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1.  Computer-Based Diagnostic Expert Systems in Rheumatology: Where Do We Stand in 2014? 
Background. The early detection of rheumatic diseases and the treatment to target have become of utmost importance to control the disease and improve its prognosis. However, establishing a diagnosis in early stages is challenging as many diseases initially present with similar symptoms and signs. Expert systems are computer programs designed to support the human decision making and have been developed in almost every field of medicine. Methods. This review focuses on the developments in the field of rheumatology to give a comprehensive insight. Medline, Embase, and Cochrane Library were searched. Results. Reports of 25 expert systems with different design and field of application were found. The performance of 19 of the identified expert systems was evaluated. The proportion of correctly diagnosed cases was between 43.1 and 99.9%. Sensitivity and specificity ranged from 62 to 100 and 88 to 98%, respectively. Conclusions. Promising diagnostic expert systems with moderate to excellent performance were identified. The validation process was in general underappreciated. None of the systems, however, seemed to have succeeded in daily practice. This review identifies optimal characteristics to increase the survival rate of expert systems and may serve as valuable information for future developments in the field.
PMCID: PMC4119620  PMID: 25114683
3.  Multidimensional associative factors for improvement in pain, function, and working capacity after rehabilitation of whiplash associated disorder: a prognostic, prospective outcome study 
Whiplash associated disorders (WAD) have dramatic consequences for individual and public health. Risk factors for better and worse outcomes are important to optimize management. This study aimed to determine short- and mid-term associative co-factors of neck pain relief, improved physical functioning, and improved working capacity (dependent variables) in patients suffering from whiplash associated disorder who participated in a standardized, inpatient pain management program.
Naturalistic, observational, prospective cohort study. Outcome was measured by standardized assessment instruments. Co-factors covered sociodemographics, comorbidities, social participation, affective health, and coping abilities. Stepwise, multivariate linear regression analysis was performed at discharge and at the 6-month follow-up.
All regression models explained high proportions of variance (53.3% – 72.1%). The corresponding baseline level was significantly associated with a change in every dependent variable (explained variances: 11.4%-56.7%). Pain relief significantly depended on improved function and vice-versa (3.4%-14.8%). Improved ability to decrease pain was associated with pain relief at discharge (9.6%). Functional improvement was associated with decreased catastrophizing (19.4%) at discharge and decreased depression (20.5%) at the 6 month follow-up.
Pain relief, improved physical function and working capacity were associated with each other. Improved coping (catastrophizing and ability to decrease pain) and reduced depression may act as important predictors for pain relief and improved function. These findings offer toe-holds for optimized therapy of chronic WAD.
PMCID: PMC3996256  PMID: 24739588
Whiplash; Prediction; Pain; Function; Coping; Catastrophizing
4.  Relevant baseline characteristics for describing patients with knee osteoarthritis: results from a Delphi survey 
Inclusion/exclusion criteria and baseline characteristics are essential for assessing the applicability of trial results to a given patient and the comparability of study populations for meta-analyses. This Delphi survey aimed to generate a set of baseline characteristics for describing patients with knee osteoarthritis enrolled in clinical studies.
Survey participants comprised clinical experts (n = 23; mean age 54 y; from 4 continents) that had authored at least two randomized trials on knee osteoarthritis. First, given a prepared list of baseline patient characteristics, the experts were asked to add characteristics they considered important for assessing comparability of patient populations in different trials that evaluated the efficacy of non-surgical interventions for treating knee osteoarthritis. Next, they were asked to rate the importance of each characteristic, on a scale of 0 (not important) to 10 (highly important), according to three outcome categories: pain, function, and structure.
Participants identified 121 baseline characteristics. A rating ≥7 points was assigned to 39 characteristics (e.g., age, depression, global knee pain, daily dose of pain killers, Kellgren-Lawrence grading); of these, 20 were related to pain, 15 to function, and 23 to structural outcomes. Global knee pain was the only baseline characteristic that fulfilled among experts the predefined consensus criteria.
Experts identified a large number of characteristics for describing patients with knee osteoarthritis. Disagreement and uncertainty prevailed over the relevance of these characteristics. Our findings justified further efforts to define appropriate, broadly acceptable sets of baseline characteristics for describing patients with knee osteoarthritis.
PMCID: PMC3882493  PMID: 24373617
Knee osteoarthritis; Baseline characteristics; Inclusion criteria; Comparability; Applicability; Clinical trial
5.  High bone turnover assessed by 18F-fluoride PET/CT in the spine and sacroiliac joints of patients with ankylosing spondylitis: comparison with inflammatory lesions detected by whole body MRI 
EJNMMI Research  2012;2:38.
This study compares the frequency and distribution of increased activity on 18 F-fluoride PET/CT with the presence of bone marrow edema on whole-body MR imaging in the spine and sacroiliac joints (SIJ) of patients with active ankylosing spondylitis (AS).
