RheumaTool, a novel clinical decision support system for the diagnosis of rheumatic diseases, and its first validation in a retrospective chart analysis.

AIMS: RheumaTool is a clinical decision support system designed to support the diagnostic process in rheumatology by presenting a differential diagnosis list after the input of clinical information. The objective of this study was to evaluate the performance of RheumaTool in detecting the correct diagnosis in referrals to a rheumatology clinic. METHODS: In this retrospective chart analysis, data were gathered from patients with musculoskeletal complaints and an uncertain diagnosis who were referred to a Swiss tertiary rheumatology outpatient clinic. Data were entered into RheumaTool in a standardised fashion, while the principal diagnoses in the medical reports were blinded. RheumaTool’s output was compared to the correct diagnoses, established either by widely accepted diagnostic criteria or through the expert consensus of independent rheumatologists. Diagnostic precision, the primary endpoint, was defined as the proportion of correctly diagnosed cases among all cases. RESULTS: One hundred and sixty cases with 46 different diseases were included in this analysis. RheumaTool correctly diagnosed 40% (95% confidence interval 32.4–48.1) of all cases. In 63.8% (95% confidence interval 55.7–71.1), the correct diagnosis was present in a differential diagnosis list consisting of a median of two diagnoses. CONCLUSION: In this first validation, RheumaTool provides a useful list of differential diagnoses. However, there is not sufficient diagnostic reliability for unfiltered data entry, especially in patients with multiple concomitant musculoskeletal disorders. This must be taken into account when using RheumaTool.

TLR3 Ligand Poly(I:C) Exerts Distinct Actions in Synovial Fibroblasts When Delivered by Extracellular Vesicles.

Extracellular vesicles (EV) can modulate the responses of cells to toll-like receptor (TLR) ligation; conversely, TLR ligands such as double-stranded RNA (dsRNA) can enhance the release of EV and influence of the composition and functions of EV cargos. Inflamed synovial joints in rheumatoid arthritis (RA) are rich in EV and extracellular RNA; besides, RNA released from necrotic synovial fluid cells can activate the TLR3 signaling in synovial fibroblasts (SFs) from patients with RA. Since EV occur prominently in synovial joints in RA and may contribute to the pathogenesis, we questioned whether EV can interact with dsRNA, a TLR3 ligand, and modify its actions in arthritis. We have used as model the effects on RA SFs, of EV released from monocyte U937 cells and peripheral blood mononuclear cells upon stimulation with Poly(I:C), a synthetic analog of dsRNA. We show that EV released from unstimulated cells and Poly(I:C)-stimulated U937 cells [Poly(I:C) EV] differ in size but bind similar amounts of Annexin V and express comparable levels of MAC-1, the receptor for dsRNA, on the vesicular membranes. Specifically, Poly(I:C) EV contain or associate with Poly(I:C) and at least partially protect Poly(I:C) from RNAse III degradation. Poly(I:C) EV shuttle Poly(I:C) to SFs and reproduce the proinflammatory and antiviral gene responses of SFs to direct stimulation with Poly(I:C). Poly(I:C) EV, however, halt the death receptor-induced apoptosis in SFs, thereby inverting the proapoptotic nature of Poly(I:C). These prosurvival effects sharply contrast with the high toxicity of cationic liposome-delivered Poly(I:C) and may reflect the route of Poly(I:C) delivery via EV or the fine-tuning of Poly(I:C) actions by molecular cargo in EV. The demonstration that EV may safeguard extracellular dsRNA and allow dsRNA to exert antiapoptotic effects on SFs highlights the potential of EV to amplify the pathogenicity of dsRNA in arthritis beyond inflammation (by concurrently enhancing the expansion of the invasive synovial stroma).

Interdisciplinary rehabilitation after whiplash injury: An observational prospective 5 years outcome study.

