Enthesitis in a European registry-based cohort of patients with psoriatic arthritis treated with tumour necrosis factor inhibitors: clinical burden, patient-reported outcomes, and treatment response.

OBJECTIVE: To explore the registration of enthesitis among biologic-naïve patients with psoriatic arthritis (PsA) initiating tumour necrosis factor inhibitor (TNFi) treatment across 12 European registries, compare the disease burden and patient-reported outcomes (PROs) between patients with and without enthesitis, and assess the enthesitis treatment response. METHOD: Demographics, clinical characteristics, and PROs at first TNFi (TNFi-1) initiation (baseline) were assessed in patients with PsA, diagnosed by a rheumatologist, with versus without assessment of entheses and between those with versus without enthesitis. Enthesitis scores and resolution frequency were identified at follow-up. RESULTS: Of 10 547 patients in the European Spondyloarthritis (EuroSpA) Research Collaboration Network initiating TNFi, 1357 underwent evaluation for enthesitis. Eight registries included a validated scoring system for enthesitis. At baseline, 874 patients underwent entheses assessment [Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) 485 patients, Spondyloarthritis Research Consortium of Canada (SPARCC) 389 patients]. Enthesitis was detected by MASES in 170/485 (35%, mean score ± sd 3.1 ± 2.4) and by SPARCC in 236/389 (61%, 4 ± 3.4). Achilles enthesitis was most frequent, by both MASES (unilateral/bilateral 28%/9%) and SPARCC (48%/18%). MASES/SPARCC baseline and follow-up scores for TNFi-1 were available for 100/105 patients. Of these, 63 patients (63%) (MASES) and 46 (43.8%) (SPARCC) achieved resolution of enthesitis. The site-specific enthesitis resolution was overall lower at SPARCC sites (peripheral; 63-80%) than at MASES sites (mainly axial; 82-100%) following TNFi-1. Disease activity and PROs were worse in patients with versus without enthesitis. CONCLUSION: Entheseal assessments are only registered in a minority of patients with PsA in routine care. When assessed, enthesitis was common, and a substantial proportion demonstrated resolution following treatment with TNFi-1.

The feasibility of existing JADAS10 cut-off values in clinical practice: a study of data from The Finnish Rheumatology Quality Register.

BACKGROUND: The ten-joint juvenile arthritis disease activity score (JADAS10) is designed to measure the level of disease activity in non-systemic juvenile idiopathic arthritis by providing a single numeric score. The clinical JADAS10 (cJADAS10) is a modification of the JADAS10 that excludes erythrocyte sedimentation rate (ESR). Three different sets of JADAS10/cJADAS10 cut-offs for disease activity states have been published, i.e., the Backström, Consolaro, and Trincianti cut-offs. The objective of this study was to investigate the performance of existing JADAS10 cut-offs in real-life settings using patient data from The Finnish Rheumatology Quality Register (FinRheuma). METHODS: Data were collected from the FinRheuma register. The proportion of patients with an active joint count (AJC) above zero when classified as being in clinically inactive disease (CID) or low disease activity (LDA) groups according to existing JADAS10/cJADAS10 cut-off levels were analyzed. RESULTS: A significantly larger proportion of the patients classified as being in CID had an AJC > 0 when using the JADAS10/cJADAS10 cut-offs by Trincianti et al. compared to those for the other cut-offs. In the LDA group, a significantly larger proportion of the polyarticular patients (35%/29%) had an AJC of two when Trincianti JADAS10/cJADAS10 cut-offs were used compared with when Backström (11%/10%) and Consolaro (7%/3%) JADAS10/cJADAS10 cut-offs were used. CONCLUSIONS: We found the cut-offs proposed by Consolaro et al. to be the most feasible, since these cut-off levels for CID do not result in the misclassification of active disease as remission, and the proportion of patients with AJC > 1 in the LDA group is lowest using these cut-offs.

Transition to adult care in Finnish adolescents with juvenile idiopathic arthritis.

