Identification and characteristics of patients with potential difficult-to-treat Psoriatic Arthritis: exploratory analyses of the Greek PsA registry.

OBJECTIVE: To present the characteristics of patients with potential difficult-to-treat (D2T) psoriatic arthritis (PsA). METHODS: We used data from the Greek multicentre registry of PsA patients. D2T-PsA was defined as follows: patients with at least 6-months disease duration, who have failed to at least 1 csDMARD and at least 2 bDMARDs/tsDMARDs with a different mechanism of action and have either at least moderate disease activity (MODA) defined as DAPSA > 14, and/or are not at minimal disease activity (MDA). Demographic and clinical characteristics were compared between D2T and non-D2T PsA patients. In two sensitivity analyses, patients classified as D2T solely according to the MODA or MDA criterion were examined separately. RESULTS: Among 467 patients included, 77 (16.5%) were considered D2T and 390 non-D2T PsA. Compared with non-D2T, patients with D2T PsA presented more commonly with extensive psoriasis (p< 0.0001) and were more likely to have higher BMI (p= 0.023) and a history of inflammatory bowel disease (p= 0.026). In the MODA and MDA sensitivity analyses, 7.5% and 12.5% of patients were considered D2T, respectively. In both sensitivity analyses, extensive psoriasis was again identified as an independent variable for D2T PsA (p= 0.001 and p= 0.008, respectively). Moreover, female gender (p= 0.034) in the MODA analysis and axial disease (p= 0.040) in the MDA analysis were independent variables for D2T PsA. CONCLUSION: Despite the availability of therapies, D2T PsA is common in real-life cohorts of patients with PsA and extensive psoriasis. High BMI, female gender, axial-disease, and history of IBD were also associated with D2T PsA.

Drs. Konsta and van der Horst-Bruinsma reply.

We thank Dr. Slouma et al1 for their earnest interest in our recent article, which examined the prevalence and radiographic progression of hip involvement in patients with ankylosing spondylitis (AS) treated with tumor necrosis factor inhibitors (TNFi).2.

Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells.

Besides being a marker of kidney disease severity, albuminuria exerts a toxic effect on renal proximal tubular epithelial cells (RPTECs). We evaluated whether an unfolded protein response (UPR) or DNA damage response (DDR) is elicited in RPTECs exposed to high albumin concentration. The deleterious outcomes of the above pathways, apoptosis, senescence, or epithelial-to-mesenchymal transition (EMT) were evaluated. Albumin caused reactive oxygen species (ROS) overproduction and protein modification, and a UPR assessed the level of crucial molecules involved in this pathway. ROS also induced a DDR evaluated by critical molecules involved in this pathway. Apoptosis ensued through the extrinsic pathway. Senescence also occurred, and the RPTECs acquired a senescence-associated secretory phenotype since they overproduced IL-1ß and TGF-ß1. The latter may contribute to the observed EMT. Agents against endoplasmic reticulum stress (ERS) only partially alleviated the above changes, while the inhibition of ROS upregulation prevented both UPR and DDR and all the subsequent harmful effects. Briefly, albumin overload causes cellular apoptosis, senescence, and EMT in RPTECs by triggering UPR and DDR. Promising anti-ERS factors are beneficial but cannot eliminate the albumin-induced deleterious effects because DDR also occurs. Factors that suppress ROS overproduction may be more effective since they could halt UPR and DDR.

Prevalence and Radiographic Progression of Hip Involvement in Patients With Ankylosing Spondylitis Treated With Tumor Necrosis Factor Inhibitors.