Whiplash injury associated disorders (WAD) cause high costs for public health care. Neck pain is number 16 on the global prevalence lists for the 50 most common sequelae. It is of importance to obtain long-term data on disability and working capacity outcomes after rehabilitation. Long-term prospective data of the outcome course of whiplash are sparse. The aim of this study was to quantify improvements of pain, function/role performance, vitality, and working capacity 5 years after whiplash injury and to compare the state of health to normative values at 5 years after rehabilitation.In this naturalistic, observational, prospective cohort study, 115 patients were assessed 5 years (60 months) after a multidisciplinary rehabilitation program. The assessment set consisted of the Short Form 36 (SF-36), parts of the North American Spine Society's cervical spine assessment questionnaire (NASS) and the coping strategies questionnaire (CSQ). The effects were quantified by effect size (ES) and standardized response mean (SRM). Score differences over the course were tested by the Wilcoxon-Mann-Whitney U test for significance.Comparing data between entry and 60 months after rehabilitation 8 of 15 parameters improved with large ES/SRM. Outcome between 6 and 60 months showed small to moderate ES/SRM. Working capacity increased from 0 at entry to rehabilitation to 21 h/wk at 6 months and to 30 h/wk at 60 months follow-up.After large improvements in health and working capacity in the mid-term, further important improvements were observed in the long-term course. It can be hypothesized that part of those can be attributed to the interventions during inpatient rehabilitation, for example, due to better coping strategies.

Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions.

A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component.

MicroRNAs interfere with DNA methylation in rheumatoid arthritis synovial fibroblasts.

BACKGROUND: The DNA of rheumatoid arthritis synovial fibroblasts (RASF) is globally hypomethylated; this contributes to an aggressive behaviour. In an attempt to remethylate these cells, we supplemented with methyl donors. We investigated the possible interference of microRNAs (miRs). MATERIAL AND METHODS: RASF were treated with L-methionine or betaine. Transcripts of de novo methyltransferases (DNMTs) and miRs were measured by real-time PCR, and a transcription PCR array was performed. Levels of homocysteine, matrix metalloproteinase-1 (MMP-1) and global DNA methylation were determined. Transfection with lipofectamine was performed with specific pre-miRs and anti-miRs, such as miR29 and let7f. RESULTS: L-methionine was more efficient to increase DNA methylation than betaine. This was associated with a reduced expression of DNMT3A mRNA in betaine-treated RASF. Betaine increases the expression of miR29 in RASF which targets DNMT3A, thereby limiting the remethylation process. Nevertheless, betaine inhibited the expression of multiple transcription factors, decreased the release of MMP-1, biosynthesis of homocysteine and cell migration. CONCLUSION: Alterations in cellular miRs profiles, in particular the upregulation of miR29, which targets DNMT3A, may limit the efficiency of betaine if it is used as DNA remethylating agent. However, L-methionine also has similar impact on miR29 expression. On the other hand, betaine has multiple other beneficial effects on the activated phenotype of RASF; it is not excluded that the effect of betaine on DNMT3A is, at least in part, indirect. Clinical trials with betaine could be promising.

Expression and Regulation of PIWIL-Proteins and PIWI-Interacting RNAs in Rheumatoid Arthritis.

OBJECTIVE: The PIWIL (P-element induced wimpy testis like protein) subfamily of argonaute proteins is essential for Piwi-interacting RNA (piRNA) biogenesis and their function to silence transposons during germ-line development. Here we explored their presence and regulation in rheumatoid arthritis (RA). METHODS: The expression of PIWIL genes in RA and osteoarthritis (OA) synovial tissues and synovial fibroblasts (SF) was analysed by Real-time PCR, immunofluorescence and Western blot. The expression of piRNAs was quantified by next generation small RNA sequencing (NGS). The regulation of PIWI/piRNAs, proliferation and methylation of LINE-1 after silencing of PIWIL genes were studied. RESULTS: PIWIL2 and 4 mRNA were similarly expressed in synovial tissues and SF from RA and OA patients. However, on the protein level only PIWIL4 was strongly expressed in SF. Using NGS up to 300 piRNAs were identified in all SF without significant differences in expression levels between RA and OASF. Of interest, the analysis of the co-expression of the detected piRNAs revealed a less tightly regulated pattern of piRNA-823, -4153 and -16659 expression in RASF. In RASF and OASF, stimulation with TNFα+IL1ß/TLR-ligands further significantly increased the expression levels of PIWIL2 and 4 mRNA and piRNA-16659 was significantly (4-fold) induced upon Poly(I:C) stimulation. Silencing of PIWIL2/4 neither affect LINE-1 methylation/expression nor proliferation of RASF. CONCLUSION: We detected a new class of small regulatory RNAs (piRNAs) and their specific binding partners (PIWIL2/4) in synovial fibroblasts. The differential regulation of co-expression of piRNAs in RASF and the induction of piRNA/Piwi-proteins by innate immune stimulators suggest a role in inflammatory processes.

