To examine the relationship of Porphyromonas gingivalis (Pg) with the presence of autoantibodies in individuals at risk for rheumatoid arthritis (RA).
Participants included: 1) a cohort enriched with HLA-DR4 and 2) those at risk for RA by virtue of having a first-degree relative with RA. None satisfied 1987 ACR RA classification criteria. Autoantibodies measured included anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF; nephelometry, IgA, IgM, IgG). Individuals were considered autoantibody positive (n = 113) with ≥ 1 positive autoantibody with individuals further categorized as `high-risk' (n = 38; positive ACPA or ≥ 2 RF assays). Autoantibody negative individuals served as comparators (n = 171). Antibody to Pg, P. intermedia (Pi), and F. nucleatum (Fn) were measured. Associations of bacterial antibodies with group status were examined using logistic regression.
Anti-Pg concentrations were higher in high-risk (p = 0.011) and autoantibody positive group (p = 0.010) than in the autoantibody negative group. There were no group differences in anti-Pi or anti-Fn concentrations. After multivariable adjustment, anti-Pg concentrations (but not anti-Pi or anti-Fn) were significantly associated with autoantibody positive and high-risk status (p < 0.05).
Immunity to Pg, but not Pi or Fn, is significantly associated with the presence of RA-related autoantibodies in individuals at risk for RA. These results support the hypothesis that infection with Pg may play a central role in the early loss of tolerance to self-antigens in RA pathogenesis.
rheumatoid arthritis; periodontitis; Porphyromonas gingivalis; Prevotella intermedia; Fusobacterium nucleatum; rheumatoid factor; anti-citrullinated protein antibody
Spondyloarthritis; squaring; vertebrae
To evaluate a multidimensional model testing disease activity, mood disturbance, and poor sleep quality as determinants of fatigue in patients with rheumatoid arthritis (RA).
The data of 106 participants were drawn from baseline of a randomized comparative efficacy trial of psychosocial interventions for RA. Sets of reliable and valid measures were used to represent model constructs. Structural equation modeling was used to test the direct effects of disease activity, mood disturbance, and poor sleep quality on fatigue, as well as the indirect effects of disease activity as mediated by mood disturbance and poor sleep quality.
The final model fit the data well, and the specified predictors explained 62% of the variance in fatigue. Higher levels of disease activity, mood disturbance, and poor sleep quality had direct effects on fatigue. Further, disease activity was indirectly related to fatigue through its effects on mood disturbance, which, in turn, was related to poor sleep quality. Mood disturbance also indirectly influenced fatigue through poor sleep quality.
The findings from this study confirmed the importance of a multidimensional framework in evaluating the contribution of disease activity, mood disturbance, and sleep quality to fatigue in RA using a structural equation approach. Mood disturbance and poor sleep quality played major roles in explaining fatigue along with patient-reported disease activity.
Rheumatoid arthritis; Fatigue; Mood; Sleep disorders; Psychological factors
To evaluate the presence of pulmonary abnormalities in subjects with rheumatoid arthritis (RA)-related autoantibody (Ab) positivity without inflammatory arthritis (IA).
42 subjects without IA but with elevations of anti-cyclic citrullinated peptide antibodies and/or 2 or more rheumatoid factor isotypes (a profile that is 96% specific for RA), 15 Ab(−) controls and 12 patients with early established seropositive RA (<1 year duration) underwent spirometry and high-resolution computed tomographic (HRCT) lung imaging.
The median age of Ab(+) subjects was 54 years-old, 52% were female and 38% were smokers (not significantly different than Ab(−) controls). No Ab(+) subject had IA on joint examination. On HRCT, 76% of Ab(+) subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities and air trapping, compared to 33% of Ab(−) controls (p=0.005). The Ab(+) subjects had similar prevalence and type of lung abnormalities compared to patients with early RA. Two Ab(+) subjects with airways disease developed IA classifiable as articular RA ~13 months after lung evaluation.
Airways abnormalities that are consistent with inflammation are common in Ab(+) subjects without IA, and similar to airways abnormalities seen in early RA. These findings suggest that the lung may be an early site of autoimmune-related injury, and potentially a site of generation of RA-related autoimmunity. Further studies are needed to define the mechanistic role of lung inflammation in the development of RA.
