Association between the Ile164 ß2 Adrenergic Receptor Polymorphism and Fatigue in Patients with Rheumatoid Arthritis.

INTRODUCTION: In the present work, the frequency of inherited polymorphisms of the beta 2 adrenergic receptor (ß2AR) gene and their association with fatigue in patients with rheumatoid arthritis (RA) was examined. METHODS: An allele-specific polymerase chain reaction was used to determine the common variants of the ß2AR at position 16, 27, and 164 in 92 German RA outpatients. Health Assessment Questionnaire (HAQ-DI), Beck Depression Inventory (BDI), Perceived Stress Questionnaire (PSQ-30), Multidimensional Fatigue Inventory (MFI-20) were utilized. RESULTS: 34.7% of German RA patients were diagnosed with associated fatigue. Fatigued patients were more likely to carry the Ile allele at position 164 (OR 7.33, 95% CI 1.09-59.8, p = 0.049). Comparing these risk factors' contribution to different fatigue dimensions revealed that Ile164 carriers only had significantly higher MFI-20 mean values for general fatigue (p = 0.014) while the clinical difference among other MFI subscales was the largest for mental fatigue (carrier: 8.23, SD: 4.22, noncarrier: 5.67, SD: 1.56, p = 0.089, Cohen's d = 0.629). Disease activity, perceived stress, and depression were also associated with fatigue with higher mean values for DAS28CRP (p = 0.038), PSQ (p < 0.001), and BDI-II (p < 0.001) in fatigued patients. Physical fatigue was correlated with disease activity (p = 0.009) and depression (p = 0.001) while mental fatigue showed associations with depression (p = 0.001) and perceived stress (p = 0.028). CONCLUSION: The discovery study indicates that the Ile164 polymorphism might in contrast to other ß2AR polymorphisms affect fatigue levels in RA patients. This association was observed especially with mental fatigue. Further replication studies are warranted to determine further role of ß2AR polymorphisms in RA patients.

Impact of pregnancy planning and preconceptual dietary training on metabolic control and offspring's outcome in phenylketonuria.

To prevent maternal phenylketonuria (PKU) syndrome low phenylalanine concentrations (target range, 120-360 µmol/L) during pregnancy are recommended for women with PKU. We evaluated the feasibility and effectiveness of current recommendations and identified factors influencing maternal metabolic control and children's outcome. Retrospective study of first successfully completed pregnancies of 85 women with PKU from 12 German centers using historical data and interviews with the women. Children's outcome was evaluated by standardized IQ tests and parental rating of child behavior. Seventy-four percent (63/85) of women started treatment before conception, 64% (54/85) reached the phenylalanine target range before conception. Pregnancy planning resulted in earlier achievement of the phenylalanine target (18 weeks before conception planned vs. 11 weeks of gestation unplanned, p < 0.001) and lower plasma phenylalanine concentrations during pregnancy, particularly in the first trimester (0-7 weeks of gestation: 247 µmol/L planned vs. 467 µmol/L unplanned, p < 0.0001; 8-12 weeks of gestation: 235 µmol/L planned vs. 414 µmol/L unplanned, p < 0.001). Preconceptual dietary training increased the success rate of achieving the phenylalanine target before conception compared to women without training (19 weeks before conception vs. 9 weeks of gestation, p < 0.001). The majority (93%) of children had normal IQ (mean 103, median age 7.3 years); however, IQ decreased with increasing phenylalanine concentration during pregnancy. Good metabolic control during pregnancy is the prerequisite to prevent maternal PKU syndrome in the offspring. This can be achieved by timely provision of detailed information, preconceptual dietary training, and careful planning of pregnancy.

[Survey of rheumatologists in Saxony, Saxony-Anhalt and Thuringia regarding the occupational situation and activities in further education: no way out of the undersupply of rheumatological care]. / Befragung von Rheumatologen in Sachsen, Sachsen-Anhalt und Thüringen zu Weiterbildungstätigkeit und beruflicher Situation: Kein Ausweg aus der rheumatologischen Unterversorgung.

