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W P Maksymowych

Publications and source records attributed to W P Maksymowych.

At least 19 recordsLinked to original sources
PubMed2006

Persistence, reproducibility, and cost-effectiveness of an intervention to improve the quality of osteoporosis care after a fracture of the wrist: results of a controlled trial.

INTRODUCTION: Older patients with fragility fractures are not commonly tested or treated for osteoporosis. Compared to usual care, a previously reported intervention led to 30% absolute increases in osteoporosis treatment within 6 months of wrist fracture. Our objective was to examine longer-term outcomes, reproducibility, and cost-effectiveness of this intervention. METHODS: We conducted an extended analysis of a non-randomized controlled trial with blinded ascertainment of outcomes that compared a multifaceted intervention to usual care controls. Patients >50 years with a wrist fracture treated in two Emergency Departments in the province of Alberta, Canada were included; those already treated for osteoporosis were excluded. Overall, 102 patients participated in this study (55 intervention and 47 controls; median age: 66 years; 78% were women). The interventions consisted of faxed physician reminders that contained osteoporosis treatment guidelines endorsed by opinion leaders and patient counseling. Controls received usual care; at 6-months post-fracture, when the original trial was completed, all controls were crossed-over to intervention. The main outcomes were rates of osteoporosis testing and treatment within 6 months (original study) and 1 year (delayed intervention) of fracture, and 1-year persistence with treatments started. From the perspective of the healthcare payer, the cost-effectiveness (using a Markov decision-analytic model) of the intervention was compared with usual care over a lifetime horizon. RESULTS: Overall, 40% of the intervention patients (vs. 10% of the controls) started treatment within 6 months post-fracture, and 82% (95%CI: 67-96%) had persisted with it at 1-year post-fracture. Delaying the intervention to controls for 6 months still led to equivalent rates of bone mineral density (BMD) testing (64 vs. 60% in the original study; p = 0.72) and osteoporosis treatment (43 vs. 40%; p = 0.77) as previously reported. Compared with usual care, the intervention strategy was dominant - per patient, it led to a $13 Canadian (U.S. $9) cost savings and a gain of 0.012 quality-adjusted life years. Base-case results were most sensitive to assumptions about treatment cost; for example, a 50% increase in the price of osteoporosis medication led to an incremental cost-effectiveness ratio of $24,250 Canadian (U.S. $17,218) per quality-adjusted life year gained. CONCLUSIONS: A pragmatic intervention directed at patients and physicians led to substantial improvements in osteoporosis treatment, even when delivered 6-months post-fracture. From the healthcare payer's perspective, the intervention appears to have led to both cost-savings and gains in life expectancy.

Aged↗
PubMed2004

Lack of association of matrix metalloproteinase 3 (MMP3) genotypes with ankylosing spondylitis susceptibility and severity.

OBJECTIVE: To study the linkage and association of ankylosing spondylitis (AS) with genotypes for matrix metalloproteinase 3 (MMP3), a gene located at chromosome 11q22.3 and lying within the 101-124 cM region observed in a recent genome-wide scan as a region associated with AS susceptibility. METHODS: MMP3 genotypes were examined in 229 pedigrees with AS, 131 sporadic AS cases and 87 Caucasian controls. Eight single-nucleotide polymorphisms (SNPs) were selected and genotyped using Taqman. Non-parametric linkage (NPL) analysis was conducted between the eight MMP3 SNPs and AS using the NPL-all statistic and two-point parametric linkage analysis using GeneHunter Plus. Unrelated AS cases and controls were compared using chi2 statistics, and family-based controls using the transmission disequilibrium test and pedigree disequilibrium test. RESULTS: None of the eight MMP3 SNPs were significantly associated with AS, either using the 131 sporadic cases alone or in analyses which combined these cases with the 226 unrelated affected AS patients derived from the pedigrees. Analysis of linkage disequilibrium (LD) demonstrated that seven of the eight SNPs studied were in strong LD except for rs626750, which is about 6 kb upstream of the 5' end of the gene. No significant linkage was observed using NPL and LODs in the families. No association was seen of any of the MMP3 SNPs with disease severity (defined by patient functioning), as measured either by the Bath Ankylosing Spondylitis Functional Index or the modified Health Assessment Questionnaire. CONCLUSION: These data suggest that MMP3 genotypes are not involved in AS susceptibility or severity.

Adult↗
PubMed2001

Clinical and radiological amelioration of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy.

