Lower total cholesterol and triglyceride levels in ankylosing spondylitis than non-inflammatory rheumatic disease controls in a 1978-98 study: a potential effect of increased physical energetics in manual occupations in the pre-2000 chronologic era.

OBJECTIVES: No article on serum lipids in ankylosing spondylitis (AS) and control subjects has been reported from USA. The primary aim of this study was to determine if any difference occurred in serum lipid levels in AS and control rheumatic disorders in two time periods, 1978-98 and 2000-10. The secondary aim was to investigate variables associated with lipid levels and if a difference was found between AS and control disorders. METHODS: The AS patients were compared to non-inflammatory rheumatic disorders (NIRDs) in 1978-98 and 2000-10 surveys and to rheumatoid arthritis (RA) in the 2000-10 survey. Patients were matched within 5 years of age, sex, and clinic or hospital source. RESULTS: In the 1978-98 survey, entry mean (SEM) serum cholesterol level [mg/dL] was highly (p<0.001) significantly lower in 69 AS [179.0 (4.8)] than 69 matched NIRD controls [208.0 (5.6)]. In 29 pairs of AS and NIRD subjects having manual labour occupations, mean (SEM) cholesterol level was additionally lower in AS [156.7 (5.9)] and higher in 29 NIRD controls [213.3 (8.6)] (p<0.001). In manual labour workers, mean (SEM) serum triglyceride was significantly lower (p=0.004) in 15 AS [110.3 (14.1)] than 14 NIRD controls [185.2 (19.3)]. In the 2000-10 survey, no lipid difference was found between AS vs. NIRD control patients. CONCLUSIONS: In the 1978-98 survey, AS had significantly lower mean serum cholesterol and triglyceride levels than NIRD control patients. Associated manual labour occupations may have significantly contributed to results, possibly related to increased energy expenditures from physical activity in the pre-2000 era.

Systematic review and meta-analysis of individual serum lipids and analysis of lipid ratios in ankylosing spondylitis and healthy control cohorts: significantly lower mean HDL-cholesterol level in ankylosing spondylitis cohorts.

OBJECTIVES: Ankylosing spondylitis (AS) is suspected to have increased risk of atherosclerosis and cardiovascular disease (CVD) mortality. This systematic review and meta-analysis aims to critically study serum lipids and lipoprotein ratios in AS compared to healthy control (HC) subjects and determine any significant difference. METHODS: English-language articles were systematically searched in PubMed, Ovid Medline, Embase (Medline records removed), and Scopus databases from 1970 to 2021. Random-effects model was used to pool results expressed as standardised mean difference (SMD) in the lipid outcomes. Lipid ratios of total ÷ HDL-C and the log10 (TG/HDL-C), i.e. atherogenic index of plasma (AIP), were analysed by histograms of differences in weighted means and weighted SDs between AS and HC exposure cohorts. RESULTS: The meta-analysis included a total of 68 articles, 47 from database search and 21 from reference reviews. Pooled Hedges' g effect size revealed no difference in mean total cholesterol, mean triglycerides, and mean LDL-C between AS and HC subjects. However, mean HDL-C was significantly (p<0.001) lower in AS than HC subjects, with pooled Hedges' g (SE) for HDL-C of -0.484 (0.092), with 95% mean CIs [-0.664, -0.305]. In comparing differencesin AS minus HC weighted means of total HDL-C ratios, 8 values in HC were below the lowest ratio in AS. CONCLUSIONS: Highly significantly lower HDL-C levels occurred in AS versus HC subjects. The lower HDL-C levels in AS than HC populations deserve further study and may be attributable to uninvestigated demographic, exercise capacity, or clinical manifestations.

Muscle dysfunction in axial spondylarthritis: the MyoSpA study.

