Mats Dehlin

Intra-Articular Fms-Like Tyrosine Kinase 3 Ligand Expression Is a Driving Force in Induction and Progression of Arthritis

Background One of the hallmarks of rheumatoid arthritis (RA) is hyperplasia and inflammation of the synovial tissue being characterized by in situ occurrence of highly differentiated leukocytes. Fms-like tyrosine kinase 3 (Flt3) has a crucial role in hematopoiesis, regulation of cell proliferation, differentiation and apoptosis. Typically, Flt3 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand (Flt3-L). The highly differentiated cellular pattern in the synovium of the RA patients made us hypothesize that Flt3-L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis. Methodology/Principal Findings To investigate occurrence of Flt3-L in RA we have measured its levels in matched serum and synovial fluid samples from 130 patients and 107 controls. To analyse the pro-inflammatory role of Flt3-L, we continuously overexpressed this protein locally in healthy mouse joints using homologous B-cell line transfected with Flt3-L gene. Additionally, recombinant Flt3-L was instillated intra-articularly in combination with peptidoglycans, a Toll Like Receptor 2-ligand with stong arthritogenic properties. Our results show significantly higher levels of Flt3-L in the synovial fluid as compared to serum levels in RA subjects (p = 0.0001). In addition, RA synovial fluid levels of Flt-3-L were significantly higher than these obtained from synovial fluids originating from non-inflammatory joint diseases (p = 0.022). Intra-articular administration of B-cell line transfected with Flt3-L gene resulted in highly erosive arthritis while inoculation of the same B-cell line without hyperexpression of Flt3-L did not induce erosivity and only in a minority of cases caused synovial proliferation! Flt3-ligand potentiated peptidoglycan induced arthritis as compared to mice injected with peptidoglycan alone (p<0.05). Conclusions/Significance Our findings indicate that Flt3-L is strongly expressed at the site of inflammation in human RA. It exerts both pro-inflammatory and tissue destructive properties once in the joint cavity. Owing to these properties, treatment attempts to neutralize this molecule should be considered in RA.

Changes in pain and insulin-like growth factor 1 in fibromyalgia during exercise: the involvement of cerebrospinal inflammatory factors and neuropeptides

AbstractIntroductionFibromyalgia (FM) is characterized by chronic pain. Impaired growth hormone responses and reduced serum insulin-like growth factor 1 (IGF-1) are common in FM. The aim was to examine changes in serum IGF-1, cerebrospinal fluid (CSF), neuropeptides, and cytokines during aerobic exercise in FM patients.MethodsIn total, 49 patients (median age, 52 years) with FM were included in the study. They were randomized to either the moderate- to high-intensity Nordic Walking (NW) program (n = 26) or the supervised low-intensity walking (LIW) program (n = 23). Patients participated in blood tests before and after 15 weeks of aerobic exercise. Changes in serum levels of free IGF-1, pain rating on a 0- to 100-mm scale, pain threshold, and 6-minute walk test (6MWT) were examined. CSF, neuropeptides, matrix metalloproteinase 3 (MMP-3), and inflammatory cytokines were determined. Nonparametric tests were used for group comparisons and correlation analyses.ResultsSerum free IGF-1 levels did not change during 15 weeks of exercise between the two groups, although the 6MWT significantly improved in the NW group (p = 0.033) when compared with LIW. Pain did not significantly change in any of the groups, but tended to decrease (p = 0.052) over time in the total group. A tendency toward a correlation was noted between baseline IGF-1 and a decrease of pain in response to exercise (r = 0.278; p = 0.059). When adjusted for age, this tendency disappeared. The change in serum free IGF-1 correlated positively with an alteration in CSF substance P (SP) levels (rs= 0.495; p = 0.072), neuropeptide Y (NPY) (rs = 0.802; p = 0.001), and pain threshold (rs = 0.276; p = 0.058). Differing CSF SP levels correlated positively to a change in pain threshold (rs= 0.600; p = 0.023), whereas the shift in CSF MMP-3 inversely correlated with an altered pain threshold (rs= -0.569; p = 0.034).ConclusionsThe baseline level of serum free IGF-1 did not change during high or low intensity of aerobic exercise. Changes in IGF-1 correlated positively with a variation in CSF SP, NPY, and pain threshold. These data indicate a beneficial role of IGF-1 during exercise in FM.Trial registration: ClinicalTrials.gov NCT00643006.

