Circulating microRNAs in extracellular vesicles as potential biomarkers for psoriatic arthritis in patients with psoriasis.

BACKGROUND: Psoriatic arthritis (PsA) develops in ~30% of patients with psoriasis. The diagnosis of PsA is challenging, and there are no reliable molecular markers in clinical use. MicroRNAs are short non-coding regulatory RNAs, which can be actively packaged into extracellular vesicles (EVs) and secreted to the circulation. OBJECTIVES: To explore whether plasma-derived EV microRNAs may serve as biomarkers for PsA in patients with psoriasis. METHODS: Plasma samples were obtained from patients with cutaneous-only psoriasis (PsC) and patients with psoriasis and PsA. Plasma EVs were isolated using miRCURY™ Exosome Isolation Kit. RNA sequencing was used to identify differentially expressed EV miRNAs in the discovery phase (PsC, n = 15; PsA, n = 14). In the validation phase (PsC, n = 29; PsA, n = 28), 41 selected miRNAs were analysed in plasma EVs by qPCR. The association of the identified miRNAs with PsA was assessed by logistic regression analysis. RESULTS: RNA sequencing identified 19 plasma EV miRNAs with significantly different levels between PsA and PsC in the discovery cohort. Significantly lower levels of plasma EV let-7b-5p and miR-30e-5p in PsA vs. PsC were confirmed in the validation cohort, and their decreased levels were found to be associated with the presence of PsA. ROC analysis revealed an AUC of 0.68 (95% CI 0.53-0.83) for let-7b-5p and 0.69 (95% CI 0.55-0.84) for miR-30e-5p. CONCLUSIONS: Circulating EV microRNA levels are altered in patients with PsA as compared with PsC. Findings of this exploratory study suggest that circulating EV microRNAs may serve as biomarkers for arthritis in psoriasis patients.

Hyaluronan concentration and molecular mass in psoriatic arthritis: biomarkers of disease severity, resistance to treatment, and outcome.

Objective: Low molecular mass hyaluronan causes inflammatory processes and can act as a pro-inflammatory cytokine in skin and other sites of activity in psoriatic arthritis (PsA). This study investigated whether the molecular mass distribution of hyaluronan (HA) in skin and the quantity of circulating HA are related to the clinical inflammatory picture in PsA with active disease and to the effect of treatment with anti-tumour necrosis factor-α (anti-TNF-α) adalimumab. Methods: Twenty patients with TNF-α-naïve active polyarticular PsA were included in this prospective clinical trial of treatment with 40 mg s.c. adalimumab according to standard procedure. Clinical activity, patients' assessments, and skin biopsies were captured at inclusion and at the 12 week follow-up. Ten healthy individuals were recruited for comparison of HA analyses. Histochemistry of skin inflammation, serum HA, and molecular mass of HA were determined. Results: Overall improvements in clinical parameters were observed. Eight of 18 patients reached minimum disease activity after 12 weeks and disease activity was significantly reduced (p < 0.0001). Patients with elevated serum HA values were significantly older, had later onset of arthritis and more deformed joints, still had swollen joints after treatment, and had more circulating inflammatory biomarkers. More severe disease pathology showed a wide spectrum of high-molecular-mass HA accompanied by low mass HA. The treatment appears partly to normalize the HA mass distribution. Conclusion: HA concentration and mass seem to be two possible factors in the inflammatory pathology of PsA acting as biomarkers for disease severity, resistance to treatment, and worse outcome.

Disease activity in and quality of life of patients with psoriatic arthritis mutilans: the Nordic PAM Study.