OBJECTIVE: To examine the prevalence of hip involvement between sexes in patients with ankylosing spondylitis (AS) treated with tumor necrosis factor inhibitors (TNFi) and to estimate the effect of TNFi on radiographic progression of hip involvement compared to the spine. METHODS: Two hundred ninety-nine patients with AS treated with TNFi (215 men; median age: 43 yrs [IQR 36-52], median disease duration: 7.6 yrs [IQR 2-15]) were evaluated for hip involvement, defined radiographically as Bath AS Radiological Hip Index (BASRI-hip) score ≥ 2. Those who received TNFi for ≥ 2 years (263/299) were assessed for radiographic progression. Radiographs of the pelvis and spine, obtained at baseline (ie, before TNFi initiation), were compared retrospectively to those obtained after 2.5 (SD 0.7) years and 7.0 (SD 2.3) years of TNFi treatment. Both hips were scored by BASRI-hip score and mean joint space width (MJSW). Spinal radiographs were scored by modified Stoke AS Spinal Score (mSASSS). RESULTS: The prevalence of hip involvement at baseline was 113/299 (38%) patients, of whom 87/215 (41%) were male and 26/84 (31%) were female (P = 0.10). In both sexes with hip involvement at baseline, BASRI-hip score and MJSW did not change significantly during follow-up. In males and females without baseline hip involvement, the BASRI-hip score remained unchanged after 2.5 (SD 0.7) years but increased significantly after 7.0 (SD 2.3) years, without reaching the cut-off of 2. In contrast, the MJSW slightly decreased at the 2 follow-up timepoints (ie, after 2.5 and 7.0 yrs). The mSASSS increased significantly during the follow-up in both sexes, regardless of hip involvement. CONCLUSION: In our study, approximately one-third of patients with AS had hip involvement, which seemed to stabilize with TNFi treatment. No sex differences in the prevalence or progression of this manifestation were found.

Disease Profile and Achievement of Therapeutic Goals in a Modern, Nationwide Cohort of 923 Patients with Psoriatic Arthritis.

Background: Psoriatic arthritis (PsA) is a heterogenous chronic inflammatory disease affecting skin, joints, entheses, and spine with various extra-musculoskeletal manifestations and comorbidities. The reported patient, disease and treatment characteristics in the modern therapeutic era are limited. Methods: In this cross-sectional, multi-centre, nationwide study, we recorded the demographic, clinical, and therapeutic characteristics as well as the comorbidities of patients with PsA seen for 1 year (1/1/2022-31/12/2022). Results: 923 patients (55% females) with a median (IQR) age of 57 (48-65) years and a mean disease duration of 9.5 years were enrolled. Family history of psoriasis and PsA was noted in 28.3% and 6.3%, respectively. Most patients had limited psoriasis (BSA<3: 83%) while enthesitis, dactylitis, nail and axial involvement reported in 48.3%, 33.2%, 43% and 25.9% of patients, respectively. Regarding comorbidities, approximately half of patients had dyslipidaemia (42%) or hypertension (45.4%), 36.8% were obese and 17% had diabetes while 22.7% had a depressive disorder. Overall, 60.1% received biologics and among them more patients treated with anti-IL-17 or -12/23 agents were on monotherapy (64.2%) compared to those on TNFi monotherapy (49.4%, p=0.0001). The median PsA activity as assessed by the DAPSA score was 6 (IQR: 2.3 - 13.1) with 46% of patients reaching minimal disease activity status (MDA). Conclusion: In this large, real life, modern cohort of patients with PsA with frequent comorbidities who were treated mainly with biologics, almost half achieved minimal disease activity. These results show the value of existing therapeutic approaches while at the same time highlight the existing unmet needs.

Long-term effect of TNF inhibitors on radiographic progression in ankylosing spondylitis is associated with time-averaged CRP levels.