Smoking is Associated with Reduced Leptin and Neuropeptide Y Levels and Higher Pain Experience in Patients with Fibromyalgia

Smoking deregulates neuroendocrine responses to pain supporting production of neuropeptide Y (NpY) by direct stimulation of nicotinic receptors or by inhibiting adipokine leptin. Present study addressed the effect of cigarette smoking on adipokines and pain parameters, in 62 women with fibromyalgia (FM) pain syndrome with unknown etiology. Pain was characterized by a visual analogue scale, tender point (TP) counts, pressure pain threshold, and neuroendocrine markers NpY and substance P (sP). Levels of IGF-1, leptin, resistin, visfatin, and adiponectin were measured in blood and cerebrospinal fluid. Current smokers (n = 18) had lower levels of leptin compared to ex-smokers (n = 25, P = 0.002), while the expected NpY increase was absent in FM patients. In smokers, this was transcribed in higher VAS-pain (P = 0.04) and TP count (P = 0.03), lower pain threshold (P = 0.01), since NpY levels were directly related to the pain threshold (rho = 0.414) and inversely related to TP counts (rho = −0.375). This study shows that patients with FM have no increase of NpY levels in response to smoking despite the low levels of leptin. Deregulation of the balance between leptin and neuropeptide Y may be one of the essential mechanisms of chronic pain in FM.

Validity of gout diagnosis in Swedish primary and secondary care - a validation study

BackgroundThe diagnostic golden standard for gout is to detect monosodium urate (MSU) crystals in synovial fluid. While some gout classification criteria include this variable, most gout diagnoses are based on clinical features. This discrepancy between clinical practice and classification criteria can hinder gout epidemiological studies. Here, the objective was to validate gout diagnoses (International Classification of Diseases (ICD)-10 gout codes) in primary and secondary care relative to five classification criteria (Rome, New York, ARA, Mexico, and Netherlands). The frequency with which MSU crystal identification was used to establish gout diagnosis was also determined.MethodsIn total, 394 patients with ≥1 ICD-10 gout diagnosis between 2009 and 2013 were identified from the medical records of two primary care centers (n = 262) and one secondary care center (n = 132) in Gothenburg, Sweden. Medical records were assessed for all classification criteria.ResultsPrimary care patients met criteria cutoffs more frequently when ≥2 gout diagnoses were made. Even then, few primary care patients met the Rome and New York cutoffs (19 % and 8 %, respectively). The ARA, Mexico, and Netherlands cutoffs were met more frequently by primary care patients with ≥2 gout diagnoses (54 %, 81 %, and 80 %, respectively). Mexico and Netherlands cutoffs were met more frequently by the rheumatology department patients (80 % and 71 %, respectively), even when patients with only 1 gout diagnosis were included. Analysis of MSU crystals served to establish gout diagnoses in only 27 % of rheumatology department and 2 % of primary care cases.ConclusionsIf a patient was deemed to have gout at ≥2 primary care center or ≥1 rheumatology-center visits according to an ICD-10 gout code, the positive predictive value of this variable in relation with the Mexico and Netherlands classification criteria was ≥80 % for both primary care and rheumatology care settings in Sweden. MSU crystal identification was rarely used to establish gout diagnosis.

Incidence of and risk factors for nephrolithiasis in patients with gout and the general population, a cohort study

BackgroundNephrolithiasis (NL) is known to be associated with gout, although there are few comparative studies on risk and risk factors for NL in gout compared to population cohorts. In this cohort study we investigated: (1) overall incidence of NL in gout (cases) and general population controls; (2) risk and risk factors (common comorbidities and medications) for first-time NL in cases and controls separately.MethodsCases (n = 29,968) and age-matched and sex-matched controls (n = 138,678) were identified from the regional healthcare database in western Sweden (VEGA). The analyzed risk factors (comorbidities and current medication use) for first-time NL, and socioeconomic factors were retrieved from VEGA and other national Swedish registers. For cases, follow up began on 1 January 2006 or on the first diagnosis of gout if this occurred later, and for controls on their index patient’s first diagnosis of gout. Follow up ended on death, emigration or 31 December 2012. Incidence rates (IR) per 1000 person-years and hazard ratios (HR) were calculated. The incidence calculations were performed for cases (regardless of prior NL) and their controls. HRs with first occurrence of NL as outcome were calculated only in those without previous NL.ResultsIn cases there were 678 NL events (IR: 6.16 events per 1000 person-years (95% CI: 5.70–6.64) and in controls 2125 NL events (IR 3.85 events per 1000 person-years (95% CI: 3.69–4.02), resulting in an age-sex-adjusted incidence rate ratio of 1.60 (95% CI:1.47–1.74).Point estimates for predictive factors were similar in cases and controls, except for a significant interaction for losartan which increased the risk of NL only in controls (HR = 1.49 (95% CI: 1.03–2.14). Loop diuretics significantly decreased the risk of NL by 30–34% in both cases and controls. Further significant predictors of NL in gout cases were male sex, diabetes and obesity and in controls male sex and kidney disease.ConclusionsThe risk (age and sex adjusted) of NL was increased by 60% in cases compared to controls. None of the commonly used medications increased the risk of NL in gout patients.

Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions for disease elements in gout

The language currently used to describe gout lacks standardization. The aim of this project was to develop a consensus statement on the labels and definitions used to describe the basic disease elements of gout.

Work disability in gout: a population-based case–control study

Objectives To examine the extent and cost of work disability among patients with gout compared with matched population controls and to analyse predictors of work disability. Methods A regional cohort study using data from Swedish national and regional registries from January 2000 through December 2012, including 4571 patients with gout of working age, with a first recorded diagnosis of gout in the years 2003–2009 and 22 482 population controls, matched by age, sex and place of residence. Differences in baseline characteristics (educational level, income, previous employment and comorbidities) and the number of work-loss days (absenteeism) due to sick leave and disability pension for 3 years after identification were calculated. Predictors for new-onset work absenteeism (>90 days/year) in a subset were determined by conditional logistic regression. Results Patients with gout (median age 53 years) had significantly more comorbidities, lower income and lower level of education than matched controls. The average work absentee rate during the 3-year follow-up period was higher among patients with gout than controls, 22% and 14%, respectively (P<0.0001). New-onset absenteeism was in multivariate analyses significantly predicted by gout (OR 1.47; 95% CI 1.23 to 1.75). Other variables independently related to new-onset absenteeism were education ≤12 years, previous unemployment and history of sick leave, in addition to several comorbidities (renal disease, cardiovascular disease, alcohol abuse and obesity). Conclusions Gout is associated with substantially higher work absenteeism and costs for society due to productivity loss, after adjusting for associated comorbidities and socioeconomic differences. Whether more intensive treatment of gout is cost-effective needs to be addressed in future studies.

Risk of cardiac rhythm disturbances and aortic regurgitation in different spondyloarthritis subtypes in comparison with general population: a register-based study from Sweden

Objectives To describe the incidence of atrioventricular (AV) block II–III, atrial fibrillation (AF), pacemaker implantation (PM) and aortic regurgitation in patients with ankylosing spondylitis (AS), undifferentiated spondyloarthritis (uSpA) and psoriatic arthritis (PsA) compared with the general population (GP) and with each other. Methods A prospective nationwide study with cohorts of patients with AS (n=6448), PsA (n=16 063) and uSpA (n=5190) and a GP (n=2 66 435) cohort, identified in 2001–2009 in the Swedish National Patient and Population registers. Follow-up began on 1 January 2006 and ended at event, death, emigration or 31 December 2012. Age-standardised and sex-standardised incidence rates and hazard ratios (HRs) were calculated. Results The highest incidence rates were noted for AF (5.5–7.4 events per 1000 person-years), followed by PM (1.0–2.0 events per 1000 person-years). HRs for AV block, AF, PM and aortic regurgitation were significantly increased in AS (HRs 2.3, 1.3, 2.1 and 1.9), uSpA (HRs 2.9, 1.3, 1.9 and 2.0) and PsA (HRs 1.5, 1.5, 1.6 and 1.8) compared with the GP cohort. The highest HRs were seen for AV block in male uSpA (HR 4.2) and AS (HR 2.5) compared with GP. Compared with PsA, significantly increased HRs were noted for PM (HR 1.5) in AS and for AV block (HR 1.8) in uSpA. Conclusions Patients with SpA are at increased risk of aortic regurgitation, cardiac rhythm disturbances and, as a probable consequence, also PM. Particularly for AF, the most common arrhythmia, increased caution is warranted, whereas AV block should be looked for especially in men with AS or uSpA.

