from randomised controlled trials were pooled where appropriate.
Both pharmacological and non‐pharmacological interventions considered to be of interest to clinicians involved in the management of AS were identified. Good evidence (level Ib) exists supporting the use of non‐steroidal anti‐inflammatory drugs (NSAIDs) and coxibs for symptomatic treatment. Non‐pharmacological treatments are also supported for maintaining function in AS. The use of conventional antirheumatoid arthritis drugs is not well supported by high level research evidence. Tumour necrosis factor inhibitors (infliximab and etanercept) have level Ib evidence supporting large treatment effects for spinal pain and function in AS over at least 6 months. Level IV evidence supports surgical interventions in specific patients.
This extensive literature review forms the evidence base considered in the development of the new ASAS/EULAR recommendations for the management of AS.
PMCID: PMC1798100  PMID: 16126792
ankylosing spondylitis; evidence based medicine; systematic review
15.  First update of the international ASAS consensus statement for the use of anti‐TNF agents in patients with ankylosing spondylitis 
Annals of the Rheumatic Diseases  2005;65(3):316-320.
To update the international recommendations for use of anti‐tumour necrosis factor (TNF) agents in the treatment of ankylosing spondylitis.
The published recommendations on anti‐TNF treatment in ankylosing spondylitis formed the basis of the update. A questionnaire was sent to the ASAS (assessment in ankylosing spondylitis) members before the final decisions were agreed upon at an international meeting of the ASAS working group.
Only minor changes to the original consensus statement were required. For the initiation of anti‐TNF treatment, there should be: a diagnosis of definitive ankylosing spondylitis (normally based on modified New York criteria); active disease for at least four weeks, as defined by a sustained Bath ankylosing spondylitis disease activity index (BASDAI) of ⩾4 on a 0–10 scale and expert opinion based on clinical findings; refractory disease, defined by failure of at least two non‐steroidal anti‐inflammatory drugs during a three month period, failure of intra‐articular steroids (if indicated), and failure of sulfasalazine in patients with predominantly peripheral arthritis; and application of the usual precautions and contraindications for biological treatment. For monitoring anti‐TNF treatment: both the ASAS core set for clinical practice and the BASDAI should be followed after the initiation of treatment. Discontinuation of anti‐TNF treatment in non‐responders should be considered after 6–12 weeks. Response is defined by improvement of at least 50% or 2 units (on a 0–10 scale) of the BASDAI.
This updated consensus statement is recommended in guiding clinical practice and as a basis for developing national guidelines. Evaluation and regular update of this consensus statement is subject to further research by the ASAS group.
PMCID: PMC1798064  PMID: 16096329
ankylosing spondylitis; tumour necrosis factor α; infliximab; etanercept; adalimumab
16.  Markov model into the cost‐utility over five years of etanercept and infliximab compared with usual care in patients with active ankylosing spondylitis 
Annals of the Rheumatic Diseases  2005;65(2):201-208.
To estimate the incremental cost‐utility of etanercept and infliximab compared with usual care in active ankylosing spondylitis.
A Markov model over five years with cycle times of three months was computed. Patients included all had active disease, defined as Bath ankylosing spondylitis disease activity index (BASDAI) ⩾4 and could reach low disease activity, defined as BASDAI <4. Non‐response to tumour necrosis factor α (TNFα) inhibitors was always followed by cessation of treatment. Response to TNFα inhibitors could be followed at any time by either relapse to BASDAI ⩾4, leading to cessation of treatment, or toxicity, leading to cessation of treatment if major. Probabilities for efficacy, relapse, and toxicity were derived from two European randomised controlled trials. Utilities and costs assigned to the BASDAI disease states were derived from a two year observational Dutch cohort. In sensitivity analyses probabilities of effectiveness, toxicity, costs, and utilities were varied.
Over five years the total quality adjusted life years varied from 2.57 to 2.89 for usual care, compared with 3.13 to 3.42 and 3.07 to 3.35 for etanercept or infliximab. Cumulative costs were between €49 555 to 69 982 for usual care compared with €59 574 to 91 183 or €28 3330 to 106 775 for etanercept and infliximab. This resulted in incremental cost‐utility ratios varying between €42 914 and 123 761 per QALY for etanercept compared with usual care and €67 207 to 237 010 for infliximab. The model was sensitive to drug prices.
