Neutrophil-elastase in chronic inflammatory bowel disease: a marker of disease activity?

BACKGROUND/AIMS: Neutrophil elastase is a proteinase which exists in granulocytes and plays an important role in the pathogenesis of inflammatory disorders. In inflammatory bowel disease there is a leukocyte infiltration of the bowel mucosa. The purpose of this study was to examine whether plasma elastase represents a reliable laboratory marker for establishing the activity of chronic inflammatory bowel disease. METHODOLOGY: We measured plasma elastase concentrations in 61 patients suffering from either Crohn's disease or ulcerative colitis and compared these data with other clinical and laboratory findings and with elastase concentrations in 40 healthy controls. The sensitivity and specificity of the elastase values in chronic IBD were calculated with the use of concomitant measurements of CRP and ESR. RESULTS: Plasma levels were found to be significantly higher in patients (49 micrograms/l) compared with healthy controls (23 micrograms/l). Patients with active disease had higher plasma levels than patients in remission. In general, the sensitivity of elastase to detect active inflammatory bowel disease was about 60%; the specificity was 65%. For patients in remission, the sensitivity was higher than 80%. However, there was a wide range of overlapping values between chronic inactive patients and those with moderately active disease. CONCLUSIONS: We conclude that plasma elastase is a useful independent marker of disease activity in inflammatory bowel disease. Especially for identifying patients in remission, the measurements of elastase seem to be more suitable than other parameters of inflammation, like CRP or ESR.     

Disease activity assessment in ankylosing spondylitis in a Chinese cohort: BASDAI or ASDAS?

Recently, the Ankylosing Spondylitis Disease Activity Score (ASDAS), a new index, has been shown to be validated and highly discriminatory in assessing ankylosing spondylitis (AS) disease activity. This study is to evaluate the performance of ASDAS in a local Chinese cohort of AS in a cross-sectional setting and to compare it with the existing instrument, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Consecutive patients with AS were recruited from a local rheumatology clinic. Data, including BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), Visual Analogue Scale (VAS) for spinal pain, and patient and physician global assessments were gathered during clinic visit. Inflammatory markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and high-sensitivity (hs)-CRP were collected. ASDAS was calculated accordingly. The discriminatory capacity of BASDAI and ASDAS was compared by: (1) standardized mean difference statistics, (2) R ² in linear regressions, and (3) area under receiver operating characteristic curve (AUC) in logistic regression models. Both ASDAS and BASDAI showed satisfactory predictive value on disease activity with reference to patient and physician global assessment. R ² in linear regression models ranged from 0.6–0.7. Both indices also demonstrated good discriminatory capacity as evidenced by a relatively high AUC (> 0.8) under the logistic regression models using either patient or physician global assessment score ≥4 and <4 as cut off of high and low disease activity status, respectively. Although we could not demonstrate significant differences in the performance between them, subgroup analysis suggested better discriminatory ability of ASDAS in the high inflammatory marker subgroup. ASDAS and BASDAI showed similarly good performance in a cross-sectional setting in a local Chinese AS cohort. ASDAS performed better in subgroup with raised inflammatory markers.     

Is disease severity in ankylosing spondylitis genetically determined?