Ten patients (6 men and 4 women), between 30 and 58 years old (median 44) with active AS, were prospectively examined with both whole-body MRI and 18 F-fluoride PET/CT. Patients fulfilled modified NY criteria and had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of at least 4. Increased radiotracer uptake in PET/CT and bone marrow edema in whole-body MRI of spine and SIJ was evaluated independently by two blinded observers for each modality. Kappa statistics were used to compare interobserver agreement as well as scores of consensus reading of the two imaging modalities.
Analysis of interobserver agreement for PET/CT yielded a kappa value of 0.68 for spinal lesions and of 0.88 for SIJ lesions. The corresponding kappa values for the MRI modality were 0.64 and 0.93, respectively. More spinal lesions were detected by MRI in comparison to PET/CT (68 vs. 38), whereas a similar number of SIJ quadrants scored positive in both modalities (19 vs. 17). Analysis of agreement of lesion detection between both imaging modalities yielded a kappa value of only 0.25 for spinal lesions and of 0.64 for SIJ lesions.
Increased 18 F-fluoride uptake in PET/CT is only modestly associated with bone marrow edema on MRI in the spine and SIJ of patients with AS, suggesting different aspects of bone involvement in AS.
PMCID: PMC3472173  PMID: 22788874
18F-fluoride PET/CT; Whole-body MRI; Ankylosing spondylitis; Syndesmophytes; Inflammation
10.  LumbSten: The lumbar spinal stenosis outcome study 
Lumbar spinal stenosis is the most frequent reason for spinal surgery in elderly people. For patients with moderate or severe symptoms different conservative and surgical treatment modalities are recommended, but knowledge about the effectiveness, in particular of the conservative treatments, is scarce. There is some evidence that surgery improves outcome in about two thirds of the patients. The aims of this study are to derive and validate a prognostic prediction aid to estimate the probability of clinically relevant improvement after surgery and to gain more knowledge about the future course of patients treated by conservative treatment modalities.
This is a prospective, multi-centre cohort study within four hospitals of Zurich, Switzerland. We will enroll patients with neurogenic claudication and lumbar spinal stenosis verified by Computer Tomography or Magnetic Resonance Imaging. Participating in the study will have no influence on treatment modality. Clinical data, including relevant prognostic data, will be collected at baseline and the Swiss Spinal Stenosis Questionnaire will be used to quantify severity of symptoms, physical function characteristics, and patient's satisfaction after treatment (primary outcome). Data on outcome will be collected 6 weeks, and 6, 12, 24 and 36 months after inclusion in the study. Applying multivariable statistical methods, a prediction rule to estimate the course after surgery will be derived.
The ultimate goal of the study is to facilitate optimal, knowledge based and individualized treatment recommendations for patients with symptomatic lumbar spinal stenosis.
PMCID: PMC2987977  PMID: 21044326
12.  Effect of the oral application of a highly selective MMP-13 inhibitor in three different animal models of rheumatoid arthritis 
Annals of the Rheumatic Diseases  2009;69(5):898-902.
To evaluate the decrease of cartilage destruction by a novel orally active and specific matrix metalloproteinase 13 (MMP-13) inhibitor in three different animal models of rheumatoid arthritis (RA).
Materials and methods
The SCID mouse co-implantation model of RA, the collagen-induced arthritis (CIA) model in mice and the antigen-induced arthritis model (AIA) in rabbits were used.
In the SCID mouse co-implantation model, the MMP-13 inhibitor reduced cartilage destruction by 75%. In the CIA model of RA, the MMP-13 inhibitor resulted in a significant and dose-dependent decrease in clinical symptoms as well as of cartilage erosion by 38% (30 mg/kg), 28% (10 mg/kg) and 21% (3 mg/kg). No significant effects were seen in the AIA model. No toxic effects were seen in all three animal models.
Although several MMPs in concert with other proteinases have a role in the process of cartilage destruction, there is a need for highly selective MMP inhibitors to reduce severe side effects that occur with non-specific inhibitors. Significant inhibition of MMP-13 reduced cartilage erosions in two of three tested animal models of RA. These results strongly support the development of this class of drugs to reduce or halt joint destruction in patients with RA.
PMCID: PMC2925150  PMID: 19497915
13.  Do MRI findings correlate with mobility tests? An explorative analysis of the test validity with regard to structure 
European Spine Journal  2006;16(6):803-812.