OBJECTIVE: To examine the potential therapeutic properties of an aminobisphosphonate, pamidronate, using clinical and laboratory outcome variables together with dynamic magnetic resonance imaging (MRI) and gadolinium augmentation in patients with spondyloarthropathy (SpA) refractory to nonsteroidal antiinflammatory drugs (NSAID). METHODS: We studied 9 patients (7 male, 2 female) of mean age 27.9 years (range 19-38) and mean disease duration of 5.5 years (range 0.5-20). Five had ankylosing spondylitis (AS), 3 had undifferentiated SpA, and one had reactive arthritis. Seven were HLA-B27 positive. Two had inflammatory bowel disease. Pamidronate (60 mg) was given intravenously on Days 1, 2, 14, 28, and 56, over 4 h in 500 ml of 5% dextrose. Clinical outcome assessments included the BASDAI (disease activity), BASFI (function), BASGI (global well being) composite visual analog instruments, and swollen and tender joint count. Laboratory variables included the erthrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Dynamic MRI with gadolinium augmentation of synovium and bone was performed at baseline and at Day 84 in the first 6 patients enrolled in the study. RESULTS: All patients completed the study and there was a significant improvement in all clinical and laboratory variables assessed. Mean swollen and tender joint count decreased by 93.8% (p = 0.017) and 98.2% (p = 0.012), respectively, and complete clinical resolution of synovitis was noted in 5 patients. BASDAI decreased by 44.2% (p = 0.028), BASFI by 47.3% (p = 0.015), and BASGI by 42.2% (p = 0.011). ESR and CRP declined by 49.4% (p = 0.012) and 66.9% (p = 0.008), respectively. Acute lymphopenia accompanied by elevated CRP levels was noted in 8 patients in the 48 h after first pamidronate infusion. Maximal rate and magnitude of enhanced MRI signal after gadolinium augmentation decreased after pamidronate therapy, especially in the bone marrow. CONCLUSION: Preliminary data from uncontrolled studies support the efficacy of pamidronate therapy for NSAID refractory SpA and warrant further evaluation in controlled trials.

Adult↗
PubMed2001

Polymorphism in the MHC-encoded LMP7 gene: association with JRA without functional significance for immunoproteasome assembly.

OBJECTIVE: To determine if a polymorphism in the immunoproteasome subunit LMP7 was associated with juvenile rheumatoid arthritis (JRA) and had functional significance. METHODS: The frequency of LMP7QQ+ vs QQ- (QK and KK genotypes) among 207 patients with JRA and 50 controls was determined. JRA subtypes were pauciarticular (53%), polyarticular (33%), and systemic (14%). Onset was before age 6 (early onset) in 60% of patients. The functional significance of the LMP7 polymorphism was determined by comparing incorporation of LMP7Q vs LMP7K into proteasomes. RESULTS: There was an increased frequency of LMP7QQ in patients vs controls (73 vs 56%; p = 0.016), mainly due to the pauciarticular and systemic JRA subtypes (p = 0.037), and more pronounced in early onset disease (77 vs 56%; p = 0.006). The association persisted with stratification for HLA-DR5(11) and -DPB 1 *0201 (p = 0.002 and 0.013). We found no difference in the relative incorporation of LMP7Q and LMP7K into proteasomes. CONCLUSIONS: These results support an association between LMP7QQ homozygosity and JRA, particularly early onset disease. The difference persists with stratification, at least for DR5(11) and DPB1*0201, suggesting that this effect is unlikely to be due to linkage disequilibrium with HLA alleles known to be associated with early onset pauciarticular JRA. Importantly, as there does not appear to be functional significance associated with the LMP7 polymorphism, this may be a marker for another as yet unidentified susceptibility locus.

Arthritis, Juvenile↗
PubMed2001

Treatment of refractory symphysitis pubis with intravenous pamidronate.

Osteitis pubis is a noninfectious painful inflammatory disorder of the symphysis pubis. Etiologic factors include urologic procedures, abdomino-perineal and gynecological surgery, and spondyloarthropathies, although many cases are idiopathic. Most respond to conservative measures consisting primarily of rest and analgesic/antiinflammatory agents. We describe 3 cases, 2 with idiopathic osteitis pubis and one that was associated with a spondyloarthropathy, that failed to respond to conservative measures but experienced clinical remission with 3 to 6 monthly courses of intravenous pamidronate. Remission was also evident in 2 patients on isotope bone scan. Followup has revealed no recurrence. Intravenous pamidronate may constitute a safe and effective treatment option for patients with refractory osteitis pubis.

Adult↗
PubMed2000

Bacterial modulation of antigen processing and presentation.