INTRODUCTION: Many regions in the middle of Germany have a deficit in specialized rheumatological care. A survey was undertaken to investigate whether the regional capacities for rheumatological advanced training are sufficient to provide an adequate number of rheumatologists in the future. METHODS: All 91 rheumatologists registered in Saxony, Saxony-Anhalt and Thuringia received a questionnaire that was sent back by 66% of the recipients (23 responses from Saxony, 19 from Saxony-Anhalt, 18 from Thuringia). Of the rheumatologists 41 were in private practice, 19 worked in an inpatient department and the mean duration of professional activity was 18 years. RESULTS: Over the last decade the number of patients treated by rheumatologists in private practices increased from 1200 to 1500 per quarter year (p < 0.001), whereas the number of first consultations rose from 100 to 130 per quarter year (p = 0.06). The waiting time for a first consultation rose from 8 to 11 weeks (p = 0.01), 32% of the responders indicated that the conditions for outpatient treatment had either improved or had remained constant during the last 10 years, whereas 60% reported a mild or marked deterioration and 48% stated that the number of rheumatologists had decreased within the same time frame. Only 20% indicated that they had a definite successor in the practice after retirement. All inpatient departments also had an outpatient office. During the last 10 years, the number of consultations per quarter year decreased from 1100 to 700 (not significant), while the waiting time doubled from 6 to 12 weeks (rounded mean). Of the rheumatologists in private practice eight are currently entitled to provide advanced education in rheumatology, with a median training period of 18 months; however, none of the responding physicians had actually brought assistant doctors to the final examination during the last decade and only one prospective rheumatologist was currently completing training in a private practice setting. Only 6 out of 12 inpatient rheumatological facilities are entitled to educate rheumatologists over the whole training period, 5 facilities were not involved in training at all and 7 indicated that they lacked applications for rheumatology training. During the last 10 years, 37 rheumatologists completed the training of which 18 went into private practice, 8 worked as general practitioners and 29 remained in the region of their initial training. CONCLUSION: Given the increase in the number of outpatients served, the volume of training activities in rheumatology is hardly sufficient to improve the deficit of rheumatological care in the middle of Germany.

New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis - Implications from the prospective multicenter VADERA II study.

OBJECTIVES: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. METHODS: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. RESULTS: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. CONCLUSIONS: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms. CLINICAL TRIAL REGISTRATION NUMBER: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).

Cost-effectiveness of early treatment of ACPA-positive rheumatoid arthritis patients with abatacept.

OBJECTIVES: Studies have reported that the presence of elevated anti-citrullinated protein antibodies (ACPA)/RF levels, together with joint erosions, is associated with higher disease burden in terms of disability and mortality in rheumatoid arthritis (RA). Abatacept has been shown to be effective in this patient population with favourable comparative data against adalimumab. However, few studies have investigated the cost-effectiveness of abatacept in this population to similar treatments such as TNFs. The objective of the study was to compare the cost-effectiveness of abatacept to adalimumab as a first bDMARD in ACPA-positive RA patients who failed treatment with methotrexate (MTX) in Germany. METHODS: A decision tree model was used to estimate the cost-effectiveness, from a payer's perspective, of different treatment sequences in RA over a two year time frame. The effectiveness criteria were defined as achieving the treatment target measured by the Disease Activity Score 28 (DAS28(CRP)<2.6; "remission"). A treatment switch to a different biologic as 2nd line and 3rd line bDMARD was allowed - in case of not achieving remission with therapy - every 6 months over a two year time period. Effectiveness data was based on randomised controlled trials (RCT) identified by an updated previous systematic literature search by the Institute for Quality and Efficiency in Health Care (IQWiG). Costs of medication and other direct medical costs were considered. Cost-effectiveness of RA treatment was investigated in ACPA-positive patients and presented as overall costs per day in remission. RESULTS: For ACPA-positive patients, treatment strategies including early treatment with abatacept had lower total costs per clinical outcome compared to later use. Treatment sequences starting with abatacept resulted in lower costs per day in remission (mean 330 €/day, range 328-333 €/day) compared to sequences starting with adalimumab (mean 384 €/day, range 378-390 €/day). Choice of the second or third biologic in the treatment sequences appears to have little impact on the costs per outcome. CONCLUSIONS: The results of this analysis suggest that in ACPA-positive RA patients treatment with abatacept appears to have lower costs per response (remission) compared to treatment with adalimumab as a first bDMARD.