OBJECTIVE: The symptoms of juvenile idiopathic arthritis (JIA) and the necessity for continuous treatment may persist in adulthood. Therefore, patients with JIA need to be appropriately transferred to adult care. We aimed to analyse the timing of the patients' transition to adult care, and patients' self-management skills with the process and the quality of the transition. METHOD: This study included 161 Finnish participants of the population-based Nordic JIA cohort who attended a 17 year follow-up appointment. Special attention was paid to the three groups: those referred by the paediatric rheumatology outpatient clinic to primary healthcare (PHC), those who were directly transferred to adult rheumatology care, and those who were later referred. RESULTS: A total of 136 patients (84%) were eligible to participate in the study, and 40% of them were directly transferred to an adult rheumatology clinic. Of the patients, 72% eventually ended up being referred to an adult rheumatology outpatient clinic. However, 16% of the patients in the PHC group had active disease during the study appointment and were referred to adult services after the study visit. CONCLUSION: This study reveals the need to improve the transition process from paediatric care to adult care and to find the variables that can indicate the need for immediate transition. Although challenging, it is important to avoid treatment delay in adult patients with JIA who may have active disease but who do not have appropriate access to an adult rheumatological outpatient clinic.

Immunogenicity of subcutaneous TNF inhibitors and its clinical significance in real-life setting in patients with spondyloarthritis.

KEY MESSAGES: Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1-2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

Pain interference and associated factors in young adults with juvenile idiopathic arthritis.

Objective: Pain is a common and distressing feature of juvenile idiopathic arthritis (JIA). Pain interference (PI) is underexplored in long-term conditions such as JIA. The aim of this study was to explore the factors associated with PI in young adults with JIA. Methods: All consecutive JIA patients aged 18-30 years in three tertiary rheumatology and rehabilitation centres in Finland between September 2015 and April 2016 were included. The patients completed questionnaires addressing demographics, disability, depressive symptoms, pain anxiety, pain intensity, and PI. PI was measured with a single item from the RAND-36 questionnaire. Five response categories were coded into three groups: patients reporting 'extremely', 'quite a bit' or 'moderate' were classified as having significant PI; 'a little bit' as having minor PI; and 'not at all' as having no PI. A leisure-time physical activity metabolic equivalent of task (LTPA MET) was calculated. Statistical comparisons between PI and categorical variables were made using chi-squared or Fisher-Freeman-Halton tests. Results: Of the total 195 patients, 97 (50%) patients reported PI. PI was associated with a wide spectrum of sociodemographic and disease-related variables. Pain intensity scores were higher in patients expressing greater PI (p < 0.001). Greater PI was associated with higher disability (p < 0.001), higher pain anxiety scores (p < 0.001), lower LTPA MET (p = 0.027), and poorer leisure-time activity (p < 0.001). Conclusions: PI is common in young adults with JIA. We suggest that PI should be taken into account in future outcome studies exploring the impact of pain in children and young adults with JIA.

Disability and health-related quality of life are associated with restricted social participation in young adults with juvenile idiopathic arthritis.

OBJECTIVES: To describe a cohort of Finnish juvenile idiopathic arthritis (JIA) patients, to recognize those young adults who are at risk of becoming socially restricted by their long-term rheumatic disease, and to assess which areas of self-rated health-related quality of life (HRQoL) are associated with the emergence of restricted social participation. METHODS: A total of 195 young adults with JIA completed questionnaires addressing demographics, health behaviour, physical activity, functional ability, HRQoL, depressive symptoms, and self-esteem. Patients were classified as having non-restricted social participation if they were engaged in studying, working, maternity leave, or military service, and restricted social participation if they were unemployed or on disability pension. RESULTS: Of the patients, 162 (83%) were considered as having non-restricted social participation and 33 (16%) restricted social participation. Among patients with restricted social participation, five (15%) were on disability pension and 28 (85%) were unemployed. Patients with restricted social participation participated less in leisure-time non-physical activities (p = 0.033), felt more disturbed during their leisure time (p = 0.010), had lower self-esteem (p = 0.005), and had higher disability scores (p = 0.024). HRQoL scores revealed statistically significant differences between the groups: physical functioning (p = 0.043), social functioning (p = 0.016), and emotional well-being (p = 0.049) were all lower in patients with restricted social participation. CONCLUSIONS: Socially restricted patients showed a higher degree of disability, and lower levels of physical functioning, self-esteem, emotional well-being, and social functioning. These patients should be recognized earlier and interventions provided to enhance their social participation.