To find out whether segmental magnetic resonance imaging (MRI) findings such as intervertebral disc degeneration (DD) and facet joint osteoarthritis (FJO) are associated with motion deficiencies as seen in common mobility tests and observed range of motion (ROM). A total of 112 female subjects, nurses and office workers, with and without low back pain, were examined by clinical experts, and lumbar mobility was measured including modified Schober, fingertip-to-floor distance (FTFD) and ZEBRIS motion analysis. An MRI of the lumbar spine was made. Mobility findings were correlated with segmental morphologic changes as seen on MRI at the levels of L1-2 through L5-S1. Only a few statistically significant correlations between MRI findings and the results of the mobility tests could be found. Lateral bending was weakly and negatively correlated to DD and FJO but only on the level of L5-S1. The FTFD showed a weak positive correlation to endplate changes on the level of L4-5. When ROM is observed by clinical experts, there are several significant relationships between MRI findings and the observed motion. There is a highly significant segmental correlation between DD and disc form alteration as seen on MRI on the level of single motion segments. Pain history and current pain level did not moderate any association between MRI and mobility. There is no clear relationship between the structural changes represented by MRI and the measured mobility tests used in this study. Our findings suggest that close observation of spinal motion may provide at least equal information about the influence of spinal structures on motion than the commonly used measured mobility tests do.
PMCID: PMC2200719  PMID: 17143634
Spine; Spine abnormalities; Spine mobility; Intervertebral disk; Facet joints; Spine range of motion
14.  DREAM is reduced in synovial fibroblasts of patients with chronic arthritic pain: is it a suitable target for peripheral pain management? 
The endogenous pain-relieving system depends in part on the regulation of nociceptive signals through binding of opioids to the corresponding opioid receptor. Interfering with the trans-repression effect of downstream regulatory element antagonist modulator (DREAM) on the transcription of the opioid dynorphin-encoding prodynorphin (pdyn) gene might enhance pain relief in the periphery.
Expression levels were measured in osteoarthritis (OA) synovial fibroblast-like cells (SFLCs) (n = 8) and in peripheral blood mononuclear cells (PBMCs) from OA patients (n = 53) and healthy controls (n = 26) by real-time polymerase chain reaction. Lysed OA SFLCs were analyzed by immunoprecipitation. Translation of DREAM mRNA was inhibited by small interfering RNAs (siRNAs). Expressions of DREAM, pdyn, and c-fos mRNAs were measured at 24, 48, and 72 hours after transfection.
The expression of DREAM mRNA was shown in both healthy and OA SFLCs as well as PBMCs. Inhibiting transcription using siRNAs led to a marked reduction in DREAM expression after 24, 48, and 72 hours. However, no significant changes in c-fos and pdyn expression occurred. In addition, DREAM mRNA expression was significantly reduced in OA patients with chronic pain (pain intensity as measured by a visual analog scale scale of greater than 40), but no pdyn expression was detectable.
To our knowledge, this is the first report showing the expression of DREAM in SFLCs and PBMCs on the mRNA level. However, DREAM protein was not detectable. Since repression of pdyn transcription persists after inhibiting DREAM translation, DREAM appears to play no functional role in the kappa opioid receptor system in OA SFLCs. Therefore, our data suggest that DREAM appears not to qualify as a target in peripheral pain management.
PMCID: PMC2483451  PMID: 18507845
15.  Influence of an outpatient multidisciplinary pain management program on the health-related quality of life and the physical fitness of chronic pain patients 
Approximately 10 to 20 percent of the population is suffering from chronic pain. Since this represents a major contribution to the costs of the health care system, more efficient measures and interventions to treat these patients are sought.
The development of general health and physical activity of patients with chronic pain was assessed in an interdisciplinary outpatient pain management program (IOPP). 36 patients with an average age of 48 years were included in the IOPP. Subjective assessment of well-being was performed at five time points (baseline, post intervention and 3, 6, and 12 months thereafter) by using standardized questionnaires. The study focused on the quality of life survey Medical Outcomes Study Short Form-36, which is a validated instrument with established reliability and sensitivity. In addition, the patients participated in physical assessment testing strength, power, endurance, and mobility.
Prior to therapy a substantial impairment was found on different levels. Marked improvements in the psychological parameters were obtained by the end of the program. No success was achieved with regard to the physical assessments.
Although many different studies have evaluated similar programs, only few of them have attained positive results such as improvements of general quality of life or of physical strength. Often no difference from the control group could be detected only some months after the intervention. In the present study no significant persistent improvement of well-being occurred. Possible reasons are either wrong instruments, wrong selection of patients or wrong interventions.
PMCID: PMC404467  PMID: 15028119
Low back pain; depression; chronification; pain intervention program; quality of life
16.  Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers 
Arthritis Research  2002;4(6):R11.