OBJECTIVES: We aimed to investigate muscle physical properties, strength, mass, physical performance, and the prevalence of sarcopenia in patients with axial spondylarthritis (axSpA) compared to the healthy controls (HC). METHODS: We performed a cross-sectional study on 54 participants: 27 patients with axSpA and 27 HC, matched by age, gender, and level of physical activity. Muscle physical properties (stiffness, tone and elasticity), muscle strength (five-times sit-to-stand [5STS] test), muscle mass, physical performance (measured through gait speed) and sarcopenia were compared between the groups. Linear regression models were conducted allowing adjustment for relevant variables. RESULTS: Patients with axSpA (mean age 36.5 (SD 7.5) years, 67% males, mean disease duration 6.5 (3.2) years) had no significant difference in segmental muscle stiffness, tone or elasticity, compared with the HC, despite showing a slight numerically higher lower lumbar (L3-L4) stiffness [median 246.5 (IQR 230.5-286.5) vs. 232.5 (211.0-293.5), p=0.38]. No participants presented sarcopenia. Patients with axSpA, compared to the HC, had lower total strength [B=1.88 (95% CI 0.43;3.33)], as well as lower strength in the upper (B=-17.02 (-27.33;-6.70)] and lower limbs [B=-11.14 (-18.25;-4.04)], independently of muscle physical properties. Patients had also significantly lower gait speed than the HC [B=-0.11 (-0.21;-0.01)], adjusted for muscle mass, strength and muscle physical properties. CONCLUSIONS: Young axSpA patients with a relatively short disease duration presented similar segmental muscle physical properties as the HC and had no sarcopenia. Patients with axSpA had reduced physical performance and lower strength compared to the HC, despite normal muscle mass, suggesting a possible muscle dysfunction. Gait characteristics may be a potential biomarker of interest in axSpA.

The role of muscle in the susceptibility and progression of axial Spondyloarthritis: The MyoSpA Study Protocol.

BACKGROUND: Axial Spondyloarthritis (axSpA) is a chronic, inflammatory rheumatic disease that affects the axial skeleton, causing pain, stiffness, and fatigue. Genetics and environmental factors such as microbiota and microtrauma are known causes of disease susceptibility and progression. Murine models of axSpA found a decisive role for biomechanical stress as an inducer of enthesitis and new bone formation. Here, we hypothesize that muscle properties in axSpA patients are compromised and influenced by genetic background. OBJECTIVES: To improve our current knowledge of axSpA physiopathology, we aim to characterize axial and peripheral muscle properties and identify genetic and protein biomarker that might explain such properties. METHODS: A cross-sectional study will be conducted on 48 participants aged 18-50 years old, involving patients with axSpA (according to ASAS classification criteria, symptoms duration < 10 years) and healthy controls matched by gender, age, and levels of physical activity. We will collect epidemiological and clinical data and perform a detailed, whole body and segmental, myofascial characterization (focusing on multifidus, brachioradialis and the gastrocnemius lateralis) concerning: a) Physical Properties (stiffness, tone and elasticity), assessed by MyotonPRO®; b) Strength, by a dynamometer; c) Mass, by bioimpedance; d) Performance through gait speed and 60-second sit-to-stand test; e) Histological and cellular/ molecular characterization through ultrasound-guided biopsies of multifidus muscle; f) Magnetic Resonance Imaging (MRI) characterization of paravertebral muscles. Furthermore, we will perform an integrated transcriptomics and proteomics analysis of peripheral blood samples. DISCUSSION: The innovative and multidisciplinary approaches of this project rely on the elucidation of myofascial physical properties in axSpA and also on the establishment of a biological signature that relates to specific muscle properties. This hitherto unstudied link between gene/protein signatures and muscle properties may enhance our understanding of axSpA physiopathology and reveal new and useful diagnostic and therapeutic targets.

Lumbar myofascial physical properties in healthy adults: myotonometry vs. shear wave elastography measurements.