OP0262 Trends and costs for gout hospitalization in sweden

Background Gout is the most common arthritic disease in the world with increasing incidence and prevalence. There are differences in gout prevalence and course of disease due to cultural, ethnical and genetic factors stressing the need for data from different parts of the world. An increase in hospitalization for gout has been shown for the last two decades in North America. Objectives We evaluated the trend for hospitalization of gout in western Sweden 2000 – 2012 and the health care costs for this 2009 – 2012. Methods Hospitalization trends for gout were studied using data from the health care consumption register in the Western Swedish Health Care Region (WSHCR) from 2000–01–01 through 2012–12–31. This area is considered to be representative for the country as a whole. Patients aged 18 years and older who were hospitalized during the study period with a principal ICD-10 diagnosis of gout (M10) at discharge were included. We calculated annual population rates for hospitalization for gout. Inflation-adjusted health care costs for the gout hospitalizations were calculated using the Cost-Per-Patient register (CPP). Dispensation of urate lowering therapy (ULT), allopurinol (M04AA01) and probenecid (M04AB01), within 6 months prior to hospitalization was identified using The Swedish Prescribed Drug Register. Results There were 1873 hospitalizations for gout (mean age 75.0–77.6 years, 61–74% men) between 2000 and 2012. Demographic characteristics were similar over the study period. From 2000 to 2012, the annual hospitalization rate for gout increased from 12.2 to 16.7 per 100 000 adults (p=0.0038). The increase was most pronounced in males aged 65 and above and over the last three years of the study. From 2009 to 2012 the inflation-adjusted health care costs for gout hospitalizations increased from 5.21 to 8.15 105 USD. The duration of hospitalizations also increased from 3 to 5 days median 2000 and 2012 respectively (p=0.021). Only a minority of patients, 19 to 27%, received ULT the 6 months preceding their hospitalization, without any obvious secular trend.Table 1 2000 2002 2004 2006 2008 2009 2010 2011 2012 Discharges, no 142 112 108 133 140 144 187 180 213 Incidence per 100 000 adults 12.2 9.5 9. 1 11.0 11.3 11.5 14.9 14.2 16.7 Men, incidence per 100 000 adults 16.1 12.3 12.9 14.4 15.7 16.0 22.0 21.1 24.3 Women, incidence per 100 000 adults 8.4 6.8 5.3 7.7 7.0 7.1 7.9 7.3 9.1 Duration, days, median (range) 3 (1–71) 3 (1–44) 5 (1–75) 5 (1–65) 5 (1–40) 5 (1–39) 5 (1–34) 5 (1–52) 5 (1–41) Age, years, mean, SD 76.2 (12.1) 74.3 (14.9) 76.3 (11.7) 77.2 (10.2) 77.4 (11.4) 76.7 (11.6) 77.6 (12.7) 75.6 (14.1) 75.0 (13.8)  18–44 3 6 1 0 5 4 8 8 4  45–64 23 16 17 19 12 11 19 28 41  65–84 83 63 67 80 85 89 100 92 108  ≥85 33 27 23 34 38 40 60 52 60 ULT, (%), 6 months before hospitalization 28 (21) 38 (27) 27 (19) 38 (20) 47 (26) 45 (21) Total cost*, 105 USD 5.21 6.8 6.6 8.15 Conclusions Incidence of hospitalization for primary gout is increasing substantially in Sweden over the last decade and this is reflected in the health care costs. The main part of this increase consists of males aged 65 and above. Only a fourth of the patients were on ULT preceding the hospitalization. These findings are further emphasized by the fact that the total amount of days for somatic inpatient care in WSHCR decreased by 9% from 2002 (1 267 900 days, mean duration 5,7 days) to 2012 (1 151 630 days, mean duration 4,9 days). The findings in this study reflects increasing incidence of the gout disease and an ageing population but also a considerable lack of treatment. Disclosure of Interest None declared

Cerebrospinal Flt3 ligand correlates to tau protein levels in primary Sjögren’s syndrome

Objectives: Primary Sjögren’s syndrome (pSS) is an autoimmune disease affecting the exocrine glands and internal organs including the central nervous system (CNS). The fms-related tyrosine kinase 3 ligand (Flt3L) is a maturation factor essential for brain homeostasis. Blood levels of Flt3L are increased in inflammatory diseases including the inflamed salivary glands in pSS. The present study evaluated the role of Flt3L in the CNS of patients with pSS and in two non-autoimmune conditions, fibromyalgia (FM) and Alzheimer’s disease (AD). Method: Levels of Flt3L were measured in cerebrospinal fluid (CSF) and serum of patients with pSS (n = 15), FM (n = 29), and AD (n = 39) and related to CNS symptoms and to markers of inflammation and degeneration. Results: Levels of CSF Flt3L in pSS and AD were significantly lower than in FM (p = 0.005 and p = 0.0003, respectively). Flt3L in pSS correlated to tau proteins [total tau (T-tau), r = 0.679; phosphorylated tau (P-tau), r = 0.646] and to a marker for microglia activation, monocyte chemoattractant protein 1 (MCP-1). Similar correlations were present in FM and AD patients. One-third of pSS patients had low levels of CSF Flt3L. This group had decreased levels of amyloid precursor protein metabolites (Aβ40 and Aβ42) in CSF, which was not seen in FM patients. Conclusions: This study shows a strong correlation between CSF Flt3L and tau proteins in pSS patients suggesting ongoing degradation/remodelling in the CNS. In pSS patients, low levels of Flt3L were linked to changes in amyloid turnover and may represent processes similar to those in AD.