OBJECTIVE: To investigate whether the impact of long-term treatment (>3 years) with TNF inhibitors (TNFi) on radiographic progression in AS is associated with the level of acute phase reactants during therapy. METHODS: One hundred and one consecutive AS patients under TNFi [65 men; age: 41.6±11 years (mean±SD), with symptom duration: 17±10 years] were included in this retrospective study. Lateral X-rays of cervical and lumbar spine, obtained before TNFi initiation, were compared to those obtained after a period of 7±2.5 (range: 3-15) years. The levels of CRP and ESR were evaluated every 6 months. The modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) assessed the radiographic damage. New syndesmophyte formation or ΔmSASSS-score/year≥1 unit/year was defined as radiographic progression. RESULTS: Forty-seven patients (46.5%) showed radiographic progression. ΔmSASS-score/year was positively correlated with both, baseline CRP (r=0.35, P<0.001) and ESR (r=0.3, P<0.01), as well as with time-averaged CRP (r=0.3, P<0.01). Furthermore, ΔmSASS-score/year was significantly higher (P<0.0001) in patients with syndesmophytes at baseline [0.9 (0.4-1.8), median (IQR)] compared to those without [0 (0-0.4)]. In the multivariate logistic regression analysis, independent risk factors for spinal radiographic progression during TNFi treatment were the presence of syndesmophytes at baseline (OR: 14.7, 95%CI:4.9-44) and the time-averaged CRP>5mg/L (OR:7.6, 95%CI: 2.5-23). No gender differences were observed. CONCLUSION: In AS patients with long standing disease, radiographic progression during TNFi treatment is significantly associated with higher levels of time-averaged CRP.

Effects of Mediterranean diet on hospital length of stay, medical expenses, and mortality in elderly, hospitalized patients: A 2-year observational study.

OBJECTIVES: The Mediterranean diet (MedDiet) has been related to reduced overall mortality and improved disease outcome. The aim of this study was to estimate the effects of the MedDiet on hospital length of stay (LOS), financial cost, and mortality (from hospitalization up to 24 mo afterward) in hospitalized patients >65 y of age. METHODS: Participating in this observational study were 183 patients >65 y of age, who were urgently admitted for any cause to the Internal Medicine Department of Argolidos General Hospital. Hospital LOS and its financial cost, mortality (during hospitalization, 6 and 24 mo after discharge), physical activity, and medical and anthropometric data were recorded and correlated with the level of adherence to the MedDiet (MedDiet score). RESULTS: In multivariate analyses, hospital LOS decreased by 0.3 d for each unit increase of MedDiet score (P < 0.0001), 2.1 d for each 1 g/dL increase of albumin (P = 0.001) and increased 0.1 d for each day of previous admissions (P < 0.0001). Extended hospitalization (P < 0.0001) and its interaction with MedDiet score (P = 0.01) remained the significantly associated variables for financial cost. Mortality risk increased 3% per each year increase of age (hazard ratio [HR], 1.03; P = 0.02) and 6% for each previous admission (HR, 1.06; P = 0.04); whereas it decreased 13% per each unit increase of MedDiet score (HR, 0.87; P < 0.0001). CONCLUSION: Adoption of the MedDiet decreases duration of admission and long-term mortality in hospitalized patients >65 y of age, with parallel reduction of relevant financial costs.

Long-Term Treatment With TNF-Alpha Inhibitors Improves Bone Mineral Density But Not Vertebral Fracture Progression in Ankylosing Spondylitis.

The aim of this cohort study was to evaluate the long-term effects of TNF inhibitors (TNFis) on BMD and the incidence of vertebral fractures (VFxs) in patients with ankylosing spondylitis (AS). Consecutive patients with active AS with TNFi treatment duration up to 4 years with available DXA scans and spine X-rays were included. BMD (classified according to the WHO criteria for osteoporosis) of the hip and lumbar spine, the VFx (classified as a Genant score >1/>20% height loss), and radiological progression (modified stoke ankylosing spondylitis spinal score [mSASSS]) scores were obtained at baseline and at 4 years of TNFi treatment. Overall, 135 AS patients were included. At baseline, 40.1% of patients had low BMD of the hip and 40.2% of the lumbar spine. This decreased to 38.1% (p = 0.03) with low hip BMD and 25.3% (p < 0.001) of the lumbar spine BMD after 4 years of TNFi treatment. VFxs were present at baseline in 11.1% of the 131 patients, which increased to 19.6% after 4 years of TNFi treatment. A Genant score ≥2, was found at baseline in 3 out of 14 VFx (21.4%) patients, which increased to 7 out of 27 VFx (25.9%) patients after 4 years. All disease activity parameters-the ankylosing spondylitis disease activity scale, the C-reactive protein, the erythrocyte sedimentation rate, and the bath ankylosing spondylitis disease activity index-decreased significantly (p < 0.001). The mean radiological progression (n = 80) increased significantly from a median mSASSS of 4.0 (1.5 to 16.0) at baseline to 6.5 (2.1 to 22.9) after 4 years of TNFi treatment (p < 0.001). Despite the improvement in BMD and the decrease in disease activity, we still found new VFxs, an increase in severity in the number and grade of VFxs, and radiographic progression during 4 years of treatment with TNFis in AS patients with long disease duration. © 2019 American Society for Bone and Mineral Research.

