[The translation of genetic risk variants to molecular disease mechanisms]. / De vertaling van genetische risicovarianten naar moleculaire ziektemechanismen.

BACKGROUND: Genetic studies have found large numbers of genetic risk variants that increase the risk to develop neuropsychiatric disorders. AIM: We aim to explain how to investigate the effects of these genetic risk variants on the expression of genes and whether this plays a potential role in neuropsychiatric disorders. METHOD: We describe the main findings of a study that we recently performed to study the association between genetic risk factors for neuropsychiatric disorders and gene expression in microglia, the immune cells of the brain. RESULTS: Part of the risk variants for neuropsychiatric disorders could be related to gene expression in microglia. These
associations were particularly strong for neurodegenerative disorders. CONCLUSION: Our study provided more insight into how genetic risk to neuropsychiatric disorders is related to gene expression in microglia. These findings show suggestions for potential new treatment options.

No association between anti-thyroidperoxidase antibodies and bipolar disorder: a study in the Dutch Bipolar Cohort and a meta-analysis.

BACKGROUND: Thyroid autoimmunity has been associated with bipolar disorder (BD). However, results from previous studies on the seroprevalence of anti-thyroid peroxidase antibodies (TPO-abs) in BD are inconsistent. OBJECTIVES: The aim of the present study is to investigate whether the seroprevalence and titer levels of TPO-abs are related to BD. METHOD: TPO-abs were measured in plasma samples of 760 patients with bipolar disorder, 261 first-degree relatives and 363 controls by enzyme-linked immunosorbent assay (ELISA). To address methodological limitations of previous studies, we assessed clinical characteristics with several (self-reported) questionnaires to investigate whether TPO-abs positivity is related to particular clinical subgroups of BD patients. We performed an additional meta-analysis of seroprevalences of TPO-abs in BD patients including data from present and previous studies. RESULTS: Seroprevalence or titer levels of TPO-abs did not significantly differ between patients with BD, their first-degree relatives, and controls. In BD patients, the prevalence of TPO-abs was unrelated to specific clinical factors, including lithium use. Our meta-analysis of twelve studies showed an overall odds ratio of 1.3 (CI 95 %: 0.7-2.3; p = 0.30), reaffirming the absence of an association of BD with TPO-abs. CONCLUSIONS: In the largest study of TPO-abs in BD to date, our findings indicate that TPO-abs are not associated with (the risk for) bipolar disorder.

Genetic and environmental influences on circulating NK and T cells and their relation to bipolar disorder.

BACKGROUND: In previous studies we found mild deficiencies of circulating T cells in patients with bipolar disorder (BD) and children at risk for BD, correlating to a higher inflammatory state. The genetic and environmental influences on these T cell deficiencies in association with BD development are unknown. OBJECTIVES: The aim is to quantify genetic and environmental factors that contribute to the association between the liability to develop BD and T cell deficiencies. METHODS: Participants of a Dutch bipolar twin study (11 monozygotic BD twin pairs, 15 dizygotic BD twin pairs, 15 monozygotic and 12 dizygotic healthy twin pairs) were included. A detailed FACS analysis of frozen stored leukocytes was carried out to determine the percentages of T cells and various other leukocyte and lymphocyte subsets. A bivariate liability threshold twin model was used to determine genetic and environmental (common and unique) influences on the correlation between BD and the various subsets. RESULTS: Lower percentages of T cells and higher percentages of NK cells were associated with the familial liability to develop BD. Neither genetic nor shared or unique environmental factors could explain the associations. Lithium usage explained part of the association for T cells, smoking in part that for NK cells. CONCLUSIONS: Our results confirm that BD is the result of a complex interaction between various genetic and environmental risk factors, in which T and NK cells act as important intermediate immune players.

Exploring longitudinal associations of histologically assessed inflammation with symptoms and radiographic damage in knee osteoarthritis: combined results of three prospective cohort studies.

