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Biomedical subjects

D O Clegg

Publications and source records attributed to D O Clegg.

At least 19 recordsLinked to original sources
PubMed2005

Psoriatic arthritis therapy: NSAIDs and traditional DMARDs.

Non-steroidal anti-inflammatory drugs (NSAIDs) and traditional disease modifying antirheumatic drugs (DMARDs) are widely used in the treatment of psoriatic arthritis (PsA), but this is based more upon clinical experience than adequate evidence from clinical trials. This report summarises the results from available trials highlighting evidence of efficacy and deficiencies with respect to effect on joints and to a lesser degree cutaneous disease. The available published data on efficacy of NSAIDs, glucocorticoids, antimalarials, sulfasalazine, gold, methotrexate, azathioprine, and ciclosporin are detailed, as well as new data on leflunomide and other novel agents. The conclusions of this review are that evidence supports marginal efficacy of sulfasalazine and perhaps gold in the treatment of peripheral psoriatic arthropathy, and methotrexate and ciclosporin are effective for treating the skin disease although evidence for improvement of the arthropathy is empirical at best. New trials with standardised and validated outcome measures are required to better assess efficacy. Evaluating newer agents, against and in combination with traditional DMARDS, may further clarify the latter's role in the future management of this condition.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Psoriatic arthritis: epidemiology, clinical features, course, and outcome.

Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population. The clinical features described initially are recognised by most experienced clinicians, although they are most distinct in early disease. Initially, PsA typically presents as an oligoarticular and mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at least 20% of patients. Patients with PsA who present with polyarticular disease are at risk for disease progression. In addition to progression of clinical and radiological damage, health related quality of life is reduced among patients with PsA. It important to note that patients included in recent drug trials resemble patients followed prospectively in a clinic.

Adult↗
PubMed2001

Laminin-5 promotes neurite outgrowth from central and peripheral chick embryonic neurons.

Laminin-5 (Ln-5) is an essential component of epithelial basal laminae that is also expressed in the developing nervous system. Here we use a convenient, simple and reproducible in vitro fluorescent assay to assess the neurite outgrowth promoting activity of purified Ln-5. Embryonic chick neurons from dorsal root ganglia, ciliary ganglia, and (to a lesser extent) retina extended neurites on Ln-5, but the neurite outgrowth promoting activity was not as great as that of Ln-1 or Ln-2. Neurons from diencephalon, telencephalon, and spinal cord did not respond to Ln-5.

Animals↗
PubMed2001

A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases.

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

Alleles↗
PubMed2000

Imaging and mapping heparin-binding sites on single fibronectin molecules with atomic force microscopy.

Fibronectin is composed of multiple homologous repeats and contains many functional domains. Two major heparin-binding domains have previously been identified: the Hep I site near the amino terminus and the Hep II site near the carboxyl terminus. The Hep II site has been considered the high-affinity heparin-binding site based on studies of fibronectin fragments. However, few studies have been carried out on heparin binding by intact fibronectin. We imaged single fibronectin molecules as well as heparin-coated gold particles bound to whole dimeric plasma fibronectin molecules with tapping mode atomic force microscopy. We observed heparin-gold particles preferentially bound at two locations that correspond to the Hep I and Hep II sites. Quantitative analysis of images of individual fibronectin-heparin-gold complexes showed that almost twice as many heparin-gold particles bound to the N-terminal Hep I site compared to the Hep II site. In contrast to previous findings with fibronectin fragments, these results suggest that the Hep I site has a binding affinity higher than or comparable to the Hep II site in the intact fibronectin molecule.

Animals↗
PubMed2000

Adhesive events in retinal development and function: the role of integrin receptors.

Cells in the developing retina contact a vast array of molecular cues in their microenvironment that are thought to guide their development. Many of these cues are embedded in the surface of neighboring cells or deposited within the extracellular matrix (ECM). Evidence has accumulated that cell-cell and cell-ECM interactions are essential in many phases of neural development, including neuroblast migration, determination of cell fate, axon outgrowth and synapse formation. In this chapter, we examine the developmental and functional roles fulfilled by integrins, a family of receptors for ECM molecules and cell adhesion molecules (CAMs). We have approached this problem by addressing a series of three questions: (1) which integrins are expressed in developing retina? (2) when and where are they expressed? and, (3) what functions do they carry out? Integrins have previously been implicated in axon extension, but new evidence suggests that they are also involved in earlier developmental events in preaxonal neuroblasts. High levels of expression of at least eight integrin subunits have been documented in these young retinal cells, and integrins containing the beta 1 subunit have been implicated in migration of adolescent retinal ganglion cells. Integrin expression persists through adulthood, both in the retina and in the neighboring layer of the retinal pigment epithelium (RPE). The integrin alpha v beta 5 has been shown to reside on the apical surface of the RPE and has been implicated in the phagocytosis of shed photoreceptor outer segments.