This review examines the mechanisms by which bacteria influence the antigenic processing of endogenous and exogenous antigens presented by class I, class II, and nonclassical MHC molecules. Consequent effects on presentation of bacterial antigens, the ability of bacteria to evade host defences, and the potential induction of autoimmunity are discussed.

Animals↗
PubMed2000

LMP2 polymorphism is associated with extraspinal disease in HLA-B27 negative Caucasian and Mexican Mestizo patients with ankylosing spondylitis.

OBJECTIVE: To determine the effects of HLA Class II genes, particularly LMP2 and previously implicated Class I genes, on susceptibility and disease expression in HLA-B27 negative ankylosing spondylitis (AS). METHODS: Patients included 41 HLA-B27 negative Caucasians from a total AS population of 546 and 17 HLA-B27 negative Mexican Mestizo. Controls included 4352 random HLA-B27 negative Caucasians. LMP2 genotype assignments were made on all patients and 282 random Caucasian controls by polymerase chain reaction-restriction fragment length polymorphism with the Cfo I restriction enzyme while HLA typing was performed on patients and controls using microcytotoxicity assays for Class I, and sequence specific probe-PCR for HLA-B60, B39, B38, and DR. RESULTS: The LMP2BB genotype was significantly decreased in Caucasian AS patients without extraspinal (ES) disease (25%) compared to AS patients with ES (64.7%) (p = 0.01) and random Caucasian controls (53.9%) (p = 0.007), even when those with colitis and psoriasis were excluded from analysis (ES+ 55.6% versus ES- 22.2%). This finding remained significant after stratification by HLA-DR. Similar trends were noted in the Mexican population. A potential role for HLA-DR8 and DR2 in susceptibility to disease was observed in Caucasian patients, although this observation requires confirmation. We could not confirm reported associations with HLA-B60 or B39. Peripheral arthritis was significantly more commonly observed in those who had had acute anterior uveitis (AAU) (75%) than in those who had not developed AAU (27.3%) (p = 0.04). CONCLUSION: HLA Class II encoded genes may have effects on disease susceptibility and/or phenotype in HLA-B27 negative individuals similar to those noted in HLA-B27 positive AS. Eccentric and axial phenotypes of disease may be immunogenetically determined.

Adult↗
PubMed2000

Anti-inflammatory and immunomodulatory therapies in spondyloarthropathies.

Although the spondyloarthropathies constitute amongst the commonest chronic inflammatory joint disorders, there have been few therapeutic advances since the introduction of nonsteroidal anti-inflammatory agents. A number of disease-modifying therapies originally developed for rheumatoid arthritis have also been examined in this class of arthritides, although placebo-controlled studies are lacking. Despite the low interest from industry, there is the promise that emerging therapies, particularly bisphosphonates and tumor necrosis factor alpha antagonists may be efficacious. Significant impediments to the development of additional therapeutic agents include a limited understanding of immunopathological events operative in early disease, disease heterogeneity, the inability to detect structural damage with adequate sensitivity, and the high cost of treatment. However, the recent development of internationally standardized and validated clinical outcome assessment tools as well as sophisticated magnetic resonance imaging are rekindling interest in these disorders.

Adjuvants, Immunologic↗
PubMed1999

Bowel permeability and CD45RO expression on circulating CD20+ B cells in patients with ankylosing spondylitis and their relatives.

OBJECTIVE: Ankylosing spondylitis (AS) is reportedly associated with subclinical endoscopic gut inflammation in up to 57% of patients. Studies of bowel permeability, however, have not consistently revealed abnormalities in these patients. CD20+CD45RO+ expression is associated with increased antigen exposure, and previous work has shown increased expression in this B cell isoform in patients with Crohn's disease and their relatives, correlating with intestinal permeability abnormalities. We sought to re-examine intestinal permeability in patients with AS and their relatives, and relate any observed alterations in permeability with evidence of increased antigen presentation as assessed by the number of circulating B cells that were CD45RO positive. METHODS: We studied small intestinal and gastric permeability by measurement of excretion of lactulose, mannitol, and sucrose in 60 patients with AS and 24 of their first-degree relatives. We also studied expression of CD20+CD45RO+ by flow cytometry in these patients. RESULTS: Both patients and first-degree relatives had significantly increased small intestinal, but not gastric, permeability compared to controls. Among patients, current users of nonsteroidal anti-inflammatory drugs (NSAID) had significantly increased small intestinal permeability compared to nonusers, but relatives not using NSAID also had increased permeability. CD20+CD45RO+ expression was increased in one-third of patients but did not correlate with permeability abnormalities. CONCLUSION: Patients with AS have altered small intestinal, but not gastric, permeability. NSAID use cannot explain all the abnormality. Bowel permeability abnormalities, possibly genetically determined, may antedate development of bowel or joint symptoms. Increased CD20+CD45RO+ expression suggests increased antigen exposure, which may be related to previous or current intestinal permeability abnormalities.