OBJECTIVE: To explore the associations between different histologically assessed, inflammatory synovial characteristics and subsequent clinical and structural aspects in knee osteoarthritis (OA). DESIGN: Knee OA patients, ranging in stage from early to advanced, were recruited from three different ongoing studies. Synovial tissue biopsies were taken and histologically assessed for six features (four inflammatory related aspects, fibrosis and fibrin deposition). Clinical aspects (WOMAC pain, functioning and stiffness and SF-36 vitality) and structural aspects (Kellgren and Lawrence (KL)-grade, joint space narrowing (JSN; 0-3) and osteophytes (0-3), and reception of total knee replacement (TKR)) were repeatedly assessed during follow-up. Associations between histology and clinical and structural aspects were analysed using linear mixed model analyses and cox proportional hazards analysis. RESULTS: Biopsies of 83 patients (median complaint duration: 5 [2-8] years) were analysed. Follow-up was a median of 1.4 [0.8-2.7] years for clinical and 1.8 [0.2-5.2] years for structural aspects. Fibrosis and fibrin deposition were inversely correlated with the inflammatory features. A higher fibrosis score was associated with a lower scores for KL-grade, JSN and osteophytes, while higher scores for perivascular oedema, synovial lining thickness and vascularisation were associated with higher scores for structural aspects during follow-up. No associations were found between each of the histological features and any of the clinical aspects or the chance for TKR during follow-up. CONCLUSIONS: Inflammatory related histological aspects are associated with subsequent increased radiological severity in knee OA, while fibrosis seems to protect against this, providing a potential therapeutic target for OA treatment.

[Spondylodiscitis as a rare manifestation of gout]. / Spondylodiscitis als zeldzame manifestatie van jicht.

BACKGROUND: Spondylodiscitis is usually caused by microorganisms, but there are also non-infectious causes. CASE DESCRIPTION: We are describing an 84-year-old man with severe pain in the side and elevated inflammation parameters. MRI of the spinal column yielded a picture suggesting spondylodiscitis. Repeated peripheral cultures and culture of a vertebral biopsy did not yield a pathogen. Intravenous antibiotics had no effect on symptoms or inflammation parameters. When the physical examination was repeated, we found arthritis in the feet and tophi. Microscopic examination of a new vertebral biopsy found urate crystals. This meant we were dealing with spondylodiscitis as manifestation of gout. Treatment with colchicine was highly successful. CONCLUSION: Spinal column gout is unknown, but seems to occur with some regularity. This disease can be symptom-free but may also lead to myelopathy or spondylodiscitis. In case of spondylodiscitis without demonstrated pathogen in patients with gout or risk factors for this, the vertebral biopsy should be evaluated for urate crystals or a dual-energy CT should be considered.

Immune dysregulation in offspring of a bipolar parent. Altered serum levels of immune growth factors at adolescent age.

Immune dysregulation plays a role in the vulnerability for mood disorders. Immune growth factors, such as Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein-2 (IGF-BP2), Epidermal Growth Factor (EGF), IL-7 and sCD25 have repeatedly been reported altered in patients with mood disorders. The aim of this study was to investigate levels of these factors in serum of adolescent bipolar offspring, who have a heightened risk for mood disorder development and to also analyze the data combined with previously published data. Growth factors were assessed by CBA/ELISA in adolescent bipolar offspring (n=96, mean age=16years) and in age- and gender-matched healthy controls (n=50). EGF belonged to a mutually correlating cluster of mainly neurotrophic compounds including S100B and BDNF, which were in general decreased in serum. IL-7, SCF, IGF-BP2 and sCD25, belonged to a different mutually correlating cluster of immune growth factors, which were in general increased: IGF-BP2 significantly in serum of offspring without a mood disorder, IL-7 and SCF in serum of offspring who had experienced a mood episode. This pattern of de- and increases was not different between bipolar offspring that developed or did not develop a mood disorder over time, apart from the IGF-BP2 level, which was near significantly higher in offspring later developing a mood disorder. Correlations with the previously published immune-cellular abnormalities were not found. In conclusion non-affected adolescents at familial mood disorder development risk were characterized by a distinct pattern of a series of compounds operating in a network of hematopoiesis, neurogenesis and inflammation.

The seroprevalence of antithyroid peroxidase antibodies in bipolar families and bipolar twins: results from two longitudinal studies.

BACKGROUND: Previous studies of our group among bipolar offspring and bipolar twins showed significant higher prevalence's and levels of antithyroid peroxidase antibodies (TPO-Abs) in offspring and co-twins (without a mood disorder) compared to controls, suggesting that TPO-Abs might be considered as vulnerability factor (trait marker) for BD development. OBJECTIVES: Here we elucidate, in the same cohorts, but now after 12- and 6-year follow-up, whether TPO-abs should be considered as a 'trait' marker for BD. The present study aims to investigate whether TPO-Abs (1) are stable over time, (2) are associated with lithium-exposure, (3) share a common genetic background with BD and are related to psychopathology. RESULTS: In bipolar offspring and twins, the prevalence of TPO-Abs is stable over time (r s = .72 p < .001 resp. r s = .82, p < .001) and not associated with lithium use. At follow-up, an increased prevalence of TPO-abs was again observed in bipolar offspring (10,4% versus 4%) and higher TPO-abs titers were still present in co-twins of bipolar cases compared to control twins [mean 1.06 IU/ml (SD .82) versus mean .82 IU/ml (SD .67)], although statistical significance was lost. CONCLUSIONS: Although our results show a trend toward an increased inherited risk of the co-occurrence of BD and thyroid autoimmunity, large-scale studies can only draw final conclusions. Nationwide epidemiological and GWAS studies reach such numbers and support the view of a possible common (autoimmune) etiology of severe mood disorders and chronic recurrent infections and autoimmunity, including thyroid autoimmunity.

