Biomedical subjects
H Mielants
Publications and source records attributed to H Mielants.
Crohn's disease associated with spondyloarthropathy: effect of TNF-alpha blockade with infliximab on articular symptoms.
Four patients with Crohn's disease and spondyloarthropathy were treated with infliximab for treatment-resistant gut inflammation. A substantial improvement in gastrointestinal signs and symptoms was noted, which was accompanied by a rapid reduction in C-reactive protein concentrations. Moreover, all four patients had a significant improvement of axial manifestations and/or peripheral arthritis, related to their spondyloarthropathy. This fast and substantial improvement of the articular manifestations of Crohn's disease after infliximab treatment warrants further investigation of the therapeutic potential of TNF-alpha blockade in other subtypes of spondyloarthropathies.
Chemical agents and enzymes used for the extraction of gut lymphocytes influence flow cytometric detection of T cell surface markers.
Chemical agents (DTT, EDTA) and enzymes (collagenase, DNAse) are often used for the generation of a single cell suspension from tissue samples. In this study, flow cytometry was used to examine the effect of chemical agents and enzymes on the expression of cell membrane markers of T lymphocytes from tonsils and peripheral blood. Expression of CD4, CD8, CD25, CD38, L-selectin, CD44, alphaEbeta7 and alpha4beta7 were studied. Incubation of lymphocytes with DTT and EDTA resulted in a decrease of CD38, alphaEbeta7 and alpha4beta7 expression. Incubation with collagenase A and DNAse resulted in a decrease of CD25, L-selectin, alphaEbeta7 and alpha4beta7. The results of this study indicate that a careful interpretation is necessary for phenotypic descriptions of lymphocyte populations obtained by enzymatic isolation techniques.
Opportunities for immune modulation in the spondyloarthropathies with special reference to gut inflammation.
The spondyloarthropathies (SpA) are a related group of disorders, characterized primarily by spondylitis, pauci-articular arthritis and enthesitis. The presence of subclinical gut inflammation in patients with SpA ranges from 25 to 75%, depending upon the type of SpA. Several data suggest that the association between gut inflammation and synovitis reflects an etiopathogenetic relationship, and that strategies which interfere with the gut inflammation may also modulate the synovitis. Here we review some standard as well as experimental drugs used in the treatment of patients with inflammatory bowel disease and discuss what is known about their effect on SpA-related locomotor manifestations. For the more experimental drugs, such as cytokines, anticytokines and anti-adhesion compounds, clinical trials in patients with SpA are still very scarce.
Focal up-regulation of E-cadherin-catenin complex in inflamed bowel mucosa but reduced expression in ulcer-associated cell lineage.
The E-cadherin-catenin complex is important for the maintenance of epithelial architecture. We studied its expression in Crohn disease, ulcerative colitis, acute ileitis, and controls. Immunohistochemical stainings for E-cadherin, alpha-catenin, beta-catenin and gamma-catenin were performed. E-cadherin messenger RNA (mRNA) was detected using riboprobes. In active inflammation, there was up-regulation of the complex. In particular, epithelium adjacent to ulcers showed increased expression of protein and mRNA, but in ulcer-associated cell lineage, the intensity of staining was weak to negative. In focal inflammation, up-regulation was found in affected areas. Reparative epithelium growing over denuded areas showed weaker expression. Since structural or functional perturbation in any of the molecules of the E-cadherin-catenin complex results in loss of intercellular adhesion, the preexistent epithelium may benefit from up-regulation to try to maintain its normal architecture under inflammatory conditions. Reduced expression in reparative epithelium and ulcer-associated cell lineage could facilitate the motility of these cells.
Non-Hodgkin's lymphoma presenting with spinal involvement.
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Comparative study of the synovial histology in rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: influence of disease duration and activity.