Rheumatoid arthritis; etiology; autoantibodies; preclinical; lung disease
About 90% of patients with systemic lupus erythematosus (SLE) are female. We hypothesize that the number of X chromosomes, not sex, is a determinate of risk of SLE. Number of X chromosomes was determined by single nucleotide typing and then confirmed by karyotype or fluorescent in situ hybridization in a large group of men with SLE. Presence of an sry gene was assessed by rtPCR. We calculated 96% confidence intervals using the Adjusted Wald method, and used Bayes’ theorem to estimate the prevalence of SLE among 47,XXY and 46,XX men. Among 316 men with SLE, 7 had 47,XXY and 1 had 46,XX. The rate of Klinefelter’s syndrome (47,XXY) was statistically different from that found in control men and from the known prevalence in the population. The 46,XX man had an sry gene, which encodes the testes determining factor, on an X chromosome as a result of an abnormal crossover during meiosis. In the case of 46,XX, 1 of 316 was statistically different from the known population prevalence of 1 in 20,000 live male births. A previously reported 46,XX man with SLE had a different molecular mechanism in which there were no common gene copy number abnormalities with our patient. Thus, men with SLE are enriched for conditions with additional X chromosomes. Especially since 46,XX men are generally normal males, except for infertility, these data suggest the number of X chromosomes, not phenotypic sex, is responsible for the sex bias of SLE.
Systemic lupus erythematosus; Klinefelter’s syndrome; male 46; XX; female bias; X chromosome
Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants.
Overall, 502 AS patients were examined, consisting of 312 who had first-degree relatives (FDR) with AS (familial) and 190 who had no FDR with AS or spondyloarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York Criteria for AS. The patients were recruited from two U.S. cohorts (NASC and PSOAS) and from the United Kingdom- Oxford cohort. The frequencies of AS susceptibility loci in IL23R, IL1R2, ANTRX2, ERAP1, two intergenic regions on chromosomes 2p15 and 21q22, and HLA-B27 status as determined by the tag SNP rs4349859 were compared between familial and sporadic cases. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size.
HLA-B27 was significantly more prevalent in familial than sporadic cases of AS (p=0.0001, OR: 4.44, CI: (2.06–9.55)). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend towards higher frequency in the multiplex cases (p=0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined.
HLA-B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA-B27 positivity. The frequency of the recently described non-MHC susceptibility loci is not markedly different between the sporadic and familial cases of AS.
The objective of this paper is to assess the contribution of disease activity, pain, and psychological factors to self-reported sleep disturbance in patients with rheumatoid arthritis (RA), and to evaluate whether depression mediates the effects of pain on sleep disturbance. The sample included 106 patients with confirmed RA participated in an assessment of their disease activity, pain, psychological functioning, and sleep disturbance during a baseline evaluation prior to participating in a prospective study to help them manage their RA. Self-measures included the Rapid Assessment of Disease Activity in Rheumatology (RADAR), the SF-36 Pain Scale, the Helplessness and Internality Subscales of the Arthritis Helplessness Index (AHI), the Active and Passive Pain Coping Scales of the Pain Management Inventory (PMI), the Center for Epidemiological Studies Depression Scale (CES-D), and the Pittsburgh Sleep Quality Index (PSQI). Hierarchical multiple regression analysis confirmed that higher income, pain, internality, and depression contributed independently to higher sleep disturbance. A mediational analysis demonstrated that depression acted as a significant mechanism through which pain contributed to sleep disturbance. Cross-sectional findings indicate that pain and depression play significant roles in self-reported sleep disturbance among patients with RA. The data suggest the importance of interventions that target pain and depression to improve sleep in this medical condition.
pain; depression; sleep disturbance; rheumatoid arthritis
Objectives. To explore whether helplessness, internality and depression would mediate the relationship between disease activity and functional limitations in patients with AS in a 12-month longitudinal study.
Methods. A total of 294 participants with AS meeting modified New York criteria completed clinical and psychological assessments at 6-month intervals. Psychological measures evaluated helplessness, depression and internality. Path analysis evaluated the direct and indirect effects of baseline disease activity on 12-month functional limitations via the psychological measures of helplessness, internality and depression at 6 months.
Results. Baseline disease activity demonstrated direct and indirect effects on 12-month functional limitations. Helplessness and depression, but not internality, served as mediators of the relationship between disease activity and functional limitations.
Conclusion. Higher baseline disease activity predicted greater functional limitations at 12 months through helplessness and depression. Our findings suggest that helplessness and depression may constitute future treatment targets in reducing functional limitations in patients with AS.