AAA-ATPase p97 suppresses apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts.

Valosin containing protein (p97) is a chaperone implicated in a large number of biological processes including endoplasmic reticulum (ER)-associated protein degradation and autophagy. Silencing of p97 in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) increased the amount of polyubiquitinated proteins, whereas silencing of its interaction partner histone deacetylase 6 (HDAC6) had no effect. Furthermore, silencing of p97 in RASFs increased not only rates of apoptotic cell death induced by TRAIL but also induced an autophagy-associated cell death during ER stress that was accompanied by the formation of polyubiquitinated protein aggregates and large vacuoles. Finally, we demonstrated an anti-arthritic effect of siRNAs targeting p97 in collagen-induced arthritis in rats. Our data indicate that p97 may be a new potential target in the treatment of RA.

Gouty arthritis: the diagnostic and therapeutic impact of dual-energy CT.

OBJECTIVES: To determine the diagnostic and therapeutic impact of dual-energy computed tomography (DECT) in gout. METHODS: Forty-three patients with (n = 20) and without a history of gout (n = 23) showing non-specific soft tissue deposits underwent DECT after unrewarding arthrocentesis. Two blinded, independent readers evaluated DECT for the presence of urate crystals. Clinical diagnosis, clinically suspected urate crystal locations, diagnostic thinking and therapeutic decisions were noted before and after DECT. Clinical 1-month follow-up was obtained. RESULTS: DECT showed urate in 26/43 patients (60 %). After DECT, clinical diagnosis of gout was withdrawn in 17/43 (40 %) and was maintained in 16/43 patients (37 %). In 10/43 patients (23 %) the diagnosis was maintained, but DECT revealed urate in clinically unsuspected locations. In 23/43 patients (53 %), a treatment-change based on DECT occurred. Changes in diagnostic thinking occurred more frequently in patients without a history of gout (p < 0.001), changes in therapeutic decisions more frequently in patients with a history of gout (p = 0.014). Clinical follow-up indicated beneficial effects of DECT-based diagnoses in 83 % of patients. CONCLUSIONS: In patients with or without a history of gout and a recent suspicion for gouty arthritis with an unrewarding arthrocentesis, DECT has a marked diagnostic and therapeutic impact when hyperdense soft-tissue deposits are present. KEY POINTS: • This study evaluates the concept of evidence-based radiology • In patients with suspected gout, DECT can help clinicians make the diagnosis • DECT has a marked impact on therapy • Clinical follow-up after 1 month indicated reliable results of DECT.

Impaired response to treatment with tumour necrosis factor α inhibitors in smokers with axial spondyloarthritis.

OBJECTIVES: To investigate the impact of smoking on the response to treatment with a first tumour necrosis factor inhibitor (TNFi) in patients with axial spondyloarthritis (axSpA) in a real-life cohort. METHODS: Patients fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA in the Swiss Clinical Quality Management Cohort were included in this study. The potential association between smoking status and differential response to TNFi in terms of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) was analysed using multiple adjusted longitudinal mixed effect models. Binary response rates at 1 year were assessed with multiple adjusted logistic analyses. RESULTS: A first TNFi was initiated in 698 patients with axSpA with available smoking status and a baseline or follow-up BASDAI assessment, of which 490 (70%) had complete covariate data. In comparison to non-smokers, current smokers demonstrated significantly smaller reductions in BASDAI and ASDAS scores upon treatment with TNFi (0.75 BASDAI units and 0.69 ASDAS units less, p=0.005 and 0.001, respectively) for patients with elevated baseline C-reactive protein (CRP) level. This effect was numerically smaller in patients with normal CRP. The odds for reaching a 50% improvement in BASDAI response or the ASAS criteria for 40% improvement after 1 year were significantly lower in current smokers than in non-smokers (0.54, 95% CI 0.31 to 0.95, p=0.03 and 0.43, 95% CI 0.24 to 0.76, p=0.004, respectively). CONCLUSIONS: Current smoking is associated with an impaired response to TNFi in axSpA.