To examine whether the lack of sufficient neoangiogenesis in systemic sclerosis (SSc) is caused by a decrease in angiogenic factors and/or an increase in angiostatic factors, the potent proangiogenic molecules vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, and the angiostatic factor endostatin were determined in patients with SSc and in healthy controls. Forty-three patients with established SSc and nine patients with pre-SSc were included in the study. Serum levels of VEGF, basic fibroblast growth factor and endostatin were measured by ELISA. Age-matched and sex-matched healthy volunteers were used as controls. Highly significant differences were found in serum levels of VEGF between SSc patients and healthy controls, whereas no differences could be detected for endostatin and basic fibroblast growth factor. Significantly higher levels of VEGF were detected in patients with Scl-70 autoantibodies and in patients with diffuse SSc. Patients with pre-SSc and short disease duration showed significant higher levels of VEGF than healthy controls, indicating that elevated serum levels of VEGF are a feature of the earliest disease stages. Patients without fingertip ulcers were found to have higher levels of VEGF than patients with fingertip ulcers. Levels of endostatin were associated with the presence of giant capillaries in nailfold capillaroscopy, but not with any other clinical parameter. The results show that the concentration of VEGF is already increased in the serum of SSc patients at the earliest stages of the disease. VEGF appears to be protective against ischemic manifestations when concentrations of VEGF exceed a certain threshold level.
PMCID: PMC153841  PMID: 12453314
basic fibroblast growth factor; endostatin; fingertip ulcers; systemic sclerosis; vascular endothelial growth factor
17.  Molecular profile of synovial fibroblasts in rheumatoid arthritis depends on the stage of proliferation 
Arthritis Research  2002;4(5):R8.
The aim of this study was to explore the molecular profile of proliferating rheumatoid arthritis synovial fibroblasts (RA-SF). Total RNA was extracted from two cultures of RA-SF (low-density [LD] proliferating cells and high-density [HD] nonproliferating cells) and suppression subtractive hybridization was performed to compare differential gene expression of these two cultures. Subtracted cDNA was subcloned, and nucleotide sequences were analyzed to identify each clone. Differential expression of distinct clones was confirmed by semiquantitative RT-PCR. The expression of certain genes in synovial tissues was examined by in situ hybridization. In both LD and HD cells, 44 clones were upregulated. Of the 88 total clones, 46 were identical to sequences that have previously been characterized. Twenty-nine clones were identical to cDNAs that have been identified, but with unknown functions so far, and 13 clones did not show any significant homology to sequences in GenBank (NCBI). Differential expression of distinct clones was confirmed by RT-PCR. In situ hybridization showed that certain genes, such as S100A4, NFAT5, unr and Fbx3, were also expressed predominantly in synovial tissues from patients with RA but not from normal individuals. The expression of distinct genes in proliferating RA-SF could also be found in RA synovium, suggesting that these molecules are involved in synovial activation in RA. Most importantly, the data indicate that the expression of certain genes in RA-SF depends on the stage of proliferation; therefore, the stage needs to be considered in any analysis of differential gene expression in SF.
PMCID: PMC125298  PMID: 12223111
differential gene expression; molecular profile; proliferation; rheumatoid arthritis; synovial fibroblasts
18.  Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis 
Annals of the Rheumatic Diseases  2013;73(10):1898-1904.
Identification of parameters for early diagnosis and treatment response would be beneficial for patients with early rheumatoid arthritis (ERA) to prevent ongoing joint damage. miRNAs have features of potential biomarkers, and an altered expression of miRNAs was shown in established rheumatoid arthritis (RA).
To analyse RA associated miRNAs in the sera of patients with ERA to find markers of early disease, clinical activity or predictors of disease outcome.
Total RNA was isolated from whole sera in ERA patients (prior to and after 3 and 12 months of therapy with disease modifying antirheumatic drugs), in patients with established RA and in healthy controls (HC) using phenol–chloroform extraction. Expression of miR-146a, miR-155, miR-223, miR-16, miR-203, miR-132 and miR-124a was analysed by TaqMan Real Time PCR.
From all analysed miRNAs, levels of miR-146a, miR-155 and miR-16 were decreased in the sera of ERA patients in comparison with established RA. A change in circulating miR-16 in the first 3 months of therapy was associated with a decrease in DAS28 in long term follow-up in ERA (p=0.002). Levels of circulating miR-223 in treatment naïve ERA correlated with C reactive protein (p=0.008), DAS28 (p=0.031) and change in DAS28 after 3 months (p=0.003) and 12 months (p=0.011) of follow-up. However, neither miR-16 nor miR-223 could distinguish ERA from HC.
Differential expression of circulating miR-146a, miR-155 and miR-16 in the sera of ERA patients may characterise an early stage of the disease. We suggest miR-223 as a marker of disease activity and miR-16 and miR-223 as possible predictors for disease outcome in ERA.
PMCID: PMC4173742  PMID: 23897768
Rheumatoid Arthritis; DAS28; Early Rheumatoid Arthritis

Results 1-18 (18)