Ankylosing spondylitis; Disease activity; Functional limitations; Depression; Internality; Helplessness
To analyse the cost-effectiveness of traditional disease-modifying anti-rheumatic drugs (tDMARDs) compared to biological therapies from the perspective of Chinese society.
A mathematical model was developed by incorporating the clinical trial data and Chinese unit costs and treatment sequences from a lifetime perspective. Hypothetical cohorts with moderate to severe RA were simulated. The primary outcome measure–quality-adjusted life years (QALYs)–was derived from disease severity (HAQ scores). Primary analysis included drug costs, monitoring costs, and other costs. Probabilistic and one-way sensitivity analyses were performed. Treatment sequences that included TNF antagonists and rituximab produced a greater number of QALYs than tDMARDs alone or TNF antagonists plus DMARDs. In comparison with tDMARDs, the incremental cost-effectiveness ratios (ICERs) for etanercept, infliximab, and adalimumab without rituximab were $77,357.7, $26,562.4 and $57,838.4 per QALY and $66,422.9, $28,780.6 and $50,937.6 per QALY, for etanercept, infliximab, and adalimumab with rituximab. No biotherapy was cost-effective under the willingness to pay threshold when the threshold was 3 times the per capita GDP of China. When 3 times the per capita GDP of Shanghai used as the threshold, infliximab and rituximab could yield nearly 90% cost-effective simulations in probabilistic sensitivity analysis.
tDMARD was the most cost-effective option in the Chinese healthcare setting. In some relatively developed regions in China, infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA.
Systemic lupus erythematosus (SLE) with central nervous system (CNS) involvement is frequent and can have high morbidity. The primary pathophysiology of SLE in the CNS is thought to be inflammation secondary to autoantibody-mediated vasculitis. Neuroimaging studies have reported hypometabolism (impending cell failure) and atrophy (late-stage pathology), but not inflammation. We used a validated index of SLE-related disease activity as a regressor for positron emission tomographic (PET) images of glucose uptake to detect the presence and regional distribution of inflammation (hypermetabolism) and tissue failure, apoptosis or atrophy (hypometabolism).
Eighty-five newly diagnosed SLE patients without focal neurological symptoms were studied. Disease activity was quantified using the SELENA SLE Disease Activity Index (SS). 18Fluoro-deoxy-glucose (FDG) PET images were analyzed by visual inspection and as group statistical parametric images using the SS score as the analysis regressor.
SS-correlated increases in glucose uptake were found throughout the white matter, most marked in heavily myelinated tracts. SS-correlated decreases were found in frontal and parietal cortex, in a pattern similar to that seen by visual inspection and in prior reports of hypometabolism.
We interpret the SS-correlated increases in glucose consumption as potential evidence of inflammation, in keeping with prior reports of hypermetabolism in inflammatory disorders. To our knowledge, this is the first imaging evidence of SLE-induced CNS inflammation in an SLE inception cohort. The dissociation between 18FDG uptake characteristics, spatial distribution, and correlation with disease activity argues that glucose hyper- and hypometabolism reflect fundamentally different aspects of the pathophysiology of CNS SLE.
systemic lupus erythematosus; positron emission tomography; glucose metabolism; SLEDAI; inflammation
Purpose. This study evaluates high-throughput autoantibody screening and determines associated systemic lupus erythematosus (SLE) clinical features in a large lupus cohort. Methods. Clinical and demographic information, along with serum samples, were obtained from each SLE study participant after appropriate informed consent. Serum samples were screened for 10 distinct SLE autoantibody specificities and examined for association with SLE ACR criteria and subcriteria using conditional logistic regression analysis. Results. In European-American SLE patients, autoantibodies against 52 kD Ro and RNP 68 are independently enriched in patients with lymphopenia, anti-La, and anti-ribosomal P are increased in patients with malar rash, and anti-dsDNA and anti-Sm are enriched in patients with proteinuria. In African-American SLE patients, cellular casts associate with autoantibodies against dsDNA, Sm, and Sm/nRNP. Conclusion. Using a high-throughput, bead-based method of autoantibody detection, anti-dsDNA is significantly enriched in patienets with SLE ACR renal criteria as has been previously described. However, lymphopenia is associated with several distinct autoantibody specificities. These findings offer meaningful information to allow clinicians and clinical investigators to understand which autoantibodies correlate with select SLE clinical manifestations across common racial groups using this novel methodology which is expanding in clinical use.