Protein tyrosine phosphatase nonreceptor type 2: an important regulator of lnterleukin-6 production in rheumatoid arthritis synovial fibroblasts.

OBJECTIVE: To investigate the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in the pathogenesis of rheumatoid arthritis (RA). METHODS: Synovial tissue samples from patients with RA and patients with osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts were stimulated with tumor necrosis factor (TNF) and interleukin-1ß (IL-1ß), lipopolysaccharide (LPS), TRAIL, or thapsigargin. The expression of PTPN2 in synovial fibroblasts and peripheral blood mononuclear cells (PBMCs) was analyzed by real-time polymerase chain reaction and Western blotting. Cell death, the release of IL-6 and IL-8, and the induction of autophagy were analyzed after PTPN2 silencing. Methylated DNA immunoprecipitation analysis was used to evaluate DNA methylation-regulated gene expression of PTPN2. RESULTS: PTPN2 was significantly overexpressed in synovial tissue samples from RA patients compared to OA patients. Patients receiving anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with nonbiologic agents. PTPN2 expression was higher in RA synovial fibroblasts (RASFs) than in OASFs. This differential expression was not regulated by DNA methylation. PTPN2 was further up-regulated after stimulation with TNF, TNF combined with IL-1ß, or LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, or systemic lupus erythematosus or healthy controls. Most interestingly, PTPN2 silencing in RASFs significantly increased the production of the inflammatory cytokine IL-6 but did not affect levels of IL-8. Moreover, functional analysis showed that high PTPN2 levels contributed to the increased apoptosis resistance of RASFs and increased autophagy. CONCLUSION: This is the first study of PTPN2 in RASFs showing that PTPN2 regulates IL-6 production, cell death, and autophagy. Our findings indicate that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts.

Performance of the new ACR/EULAR classification criteria for systemic sclerosis in clinical practice.

OBJECTIVE: The preliminary classification criteria for SSc lack sensitivity for mild/early SSc patients, therefore, the new ACR/EULAR classification criteria for SSc were developed. The objective of this study was to evaluate the performance of the new classification criteria for SSc in clinical practice in a cohort of mild/early patients. METHODS: Consecutive patients with a clinical diagnosis of SSc, based on expert opinion, were prospectively recruited and assessed according to the EULAR Scleroderma Trials and Research group (EUSTAR) and very early diagnosis of SSc (VEDOSS) recommendations. In some patients, missing values were retrieved retrospectively from the patient's records. Patients were grouped into established SSc (fulfilling the old ACR criteria) and mild/early SSc (not fulfilling the old ACR criteria). The new ACR/EULAR criteria were applied to all patients. RESULTS: Of the 304 patients available for the final analysis, 162/304 (53.3%) had established SSc and 142/304 (46.7%) had mild/early SSc. All 162 established SSc patients fulfilled the new ACR/EULAR classification criteria. The remaining 142 patients had mild/early SSc. Eighty of these 142 patients (56.3%) fulfilled the new ACR/EULAR classification criteria. Patients with mild/early SSc not fulfilling the new classification criteria were most often suffering from RP, had SSc-characteristic autoantibodies and had an SSc pattern on nailfold capillaroscopy. Taken together, the sensitivity of the new ACR/EULAR classification criteria for the overall cohort was 242/304 (79.6%) compared with 162/304 (53.3%) for the ACR criteria. CONCLUSION: In this cohort with a focus on mild/early SSc, the new ACR/EULAR classification criteria showed higher sensitivity and classified more patients as definite SSc patients than the ACR criteria.

The dermatologists' role in managing psoriatic arthritis: results of a Swiss Delphi exercise intended to improve collaboration with rheumatologists.