OBJECTIVE: To describe the social status and health-related quality of life of patients with psoriatic arthritis mutilans (PAM) in the Nordic countries. METHOD: Patients with at least one mutilated joint confirmed by radiology were studied. Disease activity involving joints and skin, physician-assessed disease activity, and patient's education and work status were recorded. Data from the 36-item Short Form Health Survey, Health Assessment Questionnaire and Dermatology Life Quality Index questionnaire were gathered and correlated with disease duration, pain, and general well-being (visual analogue scale). The controls were 58 Swedish patients with long-standing psoriatic arthritis sine PAM. RESULTS: Sixty-seven patients were included. Patients with PAM had a protracted disease history (33 ± 14 years) and disease onset at a relatively early age (30 ± 12 years). Overall inflammatory activity at inclusion was mild to moderate. The mean number of mutilated joints was 8.2 and gross deformity was found in 16% of patients. Forty per cent were treated with biological and 32% with conventional synthetic disease-modifying anti-rheumatic drugs. Forty-two per cent had retired early or were on sick leave. Impaired functional capacity with little or no ability to perform self-care or everyday tasks was reported by 21% of the patients. Patients between 45 and 60 years of age reported the most impaired quality of life in comparison to the control group. CONCLUSION: PAM seriously affects social functioning. Whether early recognition of PAM and new forms of therapy can improve disease outcome and quality of life remains to be studied.

Up-regulation of CD64-expressing monocytes with impaired FcγR function reflects disease activity in polyarticular psoriatic arthritis.

OBJECTIVES: The aim of this study was to assess monocyte Fc receptor (FcR) status and function in patients with active psoriatic arthritis (PsA) in relation to healthy controls (HC) and to disease activity. METHOD: The study population comprised 23 patients with active polyarticular PsA and 33 age- and gender-matched HC. Immunoglobulin (Ig) levels, inflammatory laboratory parameters, patient-reported outcomes of joint disease activity, skin scoring (Psoriasis Area and Severity Index, PASI), and joint status were determined in the patients. Monocytes were analysed for the expression of FcRs for IgG (FcγR) class I (CD64), IIa (CD32a), IIb (CD32b), and III (CD16), the FcR for IgA (FcαR) (CD89), and surface-bound IgG. The monocytic FcγR function was assessed by evaluating IgG immune complex (IC) binding and tumour necrosis factor (TNF)-α production following IgG-IC stimulation. The monocytes were further subdivided and analysed according to their CD14 and CD16 expression. RESULTS: The PsA patients presented elevated serum levels of IgG1, 2, and 3 and increased numbers of CD64(+) monocytes. Furthermore, the PsA monocytes exhibited increased cell-bound IgG, and the FcγR function was affected in terms of reduced IgG-IC-mediated TNF-α release. These findings correlated significantly with different markers of joint disease activity. PsA was also accompanied by an increase in the CD16 low-expressing monocyte subset. CONCLUSIONS: An intensified humoral immune response affects monocytes and their FcR status in active polyarticular PsA. The up-regulated CD64(+) monocytes seem to be have an important role in psoriatic joint inflammation. These cells may prove to be a useful target in future PsA therapeutic interventions.

Psoriatic arthritis mutilans (PAM) in the Nordic countries: demographics and disease status. The Nordic PAM study.

OBJECTIVE: To determine the prevalence and clinical characteristics of psoriatic arthritis mutilans (PAM) in the Nordic countries. METHOD: Patients with putative PAM aged ≥ 18 years were recruited. Fifty-nine patients were included after clinical examination. RESULTS: The prevalence of PAM in the adult Nordic population was estimated to be 3.69 per million inhabitants [95% confidence interval (CI) 2.75-4.63]. The female to male ratio was close to 1:1. The mean age of skin disease onset was 25 years and the mean age of onset of joint disease was 30 years. The onset of skin disease was 2 years earlier among female patients. At inclusion, the mean duration of arthritis was 27 ± 11 years for male patients and 33 ± 11 years for female patients. PAM was most frequently seen in the distal interphalangeal (DIP) joints of the toes, followed by the IP joint of the thumb and the DIP joint of the little finger on the left hand. Female and male patients had similar numbers of painful and swollen joints. Enthesitis was found in 19 patients (32%), while 38 patients (64%) had a history of dactylitis. Twenty-three of these 38 patients (61%) had a history of dactylitis in the same finger/toe as they had PAM. At the time of inclusion, 45% of the patients were found to have clear or almost clear skin. CONCLUSIONS: PAM in the Nordic countries has a low prevalence, with only three to five cases per million inhabitants. The majority of the patients present with mild skin disease.