A dynamic course of T cell defects in individuals at risk for mood disorders.

OBJECTIVES: T cell abnormalities have been repeatedly reported in adult patients with mood disorders, suggesting a role of these cells in the pathogenesis of these disorders. In the present study, we explored the dynamics of circulating T cell subsets over time in a population at high familial risk for developing a mood disorder. METHODS: Children of a parent with bipolar disorder (bipolar offspring, N=140) were assessed at three time-points: adolescence, young adulthood and adulthood. We carried out a detailed fluorescence-activated cell sorting (FACS) analysis to determine various T cell subsets from frozen stored peripheral blood mononuclear cells of bipolar offspring and age- and gender-matched healthy controls at each time-point. RESULTS: Throughout the period of observation reduced levels of CD3+ and CD3+ CD4+ T cells were observed. In bipolar offspring Th1, Th2, Th17 and natural T regulatory cells (Tregs) followed a dynamic course over time with reduced levels of Tregs in adolescence and a reduced relative number of Th1, Th17 cells in young adulthood. In post hoc analysis Tregs were inversely associated with the pro-inflammatory monocyte state determined previously (rs=-0.220, p=0.001). Significant associations between T cell subset abnormalities and psychopathology such as mood disorders were not found. CONCLUSIONS: A subtle partial T cell defect was present in bipolar offspring from adolescence through adulthood. Within this defect the dynamic change of inflammatory and regulatory T cell subsets suggests a high inflammatory state during adolescence, a reduced inflammatory state during young adulthood and a virtually normalized state at adulthood.

Prevalence and predictors of health care use in patients with early hip or knee osteoarthritis: two-year follow-up data from the CHECK cohort.

OBJECTIVE: To describe health care utilization (HCU) and predict analgesic use and health professional (HP) contact at baseline and 2 years in individuals with early symptomatic hip and/or knee osteoarthritis (OA). DESIGN: Baseline and two-year data on HCU of the 1002 participants from the multi-centre Cohort Hip & Cohort Knee study were used. Six forms of health care services were described: analgesic use, supplement use, contact with a General Practitioner (GP), contact with a HP, contact in secondary care, and alternative medicine use. Multivariable logistic regression was performed in order to identify predisposing, enabling and disease-related variables that predict analgesic use and HP contact at 2 years; treatment modalities of first choice in early OA. RESULTS: For the hip (n=170), the knee (n=414) and the hip and knee (n=418) group analgesic use (38%, 29% and 47%, respectively), contact with a GP (32%, 38% and 36%, respectively) and contact with a HP (26%, 18% and 20%, respectively), were reported most often at baseline. Contact with a GP significantly decreased, supplement use increased (to about one third), and other treatment modalities remained stable at 2 years. In all three groups, analgesic use at baseline was the strongest predictor for analgesic use at 2 years, whereas contact with a HP at baseline was the strongest predictor of contact with a HP after 2 years. Belonging to a first generation minority was a predisposing risk factor [Odds Ratio (95%-CI), 8.72 (1.55-48.97)] for analgesic use in the hip and knee group. CONCLUSIONS: In early OA, familiarity with HCU and other predisposing factors are, apart from disease-related factors strongly associated with HCU at 2 years. Further research is necessary to examine whether our findings reflect sub-optimal management of early OA in terms of efficacy and equity.

Evidence-based tailored conservative treatment of knee and hip osteoarthritis: between knowing and doing.