Serum levels of Dkk-1, sclerostin and VEGF in patients with ankylosing spondylitis and their association with smoking, and clinical, inflammatory and radiographic parameters.

OBJECTIVE: To evaluate serum Dickkopf-1 (Dkk-1), sclerostin and vascular endothelial growth factor (VEGF) levels in patients with ankylosing spondylitis (AS) compared to healthy controls as well as their association with smoking, and clinical, inflammatory and radiographic parameters. METHODS: Serum samples for total Dkk-1, sclerostin and VEGF were obtained from 57 tumour necrosis factor (TNF) inhibitor naïve patients with AS and 34 sex-, age- and body mass index (BMI)-matched controls. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), modified Stroke AS Spine Score (mSASSS) and smoking status were assessed for each patient. RESULTS: There was no significant difference in serum bone metabolism markers between AS patients and controls. Dkk-1 levels were significantly (P<0.05) higher in AS patients with elevated ESR and CRP and no syndesmophytes, and were significantly (P<0.001) correlated with sclerostin levels (r=0.592). VEGF levels were significantly (P<0.05) higher in AS patients with current and ever smoking, elevated ESR and CRP, and high BASDAI and BASFI, and were significantly (P<0.05) correlated with ESR (r=0.284), CRP (r=0.285), BASDAI (r=0.349) and BASFI (r=0.275). In multivariate regression analyses, high Dkk-1 levels were significantly (P≤0.001) associated with elevated ESR and CRP, no syndesmophytes and high sclerostin levels, and high VEGF levels significantly (P<0.05) with ever smoking, and elevated ESR and CRP. CONCLUSION: In AS, serum Dkk-1 concentrations appear to be related not only to syndesmophyte formation but also to systemic inflammation. Furthermore, high VEGF levels may be associated with smoking exposure.

Subclinical Atherosclerosis Is Not Accelerated in Patients with Ankylosing Spondylitis with Low Disease Activity: New Data and Metaanalysis of Published Studies.

OBJECTIVE: Chronic inflammatory rheumatic diseases are associated with accelerated atherosclerosis, but data in ankylosing spondylitis (AS) are limited and the relative contribution of inflammation versus classical cardiovascular (CV) risk factors remains a matter of controversy. We addressed this in an original study and a metaanalysis of previous studies. METHODS: Atheromatic plaques in carotid and femoral arteries, carotid hypertrophy [intima-media thickness (IMT), cross-sectional area], and carotid stiffness by ultrasound, as well as aortic stiffness by pulse wave velocity, were examined in consecutive nondiabetic, CV disease (CVD)-free patients with AS. Healthy individuals carefully matched 1:1 with patients for age, sex, smoking habits, hyperlipidemia, and hypertension served as controls. A metaanalysis of original studies that examined subclinical atherosclerosis in patients with AS versus controls with comparable CVD risk factors was also performed. RESULTS: Carotid and femoral atheromatic plaques were slightly less prevalent compared with controls in a contemporary cohort consisting of 67 patients with AS (82% men), aged 47.5 ± 12.5 years (mean ± SD), with a median disease duration of 12 years and a Bath AS Disease Activity Index (BASDAI) of 1.8 (interquartile range 0.4-3.6), of whom 66% were receiving anti-tumor necrosis factor (TNF) treatment. Carotid hypertrophy and stiffness, as well as aortic stiffness, were similar between patients and their matched controls. Metaanalysis of all published studies revealed a significantly increased carotid IMT, but not plaque burden, in AS versus controls. Notably, however, increased IMT was not evident in studies involving patients with low disease activity (mean BASDAI < 4) or in those studies that included > 50% of patients treated with anti-TNF. CONCLUSION: Low AS disease activity is not associated with accelerated atherosclerosis.