Fate of intravenously administered squalene and plant sterols in human subjects.

We have studied metabolism of plant sterols and squalene administered intravenously in the form of lipid emulsion mimicking chylomicrons (CM). The CM-like lipid emulsion was prepared by dissolving squalene in commercially available Intralipid. The emulsion was given as an intravenous bolus injection of 30 ml containing 6.3 mg of cholesterol, 1.9 mg of campesterol, 5.7 mg of sitosterol, 1.6 mg of stigmasterol, 18.1 mg of squalene, and 6 g of triglycerides in six healthy volunteers. Blood samples were drawn from the opposite arm before and serially 2.5 -180 min after the injections. The decay of CM squalene, plant sterols, and triglycerides was monoexponential. The half-life of CM squalene was 74 +/- 8 min, that of campesterol was 37 +/- 5 min (P < 0.01 from squalene), and those of sitosterol, stigmasterol, and triglycerides were 17 +/- 2, 15 +/- 1, and 17 +/- 2 min, respectively (P < 0.01 from squalene and campesterol). The CM squalene concentration still exceeded the baseline level 180 min after injection (P = 0.02), whereas plant sterols and triglycerides returned to the baseline level between 45 and 120 min after injection. The half-lives of squalene and campesterol were positively correlated with their fasting CM concentrations. In addition, VLDL squalene, campesterol, and triglyceride concentrations, VLDL, LDL, and HDL sitosterol concentrations, as well as VLDL and LDL stigmasterol concentrations were increased significantly. Cholesterol concentrations increased in VLDL (P < 0.05), but were unchanged in CM after injection. These data suggest that squalene clearance occurs more slowly than that of plant sterols and triglycerides from CM, and that squalene is more tightly associated with triglyceride-rich lipoproteins than are plant sterols in injected CM-like emulsions.

Acute effect of dietary stanyl ester dose on post-absorptive alpha-tocopherol, beta-carotene, retinol and retinyl palmitate concentrations.

Stanyl esters dissolved in margarine inhibit cholesterol absorption, lower sterol absorption in general, and lower serum total cholesterol, LDL-cholesterol and plant sterol levels. To find out whether stanyl esters inhibit absorption of fat-soluble vitamins and beta-carotene in acute experiments, we performed two fat-tolerance tests fortified with vitamins (retinol 0.9-3.7 mg, alpha-tocopherol 70-581 mg), beta-carotene (25-150 mg) and squalene (0.5 g) with and without 1 g of stanyl ester added to the test meal in ten healthy men. The concentrations or areas under the curves (AUC) of cholesterol, triacylglycerols, squalene and alpha-tocopherol, beta-carotene and retinyl palmitate showed typical postprandial changes in serum, chylomicrons, VLDL and VLDL infranatant (intermediate-density lipoproteins, LDL and HDL) over 24 h after the test meal without stanyl esters, and they were not affected by the addition of stanyl esters. The post-absorptive serum campesterol concentration and campesterol : cholesterol were significantly lowered at 6-9 h by stanyl ester supplementation, reflecting reduced sterol absorption efficiency. Changes in vitamin and beta-carotene AUC did not correlate with the given doses. In conclusion, the present study shows that stanyl esters dissolved in margarine do not detectably interfere in a short-term study with the absorption of alpha-tocopherol, beta-carotene or retinol measured by a 24 h oral fat-load test.

Postprandial retinyl palmitate and squalene metabolism is age dependent.