Validation of Standardized Questionnaires Evaluating Symptoms of Depression in Rheumatoid Arthritis Patients: Approaches to Screening for a Frequent Yet Underrated Challenge.

OBJECTIVE: To validate standard self-report questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to one another and to the Montgomery-Åsberg Depression Rating Scale (MADRS), a standardized structured interview. METHODS: In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks followup (T1) using the World Health Organization 5-Item Well-Being Index (WHO-5), the Patient Health Questionnaire (PHQ-9), and the Beck Depression Inventory II (BDI-II). The construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman's correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone a psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as the gold standard. RESULTS: According to Spearman's correlation coefficients, all questionnaires met convergent validity criteria (ρ > |0.50|), with the BDI-II performing best, while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (ρ < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (ρ ≥ 0.70) was the BDI-II (rs = 0.77), which also achieved the best results for both sensitivity and specificity (>80%) when using the MADRS as the gold standard. CONCLUSION: The BDI-II best met the predefined criteria, and the PHQ-9 met most of the validity criteria, with lower sensitivity and specificity.

Use of clinical scores to guide therapeutic decisions in patients with rheumatoid arthritis in daily care.

OBJECTIVES: This study focuses on the application and impact of different clinical scores for treatment changes in daily practice in patients with rheumatoid arthritis (RA), as achieving remission is a feasible aim due to considerable improvements in therapeutic options. METHODS: In this prospective study, 1467 RA patients aged 15 to 88 years (72.5% female, 27.5% male) who had undergone treatment change or were treated with a disease-modifying antirheumatic drug (DMARD) for the first time were analysed. At three consecutive visits (T-1, T0, T1), scores were used to assess disease activity, loss of function, quality of life and imaging. In addition, the impact of the scores on treatment change was addressed (numerical rating scale, 1-10). RESULTS: The most commonly used scores were the DAS28 (65% of all visits), the Hanover functional ability questionnaire (FFbH, 36%) and the HAQ (11%). Other scores for evaluating RA are of little relevance in daily practice. No scores were calculated in only 10% of visits. Among the commonly used scores, the DAS28 had the highest influence on therapy decisions, followed by HAQ and FFbH (mean weight 6.62, 4.99 and 4.41, respectively). CONCLUSIONS: In daily practice, rheumatologists very often take scores for disease activity (especially DAS28) and loss of physical function into consideration when deciding on treatment for patients with RA. However, scores for measuring structural changes or quality of life, are not yet very well established with German rheumatologists.

Relationship between placenta growth factor 1 and vascularization, dehydroepiandrosterone sulfate to dehydroepiandrosterone conversion, or aromatase expression in patients with rheumatoid arthritis and patients with osteoarthritis.

OBJECTIVE: Proliferating pannus is in many aspects similar to placental tissue. Both fibroblast-rich tissues have high vascularity, and tissue from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA) demonstrates conversion of androgenic prehormones to downstream estrogens. We undertook this study to investigate similarities between proliferating pannus and placental tissue by focusing on angiogenic placenta growth factor 1 (PlGF-1) in patients with OA and patients with RA. METHODS: We used immunohistochemistry to study the presence of PlGF-1, its synovial distribution, and the PlGF-1-expressing synovial cell type. The relationship between PlGF-1 and conversion of the biologically inactive placental prehormone dehydroepiandrosterone sulfate (DHEAS) to the biologically active dehydroepiandrosterone (DHEA) was investigated in mixed synovial cells. The effects of DHEA on PlGF-1 expression were studied by intracellular fluorescence-activated cell sorting analysis. RESULTS: PlGF-1-positive cells were detected in the lining and sublining areas in patients with RA and patients with OA, and cellular density was similar. Double staining revealed that PlGF-1-positive cells were macrophages. In RA and OA, the density of PlGF-1-positive cells correlated positively with the density of macrophages and the density of type IV collagen-positive vessels. The supernatant concentration of (3) H-DHEA after conversion from (3) H-DHEAS and the density of aromatase-positive cells were positively correlated with the density of PlGF-1-positive cells only in OA. Low DHEA concentrations (≤10(-9) M) had stimulatory effects on PlGF-1 when compared to serum concentrations (10(-8) M to 10(-7) M) in the monocytic cell line THP-1 and in primary mixed synovial cells. CONCLUSION: PlGF-1 functions similarly in inflamed synovium and in the placenta. It is related to vessel formation and, in OA patients, to androgen/estrogen conversion. Evolutionarily conserved functions of PlGF-1 for placental phenomena are obviously also present in synovial inflammation.