OBJECTIVE: The human resting myofascial tone maintains the body tone in a neutral posture, the assessment of this and other muscle physical properties (MPP) is relevant, since, it is altered in many pathological states. PATIENTS AND METHODS: Seventeen healthy subjects (8 males), between 18-50 years old, were assessed. The MPP of lower lumbar muscles was evaluated on right and left sides during prone resting position using two devices; myotonometry (stiffness, elasticity and tone) and ultrasound-based shear-wave elastography (SWE) (shear modulus). MTM measurements were performed at two anatomic points (ANp), selected by an experienced reader and at an adjacent ultra-sound determined point (USp). Myotonometry measurements of the erector spinae and SWE measurements of multifidus muscles at the L3-4 level were compared between genders and sides. The intra-reader reliability (IRR) for each device and correlations between techniques were analysed. MTM measurements performed at ANp and USp were compared. The intraclass correlation coefficient (ICC) was assessed for both devices. Correlations between stiffness (myotonometry) and shear modulus (SWE) at the respective muscle depths were assessed with Spearman correlation. RESULTS: Males had greater stiffness and tone than females, particularly on the dominant side. MPP assessed by myotonometry were not different between ANp and USp. Good/Excellent IRR was documented for measurements by MTM (ICC≥0.90) and SWE (ICC≥0.85). No correlation in myotonometry stiffness and SWE shear modulus was found. For myotonometry assessments, the addition of ultrasonography was not different from anatomic localizations. No correlation of measurements was found between devices assessing respective L3-4 level muscles. CONCLUSIONS: Gender and side differences must be considered when assessing MPP in axial muscles. For MTM assessments, the addition of ultrasonography was not different to anatomic references. No correlation was found between devices.

The axial spondyloarthritis clinical phenotype in idiopathic hypoparathyroidism: critical review of concept that muscular hypercontractility can induce enthesopathy lesions.

Idiopathic hypoparathyroidism (iH-PoPT) is a rare condition infrequently associated with axial spondyloarthritis (SpA) which may mimic ankylosing spondylitis (AS). Axial SpA is a unifying clinical term for chronic inflammatory spinal disorders, although biomechanical factors may play a role. The primary objective of this review is to critically describe the iHPoPT/SpA phenotype defined by established criteria and its differentiation from AS. Five databases were comprehensively searched without time limit to retrieve 14 (11M, 3F) iH-PoPT/SpA cases. Their demographic, clinical, laboratory, radiographic, and HLA-B27 status were compared to two national series of AS patients. Mean (SD) onset age of musculoskeletal symptoms [32.5 (9.7)] was significantly older than 943 German AS patients [25.1 (8.5), (p=0.004)] and 842 Spanish AS patients [26.1 (9.7), (p=0.030)]. Radiographic lesions of iHPoPT/SpA differ morphologically from skeletal alterations in hyperparathyroid and hypophosphataemic syndromes which often have inadequate bone mineralisation and decreased bone mineral density (BMD). Clinical musculoskeletal manifestations were greater (p<0.001) in iHPoPT/SpA than AS patients at cervical (62 vs. 10%) and hip (85 vs. 22%) localisations, respectively. Typical AS sacroiliac joint structural lesions of erosions and bony bridging were reported in only 1 iHPoPT/SpA case and HLA-B27 was positive in 2 of 10 tested. The iHPoPT/SpA phenotype may be a natural experiment on the novel concept of how chronic hypocalcaemia of iHPoPT causes axial neuromotor hypercontractility and biomechanically induces the rare SpA association. In iHPoPT/SpA, neuromuscular hyper-contractility may predispose to axial radiographic enthesopathy lesions and contribute knowledge on biomechanical contributions and pathways for further research.

Hereditary, socio-behavioural, and immuno-hormonal predictors of incident rheumatoid arthritis and therapy response influences on survival versus matched control subjects using a generalised structural equation model.

OBJECTIVES: Incident onset and survival outcomes involve multiple risk factors and complex interactions preferably investigated in a single study. A generalized structural equation model (GSEM) was used to build an integrative framework to analyse multiple risk factors for incident rheumatoid arthritis (RA) and factors affecting long-term survival outcome. METHODS: Incident RA cases (n=54) had onsets between 1977 and 1994, after cohort entry in 1974. Four cohort control (CN) subjects (n=216) were matched on entry to each case in the community-based CLUE cohort and 270 subjects were followed from 1995 through 2017. Baseline variables included demographic, RA family history, behavioural factors and z-score levels of serum immunological, cytokine, isotype rheumatoid factors (RFs), adrenal steroids, luteinising hormone, prolactin and sex steroids. Four numerical integration methods of GSEM were performed in Stata 15. RESULTS: Cohort entry factors predicting RA onset included family history of RA, cigarette smoking and IgM RF. Total survival time from cohort entry was associated with incident RA and baseline variables of age, years of completed education, cigarette smoking, immunoreactive proteins and androgenic-anabolic steroids. Mortality of RA was significantly greater than CN subjects for cases having less than good therapy responses in 1995 and only for RA onset before age 60 years. Androgenic-anabolic steroid z-scores significantly correlated with improved survival only in CN subjects with assigned onset before the age of 60. CONCLUSIONS: Successful use of GSEM is feasible in analyses of prospective incident and subsequent survival data and promises to advance understanding of risk factors, survival, and casual pathways.