OBJECTIVE: To assess the role of genes and the environment in determining the severity of ankylosing spondylitis. METHODS: One hundred seventy-three families with >1 case of ankylosing spondylitis were recruited (120 affected sibling pairs, 26 affected parent-child pairs, 20 families with both first- and second-degree relatives affected, and 7 families with only second-degree relatives affected), comprising a total of 384 affected individuals. Disease severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and functional impairment was determined using the Bath Ankylosing Spondylitis Functional Index (BASFI). Disease duration and age at onset were also studied. Variance-components modeling was used to determine the genetic and environmental components contributing to familiality of the traits examined, and complex segregation analysis was performed to assess different disease models. RESULTS: Both the disease activity and functional capacity as assessed by the BASDAI and the BASFI, respectively, were found to be highly familial (BASDAI familiality 0.51 [P = 10(-4)], BASFI familiality 0.68 [P = 3 x 10(-7)]). No significant shared environmental component was demonstrated to be associated with either the BASDAI or the BASFI. Including age at disease onset and duration of disease as covariates made no difference in the heritability assessments. A strong correlation was noted between the BASDAI and the BASFI (genetic correlation 0.9), suggesting the presence of shared determinants of these 2 measures. However, there was significant residual heritability for each measure independent of the other (BASFI residual heritability 0.48, BASDAI 0.36), perhaps indicating that not all genes influencing disease activity influence chronicity. No significant heritability of age at disease onset was found (heritability 0.18; P = 0.2). Segregation studies suggested the presence of a single major gene influencing the BASDAI and the BASFI. CONCLUSION: This study demonstrates a major genetic contribution to disease severity in ankylosing spondylitis. As with susceptibility to ankylosing spondylitis, shared environmental factors play little role in determining the disease severity.     

Is disease severity in ankylosing spondylitis genetically determined?

Objective

To assess the role of genes and the environment in determining the severity of ankylosing spondylitis.

Methods

One hundred seventy‐three families with >1 case of ankylosing spondylitis were recruited (120 affected sibling pairs, 26 affected parent–child pairs, 20 families with both first‐ and second‐degree relatives affected, and 7 families with only second‐degree relatives affected), comprising a total of 384 affected individuals. Disease severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and functional impairment was determined using the Bath Ankylosing Spondylitis Functional Index (BASFI). Disease duration and age at onset were also studied. Variance‐components modeling was used to determine the genetic and environmental components contributing to familiality of the traits examined, and complex segregation analysis was performed to assess different disease models.

Results

Both the disease activity and functional capacity as assessed by the BASDAI and the BASFI, respectively, were found to be highly familial (BASDAI familiality 0.51 [P = 10⁻⁴], BASFI familiality 0.68 [P = 3 × 10⁻⁷]). No significant shared environmental component was demonstrated to be associated with either the BASDAI or the BASFI. Including age at disease onset and duration of disease as covariates made no difference in the heritability assessments. A strong correlation was noted between the BASDAI and the BASFI (genetic correlation 0.9), suggesting the presence of shared determinants of these 2 measures. However, there was significant residual heritability for each measure independent of the other (BASFI residual heritability 0.48, BASDAI 0.36), perhaps indicating that not all genes influencing disease activity influence chronicity. No significant heritability of age at disease onset was found (heritability 0.18; P = 0.2). Segregation studies suggested the presence of a single major gene influencing the BASDAI and the BASFI.

Conclusion

This study demonstrates a major genetic contribution to disease severity in ankylosing spondylitis. As with susceptibility to ankylosing spondylitis, shared environmental factors play little role in determining the disease severity.

     

Interleukin-6 serum concentration in ankylosing spondylitis: a reliable predictor of disease progression in the subsequent year?

The aim of the present study was to evaluate whether in ankylosing spondylitis (AS), interleukin-6 (IL-6) is a reliable predictor of changes in mobility in the subsequent year. Of 261 AS patients who had been enrolled in a previous study, 128 returned for treatment at our health centre after 1 year (±3 months). The variables for mobility after 1 year (II) were compared with the findings of the previous year (I). Differences in parameters for mobility were related to the serum concentration of IL-6 in the previous year. Relation between serum concentration of IL-6 and difference (II–I) in occiput-to-wall distance (Spearman's rank correlation coefficient r _s, P value) was 0.02, 0.82; chin–chest distance −0.09, 0.31; cervical rotation −0.08, 0.39; chest expansion 0.05, 0.54; finger–floor distance −0.02, 0.84; Ott sign (flexibility of the thoracic spine) −0.11, 0.22; Schober sign 0.01, 0.94. After 1 year there was a significant improvement in cervical rotation in patients with low IL-6 serum concentration (lower quartile), but not in those with high levels of IL-6 (upper quartile). No further difference was seen between patients with high or low levels of IL-6. The present data suggest that the serum concentration of IL-6 does not allow a prediction of disease progression in the subsequent year. Received: 15 September 1999 / Accepted: 20 January 2000     

Juvenile ankylosing spondylitis—is it the same disease as adult ankylosing spondylitis?