Transition of young adults with phenylketonuria from pediatric to adult care.

BACKGROUND: Transition from pediatric to adult health care is a particularly vulnerable period for patients with inborn metabolic diseases. Aim of the present study was to evaluate the current transition situation of patients with phenylketonuria (PKU) in Leipzig, Germany, by analysis of the medical care, metabolic control, patients' satisfaction, socio-economic and psychosocial status, in order to identify areas of weakness and potential improvement. METHODS: Patients who had been transferred from pediatric to adult medical care between 2005 and 2008 were identified. An interview was performed using a questionnaire. Pediatric case notes and the present physician's case notes were analyzed retrospectively. Socio-demographic data were compared to data derived from the annual statistics of the city of Leipzig, Germany in 2008. RESULTS: seventy two transferred patients were identified and included in the study, 48 patients responded to the questionnaire, the data of 24 non-responders were analysed retrospectively. About 90% of the responding patients with PKU were satisfied with the current transition situation. However, they agreed to several suggestions of improvement. Most specifically an interdisciplinary appointment before the definite transfer to the adult clinics was asked for. At the time of transition, most of the patients were in good metabolic control according to current treatment guidelines (median dried blood phenylalanine concentration 853 µmol/l before versus 690 µmol/l after transition). Of the interviewed patients 92% were still on a low phenylalanine diet in combination with the intake of a phenylalanine free amino acid mixture. Of the interviewees 77% carried a secondary school certificate or a secondary modern school qualification, but only 19% had achieved senior high school diploma (controls 38.2%). Marital status was comparable with the population of Leipzig. However, fewer patients with PKU had children (15% versus 37%). CONCLUSION: Transition of patients with PKU from pediatric to adult care seems to be successful in Leipzig. Patients were mostly satisfied with the transition situation. Still, some suggestions for improvements appeared to be desirable. During transition medical care and metabolic control were stable. However, with regard to psychosocial and socioeconomic data differences to the control population were detected.

A case of maternal PKU syndrome despite intensive patient counseling.

We report on a 21-year-old woman with classic phenylketonuria, who presented at our outpatient clinic at week 14 of pregnancy. Despite intensive preconceptional counselling about the risk of raised Phenylalanine (Phe) levels for the offspring and nutritional consultations about the necessity to be on a Phe-restricted diet she had elevated blood Phe concentrations. Phe level could be lowered to the recommended range during a stay as an inpatient, but the patient was not able to maintain the recommended levels due to non-compliance. The patient delivered a newborn with classic maternal PKU syndrome (microcephaly, brachygnathia, congenital heart defect and psychomotoric retardation), which is nowadays rarely seen under preconceptional Phe-restricted diet. With more PKU patients reaching the childbearing age, intensive preconception counselling about maternal PKU syndrome is of pivotal importance for the women. However, a major factor in preventing Phe embryopathy is patient compliance in keeping the diet, which was insufficient in the case presented.

Intracellular calcium responses to cholinergic stimulation of lymphocytes from healthy donors and patients with rheumatoid arthritis.

This study was performed to identify the role of cholinergic stimulation on changes of intracellular calcium concentrations as intracellular messenger of neuroimmune interaction. Incubation of PBMC with acetylcholine (ACh) leads to Ca(2+) oscillations in healthy controls. PBMC from rheumatoid arthritis (RA) patients exhibited increased basal Ca(2+) concentrations with a significantly reduced capacity to respond upon ACh stimulation compared to healthy controls. It can be assumed that cholinergic signals in PBMC are mediated via the nicotinergic type of ACh receptors, causing changes in intracellular Ca(2+) concentrations with various types of oscillations. The significantly decreased modulation of intracellular Ca(2+) levels by ACh in PBMC of RA patients points further to a disturbed neuroimmune interaction in this chronic disease.

Failure of catecholamines to shift T-cell cytokine responses toward a Th2 profile in patients with rheumatoid arthritis.