Adaptation of the Psoriatic Arthritis Quality of Life (PsAQoL) instrument for Sweden.

OBJECTIVE: The Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire is the first disease-specific patient-derived instrument for assessing QoL in patients with PsA and has been extensively validated in this population. The aim of the adaptation process reported here was to develop a Swedish version of the PsAQoL that was equivalent to, and met the same psychometric and acceptability standards as, the original instrument, which was developed in the UK. METHOD: Translation of the original questionnaire into Swedish was performed by a professional and a lay panel. Field testing for face and content validity was performed by interviewing 13 patients. Finally, 123 patients with PsA were included in a test-retest postal survey designed to test reproducibility and construct validity. The PsAQoL was administered on two occasions approximately 2 weeks apart. The Nottingham Health Profile (NHP) was used as a comparator instrument. RESULTS: The Swedish version of the PsAQoL questionnaire showed good reliability at both time points and, as expected, correlated with the NHP. The scale was able to distinguish between groups based on self-reported general health and flare-up. Patients with active symptoms of both arthritis and psoriasis had worse QoL. The results also indicated that duration of disease has a progressive impact on PsAQoL scores. CONCLUSIONS: This study provides evidence that the adapted PsAQoL can be used for clinical studies in Swedish patients. The instrument provides valuable information on the long-term effects of PsA on QoL.

Ultrasound and power Doppler evaluation of the hand and wrist in patients with psoriatic arthritis.

PURPOSE: To evaluate the ability of high-resolution and power Doppler sonography in detecting joint and tendon abnormalities in patients with psoriatic arthritis (PsA) of the hands and wrists compared with clinical and radiological findings. MATERIAL AND METHODS: Thirty-six patients with psoriatic arthritis of the hands and wrists and 10 healthy controls were examined with ultrasound (US). The degree of synovial proliferation, tenosynovitis, presence of joint effusion as well as the vascularity of synovial tissue was estimated. US findings were scored using a newly devised scoring system. RESULTS: Thirty-two patients had articular synovial proliferation and/or tenosynovitis/ tendinitis or joint effusion in one or more joints according to US. Twenty-two patients had tendon changes; only five had joint effusion. The synovial, Doppler, and total articular-teno scores were all significantly correlated to the number of swollen joints. The scores, however, did not correlate to other clinical or laboratory measurements of disease activity. CONCLUSION: US proved effective in demonstrating PsA involvement of the hands and wrists and was more sensitive than clinical examination in detecting pathology. Long-term follow-up studies are needed to evaluate whether this can change the traditional approach for assessing involvement of joints and tendons in PsA.

IgA antibodies to gliadin and coeliac disease in psoriatic arthritis.

OBJECTIVES: To find out whether patients with psoriatic arthritis (PsoA) have an increased prevalence of antibodies to gliadin (AGA) and of coeliac disease. METHODS: One hundred and fourteen PsoA patients with skin disease of 20+/-13 yr and joint disease of 11+/-10 yr duration answered a questionnaire concerning their medical history and underwent clinical examination, including radiology. Serum IgA AGA and IgG AGA, IgA antibodies to endomysium and immunoglobulins, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration were determined. RESULTS: Five of the 114 patients (4.4%) had coeliac disease. After exclusion of these five patients, the mean IgA AGA concentration was significantly higher (P=0.0005) than that in a reference group. None of the patients had IgA antibodies to endomysium. The mean serum IgA concentration was significantly increased and IgM decreased. Patients with a high concentration of IgA AGA had significantly higher ESR and CRP and a longer duration of morning stiffness than those with a low AGA concentration. CONCLUSIONS: Patients with PsoA have an increased prevalence of raised serum IgA AGA and of coeliac disease. Patients with raised IgA AGA seem to have more pronounced inflammation than those with a low IgA AGA concentration.