OBJECTIVE: Insufficient data are available on the efficacy of combined conservative interventions recommended by treatment guidelines for knee/hip osteoarthritis (OA). The aims of this observational cohort study were (i) to estimate the results of an evidence-based 12-week tailored multimodal conservative treatment protocol for patients with knee/hip OA and (ii) to identify predictors for response. METHODS: After obtaining data on previous OA-related interventions, multimodal treatment was offered to patients with knee and/or hip OA at a specialized outpatient clinic. Treatment with analgesics was tailored using a numeric rating scale (NRS) for pain, aiming for NRS ≤ 4. The following outcome measures were assessed: (i) the proportion of patients fulfilling OMERACT-OARSI (Outcome Measures in Rheumatoid Arthritis Clinical Trials/Osteoarthritis Research Society International) responder criteria and (ii) the proportion of patients with NRS pain ≤ 4 after 12 weeks. RESULTS: A total of 183 out of 299 patients was included. OMERACT-OARSI responder criteria were fulfilled at 12 weeks in 47% of patients; 39% reached NRS pain ≤ 4. The only independent predictor for response was the number of previously used non-steroidal anti-inflammatory drugs (NSAIDs). The majority of patients had not been exposed adequately to conservative treatment modalities for knee and/or hip OA in the past (81%). CONCLUSION: Evidence-based multimodal conservative treatment using a standardized protocol for knee and/or hip OA is feasible and successful in 47% of patients. In general, response could not be predicted. Basic first-line recommended conservative treatment options have not been used adequately prior to referral to secondary care in the vast majority of patients.

Measurement characteristics of a new rapid anti-CCP2 test compared to the anti-CCP2 ELISA.

OBJECTIVE: Anti-cyclic citrullinated peptide (CCP)2 antibody status is an important diagnostic tool in the work-up of undifferentiated arthritis (UA)/early rheumatoid arthritis (RA) but the results of the enzyme-linked immunosorbent assay (ELISA) are only available a few days after the test. The aim of this study was to assess the measurement characteristics of a rapid anti-CCP2 test compared to the usual anti-CCP2 ELISA test. METHODS: In the first phase, rapid anti-CCP2 (CCPoint) tests were performed in capillary blood obtained by finger puncture (CAP), in venous blood from a clot tube (CLOT) and in serum (SERUM) in consenting RA patients. Anti-CCP2 measured in serum using the anti-CCP2 ELISA (ELISA) was set as the gold standard (reference). In the second phase of the study, specificity versus RA was confirmed in consenting non-RA patients and healthy controls. The anti-CCP2 results were negative (no visible line or anti-CCP2<25 U/mL) or positive (visible line or anti-CCP2> or =25 U/mL). RESULTS: A total of 880 subjects (109 RA patients, 351 non-RA patients and 420 healthy controls) were enrolled in this study. For the RA patients, 5%, 15%, and 1% of CAP, CLOT and SERUM tests, respectively, were inconclusive. The sensitivity and specificity of CAP compared with ELISA were 95% (95% CI 90-100) and 95% (95% CI 89-100), respectively, and the corresponding values for SERUM were 97% (95% CI 93-100) and 98 (95% CI 94-100). The specificity for RA versus non-RA and healthy controls was 99% (95% CI 97-100) and 99% (95% CI 98-100), respectively. CONCLUSION: The CCPoint test is a fast, valid and reliable anti-CCP2 test in both capillary blood and serum but not directly in venous blood.

Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study.

OBJECTIVES: In clinical trials only a small subset of patients with rheumatoid arthritis (RA) benefits from higher than standard dose of infliximab (>3 mg/kg/8 weeks). However, dose escalation of infliximab is frequently applied in clinical practice. Individual adjustment of infliximab treatment based on actual disease activity, instead of subjective clinical judgement, could prevent possible unwarranted dose escalation. METHODS: The infliximab dose of all patients with RA treated at our centre was decreased from 5 mg/kg to 3 mg/kg, leaving dosing intervals unaltered. Subsequently patients were followed for at least three infusions. At every visit, 28-joint Disease Activity Score (DAS28), infliximab serum trough levels and anti-infliximab antibody levels were assessed. Inversed European League Against Rheumatism (EULAR) criteria (flare criteria) were used as the endpoint. RESULTS: A total of 18 patients were included in the study. Mean (SD) DAS28 scores before dose reduction and after first and second low dose were 3.2 (1.2), 3.2 (1.8) and 3.3 (1.2), respectively (values not significant). One patient (6%, 95% CI 0% to 17%) developed a persistent flare that subsided after increasing infliximab doses and one patient stopped infliximab because of a lupus-like reaction. In all other patients (n=16) lowering infliximab resulted in unaltered disease activity. Infliximab levels showed that most patients had either low- (<1 mg/litre) or high (>5 mg/litre) serum trough levels. Anti-infliximab antibodies were detected in four patients. CONCLUSION: Infliximab dosages of 5 mg/kg can be lowered in the majority of patients with RA using DAS28-guided dose titration without increase of disease activity. Lowering the dose of infliximab should be considered in every patient receiving higher doses infliximab.