Most of our awake time is spent in a postprandial state. It has not been investigated in detail whether the post-prandial clearance of triglyceride-rich lipoproteins is age dependent. In addition, postabsorptive squalene metabolism has not been studied in relation to age. Accordingly, we investigated postprandial lipid metabolism in six young (22-25 years of age) and eight old (78-79 years of age) healthy men by use of an oral fat load containing 345,000 IU of vitamin A and 0.5 g of squalene as postprandial markers. Postprandial samples were drawn after 3, 4, 6, 9, 12 and 24 hours after the fat load. The retinyl palmitate area under the incremental curve of the old subjects was higher in plasma than that of the young subjects (p < .01). The pattern of postprandial very low density lipoprotein squalene responses differed significantly in the old compared with the young subjects (p < .01), but the areas under the incremental curve did not differ. Postprandial retinyl palmitate and squalene concentrations correlated significantly at 3-12 hours (p < .01). These data suggest that postprandial lipoprotein metabolism measured by retinyl palmitate and squalene is retarded with increasing age.

Dietary squalene increases cholesterol synthesis measured with serum non-cholesterol sterols after a single oral dose in humans.

Studies considering long-term squalene consumption have revealed no consistent effects on serum cholesterol levels but the immediate effect of dietary squalene on cholesterol synthesis has not been studied. Thus, the effect of a single dose of dietary squalene on postprandial lipid metabolism was studied in 16 male volunteeers aged 22-79 years. Two oral fat meals a week apart were administered to every subject, one without (control) and the other with 500 mg of squalene. Lipids, retinyl palmitate, squalene and non-cholesterol sterols were measured at baseline and after 3, 4, 6, 9, 12 and 24 h postprandially in plasma, chylomicron, VLDL and VLDL bottom and, in six randomly chosen subjects, also in IDL, LDL and HDL. In the fasting samples, squalene was mainly transported in LDL and HDL, whereas in squalene-supplemented postprandium most of squalene was carried in the triglyceride-rich lipoproteins. Postprandial squalene and retinyl palmitate curves closely resembled each other. After the squalene-enriched dietary fat load, squalene was significantly increased compared to control fat loads in plasma, chylomicrons, VLDL and IDL. Squalene addition increased significantly lathosterol/campesterol ratio in chylomicrons and VLDL at 12 h and in VLDL bottom at 9-12 h, and increased significantly VLDL lanosterol/campesterol ratio at 12 h, indicating enhanced cholesterol synthesis caused by squalene. Plasma plant sterol levels remained unchanged. In conclusion, a single oral dose of squalene representing a potential daily dietary amount increases cholesterol synthesis within 9-12 h detected in chylomicrons, VLDL and VLDL bottom.

Effect of stanol ester on postabsorptive squalene and retinyl palmitate.

Stanol ester dissolved in margarine inhibits cholesterol absorption in general and, despite increasing cholesterol synthesis, decreases serum total and low-density lipoprotein (LDL) cholesterol levels, but its effects on postprandial lipid metabolism are unknown. We performed fat tolerance tests in 11 men at baseline and during short-term stanol ester consumption without and with stanol esters added to the test meal also containing retinol and squalene. Cholesterol, triglycerides, retinyl palmitate, and squalene were analyzed in plasma, chylomicrons, and very-low-density lipoprotein (VLDL) at baseline and 3, 4, 6, 9, 12, and 24 hours after the test meal. Serum total and LDL cholesterol only tended to diminish after the 2-week stanol ester consumption. However, the proportion of plasma plant sterol and cholesterol-precursor sterol to cholesterol was significantly altered, suggesting that cholesterol absorption was diminished and cholesterol synthesis was increased. Postprandial peak times of squalene and retinyl palmitate in plasma, chylomicrons, and VLDL were significantly reduced by stanol esters, but their concentrations in chylomicrons were unchanged. Stanol esters reduced the VLDL squalene peak concentration by 23% (P < .05) and the incremental area under the curve (AUIC) in plasma and VLDL by 22% and 32% (P < .01 for both). Chylomicron remnant metabolism measured with triglycerides only tended to diminish. The effects of stanol esters in the diet only and both in the diet and with supplementation did not differ significantly. We conclude that dietary stanol esters reduce postprandial lipoproteins measured with dietary retinyl palmitate and especially squalene, and the reduction is observed even though serum total and LDL cholesterol are only inconsistently decreased after short-term stanol ester consumption.