Objectives Juvenile and adult forms of ankylosing spondylitis (AS) have been shown to have different clinical presentation and outcome in Caucasians. We did this retrospective analysis to see if similar differences exist in the Indian population.Patients and methods Case records of 210 Indian patients diagnosed with AS according to modified New York criteria were reviewed. Data were collected regarding age of onset, clinical features, drug treatment, and outcome at last follow-up. Patients with onset before 17 years of age were classified as having juvenile AS (JAS) and the rest with adult AS (AAS).Results There were 150 patients with AAS and 60 with JAS. The latter had higher male preponderance, more frequent onset with peripheral arthritis, and greater involvement of hip and knee joints. Valvular dysfunction was seen only in patients with JAS.Conclusion In this group of subjects, juvenile AS had onset more often with oligoarthritis and enthesitis than with spinal disease. Hip and knee joint involvement was more common in JAS than AAS.     

B2 microglobulin: is it a reliable marker of activity in inflammatory bowel disease?

OBJECTIVES: The aims of this study were to investigate a possible positive correlation between B2-microglobulin (B2-M) serum levels and the severity and activity of inflammatory bowel disease (IBD); and to examine whether B2-M levels reflect IBD extent. METHODS: We examined B2-M serum levels in 87 ulcerative colitis (UC) patients, 74 with Crohn's disease (CD) and 68 control subjects, using an enzymatic method. The reliability of the measuring method was assessed by evaluating serum B2-M in 18 patients suffering from chronic renal failure (CRF). The severity and activity of IBD was estimated using the van Hees Activity Index and the True-love-Witts criteria for CD and UC patients respectively. Endoscopic evaluation for UC patients was done according to Baron's et al. classification; Riley's et al. criteria were used for histological evaluation. RESULTS: B2-M serum levels were significantly increased in all CD patients except those in remission. After 6 months treatment a second blood sample taken from CD patients with initially elevated B2-M levels proved to be compatible with CD severity at that time. Such a positive correlation was not assessed in UC patients; therefore, a second blood sample was considered unnecessary. Furthermore, CD patients with pancolitis, ileal-caecal, or small intestinal disease had higher B2-M levels than those with left-sided, anal, or perianal disease. CONCLUSIONS: B2-M serum levels could prove to be a useful marker in assessing not only the activity, severity, and extent of CD but the treatment efficacy as well.     

Concordance of disease severity among family members with ankylosing spondylitis?

OBJECTIVE: The heritability of disease activity and function in ankylosing spondylitis (AS) have been estimated at 0.51 and 0.63 (i.e., 51% and 63%), respectively. We examined the concordance of disease severity among family members in terms of disease activity, function, radiological change, prevalence of iritis, and juvenile onset. METHODS: Disease activity and functional impairment due to AS were studied using the Bath AS Disease Activity Index (BASDAI) and Functional Index (BASFI) self-administered questionnaires; radiographic involvement was measured using the Bath AS Radiology Index (BASRI) scale. Familial correlation of BASDAI and BASFI was assessed in 406 families with 2 or more cases, using the program PAP. Parent-child and sibling-sibling concordance for iritis and juvenile AS were also studied in these families. Heritability of radiological disease severity based on the BASRI was assessed in 29 families containing 60 affected individuals using the program SOLAR. RESULTS: Correlations between parent-child pairs for disease activity and function were 0.07 for both. Correlations between sibling pairs for disease activity and function were 0.27 and 0.36, respectively. The children of AS parents with iritis were more likely to develop iritis [27/71 (38%)] than children of non-iritis AS parents [13/70 (19%)] (p = 0.01). Parents with JAS were more likely to have children with JAS [17/30 (57%) compared to non-JAS parents 34/111 (30%)] (p = 0.002). The heritability of radiological disease severity based on the BASRI was 0.62. CONCLUSION: While correlation in severity between parent and child is poor, siblings do resemble each other in terms of severity, supporting the findings of segregation studies indicating significant genetic dominance in the heritable component of disease activity. Significant parent-child concordance for iritis and juvenile disease onset suggest that there are genetic risk factors for these traits independent of those determining the risk of AS itself. The finding of significant heritability of radiological change (BASRI) provides support using an objective measure for the observed heritability of the questionnaire-assessed disease severity scores, BASDAI and BASFI.     