To examine the clinical and radiographic features in men and women in the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, a large well‐defined cross‐sectional study of patients with AS, in order to understand the influence of gender in determining the severity of ankylosing spondylitis.
Extensive clinical assessments and spine radiographs were performed in 302 men and 100 women with AS of ⩾20 years duration. Radiographs were scored using the Bath Ankylosing Spondylitis Radiographic Index Spine (BASRI‐spine) score (range 2–12). Functional impairment was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire for the Spondyloarthropathies (HAQ‐S).
Radiographic severity was worse among men. The unadjusted median BASRI‐spine score for men was 10, compared with 6.5 for women (p<0.001). Functional disability, as measured by the BASFI and HAQ‐S, was not different between men and women. However, after adjusting for radiographic spinal damage, women were found to report worse functioning than men at any given level of radiographic damage. Women had a slightly earlier age of disease onset; however, disease duration was identical in both groups. Women more frequently reported family histories of AS in first‐degree relatives and were more likely to be treated with intra‐articular steroids, sulphasalazine and prednisone.
Among patients with longstanding AS, men have more severe radiographic changes; findings of treatment differences suggest that women may have more peripheral arthritis. At any given level of radiographic damage, self‐reported functional limitations were worse for women.
To examine the relationships between physical, psychological, and social factors and health-related quality of life (HRQOL) and disability in rheumatoid arthritis (RA).
A sample of 106 patients with rheumatoid arthritis (RA) completed measures of self-reported disease activity and psychosocial functioning, including coping, personal mastery, social network, perceived stress, illness beliefs, the SF-36 and Health Assessment Questionnaire Disability Index (HAQ-DI). In addition, physician-based assessment of disease activity using the Disease Activity Scale (DAS 28) was obtained. Hierarchical multiple regression analyses were used to evaluate the relationships between psychosocial factors and scores on the SF-36 and HAQ-DI.
Lower self-reported disease activity and higher active coping were significantly related to SF-36 physical functioning scores, whereas lower self-reported disease activity, higher personal mastery, and lower perceived stress contributed to higher SF-36 mental health functioning. Higher self-reported disease activity and lower helplessness were associated with greater disability as indexed by the HAQ-DI. The DAS 28 was unrelated to these outcomes.
The findings highlight the importance of targeting psychological factors to enhance HRQOL in the clinical management of RA patients.
Health-related quality of life; psychological factors; rheumatoid arthritis
To identify differentially expressed genes in peripheral blood cells
(PBC) of patients with ankylosing spondylitis (AS) relative to healthy
controls and controls with systemic inflammation.
We investigated PBC samples of 16 patients with AS and 14 matched
controls, in addition to systemic lupus erythematosus (SLE) and systemic
sclerosis (SSc) samples utilizing Illumina Human Ref-8 BeadChips. Candidate genes were confirmed using
quantitative PCR. Subsequently, these genes were also validated in a
separate sample of 27 patients with AS [before and after antitumor necrosis
factor (anti-TNF) treatment] and 27 matched controls.
We identified 83 differentially expressed transcripts between AS
patients and controls. This gene list was filtered through the lists of
differentially expressed transcripts in SLE and SSc, which resulted in
identification of 52 uniquely dysregulated transcripts in AS. Many of the
differentially expressed genes belonged to Toll-like receptor (TLR) and
related pathways. TLR4 and TLR5 were the
only dysregulated TLR subtypes among AS patients. We confirmed the
overexpression of TLR4 and TLR5 in AS
patients in comparison to controls (p = 0.012 and p = 0.006, respectively)
and SLE (p = 0.002, p = 0.008) using quantitative PCR in the same sample.
Similarly, TLR4 (p = 0.007) and TLR5 (p =
0.012) were significantly upregulated among the AS patients before anti-TNF
treatment in the confirmatory sample. TLR4 (p = 0.002) and
TLR5 (p = 0.025) decreased significantly after anti-TNF
PBC gene expression profiling in AS shows an upregulation of
TLR4 and TLR5. This supports the
importance of TLR subtypes in the pathogenesis of AS that are responsible
for the immune response to Gram-negative bacteria.
ANKYLOSING SPONDYLITIS; TOLL-LIKE RECEPTORS; IMMUNE SYSTEM; AUTOIMMUNITY; BACTERIA; GENE EXPRESSION PROFILING
To replicate and refine the reported association of ankylosing spondylitis (AS) with two non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1.
Firstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls.