Sleep disturbances in outpatients with ankylosing spondylitisa questionnaire study with gender implications.

OBJECTIVE: To study the sleep pattern in ankylosing spondylitis, and to investigate gender differences in sleep, pain, and fatigue. METHODS: Forty-three male and 27 female patients with ankylosing spondylitis completed a sleep questionnaire and the results were compared with earlier findings in 3,558 persons randomly selected from the general population. RESULTS: Too little sleep was reported by 80.8% of the female and 50.0% of the male patients, compared to 28.8% and 21.8% respectively in the reference group (p<0.0001). The main reason was pain in the pre-sleep and sleep-periods (p<0.0001). Daytime fatigue was a major problem (p<0.0001). Higher correlation was found between pain and daytime fatigue than between sleep disturbance and daytime fatigue. CONCLUSION: Sleep disturbance is a significant problem in ankylosing spondylitis. The disturbance is closely related to pain at bedtime and during the night. Gender differences exist in the subjective sleep disturbance, fatigue, and pain.

[11C]Hyaluronan uptake with positron emission tomography in liver disease.

BACKGROUND: A hyaluronan-loading test has been developed for assessment of hyaluronan kinetics and applied in patients with liver and joint diseases. This test describes the metabolic process of hyaluronan but cannot define the specific contribution of different organs. A method for labelling of hyaluronan with the short-lived positron-emitting radionuclide 11C has been published and in this study applied in healthy subjects and liver diseases. MATERIALS AND METHODS: Positron emission tomography (PET) was used for the regional assessment and quantification of [11C]hyaluronan uptake in three healthy subjects, four patients with alcoholic liver cirrhosis, one with alcoholic hepatitis and one with liver steatosis. After intravenous administration of 60 MBq of 11C-labelled hyaluronan, a 55-min PET scan was performed over the liver and plasma radioactivity was analysed. Rate constants describing the transport of the [11C]hyaluronan tracer from plasma to the liver were calculated. RESULTS: High uptake was observed in the liver combined with a rapid elimination of tracer from plasma. The liver uptake rate (k1) was significantly lower in patients (0.018 min-1) than in healthy subjects (0.043 min-1, P = 0.002). The rate constants seem to be related to the severity of the disease as defined by the Child-Pugh score. CONCLUSIONS: The study suggests that PET with [11C]hyaluronan could be an accurate method by which to assess liver dysfunction, in conditions where endothelial cell function is impaired. The possibility of quantification over extended portions of the body also opens up possibilities to explore regional differences in liver function and to assess other elimination routes of hyaluronan.

Anxiety and depression in patients with primary Sjögren's syndrome.

OBJECTIVE: To examine the degree of anxiety and depression and to assess well being and general symptoms in patients with primary Sjögren's syndrome (SS). METHODS: A standardized questionnaire, the Hospital Anxiety and Depression Scale, was used to examine the degree of anxiety and depression in patients with primary SS (n = 62) and in age matched healthy female controls. The Gothenburg quality of life instrument (GQOL) was used to assess well being and general symptoms. Patients with rheumatoid arthritis (RA; n = 38) were used as patient controls. RESULTS: The patients with primary SS had significantly higher scoring rate for "possible" clinical anxiety (48%) and for "possible" clinical depression (32%) compared with reference groups (p<0.05). The physical and mental well being of the patients with primary SS were significantly reduced compared with controls. Furthermore, patients with primary SS complained more commonly of low mood, irritability, headache, gastrointestinal symptoms, and impaired concentration and memory than the patients with RA. CONCLUSION: The results indicate that patients with primary SS often have psychiatric symptoms and worse well being, which may affect their quality of life.

Production and elimination of hyaluronan in rheumatoid arthritis patients: estimation with a loading test.