Delayed postprandial retinyl palmitate and squalene removal in a patient heterozygous for apolipoprotein A-IFIN mutation (Leu 159-->Arg) and low HDL cholesterol level without coronary artery disease.

A low HDL cholesterol level is frequently but not consistently associated with inefficient postprandial fat clearance. We studied triglycerides, retinyl palmitate and squalene and apolipoprotein B-48 after a fat loading test in one subject heterozygous for a novel point mutation of apolipoprotein A-I (A-IFIN, Leu 159-->Arg) and low HDL cholesterol level without coronary artery disease, and in 16 healthy controls with the same apolipoprotein E phenotype, 3/3, as the proband. HDL cholesterol and apolipoprotein A-I levels were 0.32 mmol/l and 57 mg/dl in the proband, and 1.29 +/- 0.12 mmol/l (mean +/- S.E.) and 126 +/- 4 mg/dl in the controls. The peak concentration for triglycerides in plasma, chylomicrons and VLDL occurred at 4 h both in the case and controls. However, the peak concentrations for retinyl palmitate and squalene in chylomicrons and VLDL were delayed to 12 h in the proband compared with 4 and 9 h in the controls. The peak of apolipoprotein B-48 occurred at 6 h in the proband and at 4 h in the controls, so that triglycerides, apolipoprotein B-48 and retinyl palmitate and squalene peaked differently. After 24 h, retinyl palmitate, squalene, and apolipoprotein B-48 had returned to the baseline levels. The results show for the first time an impaired postprandial lipoprotein removal in a case heterozygote with moderately low HDL cholesterol due to an apolipoprotein A-1 mutation not associated with coronary artery disease.

Postprandial vitamin A and squalene clearances and cholesterol synthesis off and on lovastatin treatment in type III hyperlipoproteinemia.

Postprandial fat clearance and absorption, fecal elimination and synthesis of cholesterol, bile acid synthesis, and cholesterol precursors and plant sterols in serum were studied in five patients with type III dyslipoproteinemia off and on lovastatin. The basal values were related to those in nontreated normolipidemic control subjects with apolipoprotein E3/3 phenotype (apo E3 controls, n = 16). On regular home diets, cholesterol precursor concentrations and cholesterol precursor/cholesterol ratios were high in the type III group. However, cholesterol absorption efficiency, bile acid and cholesterol synthesis measured with sterol balance technique and the precursor sterol/plant sterol ratios in serum were similar to the control values, suggesting that cholesterol absorption and metabolism was normal in these subjects. Lovastatin normalized the increased lipoprotein concentrations and reduced biliary cholesterol secretion, absolute absorption of cholesterol, precursor sterol/cholesterol and precursor sterol/plant sterol ratios in serum, fecal neutral and total sterol outputs and cholesterol synthesis. Lovastatin had no effect on cholesterol absorption efficiency or bile acid synthesis. Despite normalization of the triglyceride-rich lipoprotein levels by lovastatin, the postprandial vitamin A and squalene peak concentrations and the areas under the curves remained above the control ranges. The findings show that in type III hyperlipidemia, the precursor sterol/cholesterol ratios do not predict cholesterol synthesis. The latter, bile acid synthesis, precursor sterol/plant sterol ratios in serum, and cholesterol absorption are normal under basal conditions. The normalization of increased lipids by lovastatin is mainly due to reduced synthesis and absolute absorption of cholesterol, while the retarded postprandial fat clearance was not normalized by the drug.