To further understand the role of neuro-immunological interactions in the pathogenesis of rheumatoid arthritis (RA), we studied the influence of sympathetic neurotransmitters on cytokine production of T cells in patients with RA. T cells were isolated from peripheral blood of RA patients or healthy donors (HDs), and stimulated via CD3 and CD28. Co-incubation was carried out with epinephrine or norepinephrine in concentrations ranging from 10(-5) M to 10(-11) M. Interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-10 were determined in the culture supernatant with enzyme-linked immunosorbent assay. In addition, IFN-gamma and IL-10 were evaluated with intracellular cytokine staining. Furthermore, basal and agonist-induced cAMP levels and catecholamine-induced apoptosis of T cells were measured. Catecholamines inhibited the synthesis of IFN-gamma, TNF-alpha, and IL-10 at a concentration of 10(-5) M. In addition, IFN-gamma release was suppressed by 10(-7) M epinephrine. Lower catecholamine concentrations exerted no significant effect. A reduced IL-4 production upon co-incubation with 10(-5) M epinephrine was observed in RA patients only. The inhibitory effect of catecholamines on IFN-gamma production was lower in RA patients as compared with HDs. In RA patients, a catecholamine-induced shift toward a Th2 (type 2) polarised cytokine profile was abrogated. Evaluation of intracellular cytokines revealed that CD8-positive T cells were accountable for the impaired catecholaminergic control of IFN-gamma production. The highly significant negative correlation between age and catecholamine effects in HDs was not found in RA patients. Basal and stimulated cAMP levels in T-cell subsets and catecholamine-induced apoptosis did not differ between RA patients and HDs. RA patients demonstrate an impaired inhibitory effect of catecholamines on IFN-gamma production together with a failure to induce a shift of T-cell cytokine responses toward a Th2-like profile. Such an unfavorable situation is a perpetuating factor for inflammation.

Influence of catecholamines on cytokine production and expression of adhesion molecules of human neutrophils in vitro.

The impact of catecholamines on cytokine production and expression of adhesion molecules by human neutrophils was evaluated in vitro. Neutrophils were separated from venous blood of healthy subjects. The generation of intracellular cyclic adenosine monophosphate (cAMP) and Ca2+ was determined after incubation with catecholamines. Resting and lipopolysaccharide (LPS)-activated neutrophils were tested for synthesis of interleukins (IL-6, IL-8) and tumor necrosis factor alpha (TNF-alpha). In addition, the expression of the adhesion molecules CD15, CD44, and CD54 was evaluated in resting and activated neutrophils. Increasing concentrations (1 nM-1 mM) of epinephrine (EPI) were used to study the influence of activation of beta2-adrenergic receptors (beta2R) on cytokine production and adhesion molecule expression. Incubation with catecholamines induced an increase in cAMP but not Ca2+ in neutrophils. Only IL-8 was detected following stimulation with LPS and was unchanged upon co-incubation with EPI. The expression of CD15 and CD44 decreased spontaneously in vitro. The density of CD44 increased in the presence of very high doses of EPI (1 mM). Expression of CD54 on resting neutrophils increased upon activation. The density of CD54 on activated neutrophils was reduced upon co-incubation with 1 mM EPI for 6 h. However, 1 mM EPI for 12 and 18 h decreased the spontaneous loss of CD54 on resting neutrophils. Beta2R are functionally coupled to signalling cascades in human neutrophils. Nevertheless, the impact of catecholamines on IL-8 synthesis and expression of CD15, CD44, and CD54 is limited.

Autonomic dysfunction in rheumatic diseases.

Patients who have rheumatic diseases often present with dysfunctions that are related to the autonomic nervous system (ANS) and are due to peripheral autonomic neuropathy or central changes. This article describes the prevalence of autonomic dysfunctions in patients who have rheumatic diseases. In the second part of this article, another form of ANS dysfunction-complex regional pain syndromes-is demonstrated. Clinically, these syndromes are characterized by pain (spontaneous, hyperalgesia, allodynia); active movement disorders, including an increased physiologic tremor, abnormal regulation of blood flow and sweating, edema of skin and subcutaneous tissues; and trophic changes of skin, appendages of skin, and subcutaneous tissues. In conclusion, this discussion shows that alterations of the ANS occur in rheumatic and related diseases, that these alterations may be involved in the pathogenesis of these diseases, and that we need more refined methods to study the changes that are related to the ANS.