OBJECTIVE: To evaluate the benefit of determining the maximal elimination rate (Vmax) and the endogenous production of hyaluronan (HYA) in relation to the basal HYA concentration (c0) in rheumatoid arthritis (RA) patients; and to evaluate the compatibility of a new model for HYA kinetics, taking renal elimination into separate account in the overall clearance of HYA from the blood. METHODS: The calculations of production and elimination of HYA were based on the HYA loading test, which was performed in 21 patients with RA and 15 healthy controls. A blood sample was drawn before the loading test, followed by an intravenous (i.v.) injection of HYA as a single bolus dose of 7.5 mg. Blood samples were taken regularly during the next 60 minutes. A theoretical model with computational analysis of the data collected was used for calculating HYA production and elimination. RESULTS: Patients with RA had significantly higher c0 than healthy controls, although in 10 of 21 patients c0 was within the normal range. The RA patients also had higher Vmax than healthy controls, but the difference was not significant. The calculated production of HYA was increased in RA patients (P = .001) and correlated with c0 (P < .0001). The new model for HYA kinetics, in which the renal elimination was taken separately into account, proved to be more compatible than the previous model. CONCLUSION: The HYA loading test can help determine whether the increased serum level of HYA in RA patients is due to a high production or reduced elimination of HYA or both.

Is serum hyaluronan a helpful tool in the management of patients with liver diseases?

The results of serial determinations of serum hyaluronan indicate a prognostic value in progressive liver damage. In primary biliary cirrhosis and in cirrhotic alcoholic liver diseases serum hyaluronan level discriminates between early and advanced disease. In alcoholic liver disease serum hyaluronan can be applied as assessment of haemodynamic changes. Serum hyaluronan is of use as a non-invasive index of liver fibrosis in chronic viral hepatitis. A reversible defect in the hyaluronan receptor of the hepatic endothelial cells was suggested following studies on paracetamol-induced acute liver damage. In liver transplantation, graft function can be predicted by determination of the venous effluent of hyaluronan.

Evaluation of various models of hyaluronan kinetics for assessment of liver function.

The purpose of this study of various models of hyaluronan kinetics has been to find the most appropriate model for estimation of parameters which characterize liver endothelial cell function. Five theoretical models for serum hyaluronan distribution and elimination were evaluated by computer analysis of serial measurements of the mass concentration of hyaluronan in serum following an intravenous bolus dose. Three of the models were based on one-compartment distribution of intravenously injected hyaluronan. Model 1A, with assumed first-order elimination, was found to be compatible with measured data and had identifiable parameters. Model 1B, with assumed non-linear Michaelis-Menten kinetics, was also found to be compatible but the Michaelis-Menten constant (K(m)) was not well determined. In model 1C, with non-linear Michaelis-Menten elimination kinetics, K(m) was set to a fixed value of 340 micrograms l-1, and the remaining parameters were well determined and the model was found to be compatible. Two models with an assumed two-compartment distribution of intravenously injected hyaluronan, were not acceptable due to unidentified parameters not discriminating between patients and healthy persons. In conclusion, model 1C, with one-compartment distribution and non-linear Michaelis-Menten kinetics, best fulfilled the criteria of validity and was accepted for further evaluation of clinical materials.

Markers of cartilage matrix metabolism in human joint fluid and serum: the effect of exercise.

The concentrations of cartilage proteoglycan (aggrecan), stromelysin-1, tissue inhibitor of metalloproteinases-1 (TIMP-1) and procollagen II C-propeptide in knee joint fluid and the levels of aggrecan, hyaluronan and keratan sulfate in serum were measured before and after exercise in 33 healthy athletes. The samples before exercise were obtained after 24 h rest from running or soccer and the samples after exercise were obtained 30-60 min after the exercise. Nine athletes ran on a treadmill for 60 min, 16 ran on road for 80 min and 8 played one soccer game (90 min). A reference group of 28 patients with knee pain but not evidence of joint pathology or injury was used for comparison. In joint fluid no single marker from the degradative processes in cartilage matrix changed significantly with exercise but all showed a rising trend. All markers except stromelysin showed lower concentrations in athletes at rest compared to the reference group. In serum from runners before exercise the concentration of keratan sulfate was significantly higher than in both the soccer and reference groups and further increased after exercise. The increase in markers after exercise may reflect an effect of mechanical loading in combination with a possible high turnover rate of body cartilage matrix in these individuals.