BACKGROUND: Psoriatic arthritis (PsA) substantially impacts the management of psoriatic disease. OBJECTIVE: This study aimed to generate an interdisciplinary national consensus on recommendations of how PsA should be managed. METHODS: Based on a systematic literature search, an interdisciplinary expert group identified important domains and went through 3 rounds of a Delphi exercise, followed by a nominal group discussion to generate specific recommendations. RESULTS: A strong consensus was reached on numerous central messages regarding the impact of PsA, screening procedures, organization of the interaction between dermatologists and rheumatologists, and treatment goals. CONCLUSION: These recommendations can serve as a template for similar initiatives in other countries. At the same time, they highlight the need to take into account the impact of the respective national health care system.

Treatment with tumor necrosis factor inhibitors in axial spondyloarthritis: comparison between private rheumatology practices and academic centers in a large observational cohort.

OBJECTIVE: To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers. METHODS: We compared newly initiated TNF inhibition for axSpA in 363 patients enrolled in private practices with 100 patients recruited in 6 university hospitals within the Swiss Clinical Quality Management (SCQM) cohort. RESULTS: All patients had been treated with ≥ 1 nonsteroidal antiinflammatory drug and > 70% of patients had a baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 before anti-TNF agent initiation. The proportion of patients with nonradiographic axSpA (nr-axSpA) treated with TNF inhibitors was higher in hospitals versus private practices (30.4% vs 18.7%, p = 0.02). The burden of disease as assessed by patient-reported outcomes at baseline was slightly higher in the hospital setting. Mean levels (± SD) of the Ankylosing Spondylitis Disease Activity Score were, however, virtually identical in private practices and academic centers (3.4 ± 1.0 vs 3.4 ± 0.9, p = 0.68). An Assessment of SpondyloArthritis international Society (ASAS40) response at 1 year was reached for ankylosing spondylitis in 51.7% in private practices and 52.9% in university hospitals (p = 1.0) and for nr-axSpA in 27.5% versus 25.0%, respectively (p = 1.0). CONCLUSION: With the exception of a lower proportion of patients with nr-axSpA newly treated with anti-TNF agents in private practices in comparison to academic centers, adherence to ASAS treatment recommendations for TNF inhibition was equally high, and similar response rates to TNF blockers were achieved in both clinical settings.

Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database.

OBJECTIVES: To identify predictive parameters for the progression of skin fibrosis within 1 year in patients with diffuse cutaneous SSc (dcSSc). METHODS: An observational study using the EUSTAR database was performed. Inclusion criteria were dcSSc, American College of Rheumatology (ACR) criteria fulfilled, modified Rodnan skin score (MRSS) ≥7 at baseline visit, valid data for MRSS at 2nd visit, and available follow-up of 12±2 months. Worsening of skin fibrosis was defined as increase in MRSS >5 points and ≥25% from baseline to 2nd visit. In the univariate analysis, patients with progressive fibrosis were compared with non-progressors, and predictive markers with p<0.2 were included in the logistic regression analysis. The prediction models were then validated in a second cohort. RESULTS: A total of 637 dcSSc patients were eligible. Univariate analyses identified joint synovitis, short disease duration (≤15 months), short disease duration in females/patients without creatine kinase (CK) elevation, low baseline MRSS (≤22/51), and absence of oesophageal symptoms as potential predictors for progressive skin fibrosis. In the multivariate analysis, by employing combinations of the predictors, 17 models with varying prediction success were generated, allowing cohort enrichment from 9.7% progressive patients in the whole cohort to 44.4% in the optimised enrichment cohort. Using a second validation cohort of 188 dcSSc patients, short disease duration, low baseline MRSS and joint synovitis were confirmed as independent predictors of progressive skin fibrosis within 1 year resulting in a 4.5-fold increased prediction success rate. CONCLUSIONS: Our study provides novel, evidence-based criteria for the enrichment of dcSSc cohorts with patients who experience worsening of skin fibrosis which allows improved clinical trial design.

Epigenome analysis reveals TBX5 as a novel transcription factor involved in the activation of rheumatoid arthritis synovial fibroblasts.