The association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified.
The region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.
To investigate the role of psychological variables in self-reported disease activity in patients with Ankylosing Spondylitis (AS), while controlling for demographic and medical variables.
Patients and Methods
294 AS patients meeting modified New York Criteria completed psychological measures evaluating depression, resilience, active and passive coping, internality and helplessness. Demographic, clinical, and radiologic data were also collected. Univariate and multivariate analyses were completed to determine the strength of the correlation of psychological variables with disease activity, as measured by the Bath AS Disease Activity Index (BASDAI).
In the multivariate regression analysis, the psychological variables contributed significantly to the variance in BASDAI scores, adding an additional 33% to the overall R-square beyond that accounted for by demographic and medical variables (combined R-square 18%). Specifically, Arthritis Helplessness and Depression accounted for the most significant portion of the variance in BASDAI scores in the final model.
Arthritis helplessness and depression accounted for significant variability in self-reported disease activity beyond clinical and demographic variables in patients with AS. These findings have important clinical implications in the treatment and monitoring of disease activity in AS, and suggest potential avenues of intervention.
Ankylosing Spondylitis; disease activity; psychosocial factors
To describe a large, multi-center prospective cohort study of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the utility of such a study in investigating the natural history of RA development.
1058 FDRs, none of whom met the American College of Rheumatology (ACR) criteria for RA, have been enrolled into a prospective study investigating genetic and environmental influences on the development of RA-related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit is described for these FDRs, and the relationship is examined between genetic factors, autoantibodies, inflammation, and joint disease.
Fifty-five percent of FDRs have ≥1 copy of the shared epitope (SE); 20% have ≥1 copy of PTPN22 polymorphism; ~16% are positive for rheumatoid factor (RF, including isotypes), and/or anti-cyclic citrullinated peptide (anti-CCP) antibody. RF-IgM positivity is associated with ≥1 tender joint/s on examination (OR 2.50, 95% CI 1.27 to 4.89, p<0.01), and elevated levels of CRP (OR 5.31, 95% CI 1.45 to 19.52, p = 0.01).
FDRs without RA demonstrate high prevalence of genetic risk factors and RA-related autoantibodies. Additionally, RF association with tender joints and elevated CRP suggests autoantibodies are a valid intermediate marker of RA-related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic, epidemiologic factors and the development of RA-related autoimmunity.
rheumatoid arthritis; epidemiology; environmental factors; first-degree relatives; pre-clinical rheumatoid arthritis
The objective of the present study was to assess heritability of clinical and radiographic features of hand osteoarthritis (OA) in affected patients and their siblings.
A convenience sample of patients with clinical and radiographic hand OA and their siblings were evaluated by examination and radiography. Radiographs were scored for hand OA features by radiographic atlas. The heritability of hand OA phenotypes was assessed for clinical and radiographic measures based on anatomic locations and radiographic characteristics. Phenotypic data were transformed to reduce non-normality, if necessary. A variance components approach was used to calculate heritability.
One hundred and thirty-six probands with hand OA and their sibling(s) were enrolled. By anatomic location, the highest heritability was seen with involvement of the first interphalangeal joint (h2 = 0.63, P = 0.00004), the first carpometacarpal joint (h2 = 0.38, P = 0.01), the distal interphalangeal joints (h2 = 0.36, P = 0.02), and the proximal interphalangeal joints (h2 = 0.30, P = 0.03) with osteophytes. The number and severity of joints with osteophyte involvement was heritable overall (h2 = 0.38, P = 0.008 for number and h2 = 0.35, P = 0.01 for severity) and for all interphalangeal joints (h2 = 0.42, P = 0.004 and h2 = 0.33, P = 0.02). The severity of carpometacarpal joint involvement was also heritable (h2 = 0.53, P = 0.0006). Similar results were obtained when the analysis was limited to the Caucasian sample.
In a population with clinical and radiographic hand OA and their siblings, the presence of osteophytes was the most sensitive biomarker for hand OA heritability. Significant heritability was detected for anatomic phenotypes by joint location, severity of joint involvement with osteophytes as well as for overall number and degree of hand OA involvement. These findings are in agreement with the strong genetic predisposition for hand OA reported by others. The results support phenotyping based on severity of osteophytes and a joint-specific approach. More specific phenotypes may hold greater promise in the study of genetics in hand OA.
To evaluate the association between rheumatoid arthritis (RA)-related autoantibodies and plasma 25, OH vitamin D in subjects at risk for RA.