Adult↗
PubMed1998

Association between MICA gene A4 allele and acute anterior uveitis in white patients with and without HLA-B27.

PURPOSE: Acute anterior uveitis is strongly associated with the HLA-B27 antigen and triggered by the involvement of some external factors. However, it is uncertain whether HLA-B27 itself or other gene(s) near the HLA-B region in a linkage disequilibrium with HLA-B27 predispose to this uveitis. We therefore investigated microsatellite polymorphism in the transmembrane region of the major histocompatibility complex class I chain-related gene A (MICA), located 47 kilobases (kb) on the centromeric side of the HLA-B gene on the short arm of chromosome 6 within 6p21.3. METHODS: We examined the following patients for MICA gene polymorphism by means of polymerase chain reaction and subsequent automated fragment detection by fluorescent-based technology: 64 (37 HLA-B27-positive and 27 HLA-B27-negative) whites with acute anterior uveitis, 74 (67 HLA-B27-negative and 7 HLA-B27-positive) ethnically matched random controls, and 36 HLA-B27-positive healthy controls. RESULTS: The microsatellite allele consisting of four repetitions of GCT/AGC (designated A4 allele) was present at the significantly higher phenotype frequency (71.9%) in the patient group than in the ethnically matched random control group (13.5%) (P < .0000001, corrected P < .0000001). The A4 allele was strongly linked to HLA-B27 in a white population. However, the A4 allele was also found at the significantly higher phenotype frequency (37.0%) even in the HLA-B27-negative patient group than in the ethnically matched HLA-B27-negative control group (4.5%) (P = .0086, corrected P = .043). CONCLUSIONS: These results suggest that the MICA gene itself or other nearby gene(s) linked to the MICA A4 allele may be involved in the development of acute anterior uveitis in a white population.

Acute Disease↗
PubMed1998

Invasion by Salmonella typhimurium induces increased expression of the LMP, MECL, and PA28 proteasome genes and changes in the peptide repertoire of HLA-B27.

We have analyzed proteasomal adaptation and associated changes in the B27-bound peptide repertoire in response to cellular invasion with Salmonella. The peptide repertoire of HLA-B27 complexes was analyzed by two different methods: (i) high-pressure liquid chromatography (HPLC) profiles of newly synthesized peptides eluted from B27 following metabolic labeling with arginine and (ii) reactivities with two B27 monoclonal antibodies, Ye-2 and B27.M2, sensitive to peptide-induced conformational changes. LMP, MECL, and PA28 expression was analyzed by reverse transcription-PCR (RT-PCR) of mRNA and by Western blot analysis for LMP2. Invasion of HLA-B27-transfected HeLa cells by Salmonella typhimurium induced significant changes in the reactivities of HLA-B27 with these two antibodies, which was accompanied by significant quantitative and qualitative changes in the HPLC profile of peptides eluted from HLA-B27. We also observed increases in the RT-PCR values for the LMP2, LMP7, and MECL proteasome subunit genes, as well as the proteasomal activator PA28alpha and -beta genes, and increased expression of the LMP2 protein by Western blotting. Upregulation of LMP2, but not LMP7, gene expression showed a close correlation with the changes in antibody reactivities observed upon bacterial invasion. We observed similar changes in reactivity with the Ye-2 or the B27.M2 antibody of lymphoblastoid cells upon gamma interferon treatment, which significantly correlated with the increased RT-PCR values for the LMP2 gene. This was accompanied by consistent HPLC profile changes for eluted peptides. Thus, Salmonella invasion leads to serologically recognizable changes in the B27-bound peptide repertoire, which may include peptides of host origin potentially through modulation of proteasome LMP2 subunit expression and, as a consequence, proteasomal activities.

Antigen Presentation↗
PubMed1998

Ossification of the posterior longitudinal ligament in three geographically and genetically different populations of ankylosing spondylitis and other spondyloarthropathies.