Etanercept and infliximab have large clinical effects in ankylosing spondylitis. The present model suggests the high drug costs restricts efficient use in all patients who have a BASDAI >4. The validity of the model is limited by insufficient insight in the natural course of the disease and long term effectiveness and toxicity of TNFα inhibitors.
PMCID: PMC1798006  PMID: 16014677
ankylosing spondylitis; etanercept; infliximab; TNFα inhibitors; cost‐effectiveness
17.  Dissemination and evaluation of the ASAS/EULAR recommendations for the management of ankylosing spondylitis: results of a study among 1507 rheumatologists 
Annals of the Rheumatic Diseases  2008;67(6):782-788.
Ten ASAS/EULAR recommendations for the management of ankylosing spondylitis (AS) were published in 2006.
(a) To disseminate and (b) to evaluate conceptual agreement with, and (c) application of, these recommendations as well as (d) potential barriers to the application.
A questionnaire was sent to rheumatologists in 10 countries. It included (a) the text of the recommendations; (b) rheumatologists’ demographic variables; (c) two numerical rating scales from 1 to 10 for each recommendation: conceptual agreement with, and application of, the recommendation (10 indicates maximal agreement and maximal application); and (d) a list of potential barriers to the application of the recommendation. Statistical analysis included descriptive and multivariate analyses.
7206 questionnaires were sent out; 1507 (21%) were returned. Of the 1507 answering rheumatologists, 62% were men, mean (SD) age 49 (9) years, and 34% had an academic position. Conceptual agreement with the recommendations was high (mean (SD) for all recommendations 8.9 (0.9)). Self-reported application was also high (8.2 (1.0)). The difference between agreement and application varied across recommendations and countries. The most pronounced discrepancies were reported for use of anti-tumour necrosis factor drugs in a few countries, with funding as the most commonly reported barrier for application of this recommendation.
This large project has helped the dissemination of the ASAS/EULAR recommendations for the management of AS and shows that conceptual agreement with the recommendations is very high. The project also highlights inequalities in access to healthcare for European citizens with AS.
PMCID: PMC2565578  PMID: 18055468
19.  Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks 
Annals of the Rheumatic Diseases  2005;64(11):1557-1562.
Objective: To evaluate the continued safety and durability of clinical response in patients with ankylosing spondylitis receiving etanercept.
Methods: 277 patients who had participated in a previous randomised, double blind, placebo controlled 24 week trial were eligible to continue in this open label extension study. All patients who enrolled in the open label extension (n = 257) received subcutaneous etanercept 25 mg twice weekly for up to 72 weeks, for a combined 96 weeks of cumulative trial and open label experience. For the patients who had received etanercept for 24 weeks in the double blind trial, this represented almost 2 years of continuous etanercept treatment.
Results: Patients continuing etanercept treatment had a sustained response for almost 2 years, with 74% achieving an ASsessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks of etanercept treatment. Patients who had received placebo in the preceding double blind trial had similar responses, with 70% of patients attaining an ASAS 20 response after 24 weeks of etanercept treatment and 78% achieving an ASAS 20 response after 72 weeks. Improved spinal mobility was seen in both groups. Etanercept was well tolerated in patients treated for up to 96 weeks.
Conclusion: The subcutaneous administration of twice weekly doses of etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis for nearly 2 years.
PMCID: PMC1755272  PMID: 15843448
20.  Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumour necrosis factor α antibody infliximab 
Annals of the Rheumatic Diseases  2005;64(10):1462-1466.
Background: Anti-tumour necrosis factor (TNF) treatment is clinically efficacious in patients with active ankylosing spondylitis (AS) and leads to improvement of spinal inflammation, as assessed by magnetic resonance imaging. It is unclear whether anti-TNF treatment affects chronic spinal changes in AS.
Objectives: To analyse the effect of infliximab on the radiographic course of AS over 2 years.