Biomechanical properties of low back myofascial tissue in younger adult ankylosing spondylitis patients and matched healthy control subjects.

BACKGROUND: Ankylosing spondylitis is a degenerative and inflammatory rheumatologic disorder that primarily affects the spine. Delayed diagnosis leads to debilitating spinal damage. This study examines biomechanical properties of non-contracting (resting) human lower lumbar myofascia in ankylosing spondylitis patients and matched healthy control subjects. METHODS: Biomechanical properties of stiffness, frequency, decrement, stress relaxation time, and creep were quantified from 24 ankylosing spondylitis patients (19 male, 5 female) and 24 age- and sex-matched control subjects in prone position on both sides initially and after 10 min rest. Concurrent surface electromyography measurements were performed to ensure resting state. Statistical analyses were conducted, and significance was set at p < 0.05. FINDINGS: Decreased lumbar muscle elasticity (inverse of decrement) was primarily correlated with disease duration in ankylosing spondylitis subjects, whereas BMI was the primary correlate in control subjects. In ankylosing spondylitis and control groups, significant positive correlations were observed between the linear elastic properties of stiffness and frequency as well as between the viscoelastic parameters of stress relaxation time and creep. The preceding groups also showed significant negative correlations between the linear elastic and viscoelastic properties. INTERPRETATION: Findings indicate that increased disease duration is associated with decreased tissue elasticity or myofascial degradation. Both ankylosing spondylitis and healthy subjects revealed similar correlations between the linear and viscoelastic properties which suggest that the disease does not directly alter their inherent interrelations. The novel results that stiffness is greater in AS than normal subjects, whereas decrement is significantly correlated with AS disease duration deserves further investigation of the biomechanical properties and their underlying mechanisms.

Preclinical biomarker associations with both incident rheumatoid arthritis and its subsequent mortality: sex effects in a 41-year, community-based, case-control cohort study.

OBJECTIVES: To identify sex effects and preclinical serum biomarker associations with both incident rheumatoid arthritis (RA) and its subsequent mortality, using a 41-year, community-based, case-control cohort. METHODS: After cohort entry in 1974, incident RA cases (n=54) had clinical onsets between 1977 and 1994. Cohort control (CN) subjects were individually matched on entry to cases (4 CN:1 RA, n=216). All subjects were followed for survival from 1995 through 2015. Ranks (1-5) of preclinical z-scores within each set of 1 RA and 4 matched CN were analysed for associations with incident RA and mortality. Survival was evaluated using Cox proportional hazards models. RESULTS: Preclinical serum IgG RF z-score ranks associated with incident RA in 90 males (18 RA, 72 CN). Cigarette smoking, androstenedione, pregnenolone, and sIL-2Rα ranks associated with incident RA in 180 females (36 RA, 144 CN). Total percentile mortality was greater (p=0.003) in RA (70.4) vs. CN (49.9) and equivalently increased in female RA (69.4) vs. CN (49.3) and in male RA (72.2) vs. CN (43.1) subjects. Percentile respiratory-related CODs were greater (p=0.009) only in the female RA cases (16.7) vs. CN (3.5). Ranks of preclinical hsCRP (p=0.028) and sIL-2Rα (p=0.030) independently associated with 140 total deaths, as did sTNF-R1 (p=0.003) and hsCRP (p=0.005) with 50 CVD deaths. Latter biomarker association were significant in females. Therapy responses in 1995 significantly associated with subsequent mortality. CONCLUSIONS: Sex effects were important in preclinical biomarker associations with incident RA, total and CVD mortality as well as occurrence of respiratory deaths.

Increased mortality of incident rheumatoid arthritis versus matched non-RA control subjects: a community-based long-term prospective cohort study.