In 1210 subjects without RA, 76 were positive for either anti-CCP antibodies or for at least two or more RFs (RF measured by nephelometry, RF-IgM, -IgG, -IgA). 25, OH vitamin D was measured in these cases and 154 autoantibody-negative controls from this cohort.
25, OH vitamin D levels did not differ between cases and controls (adjusted OR:1.23, 95% CI: 0.93–1.63).
Vitamin D levels are not associated with RA-related autoimmunity in unaffected subjects at increased risk for RA.
vitamin D; rheumatoid arthritis; autoantibodies
Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) share similarities and are classified as spondyloarthropathies. In IBD, anti-Saccharomyces cerevisiae antibody (ASCA), anti-I2 (associated with anti-Pseudomonas activity), anti-Escherichia coli outer membrane porin C (anti-OmpC), anti-flagellin (anti-CBir1), and antineutrophil cytoplasmic antibodies (ANCA) possess clinical significance. Because of the overlap between the two conditions, a pilot study was designed to compare the frequency of these antibodies in AS patients compared to normal controls.
Serum stored from 80 AS patients and 80 control subjects was available for analysis. ASCA, anti-I2, anti-OmpC, anti-CBir1, and ANCA studies were completed on all serum samples using Enzyme-Linked Immunosorbent Assay (ELISA) methodology. The following analyses were performed: comparison of positivity based on the established values in IBD, median values, the number of subjects in each serology in the 4th quartile of a normal distribution, and the mean quartile sum of all the antibodies.
There was no difference in positivity rates between AS and control groups with the established IBD values. The median anti-I2 response was significantly higher in AS than in controls (11.78 vs 7.86, p = 0.017). Significantly more AS patients had quartile scores of 4 for the following antibody responses: ASCA IgG (26% vs 13%, p = 0.016, OR = 2.49, CI 1.168 - 5.313), ASCA IgG and IgA (27% vs 12%, p = 0.006, OR = 2.9, CI: 1.342 - 6.264), and anti - I2 (25% vs 14%, p = 0.0424, OR = 2.15, CI: 1.018 - 4.538). The mean quartile sum of the antibody responses was elevated in AS patients when ANCA was excluded (10.526 vs 9.519, p = 0.03). When ANCA was included, this difference lost significance.
The data from this pilot study points towards mucosal dysregulation as an important pathway in AS. We were able to demonstrate that anti-I2 could play a pathologic role in AS. The elevated mean total antibody response being significant only with ANCA exclusion is consistent with the histopathological evidence that intestinal inflammation in AS is similar to Crohn's disease. To better define the roles of these antibodies in AS, larger studies with more precisely defined patient characteristics are required.
We sought to identify specific occupational activities associated with functional limitations and radiographic damage in patients with longstanding ankylosing spondylitis (AS).
We asked patients diagnosed with AS for ≥20 years to report all past occupations, which we mapped to specific physical activities using the Occupational Information Network, which is the US Department of Labor job classification database. For each occupation reported, we obtained ratings for 13 physical abilities of the worker and 13 aspects of the work environment or work tasks (work context) thought to be most relevant to patients with AS. Averages for each measure, weighted by the number of years in each job, were related to the degree of functional limitation as assessed by the Bath AS Functional Index (BASFI) and to the extent of spinal radiographic damage as assessed by the Bath AS Radiology Index for the spine (BASRI-s).
Among 397 patients, those with a history of jobs requiring dynamic flexibility (the ability to repeatedly bend, stretch, twist, or reach) had more functional limitations than those whose past jobs required little or no dynamic flexibility (adjusted mean BASFI score 48.3 in the top quartile versus 38.1 in all others). Those whose past jobs required more dynamic flexibility, extent flexibility, and exposure to whole body vibration also had significantly higher BASRI-s scores.
Bending, twisting, and stretching are the occupational activities associated with greater functional limitations and radiographic damage in patients with longstanding AS. Exposure to whole body vibration was also associated with more radiographic damage.
To identify risk factors for functional limitations in patients with ankylosing spondylitis (AS) of at least 20 years duration.