Methods: Complete sets of lateral radiographs of the cervical spine and lumbar spine were available from 82 patients from two sources: 41 patients (group 1) had been treated with infliximab (5 mg/kg/6 weeks) as part of a recent randomised controlled trial and 41 patients (group 2) were part of the early German AS cohort (GESPIC), without controlled interventions. Radiographs were obtained at baseline and after 2 years and scored by the modified Stokes AS Spinal Score (mSASSS).
Results: Patients in the infliximab group were older, had a longer disease duration, and more radiographic damage at baseline. The mean (SD) mSASSS change was 0.4 (2.7) and 0.7 (2.8) for groups 1 and 2, respectively (p = NS). Radiographic damage at baseline was a predictor for more radiographic progression. Patients with baseline damage who were treated with infliximab showed a trend for less radiographic progression. No correlations between clinical parameters and radiographic progression were found.
Conclusions: Patients with AS treated with infliximab had less radiographic progression after 2 years. Patients with prevalent radiographic damage are prone to develop more damage over time. Infliximab may decelerate radiographic progression in such patients. Larger studies are needed to prove that anti-TNF treatment inhibits structural damage.
PMCID: PMC1755223  PMID: 15778240
22.  Magnetic resonance imaging of the spine and the sacroiliac joints in ankylosing spondylitis and undifferentiated spondyloarthritis during treatment with etanercept 
Annals of the Rheumatic Diseases  2005;64(9):1305-1310.
Objective: To assess the changes in inflammatory lesions of the spine and the sacroiliac (SI) joints as detected by magnetic resonance imaging (MRI) in patients with ankylosing spondylitis (AS) and undifferentiated spondyloarthritis (uSpA) with predominant axial symptoms during treatment with etanercept.
Methods: MRI of the spine and/or the SI joints of patients with active AS or axial uSpA was performed at baseline (TP0, n = 25), after 6 weeks (TP1, n = 20), and after 24 weeks of continuous treatment with etanercept (TP2, n = 12). T1 weighted spin echo pre -(T1), post-gadolinium (T1/Gd-DTPA) and short tau inversion recovery (STIR) MRI sequences were used to assess chronic and active spinal lesions using the scoring system ASspiMRI. Active and chronic SI lesions were assessed using a simple scoring system.
Results: By use of the definite STIR sequence, significant regression of spinal inflammation was already seen already after 6 weeks in the patients treated with etanercept (mean (SD) 11.2 (13.8) at TP0 v 6.8 (7.9) at TP1; p = 0.023) but not in patients treated with placebo. Continuous treatment with etanercept for 24 weeks reduced active spinal changes by 69% (p = 0.012). T1/Gd-DTPA sequences gave similar results. There was only a trend for a decrease of active inflammatory lesions of the SI joints.
Conclusions: Etanercept treatment in patients with active AS and uSpA leads to regression of active inflammatory lesions of the spine as depicted by MRI. The potential role of etanercept on deceleration of chronic spinal changes needs further study.
PMCID: PMC1755637  PMID: 15778243
23.  Assessment of acute spinal inflammation in patients with ankylosing spondylitis by magnetic resonance imaging: a comparison between contrast enhanced T1 and short tau inversion recovery (STIR) sequences 
Annals of the Rheumatic Diseases  2005;64(8):1141-1144.
Objectives: To compare the performance of two different MRI sequences—T1 weighted, fat saturated, spin echo after application of contrast medium, and short τ inversion recovery (STIR) sequences—to detect spinal inflammation in patients with ankylosing spondylitis (AS).
Methods: Both MRI sequences were performed in 38 patients with active AS and compared using the MRI activity scoring system, ASspiMRI-a. One vertebral unit (VU) was defined as the region between two virtual lines drawn through the middle of each vertebral body.
Results: Intraclass correlation coefficients were excellent—0.91 and 0.86 for the Gd-DTPA and STIR sequences, respectively. The overall correlation of the single MRI scores for both sequences was also good (r = 0.84, p = 0.01). The intrarater variance was 6.71 and 9.41 and the interrater variance was 13.16 and 19.04 for the Gd-DTPA and STIR sequences, respectively. The smallest detectable distance was 4.7 and 5.6 for the Gd-DTPA and STIR sequences, respectively. The concordance rate for both sequences was 83.5% (range 80.5–87.7% in the three spinal segments). Inflammatory spinal lesions were found in 10.1% of the VUs in the STIR sequence but not in the T1/Gd-DTPA sequence, while the T1/Gd-DTPA sequence showed inflammatory lesions in 6.4% of the VUs that were found normal by STIR.