Plasma metabolomic profiling suggests early indications for predisposition to latent insulin resistance in children conceived by ICSI.

BACKGROUND: There have been increasing indications about an epigenetically-based elevated predisposition of assisted reproductive technology (ART) offspring to insulin resistance, which can lead to an unfavorable cardio-metabolic profile in adult life. However, the relevant long-term systematic molecular studies are limited, especially for the IntraCytoplasmic Sperm Injection (ICSI) method, introduced in 1992. In this study, we carefully defined a group of 42 prepubertal ICSI and 42 naturally conceived (NC) children. We assessed differences in their metabolic profile based on biochemical measurements, while, for a subgroup, plasma metabolomic analysis was also performed, investigating any relevant insulin resistance indices. METHODS & RESULTS: Auxological and biochemical parameters of 42 6.8±2.1 yrs old ICSI-conceived and 42 age-matched controls were measured. Significant differences between the groups were determined using univariate and multivariate statistics, indicating low urea and low-grade inflammation markers (YKL-40, hsCRP) and high triiodothyronine (T3) in ICSI-children compared to controls. Moreover, plasma metabolomic analysis carried out for a subgroup of 10 ICSI- and 10 NC girls using Gas Chromatography-Mass Spectrometry (GC-MS) indicated clear differences between the two groups, characterized by 36 metabolites linked to obesity, insulin resistance and metabolic syndrome. Notably, the distinction between the two girl subgroups was accentuated when both their biochemical and metabolomic measurements were employed. CONCLUSIONS: The present study contributes a large auxological and biochemical dataset of a well-defined group of pre-pubertal ICSI-conceived subjects to the research of the ART effect to the offspring's health. Moreover, it is the first time that the relevant usefulness of metabolomics was investigated. The acquired results are consistent with early insulin resistance in ICSI-offspring, paving the way for further systematic investigations. These data support that metabolomics may unravel metabolic differences before they become clinically or biochemically evident, underlining its utility in the ART research.

Increased levels of soluble TNF-like cytokine 1A in ankylosing spondylitis.

OBJECTIVE: To determine the expression of soluble TNF-like cytokine 1A (sTL1A), a new member of the TNF superfamily, in patients with AS. METHODS: Seventy-five consecutive patients with AS [61 males, mean (S.D.) age: 47.2 (15.5) years, disease duration: 20.3 (13.9) years] were included in this study. Forty-four patients were anti-TNF treatment naïve, whereas the remaining patients were on infliximab (n = 21), adalimumab (n = 3) or etanercept (n = 7). The patients' perceived disease activity was recorded by BASDAI and AS DAS using serum CRP levels (ASDAS-CRP), whereas functional status was assessed by BASFI and measurements of spinal mobility (AS Metrology). Serum concentrations of TL1A were measured by ELISA. Twenty-five age- and sex-matched healthy individuals served as controls. RESULTS: Anti-TNF treatment-naïve patients demonstrated a 2.6-fold higher sTL1A average value [mean (s.e.m.) 581 (157.5) pg/ml] compared with healthy controls [226.7 (48.24) pg/ml, P = 0.042]. The sTL1A levels of anti-TNF-treated patients [178 (42)] were significantly lower than anti-TNF treatment-naïve patients (3.3-fold decrease, P = 0.0038) and comparable to those of healthy controls. No significant association was found between sTL1A level and functional status (BASFI score, AS Metrology parameters) or CRP measured in the same sera; however, a positive correlation was observed between individual levels of sTL1A and both BASDAI (P = 0.008) and ASDAS-CRP (P = 0.058) scores suggesting that sTL1A levels may reflect disease activity in patients with AS. CONCLUSION: TL1A is up-regulated in AS, associates with disease activity and is influenced by anti-TNF treatment, suggesting that TL1A may be of pathogenic and potentially of therapeutic importance in AS patients.