Patients with AS for 20 years or more were enrolled in the cross-sectional component of PSOAS (Prospective Study of Outcomes in AS). All patients had clinical evaluations, and completed questionnaires on functional limitations and potential risk factors. Functional limitations were assessed using the Bath AS Functional Index (BASFI; range 0—100, higher scores indicate more limitations) and the Health Assessment Questionnaire for the Spondyloarthropathies (HAQS). Risk factors included demographic characteristics, duration of AS, smoking, number of comorbid medical conditions, recalled level of recreational activity in teens and twenties, occupational physical activity throughout life (rated 1 = little, 2 = moderate, 3 = heavy, and weighted by the number of years in each job), and history of AS in a first degree relative.
The 326 patients (74% men) had a mean (“ standard deviation) age of 55.0 ” 10.7 years, a mean duration of AS symptoms of 31.7 “ 10.2 years, and a mean BASFI of 40.7 ” 25.6. BASFI scores increased with higher lifetime occupational physical activity (correlation r = .31; p < .0001), the number of comorbid conditions (r = .25; p < .0001), and the duration of AS (r = .12; p = .04). BASFI scores were higher among current smokers compared to former/nonsmokers (55.5 versus 38.9; p = .0002), and among nonwhites compared to whites (49.9 versus 39.3; p = .04). In multivariable analyses, lifetime occupational physical activity, current smoking, education level, number of comorbid conditions, and family history were significantly associated with BASFI scores. The same risk factors were associated with the HAQS.
Functional limitations in patients with AS for 20 years or more are greater among those with a history of more physically demanding jobs, more comorbid conditions, and among smokers, and are less severe among those with higher levels of education and a family history of AS.
We found that the plasma of patients with active systemic lupus erythematosus (SLE) could induce a human B-cell line (Ramos) to express high levels of immune accessory molecules that are commonly found on blood B cells of patients with active SLE. The ability of SLE plasma to induce such phenotypic changes could be abrogated by neutralizing antibodies specific for the CD40 ligand (CD154) but not by antibodies to TNF-α. Immunoprecipitation studies with anti-CD154 identified a 20-kDa protein in the plasma of SLE patients with active disease, but not in plasma of normal donors, indicating that such plasma contained soluble CD154 (sCD154). Using a quantitative ELISA method, we found that the plasma of patients with active disease had levels of sCD154 that were significantly higher than those found in plasma of normal donors. Levels of CD154 transcripts in SLE blood lymphocytes correlated with the relative concentrations of sCD154 found in SLE plasma. Furthermore, plasma levels of sCD154 correlated with the titers of anti–double-stranded DNA autoantibody and with clinical disease activity. These studies indicate that sCD154 of patients with SLE may act as a functional ligand for CD40 that is associated with SLE disease activity.
Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) are similar chronic inflammatory diseases whose definitive etiology is unknown. Following recent clinical and genetic evidence supporting an intertwined pathogenic relationship, we conducted a pilot study to measure fecal calprotectin (fCAL) and IBD-related serologies in AS patients.
Consecutive AS patients were recruited from a long-term prospectively collected longitudinal AS cohort at Cedars-Sinai Medical Center. Controls were recruited from Cedars-Sinai Medical Center employees or spouses of patients with AS. Sera were tested by ELISA for IBD-associated serologies (antineutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibody IgG and IgA, anti-I2, anti-OmpC, and anti-CBir1). The Bath Ankylosing Spondylitis Disease Activity Index, the Bath Ankylosing Spondylitis Functional Index, and the Bath Ankylosing Spondylitis Radiology Index were completed for AS patients.
A total of 81 subjects (39 AS patients and 42 controls) were included for analysis. The average age of AS patients was 47 years and the average disease duration was 22 years. AS patients were predominantly male; 76% were HLA-B27-positive. Median fCAL levels were 42 μg/g and 17 μg/g in the AS group and controls, respectively (P < 0.001). When using the manufacturer's recommended cutoff value for positivity of 50 μg/g, stool samples of 41% of AS patients and 10% of controls were positive for fCAL (P = 0.0016). With the exception of ANCA, there were no significant differences in antibody levels between patients and controls. Median ANCA was 6.9 ELISA units in AS patients and 4.3 ELISA units in the controls. Among AS patients stratified by fCAL level, there were statistically significant differences between patients and controls for multiple IBD-associated antibodies.
Calprotectin levels were elevated in 41% of patients with AS with a cutoff value for positivity of 50 μg/g. fCAL-positive AS patients displayed higher medians of most IBD-specific antibodies when compared with healthy controls or fCAL-negative AS patients. Further studies are needed to determine whether fCAL can be used to identify and characterize a subgroup of AS patients whose disease might be driven by subclinical bowel inflammation.