Conclusions: Both MRI techniques can evaluate active spinal lesions in patients with AS. More spinal lesions are detected by the STIR sequence, but the reliability between readings and readers is better for the Gd-DTPA sequence. The ASspiMRI-a is a reliable instrument for evaluating acute spinal changes in AS.
PMCID: PMC1755589  PMID: 15650011
24.  Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis 
Annals of the Rheumatic Diseases  2008;68(2):175-182.
To evaluate the relationship between bone mineral density (BMD) and biomarkers of bone turnover and inflammation in patients with ankylosing spondylitis (AS) treated with infliximab.
Patients (n = 279) were randomly assigned (3:8) to receive placebo or 5 mg/kg infliximab every 6 weeks through week 96. At week 24, placebo-treated patients crossed over to infliximab 5 mg/kg. Starting at week 36, patients treated with infliximab received dose escalations to 7.5 mg/kg. Hip and spine BMD were measured (baseline, week 24, week 102) using dual-energy x-ray absorptiometry. Sera were analysed (baseline, week 24, week 102) for levels of bone alkaline phosphatase (BAP), osteocalcin, C-terminal cross-linking telopeptide of type I collagen (CTX), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) and transforming growth factor-β.
Patients treated with infliximab showed significantly greater median increases in BMD of the spine (2.5%, p<0.001) and hip (0.5%, p = 0.033) at week 24 than those who received placebo (0.5% and 0.2% respectively). Baseline levels of IL-6, VEGF, osteocalcin, BAP and CTX were significantly correlated with increases in spinal BMD at weeks 24 and 102 in the infliximab group. In a multiple regression analysis, high baseline osteocalcin levels and early increases in BAP at week 2 were significantly associated with increases in BMD scores of the spine (week 102) and hip (weeks 24 and 102) in the infliximab group.
Patients with AS who received infliximab showed significant increases in BMD scores over 2 years. While many significant correlations were observed between BMD scores of the hip and spine and biomarker levels, high baseline osteocalcin levels and early increases in BAP were consistently associated with increases in BMD scores.
PMCID: PMC2605572  PMID: 18495735
25.  Inflammation in ankylosing spondylitis: a systematic description of the extent and frequency of acute spinal changes using magnetic resonance imaging 
Annals of the Rheumatic Diseases  2004;64(5):730-734.
Background: Magnetic resonance imaging (MRI) is increasingly used to detect inflammation in the spine of patients with ankylosing spondylitis (AS).
Objectives: To detect differentially the presence and extent of inflammation in the three spinal segments of patients with AS by MRI.
Methods: In 38 patients with active AS, acute spinal lesions were assessed by T1 weighted, gadolinium enhanced, spin echo MRI (T1/Gd-DTPA) and short τ inversion recovery (STIR) sequences. MRI was quantified by the validated scoring system ASspiMRI-a. Acute spinal lesions were detected in the whole spine and in each spinal segment. One vertebral unit (VU) was defined as the region between two virtual lines drawn through the middle of each vertebral body.
Results: A greater number of inflammatory spinal lesions were found by the STIR sequence than by Gd-DTPA: inflammation was present in 30.6% of the VUs as assessed by STIR, compared with 26.8% of the same VUs assessed by T1/Gd-DTPA. Inflammation was found more commonly in the thoracic spine (TS) than in the cervical (CS) or the lumbar spine (LS) with both techniques. When STIR was used, spinal inflammation in the CS, the TS, and LS was detected in 10/38 (26%), 28/38 (74%), and 9/38 (24%) patients, respectively. The VU T7/8 was found to be the VU most often affected by both techniques (27.8% by T1/Gd-DTPA and 34.5% by STIR).
Conclusions: Spinal inflammation is a common manifestation in patients with AS, and appears more frequently in the TS. The scoring system ASspiMRI-a can be used for evaluation of acute spinal changes in AS.
PMCID: PMC1755467  PMID: 15458963

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