Sleep disturbances and interleukin 6 receptor inhibition in rheumatoid arthritis.

OBJECTIVE: Interleukin 6 (IL-6)-mediated interactions have been associated with sleep disturbances in healthy subjects. In this pilot study we examined whether administration of the IL-6 receptor antagonist tocilizumab in patients with rheumatoid arthritis (RA) affects sleep disturbances. METHODS: Fifteen patients (13 women) with sleep disturbances at baseline received 6 monthly infusions of tocilizumab 8 mg/kg for moderately or severely active RA. Sleep quality was assessed by Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness by Epworth Sleepiness Scale, disease activity by the 28-joint Disease Activity Score-erythrocyte sedimentation rate, functional disability by Health Assessment Questionnaire Disability Index (HAQ-DI), and fatigue by the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale; FFS) at baseline and first, second, third, and sixth month of treatment. Medications used before enrollment remained unchanged during followup. RESULTS: Sleep quality improved and daytime sleepiness decreased significantly at first-month assessment (p < 0.00001 and p < 0.004, respectively, by repeated measurement analysis) compared to baseline, and these changes became more evident through 6 months. Disease activity decreased, fatigue decreased, and functional status improved significantly. Changes in PSQI score over time were not associated with the corresponding changes in DAS28-ESR (r = 0.37, p = 0.17), but correlated significantly with HAQ-DI changes (r = 0.60, p = 0.02) and marginally with changes in FFS scores (r = -0.46, p = 0.08). CONCLUSION: Improvement of sleep quality after tocilizumab treatment in patients with RA does not appear to directly result from decreased disease activity, further suggesting that aberrant IL-6 regulation is associated with sleep disturbances.

Early effects of IL-6 receptor inhibition on bone homeostasis: a pilot study in women with rheumatoid arthritis.

OBJECTIVES: A critical role of interleukin-6 (IL-6) in bone homeostasis has been suggested in experimental studies. We examined whether inhibition of IL-6 receptor in patients with rheumatoid arthritis (RA) results in early alterations of circulating markers of bone remodelling. METHODS: Circulating levels of osteoprotegerin, receptor activator of nuclear factor-kappaB ligand (RANKL), Wnt signalling pathway inhibitors Dickkopf-1 (Dkk-1) and sclerostin, markers of bone resorption (C-terminal cross-linking telopeptide of collagen type-I (CTX), tartrate-resistant acid phosphatase isoform-5b) and bone formation (bone-specific alkaline-phosphatase, osteocalcin) were examined in 22 women with active RA before and after two monthly infusions of tocilizumab (8mg/kg each); 'healthy', non-osteopenic, 1:1 age-matched women served as controls. RESULTS: At baseline, osteoprotegerin/RANKL ratio in patients was lower than controls by 5-fold; circulating osteoprotegerin correlated negatively with corresponding 28-joint-count disease activity scores and circulating RANKL correlated positively with C-reactive protein. Also, Dkk-1, sclerostin, CTX and osteocalcin levels were higher in RA than controls. After two months, osteoprotegerin/RANKL ratio increased, Dkk-1 decreased and sclerostin increased comparing to baseline; other markers did not change significantly. Increases of osteoprotegerin/RANKL ratio were more prominent in 10 patients who achieved remission or low disease activity after tocilizumab than in 12 patients who did not. In contrast, the significant alterations of both Wnt inhibitors were comparable between these patient subgroups. CONCLUSIONS: Anti-IL-6 therapy induced suppression of the inflammatory response affects rapidly the disrupted bone homeostasis in active RA. An additional, possibly specific, effect of IL-6 receptor inhibition on bone remodelling in humans should be further examined.