Labelling of polysaccharides using [11C]cyanogen bromide. In vivo and in vitro evaluation of 11C-hyaluronan uptake kinetics.

A method for the 11C-labelling of polysaccharides in high specific radioactivity is described. Dextran and hyaluronan were treated with [11C]cyanogen bromide in aqueous solution at pH 11.5 to give 30-47% radiochemical yields with higher than 98% radiochemical purity in synthesis times of 24-26 min counted from the end of bombardment. Specific radioactivities at the end of synthesis ranged from 0.12 to 3.1 Ci/mumol. The biodistribution kinetics of [11C]hyaluronan injected intravenously was studied in rats by means of positron emission tomography, showing a rapid and displaceable uptake in liver. Uptake and displacement of [11C]hyaluronan was also demonstrated in cultured rat liver endothelial cells.

Serum hyaluronan and aminoterminal propeptide of type III procollagen: variation with age.

The serum levels of hyaluronan and the aminoterminal propeptide of Type III procollagen (PIIINP) were compared in 585 healthy individuals as a function of age. Newborn children displayed high hyaluronan (695 +/- 634 micrograms l-1, mean +/- SD) and PIIINP (295 +/- 152 micrograms l-1) values. The values were not correlated to the gestational week in which the children were born or to the birth weight but there was a significant correlation (p < 0.05) between the hyaluronan and PIIINP levels. During the first year the levels dropped and in childhood (1-16 years of age) both hyaluronan and PIIINP levels were fairly constant at 27 +/- 16 and 22 +/- 8.4 micrograms l-1, respectively. The PIIINP level showed a marked drop in adults compared to children. The drop continued to about 50 years of age (6.5 +/- 2.2 micrograms l-1) and then there was a slight increase in elderly people. The hyaluronan showed a continued increase with age from the level at 16 years of 29 +/- 17 micrograms l-1 to a mean value of 177 +/- 133 micrograms l-1 in people over 75 years. There was no increase in serum hyaluronan in women during pregnancy but the PIINP level increased in the later part of the gestational period. There was no correlation between the serum values of hyaluronan and PIIINP when compared throughout the life span which indicates that the blood levels of the two markers are regulated by independent factors.

A hyaluronan-loading test applied to patients with liver and joint diseases.

The serum hyaluronan disappearance data, after an intravenous bolus injection of hyaluronan, were evaluated in terms of model-based parameters. The loading test was performed in 10 healthy persons (basal serum hyaluronan concentration, C0, 24.9 +/- 8.9 micrograms/l [mean +/- S.D.]), 6 patients with joint disease (62.3 +/- 41.1 micrograms/l) and 19 patients with liver disease (206 +/- 214 micrograms/l). The highest maximum Michaelis-Menten elimination rate (Vmax = 287 +/- 86 micrograms/min) was found in patients with joint disease, significantly higher than in healthy persons (Vmax = 179 +/- 16, P = 0.0015) and in patients with liver disease (Vmax = 149 +/- 59, P = 0.0002). C0 and Vmax were evaluated as discriminants for assessment of residual liver function. In patients with liver disease C0 correlated with liver function score (r = 0.875, P < 0.0001) and serum albumin concentration (r = -0.813, P < 0.0001). The Vmax parameter did not correlate with conventional liver function tests or with the liver score but a significantly negative correlation of Vmax with C0 was found in patients with liver disease. A combination of the C0 level and the Vmax parameter was found to discriminate between healthy persons, patients with joint disease and patients with liver disease and should be of benefit in separating patients, with or without elevated serum hyaluronan levels, into groups having increased influx or reduced elimination, respectively, of circulating hyaluronan.