Animals↗
PubMed1999

Imaging real-time proteolysis of single collagen I molecules with an atomic force microscope.

The dynamic process of synthesis and degradation of extracellular matrix molecules, including various collagens, is important in normal physiological functions and pathological conditions. Existing models of collagen enzymatic degradation reactions are derived from bulk biochemical assays. In this study, we have imaged in real-time individual collagen I molecules and their proteolysis by Clostridium histolyticum collagenases in phosphate-buffered saline (PBS) with atomic force microscopy (AFM). We have also imaged the likely binding and unbinding of collagenase molecules to single triple-helical collagen I molecules and subsequent proteolysis of subsets of the collagen molecules. The proteolysis of collagen molecules was inhibited by reduced calcium and acidification. Results from AFM study of collagen proteolysis are consistent with SDS-PAGE biochemical assays. The real-time proteolysis of single collagen I molecules followed simple Michaelis-Menton kinetics previously derived from bulk biochemical assays. This is the first report of imaging real-time proteolysis of single macromolecules and its inhibition on a molecular scale. A strong correspondence between the kinetics of proteolysis of single collagen molecules and the kinetics of proteolysis derived from bulk biochemical assays will have a wide applicability in examining real-time enzymatic reactions and their regulation at single molecule structural level. Such real-time study of single molecule proteolysis could provide a better understanding of the interactions between proteases and target proteins as well as proteases and protease inhibitors.

Aluminum Silicates↗
PubMed1999

Global statistical tests for comparing multiple outcomes in rheumatoid arthritis trials. MIRA Trial Group.

OBJECTIVE: To evaluate global statistical tests (GSTs) of treatment effectiveness for rheumatoid arthritis (RA) trials measuring multiple outcomes. METHODS: Using outcome measures from American College of Rheumatology (ACR) core set variables available in 3 RA trials, GSTs were calculated using the O'Brien ranking procedure and a procedure for binary data. GSTs take correlations among outcomes into account. Power calculations using 1 trial data set provide comparisons of GSTs and ACR criteria for improvement. RESULTS: Spearman correlations among outcomes ranged from 0.21 to 0.73. Erythrocyte sedimentation rate had the lowest correlation with other outcomes in all 3 trials. Within a trial, joint swelling and joint tenderness or patient and physician assessment had the highest correlations, depending on the trial. Results were consistent with results using the ACR criteria, although the GST was more powerful. CONCLUSION: GSTs are a useful tool for comparing treatment effects across multiple clinically meaningful outcome measures. The GST allows easy inclusion of validated, reliable new measures that are not a part of ACR criteria, such as quality of life, and can be computed with or without selecting a cutoff point defining patient improvement. GSTs should be considered for rheumatic disease treatment trials.

Arthritis, Rheumatoid↗
PubMed1999

Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study.

OBJECTIVE: To determine if the peripheral articular manifestations of the seronegative spondylarthropathies (SNSA) respond differently than the axial manifestations to treatment with sulfasalazine (SSZ). METHODS: This is a reanalysis of a previously reported series of randomized, double-blind, placebo-controlled, multicenter trials comparing the effects of SSZ, 2,000 mg/day, and placebo on the axial and peripheral articular manifestations of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and reactive arthritis (ReA; Reiter's syndrome). Patients were classified as treatment responders on the basis of meeting predefined improvement criteria in 4 outcome measures: namely, patient and physician global assessments in all patients, morning stiffness and back pain in patients with axial manifestations, and joint pain/tenderness scores and joint swelling scores in patients with peripheral articular manifestations. RESULTS: Six hundred nineteen SNSA patients (264 AS, 221 PsA, and 134 ReA) were studied. One hundred eighty-seven of these patients had only axial manifestations of their disease, while 432 patients had peripheral articular manifestations. Of the patients with axial disease, 40.2% of the SSZ group and 43.3% of the placebo group met the predefined response criteria (P = 0.67). Of the peripheral articular group, 59.0% of the SSZ-treated patients and 42.7% of the placebo-treated patients showed a response (P = 0.0007). CONCLUSION: In a large group of affected individuals, the response of SNSA patients to SSZ appears to be related to the articular manifestations of their disease. These data demonstrate that the axial and peripheral articular manifestations of SNSA respond differently to treatment with SSZ. In SNSA patients with persistently active peripheral arthritis, SSZ is safe, well tolerated, and effective.