In this study, we analyzed the methylation status of human promoters in rheumatoid arthritis synovial fibroblasts (RASF). Differentially methylated genes between RASF and osteoarthritis synovial fibroblasts (OASF) were identified by methylated DNA immunoprecipitation and hybridization to human promoter tiling arrays. The methylation status was confirmed by pyrosequencing. Gene and protein expression of differentially methylated genes was evaluated with real-time PCR, Western blot, and immunohistochemistry. Chromatin immunoprecipitation was used to measure the gene promoter-associated acetylation and methylation of histones. Transcription factor-specific targets were identified with microarray and luciferase assays. We found that the transcription factor T-box transcription factor 5 (TBX5) was less methylated in rheumatoid arthritis (RA) synovium and RASF than in osteoarthritis (OA) samples. Demethylation of the TBX5 promoter in RASF and RA synovium was accompanied by higher TBX5 expression than in OASF and OA synovium. In RA synovium, TBX5 expression was primarily localized to the synovial lining. In addition, the TBX5 locus was enriched in activating chromatin marks, such as histone 4 lysine 4 trimethylation and histone acetylation, in RASF. In our functional studies, we observed that 790 genes were differentially expressed by 2-6-fold after overexpression of TBX5 in OASF. Bioinformatic analysis of these genes revealed that the chemokines IL-8, CXCL12, and CCL20 were common targets of TBX5 in OASF. Taken together, our data show that TBX5 is a novel inducer of important chemokines in RASF. Thus, we conclude that RASF contribute to the inflammatory processes operating in the pathogenesis of RA via epigenetic control of TBX5.

Swiss Diagnosis Related Groups: a prospective study in rehabilitation comparing outcome before and after its introduction into acute health care.

OBJECTIVE: To compare general health and the health-related quality of life of patients admitted to inpatient rehabilitation after a stay in an acute hospital before and after the introduction of Swiss Diagnosis Related Groups (SwissDRG). METHODS: Consecutively referred patients with disorders of the lower extremities (LEX) or lumbar spine (LS) were evaluated by standardised outcome assessment instruments and for various co-factors. State (at entry to rehabilitation) and change of health (between entry and discharge from rehabilitation) were then compared between the cohorts before and after introduction of SwissDRG. RESULTS: In LEX (n = 234), state of health, measured by the instruments' scores at entry, was not significantly different before and after SwissDRG, except for emotional role (worse state after SwissDRG, p = 0.021). These results were consistent for the LS group (n = 161). Change of health from entry to dismissal was comparable before and after DRG in the LEX group, whereas in the LS group, improvements after SwissDRG were significantly smaller in physical role (p = 0.042), bodily pain (p = 0.012) and physical component summary (p = 0.009) than before SwissDRG. Duration of stay in an acute hospital and duration of stay in the rehabilitation clinic were comparable before and after SwissDRG in both groups. CONCLUSIONS: While state of health was comparable in both diagnostic groups, some dimensions in the LS group revealed lesser improvements after introduction of SwissDRG compared to before. In analogy to long-term observations after the introduction of DRG in Germany, it is possible that greater differences will also be identified in Switzerland by future studies.

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.

Multidimensional associative factors for improvement in pain, function, and working capacity after rehabilitation of whiplash associated disorder: a prognostic, prospective outcome study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Smoking induces transcription of the heat shock protein system in the joints.

OBJECTIVES: Smoking increases the risk of developing rheumatoid arthritis (RA) and worsens the course of the disease. In the current study we analysed whether smoking can affect gene expression directly in the joints. METHODS: Synovial fibroblasts were incubated with 5% cigarette smoke extract and changes in gene expression were detected using whole genome microarrays and verified with real-time PCR. Synovial tissues were obtained from smoking and non-smoking patients with RA undergoing joint replacement surgery and from mice exposed to cigarette smoke or ambient air in a whole body exposure chamber for 3 weeks. RESULTS: Microarray and real-time PCR analysis showed a significant upregulation of the heat shock proteins DnaJA4, DnaJB4, DnaJC6, HspB8 and Hsp70 after stimulation of synovial fibroblasts with 5% cigarette smoke extract. Similarly, in synovial tissues of smokers with RA the expression of DnaJB4, DnaJC6, HspB8 and Hsp70 was significantly higher compared with non-smokers with RA. Upregulation of DnaJB4 and DnaJC6 in joints by smoking was also confirmed in mice exposed to cigarette smoke. CONCLUSIONS: Our data clearly show that smoking can change gene expression in the joints, which can lead to the activation of signalling pathways that promote development of autoimmunity and chronic joint inflammation.