Cardiovascular involvement in Crohn’s disease in the absence of ankylosing spondylitis

We describe a patient who had aortic regurgitation associated with Crohn’s disease in the absence of ankylosing spondylitis. Aortitis and aortic insufficiency are fairly uncommon in Crohn’s disease. The patient required aortic valve replacement because of severely uncoated cusps secondary to inflammation of the aortic wall and aortic valve. There was a saccular formation just above the right non-coronary commissure. This sac was closed with a pericardial patch. Pledgeted sutures were used for implantation of the prosthetic valve to avoid periprosthetic leakage. The right coronary ostium had narrowed due to aortic wall thickening. A right internal thoracic artery to right coronary artery bypass was done since there was no necessity for proximal anastomosis.     

Disease activity in longstanding ankylosing spondylitis—a correlation of clinical and magnetic resonance imaging findings

We evaluated magnetic resonance imaging (MRI) changes in ankylosing spondylitis (AS) patients with longstanding disease and investigated whether there is any relationship between MRI findings and validated methods of disease assessment. A total of 34 AS patients with disease duration greater than 10 years were included in this observational cross-sectional study (26 men, 8 women). The main outcome measures were Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Global assessment (BASG), Bath Ankylosing Spondylitis Metrology Index (BASMI), MRI of the thoracic and lumbar spine (AS spi MRI A) and measurement of serum erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), plasma viscosity (PV) and immunoglobulin A (Ig A). The median scores for the acute lesions based on AS spi MRI A scoring system was 2.5 (0–4.12). The respective mean ESR and CRP were 36 (SD, 24.00) mm/h and 14.19 (SD, 24.00) mg/l with the median PV of 1.8 (1.75–1.87). The median BASG, BASFI and BASDAI were 4.55 (2.37–5.55), 4.40(2.31–5.47) and 4.32 (3.07–6.48), respectively. No significant correlations were found between the acute MRI scores and each of the clinical instruments and laboratory markers of inflammation. In this study, majority of AS patients with longstanding disease had very low AS spi MRI A scores or no evidence of spinal inflammatory lesions. Our study would suggest that MRI should be used along with other measures of disease activity in the assessment of symptomatic AS patients with longstanding disease.     

Is there a preferred method for scoring activity of the spine by magnetic resonance imaging in ankylosing spondylitis?

This report summarizes the discussion during a module update at OMERACT 8 on scoring methods for activity in the spine on magnetic resonance imaging. The conclusion was that the 3 available scoring methods are all very good with respect to discrimination and feasibility: the Ankylosing Spondylitis spine MRI score for activity (ASspiMRI-a), the Berlin method (a modification of the ASspiMRI-a), and the Spondyloarthritis Research Consortium of Canada Magnetic Resonance Imaging Index for Assessment of Spinal Inflammation in AS (SPARCC). All 3 methods were judged to be similar with respect to responsiveness and discrimination, although the differences in between-reader intraclass correlation coefficients (ICC) were judged to be relevant (the SPARCC method provided consistently higher ICC). The Berlin and SPARCC methods were preferred most frequently. The development of a new method combining the best elements of all methods is an additional possibility.     

Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis?

Objective

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.

Methods

Overall, 502 AS patients were examined, consisting of 312 patients who had first‐degree relatives (FDRs) with AS (familial) and 190 patients who had no FDRs with AS or spondylarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York criteria for AS. The patients were recruited from 2 US cohorts (the North American Spondylitis Consortium and the Prospective Study of Outcomes in Ankylosing Spondylitis) and from the UK‐Oxford cohort. The frequencies of AS susceptibility loci in IL‐23R, IL1R2, ANTXR2, ERAP‐1, 2 intergenic regions on chromosomes 2p15 and 21q22, and HLA–B27 status as determined by the tag single‐nucleotide polymorphism (SNP) rs4349859 were compared between familial and sporadic cases of AS. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size.

Results

HLA–B27 was significantly more prevalent in familial than sporadic cases of AS (odds ratio 4.44 [95% confidence interval 2.06, 9.55], P = 0.0001). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend toward 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.

Conclusion

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–major histocompatibility complex susceptibility loci is not markedly different between the sporadic and familial cases of AS.     

Does physical therapy still have a place in the treatment of ankylosing spondylitis?

PURPOSE OF REVIEW: To review studies of various physical therapy programs in ankylosing spondylitis and identify their benefits and potential indications in the treatment of this disease. RECENT FINDINGS: Various exercise and physical therapy programs have been evaluated in clinical studies. Home exercise programs have been shown to improve symptoms, mobility, function and overall quality of life. Formal physical therapy under the supervision of a physical therapist has been shown to improve posture, fitness, mobility, function and mood. Water therapy may improve symptoms, function and overall sense of health. Inpatient rehabilitation may provide rapid short-term improvement in pain and stiffness, mobility, function and quality of life for patients with severe active disease. SUMMARY: Despite the advances in the pharmacological therapy of ankylosing spondylitis, physical therapy remains an essential part of the management plan. Even though data are not sufficient to determine which specific physical therapy program should be recommended, physicians should implement such nonpharmacological therapy as part of a comprehensive management strategy for this disease. All patients should receive instructions on proper posture and home exercises and be encouraged to perform water exercises if they can. Formal physical therapy and, in most severe cases, inpatient rehabilitation may be of benefit to select patients with ankylosing spondylitis.     

High-frequency sensorineural hearing loss in patients with ankylosing spondylitis: is it an extrarticuler feature of disease?

Objective The aim of this study was to investigate the ear involvement, especially at extended higher frequencies than those previously studied, in patients with ankylosing spondylitis (AS). Patients and methods We prospectively evaluated 45 consecutive patients with AS. All patients underwent a complete physical examination of the ear, nose, and throat and an audiologic evaluation that included pure-tone audiometry at conventional and extended high frequencies, the determination of a speech discrimination score and the uncomfortable loudness level, and impedance audiometry. Thirty healthy volunteers were included as controls. Results The mean age of the patients was 39.6 ± 9.1 years (range 19–63 years) and that of the controls was 10.6 ± 8.1 years (range 1–30 years). There was no statistically significant difference between the two groups with respect to conventional frequency air conduction threshold and bone conduction threshold. There was a statistically significant difference at 14,000–16,000 Hz at extended high frequencies in 32 patients with AS (71.1%) versus 12 controls (40%). At 14,000–16,000 Hz, eight patients demonstrated a sensorineural hearing loss caused by extraspinal involvement. There was a significant difference between the patients with or without extraspinal involvement, and a positive correlation was noted between the duration of disease and the hearing level at 10,000–16,000 Hz. Conclusion Sensorineural hearing loss, especially at extended high frequencies, is common in patients with AS and may be an extra-articular feature of that disease. A long duration of disease and extraspinal involvement are important parameters for ear involvement in patients with AS.