Adult↗
PubMed1999

The prevalence of sacroilitis in psoriatic arthritis: new perspectives from a large, multicenter cohort. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine the prevalence of radiographic evidence of sacroiliitis in a large population of patients with psoriatic arthritis. PATIENTS AND DESIGN: Patients were recruited from 15 clinical centers. This was part of a large, multicenter study of patients with an established diagnosis of ankylosing spondylitis, psoriatic arthritis, or reactive arthritis. For this cohort, an established diagnosis of psoriatic arthritis was required, with cutaneous manifestations and involvement of at least three appendicular joints. At entry, patients were not selected for the presence of axial involvement. Radiographs - one anteroposterior view of the pelvis and one oblique view of each sacroiliac joint - were graded using the New York classification scale by a musculoskeletal radiologist masked to the specific diagnosis and clinical symptoms. Re-evaluation of 10% of the films 3 years later quantified intraobserver variability. RESULTS: Two hundred and two patients with psoriatic arthritis were studied. Duration of the disease averaged 12 years; all patients had psoriasis and peripheral arthritis. The prevalence of radiographic evidence of sacroiliitis (grade 2 or higher) was 78%; 71% of these had grade 3 disease. CONCLUSIONS: Previously reported prevalence of sacroiliitis in patients with psoriatic arthritis ranges from 30% to 50%. The prevalence of radiographic evidence of sacroiliitis in this large multicenter cohort of patients with appendicular psoriatic arthritis was substantially higher.

Arthritis, Psoriatic↗
PubMed1999

Early undifferentiated connective tissue disease (CTD). VI. An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated CTD.

OBJECTIVE: (1) To review the diagnoses after 10 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD). (2) To examine the death rates and disease remissions in these patients. METHODS: This inception cohort of 410 patients had less than one year of signs and/or symptoms of CTD. Diagnoses of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and poly/dermatomyositis (PM/DM) were made in 197 patients using accepted diagnostic and classification criteria. Diagnoses of undifferentiated CTD were made in 213 patients. These latter patients were placed in 3 categories: isolated Raynaud's phenomenon (RP), unexplained polyarthritis (UPA), and undifferentiated CTD (UCTD), defined as meeting at least 3 of 11 specific manifestations of CTD. The diagnoses and remissions in all patients after 10 years were determined. RESULTS: Patients with well established CTD tended to remain with the original diagnosis. The 10 year survival was at least 87% in all diagnostic categories, with the exception of SSc, in which it was 56%. The progression of UPA to RA occurred infrequently. The presence of antinuclear antibodies suggested that UPA may develop additional symptoms and/or a specific diagnosis, and RP in these patients increased the likelihood of progressing to UCTD or a specific well established CTD. Ten percent of patients with RP progressed to SSc. In patients with UCTD, joint pain/tenderness and swelling counts were associated with progression to other diagnoses including RA, while either serositis, malar rash, or discoid lupus suggested the eventual diagnosis of SLE. CONCLUSION: The survival of patients with SSc was poor, with most dying early in the course of their disease. Remissions were seen in all groups of patients except SSc. The remissions were sometimes transient in SLE. Undifferentiated disease at initial examination within 12 months of onset usually remains undifferentiated.

Connective Tissue Diseases↗
PubMed1999

Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Department of Veterans Affairs Cooperative Study Group on Seronegative Spondyloarthropathies.

OBJECTIVE: To determine differences in disease onset, extent, and manifestations of psoriasis among patients with active, inflammatory psoriatic arthritis (PsA), and to examine relationships that may exist between psoriasis and PsA. METHODS: Baseline demographic, clinical, and laboratory data were analyzed from 221 patients enrolled in a multicenter cooperative study, and relationships between measures of psoriasis and PsA were determined. RESULTS: Mean percentage of body surface area (BSA) affected by psoriasis was modest (12+/-17), and mean severity of erythema, induration, and scaling was moderate (4.9+/-2.1 on a 0-9 scale). Spanish Americans tended to have a higher mean percentage of BSA (18.5%) than Caucasians (11%; p = 0.067), as well as higher target lesion severity (5.55 vs. 4.84; p = 0.077). Patients with psoriatic nail disease (180/221, 81%) had significantly greater number of involved distal interphalangeal (DIP) joints (p = 0.004). There were no other significant associations of skin pattern or regional involvement with PsA. CONCLUSION: Patients with active PsA have generally mild skin disease, and baseline relationships between psoriasis and PsA tend to be weak except for nail involvement and DIP joint activity.

Arthritis↗
PubMed1998

Structures and dynamic motion of laminin-1 as observed by atomic force microscopy.

Laminins are a family of multifunctional extracellular matrix glycoproteins that play important roles in the development and maintenance of tissue organization via their interactions with cells and other extracellular matrix proteins. To understand the structural basis of laminins' functions, we examined the motion of laminin-1 (Ln-1) in physiological buffers using atomic force microscopy. While many Ln-1 molecules assumed the expected cruciform structure, unexpected dynamic movements of the Ln-1 arms were observed in aqueous environments. These dynamic movements of the Ln-1 arms may contribute to the diversity of laminin functions.

Animals↗
PubMed1998

Interactions of type IV collagen and its domains with human mesangial cells.