OBJECTIVES: To compare the macroscopic and microscopic characteristics of synovial tissue in rheumatoid arthritis (RA), spondyloarthropathy (SpA), and osteoarthritis (OA) after exclusion of possible biases induced by disease duration or activity, or both. METHODS: Synovial biopsy specimens were obtained by needle arthroscopy in patients with early RA (n=16), late RA (n=14), early SpA (n=23), and OA (n=12). Macroscopic and microscopic features were scored on a four point scale and analysed as a function of disease duration (early versus late RA), local and systemic disease activity, and diagnosis. RESULTS: Except for the maximal synovial lining thickness, no significant differences were seen between early and late RA. For disease activity, synovial histology was only weakly correlated with C reactive protein in RA, but seemed to be strongly dependent on effusion of the biopsied joint in all disease groups. After stratification for local disease activity, no disease related differences were found in patients without joint effusion. In contrast, important differences were found between patients with RA and SpA with active joint effusion. Synovial vascularity was macroscopically increased in SpA versus RA (p=0.017). A straight vessel pattern was only seen in RA, while tortuous vessels were preferentially seen in SpA. Vascularity was also microscopically increased in SpA compared with RA (p=0.031), and correlated with the macroscopic vascularity (r(s)=0.36, p=0.036). CD3+ (p=0.008), CD4+ (p=0.008), and CD20+ (p=0.024) lymphocytes were overrepresented in RA compared with SpA. The integrin expression in RA was characterised by a decrease of alphaVbeta3 in the synovial lining (p=0.006) and an increase of alphaVbeta5 in the sublining (p<0.001). CONCLUSIONS: The immune architecture of the synovial membrane is more dependent on local disease activity than on disease duration. Synovium obtained from clinically affected joints shows important histological differences between RA and SpA.
Subclinical gut inflammation in spondyloarthropathy patients is associated with upregulation of the E-cadherin/catenin complex.
OBJECTIVE: Previously an upregulation of E-cadherin and its associated molecules alpha-catenin, beta-catenin and plakoglobin has been demonstrated in clinically overt inflammatory bowel disease (IBD). The aim of this study was to investigate the expression of the E-cadherin/catenin complex in subclinically inflamed bowel mucosa from spondyloarthropathy (SpA) patients. METHODS: Ileal and colonic biopsy specimens from 19 SpA patients with subclinical inflammatory gut lesions and from seven controls were stained with monoclonal antibodies against E-cadherin, beta-catenin and plakoglobin and a polyclonal antibody against alpha-catenin. E-cadherin mRNA was detected using a riboprobe. Inflammation was histologically classified into acute, chronic active and chronic quiescent forms. RESULTS: In acute and chronic active bowel inflammation of SpA patients, upregulation of the E-cadherin/catenin glycoprotein complex could be observed. Chronic lesions in a quiescent state did not show such an upregulation. Furthermore, chronic inflammation was associated with an increase in E-cadherin mRNA. CONCLUSIONS: As some of the SpA patients with subclinical gut inflammation develop IBD, upregulation of the E-cadherin/catenin complex in inflamed bowel mucosa from SpA patients may point to early cellular changes in the development of IBD. However, at present it cannot be excluded that increased E-cadherin/catenin complex expression is a bystander phenomenon of active inflammation.
Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha (infliximab) in spondyloarthropathy: an open pilot study.
OBJECTIVE: To evaluate the efficacy and safety of a loading dose regimen of three intravenous infusions with infliximab in patients with active spondyloarthropathy. METHODS: A monocentre, open-label pilot study of 21 patients with different subtypes of spondyloarthropathy was conducted. Treatment resistant patients with active disease (fulfilling inclusion criteria) received three infusions of 5 mg/kg infliximab (at weeks 0, 2, and 6). Standard clinical assessments were performed at baseline, and on days 3, 7, and 14, and from then on every two weeks. In patients who fulfilled criteria for ankylosing spondylitis, axial assessment was performed at baseline and on days 14, 42, and 84. RESULTS: In all global assessments (visual analogue scale of patient global assessment, patient pain assessment, doctor global assessment), erythrocyte sedimentation rate, and C reactive protein, a highly significant decrease could be seen already at day 3 (compared with baseline), which was maintained up to day 84. In patients with peripheral disease (n=18), tender and swollen joint count significantly decreased. In patients with axial disease (n=11), functional and disease activity indices significantly improved. Moreover in eight patients with psoriatic arthritis a significant decrease of the psoriasis area and severity index was observed. The treatment was well tolerated in all patients; no significant adverse events were seen. CONCLUSION: In this open-label pilot study of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha in patients with active spondyloarthropathy, there was a fast and significant improvement of axial and peripheral articular manifestations, without major adverse experiences.