OBJECTIVES: This study aimed to critically investigate all-cause and major-cause mortality of incident rheumatoid arthritis (RA) cases versus matched non-RA comparison (CN) subjects in a long-term prospective cohort. METHODS: Baseline 1974 cohort entry demographic and serum biomarker data on 54 incident RA patients and 216 matched CN subjects were related to their mortality from 1995 through 2015. Mortality of RA patients was also analysed by 3 categories of course responses to therapy assigned by the sole community rheumatologist in 1995 (19 good, 23 fair, and 12 limited). Cox proportional hazards regression models including baseline covariates were used to determine survival from all-causes, cardiovascular disease (CVD), respiratory-related, malignancies, and other causes of death (CODs). RESULTS: Total deaths occurred in 38 (70.4 percent) of 54 RA and 102 (47.7 percent) of 216 CN (p=0.003). Total mortality remained greater (p=0.011) in RA versus CN subjects after adjustment for baseline demographic covariates (HR= 1.66, 95% CI 1.12-2.46). Respiratory-related CODs were also greater (p=0.047) in RA versus CN (HR= 2.69, 95% CI 1.02-7.14) subjects. The RA patients' responses to therapy in 1995 significantly (p=0.004) predicted total mortality. Baseline serum immunological and steroid biomarkers independently predicted total, CVD, and other and unknown CODs. Pre-clinical (1974) ranked biomarker z-score values (1 = lowest, 5 = highest) within matched sets of 1 RA and 4 CN study subjects independently associated with mortality from 1995 through 2015, for both total (CRP, p=0.028 and sIL-2Rα, p=0.030) and CVD (CRP, p=0.005 and sTNF-R1, p=0.003) deaths. CONCLUSIONS: Total mortality and respiratory-related CODs were greater in incident RA versus CN subjects. The 35 RA cases who had fair or limited course responses to rheumatologist's therapy had greater mortality than their matched CN, whereas the 19 good RA responders had equivalent survival to CN subjects. The independent CRP and sTNF-R1 biomarker associations with CVD deaths were enhanced by a gradient of their dichotomous z-score values in survival models.

Stiffness of resting lumbar myofascia in healthy young subjects quantified using a handheld myotonometer and concurrently with surface electromyography monitoring.

This study aimed to non-invasively quantify passive stiffness of superficial myofascia at a lower lumbar (L3-L4) anatomical level in young healthy male and female subjects and investigate its possible morphological variation. Resting prone lumbar myofascial measurements were quantified using MyotonPro(®) and statistically analyzed in 20 young healthy individuals over 3-weekly intervals, concurrently with surface electromyography (sEMG). Averaged mean ± SE stiffness (Newton/meter) over three weeks was significantly (p < 0.001) greater in males (247.8 ± 11.3) than females (208.4 ± 11.3), on the right (237.7 ± 12.8) than left sides (218.5 ± 12.3), at 10-min (231.4 ± 9.1) than initial baseline (224.8 ± 9.1) values. A polymorphism of stiffness values in 10 male and 10 female subjects was suggested by box plot analyses of the 3 weekly measurements and greater inter-individual than intra-individual variances. Greater knowledge of lumbar myofascial stiffness can improve understanding of their contributions in health and chronic low back disorders.

Sexual Dimorphisms of Adrenal Steroids, Sex Hormones, and Immunological Biomarkers and Possible Risk Factors for Developing Rheumatoid Arthritis.

Innate immunity and immunological biomarkers are believed to be interrelated with sex hormones and other neuroendocrine factors. Sexual dimorphism mechanisms may be operating in certain rheumatic and inflammatory diseases which occur more frequently in women than men, as rheumatoid arthritis (RA). Less data have been available on altered interrelations of the combined neuroendocrine and immune (NEI) systems as risk factors for development of certain diseases. In this study, serological interrelations of NEI biomarkers are analyzed before symptomatic onset of RA (pre-RA) versus control (CN) subjects, stratified by sex. Sexual dimorphism was found in serum levels of acute serum amyloid A (ASAA), soluble interleukin-2 receptor alpha (sIL-2Rα), and soluble tumor necrosis factor receptor 1 (sTNF-R1). Multiple steroidal and hormonal (neuroendocrine) factors also showed highly (p < 0.001) significant sexual dimorphism in their assayed values, but less for cortisol (p = 0.012), and not for 17-hydroxyprogesterone (p = 0.176). After stratification by sex and risk of developing RA, differential NEI correlational patterns were observed in the interplay of the NEI systems between the pre-RA and CN groups, which deserve further investigation.