Type IV collagen (COL-IV) interacts with a variety of cell types. We present evidence that human mesangial cells (HMC) bind directly to COL-IV, its major triple helical domain, and the main non-collagenous, NC1 domain. A synthetic peptide, HEP-III, and its triple helical counterpart (THP-III), previously reported to be a heparin-binding domain, also promoted approximately 15% adhesion of HMC. HMC bound to solid-phase-immobilized, intact COL-IV (approximately 75%), isolated NC1 domain (approximately 15%), and a pepsin-derived triple helical fragment,which lacks Hep-III (approximately 65%). We further examined inhibition of HMC adhesion to COL-IV and its domains by using anti-integrin antibodies. Blocking monoclonal antibodies against the alpha2 integrin resulted in 70% inhibition of adhesion to COL-IV and 80% inhibition to HEP-III. Moderate inhibition was observed on the NC1 and triple helical fragments. Anti-alpha1 antibodies inhibited the binding of HMC to COL-IV, the NC1, and triple helical domains, but not to peptide HEP-III. Anti-beta1 antibodies inhibited almost completely (>95%) the adhesion to COL-IV, the NC1, and triple helical fragments; inhibition on HEP-III was approximately 30%. Affinity chromatography studies with solid-phase HEP-III and mesangial cell lysate also demonstrated the presence of integrin alpha2 beta1 along with alpha3 beta1. We conclude that alpha2 beta1 and alpha1 beta1 integrins mediate HMC adhesion to COL-IV. Peptide HEP-III is a major, specific site for alpha2 integrin-mediated binding of mesangial cells to COL-IV. Both the alpha1 beta1 and alpha2 beta1 integrins interact with the NC1 and triple helical fragments of COL-IV. Therefore, we demonstrate that several sites for integrin-mediated interactions exist on several collagenous and non-collagenous domains of COL-IV.

Antibodies, Monoclonal↗
PubMed1998

Modelling the major histocompatibility complex susceptibility to RA using the MASC method.

To explain the association between HLA-DRB1 gene and rheumatoid arthritis (RA), two main hypotheses have been proposed. The first, the shared epitope hypothesis, assumes a direct role of DRB1 in RA susceptibility. The second hypothesis assumes a recessive disease susceptibility gene in linkage disequilibrium with DRB1. To investigate these two hypotheses, we analysed data on the HLA-DRB1 and TNF-LT loci in 49 affected sib-pairs. We used the Marker Association Segregation Chi-square (MASC) method in which the genotype distribution of markers among index cases and the haplotype sharing in affected sib-pairs are jointly taken into account. With DRB1 data alone, both hypotheses were shown to fit but with analysis of TNF data, both hypotheses were strongly rejected. Thus the TNF data provided additional information for a better understanding of genetic susceptibility to RA than was previously possible using only HLA-DR data. A theoretical standpoint is addressed here on the advisability of using different linked markers in a candidate region for modelling the contribution of this region in disease susceptibility.

Adolescent↗
PubMed1998

Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial.

OBJECTIVE: Oral administration of cartilage-derived type II collagen (CII) has been shown to ameliorate arthritis in animal models of joint inflammation, and preliminary studies have suggested that this novel therapy is clinically beneficial and safe in patients with rheumatoid arthritis (RA). The present study was undertaken to test the safety and efficacy of 4 different dosages of orally administered CII in patients with RA. METHODS: Two hundred seventy-four patients with active RA were enrolled at 6 different sites and randomized to receive placebo or 1 of 4 dosages (20, 100, 500, or 2,500 microg/day) of oral CII for 24 weeks. Efficacy parameters were assessed monthly. Cumulative response rates (percentage of patients meeting the criteria for response at any time during the study) were analyzed utilizing 3 sets of composite criteria: the Paulus criteria, the American College of Rheumatology criteria for improvement in RA, and a requirement for > or = 30% reduction in both swollen and tender joint counts. RESULTS: Eighty-three percent of patients completed 24 weeks of treatment. Numeric trends in favor of the 20 microg/day treatment group were seen with all 3 cumulative composite measures. However, a statistically significant increase (P = 0.035) in response rate for the 20 microg/day group versus placebo was detected using only the Paulus criteria. The presence of serum antibodies to CII at baseline was significantly associated with an increased likelihood of responding to treatment. No treatment-related adverse events were detected. The efficacy seen with the lowest dosage is consistent with the findings of animal studies and with known mechanisms of oral tolerance in which lower doses of orally administered autoantigens preferentially induce disease-suppressing regulatory cells. CONCLUSION: Positive effects were observed with CII at the lowest dosage tested, and the presence of serum antibodies to CII at baseline may predict response to therapy. No side effects were associated with this novel therapeutic agent. Further controlled studies are required to assess the efficacy of this treatment approach.

Administration, Oral↗