The zygapophyseal joint determines morphology of the enthesophyte.
OBJECTIVE: To determine the contribution of zygapophyseal joint ankylosis on the morphology of the spinal enthesophyte. METHODS: Radiographic analysis of lumbar spine in ankylosing spondylitis (AS) patients with different types of enthesophytes. Computerized axial tomographic analysis of the zygapophyseal (ZA) joints of the lumbar spine of AS patients with chunky enthesophytes and bridging syndesmophytes. RESULTS: Four patients with AS were selected for the simultaneous presence of chunky enthesophytes and bridging syndesmophytes. At the levels with bridging syndesmophytes at least one ZA joint was ankylosed. At the levels with chunky enthesophytes alone the ZA joints were not ankylosed. CONCLUSION: The morphology of the enthesophytes is influenced by the presence of ankylosis in the ZA joint.
Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association.
OBJECTIVE: To determine the overall prevalence of spondyloarthropathy (SpA) among patients with inflammatory bowel disease (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)]. METHODS: One hundred three consecutive patients with IBD from a gastroenterology unit were questioned and examined for SpA symptoms. Patients previously diagnosed with SpA were excluded. All patients were questioned and examined for SpA symptoms such as inflammatory back pain, joint swelling, enthesitis, and psoriasis or a specific family history. Radiographs were taken of all sacroiliac joints. HLA loci A, B, C, and DR were determined in all patients. RESULTS: Thirty-nine percent of the patients with IBD had clinical articular manifestations: 30% had inflammatory back pain, 10% had synovitis, and 7% had a peripheral enthesopathy. The majority (90%) of patients with rheumatic complaints fulfilled the classification criteria for SpA and 10% fulfilled the criteria for ankylosing spondylitis. Asymptomatic sacroiliitis was found in an additional 18% of the patients. Moreover, sacroiliitis, symptomatic or asymptomatic, was related to the disease duration. HLA-B27 conferred an additional risk for inflammatory low back pain in patients with IBD. CONCLUSION: Articular involvement in IBD can be classified as SpA. The appearance of SpA occurs irrespective of the extent of the bowel disease. Moreover, asymptomatic sacroiliac involvement is a common manifestation in IBD and it is related to disease duration, suggesting evidence for a related pathogenic mechanism.
Polyarteritis nodosa mimicking polymyalgia rheumatica.
We report a case of polyarteritis nodosa with a clinical presentation mimicking polymyalgia rheumatica, as well as pathological findings of non-giant-cell arteritis on temporal artery biopsy with symptoms of jaw claudication. Although certain clinical syndromes have been attributed to specific types of systemic vasculitis, considerable overlap occurs. Obtaining tissue biopsy in cases of vasculitis is mandatory for diagnosis and classification.
Candida glabrata arthritis: case report and review of the literature of Candida arthritis.
We report a case of arthritis due to Candida (Torulopsis) glabrata in two different joints at different times in the same patient. The first episode of arthritis was situated in the right ankle and lasted more than 1 year before the patient agreed to the proposed treatment. Therapy with intravenous amphotericin B and oral fluconazole failed. A cure was achieved with weekly intra-articular administration of amphotericin B, which was continued for more than 20 weeks and combined with oral itraconazole. Several weeks later the patient developed Candida glabrata arthritis of the left knee while still taking itraconazole. Immediately, intravenous amphotericin B therapy was started and was successful. Because there were no previous invasive point manipulations or trauma, the infections were considered to be haematogenously disseminated. Chronic corticosteroid and repeated antibiotic therapy for infectious exacerbations of chronic obstructive pulmonary disease and alcohol abuse are the presumed risk factors in this otherwise immunocompetent patient.
Defining disease activity in ankylosing spondylitis: is a combination of variables (Bath Ankylosing Spondylitis Disease Activity Index) an appropriate instrument?
OBJECTIVE: Disease activity has been defined using a self-administered instrument, focusing on fatigue, axial pain, peripheral pain, enthesopathy and morning stiffness [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)]. This validated instrument is simple and takes 40 s to complete, but whether the index is an accurate expression of the component parts, or whether additional weighting would enhance its efficacy, is unclear. METHODS: Four hundred and seventy-three patients with ankylosing spondylitis received placebo or active non-steroidal anti-inflammatory drug (NSAID) for 6 weeks, and changes between entry and completion were captured by BASDAI and the individual components. Principle component analysis (PCA) was used to explore the best combinations of variables in decreasing order of explained total dispersion and to assess whether a single sum (or algebraic expression) best defined disease activity status. RESULTS: At entry, the correlation between BASDAI and the first axis was 0.99, 0.11 with the second, and zero thereafter. Data at study end and relating to change revealed a 100% correlation (R = 1) between the first axis and the sum, with zero for the remainder. CONCLUSIONS: The data support BASDAI as being a valid and appropriate composite to define disease activity in ankylosing spondylitis. Developed as a simple sum of its components, BASDAI has excellent content validity.
A comparative study of the usefulness of the Bath Ankylosing Spondylitis Functional Index and the Dougados Functional Index in the assessment of ankylosing spondylitis.
To determine whether the Bath Ankylosing Spondylitis Functional Index (BASFI, score 0-10) or Dougados Functional Index (DFI, score 0-40) is superior in measuring physical function in ankylosing spondylitis (AS) we studied 191 consecutive outpatients with AS in the Netherlands, France, and Belgium. The participating centers are secondary and tertiary referral centers. The external criterion for disease activity (DA) was: both patient and physician assessment of disease activity on a visual analog scale (VAS) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The external criterion for damage was 2 radiological scores of the spine; BASRI-s (Bath Ankylosing Spondylitis Radiology Index-spine) and a modified SASSS (Stoke Ankylosing Spondylitis Spine Score). Median scores for BASFI and DFI were 2.5 (range 0-10) and 8.5 (range 0-35), respectively. Spearman correlation coefficient between both indexes was 0.89. The average correlation with disease activity variables was 0.42 for BASFI and 0.41 for DFI. For both BASFI and DFI the correlation with BASRI-s was 0.42 and with SASSS 0.36. When distinguishing between patients with high and low disease activity, sensitivity for both indexes was between 76 and 94%, while specificity was between 66 and 87% for all 3 DA measures. Average misclassification between BASFI, DFI and DA was 23 and 27%, respectively. Both BASFI and DFI correlate equally well with disease activity and damage.
Outcome variables in ankylosing spondylitis: evaluation of their relevance and discriminant capacity.
The clinical status of ankylosing spondylitis (AS) can be defined by several domains (e.g., pain, function, metrology, laboratory) and subcomponents within each domain (e.g., pain using visual analog scale, Schober's within metrology). Our aim was (1) To define groups of highly correlated variables in order to determine the most relevant; and (2) to evaluate the capacity of different clinical and biological variables that best discriminate between placebo and active nonsteroidal drugs in AS. Patients with active AS (n=423) were followed prospectively over 6 weeks while receiving placebo (n=121) or active nonsteroidal antiinflammatory drugs (n=352). Eighteen variables were studied, including global assessment, pain, stiffness, functional indices, metrology, disease activity index, and laboratory markers. Statistics included (1) Evaluation of the relevance of the different domains by multivariate analysis (CART tree-structure classification; variable clustering); and (2) evaluation of the discriminant capacity by univariate analysis [i.e., differences in the standardized response mean (SRM) (mean change/SD) between placebo and active drug. A value > or =0.60 was considered relevant]. Four clusters were identified (patient's subjective perception, inflammatory symptoms, metrology, laboratory data) with multiple correlation R2 revealing the most relevant variables to be the Bath Ankylosing Spondylitis Functional Index (BASFI; 0.75), night pain (0.62), Schober's test (0.58), and platelet count (0.55), respectively, within each cluster. In terms of discriminant power (SRM) the patient perceived global status (0.84), lumbar pain (0.73), night pain (0.71), physician global assessment (0.66), and BASFI (0.65) were most relevant in the univariate analysis. Among the 4 most relevant domains are subjective perception, inflammatory symptoms, metrology, and laboratory. Multivariate analysis of the data reveals that the spinal pain and the patient global assessment are the variables that best discriminate between placebo and active nonsteroidal drug in short term studies.
Relative value of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis.
Our aim was to determine whether C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) is more appropriate in measuring disease activity in ankylosing spondylitis (AS). We studied 191 consecutive outpatients with AS in The Netherlands, France, and Belgium. Patients were attending secondary and tertiary referral centers. The external criterion for disease activity was: physician and patient assessment of disease activity on a visual analog scale (VAS) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). In each measure we defined 3 levels of disease activity: no activity, ambiguous activity, and definite disease activity. The patients with AS (modified New York criteria) were divided into 2 groups: those with spinal involvement only (n=149) and those who also had peripheral arthritis and/or inflammatory bowel disease (IBD) (n=42). For each criterion of disease activity, the patients with no activity and with definite activity were included in receiver operator curves and used to determine cutoff values with the highest sensitivity and specificity. We also calculated Spearman correlations. The median CRP and ESR were 16 mg/l and 13 mm/h, respectively, in the spinal group and 25 mg/l and 21 mm/h, respectively, in the peripheral/IBD group. In both groups the Spearman correlation coefficients between CRP and ESR were around 0.50. There was moderate to poor correlation between CRP, ESR, and the 3 disease activity variables (0.06-0.48). Sensitivity for both ESR and CRP was 100% for physician assessment and between 44 and 78% for patient assessment of disease activity and the BASDAI, while specificity was between 44 and 84% for all disease activity measures. The positive predictive values of CRP and ESR in our setting were low (0.15-0.69). We conclude that neither CRP nor ESR is superior to assess disease activity.
Radiological scoring methods in ankylosing spondylitis: reliability and sensitivity to change over one year.
Our aim was to compare reliability and sensitivity to change of different radiological scoring methods in ankylosing spondylitis (AS). Two trained observers scored 30 AS radiographs twice with an interval of 4 weeks. The same two observers scored 187 AS radiographs in pairs, at baseline and after one year followup, to measure change and agreement on change. The sacroiliac (SI) joints were scored in 5 grades by the New York method and the SASSS (Stoke Ankylosing Spondylitis Spine Score). Hips were graded 0-5 (according to Larsen). Cervical and lumbar spine were graded (0-4, Bath Ankylosing Spondylitis Radiological Index, BASRI), and scored in detail (0-72, SASSS). SASSS of the cervical and lumbar spine scored on the anterior sites of the vertebrae proved most reliable, with both intra and interobserver intraclass correlation coefficients (ICC) between 0.87 and 0.97. BASRI was only moderately reliable, with Cohen's kappa ranging between 0.50 and 0.82 for intra, and 0.38-0.64 for interobserver reliability. Similarly, SI joint scores (New York, SASSS) showed intraobserver kappa between 0.56 and 0.84, and interobserver reliability with kappa between 0.37 and 0.47. Larsen hip scores proved unreliable: moderate intraobserver kappa of 0.47-0.58 and low interobserver kappa of 0.29. After retraining, interobserver kappa did not improve (0.45 and 0.17). In retrospect, a one year period was too short to measure sensitivity to change. Observers agreed that no change occurred in up to 89% of cases. A measurable change of deterioration or improvement occurred rarely. We conclude that in AS, only the SASSS method for the spine and the BASRI reached good reliability. Other methods for spine, SI joints, and hips were moderately reliable at best. There was moderate to good agreement on no change between the observers. No method showed change over a period of one year in a considerable number of patients.