STUDY DESIGN: Cross sectional. RESEARCH QUESTIONS: (a) Is any clinical variable of ankylosing spondylitis (AS) associated with the presence of ossification of the posterior longitudinal ligament (OPLL)? and (b) Is OPLL present in patients with AS from different geographical or genetic backgrounds? METHODS: Three groups were assembled: (1) a prospective group of 103 consecutive AS patients from two community based rheumatology clinics from Guadalajara, who were evaluated using: a questionnaire with disease characteristics variables; clinical assessment by a neurologist; lateral radiographic views of the cervical spine and somatosensory evoked potentials (SSEP). (2) Fifty one spondyloarthropathies (SpA) patients from Mexico city whose cervical spine films were retrospectively reviewed. (3) Thirty nine AS patients from Edmonton, Canada whose cervical spine films were retrospectively reviewed and compared with 72 controls. RESULTS: Group 1: 74% of the 103 patients were men and 86% were HLA-B27 positive. The mean age was 35 years, and mean (SD) disease duration 10 (8) years. OPLL was reported in 16 patients (15.5%; 95% CI 9, 22). OPLL was statistically associated with older age (p = 0.001), longer disease duration (p = 0.001), clinical myelopathy (p = 0.03), worst functional index (p = 0.042), restricted axial movement measurements (all p < 0.001), radiological sacroilitis (p < 0.001 for linear association), osteitis pubis (p = 0.009), hip involvement (p = 0.006 for linear association), and abnormal SSEP (p = 0.008). Group 2: 92% of 51 patients were men; the mean age was 30 years and the mean (SD) disease duration 11 (7) years. OPLL was reported in 15 (29%, 95% CI 17, 41) patients (nine AS, two psoriatic arthritis, three juvenile AS, and one Reiter's syndrome). Group 3: 95% of the 39 patients were men; the mean of age was 46 years and disease duration of 18 (10) years. OPLL was reported in nine (23%; 95% CI 10, 36) patients, including one with psoriatic arthritis, and two with Crohn's disease. OPLL was observed in two of the control group. CONCLUSIONS: The prevalence of OPLL in AS and SpA is higher than previously recognised and seems to be associated with variables identifying more severe axial disease.

Adult↗
PubMed1998

An open study of pamidronate in the treatment of refractory ankylosing spondylitis.

OBJECTIVE: Bisphosphonates inhibit the development of delayed type hypersensitivity chronic inflammation and suppress inflammation and cartilage/bone erosion in diverse murine arthritis models. We evaluated antiinflammatory properties of the bisphosphonate pamidronate in patients with ankylosing spondylitis (AS) refractory to nonsteroidal antiinflammatory drugs. METHODS: Patients included 14 men and 2 women. The first group of 8 patients (Group 1) received pamidronate as a 30 mg intravenous infusion once a month for 3 months, followed by a 60 mg dose once a month for an additional 3 months. Eight additional patients (Group 2) received only the 60 mg dose once a month for 3 months. Clinical assessments included the BASDAI (Bath AS Disease Activity Index), BASFI (Functional Index), and BASMI (Metrology Index), and laboratory assessments hemoglobin and erythrocyte sedimentation rate (ESR) at baseline and one month after final 60 mg dose of pamidronate. Mean BASDAI score at study entry was 6.7 for both groups. RESULTS: A significant improvement was observed in disease activity score in Group 1 after 6 monthly infusions of pamidronate (mean BASDAI 4.21; p = 0.03), in the BASMI score (p = 0.01), and the ESR (p = 0.009). A significant improvement in the BASMI was noted in Group 2 patients (p = 0.007) after 3 monthly infusions of pamidronate, but not in the BASDAI score (mean 5.01; p = 0.07) or the ESR (p = 0.12). CONCLUSION: Preliminary data suggest pamidronate may possess antiinflammatory activity in patients with AS, particularly with prolonged administration; this agent deserves further evaluation in a controlled trial.

Adult↗
PubMed1998

Managing acute osteoporotic vertebral fractures with calcitonin.

OBJECTIVE: To inform family physicians of current issues in the management of acute vertebral fractures and to examine the evidence specifically supporting a role for calcitonin in ameliorating pain. QUALITY OF EVIDENCE: Recommendations for use of calcitonin were based primarily on a MEDLINE review of the literature for randomized, double-blind, placebo-controlled trials. The MEDLINE search was conducted from 1966 to the present using key words calcitonin, osteoporosis, pain, and vertebral fracture. Additional studies were identified by searching bibliographies of review articles. Eight trials were identified, and the conclusions drawn were based on data reported in all eight trials. MAIN FINDINGS: Several randomized, placebo-controlled studies demonstrated that calcitonin had a rapid onset and a strong analgesic effect on patients with acute vertebral fractures. Nasal and subcutaneous administration were both beneficial. Pain relief occurred within the first 2 weeks, could continue for at least 4 months, and might occur if treatment were instituted any time within the first year after fracture. Side effects were generally inconvenient rather than serious. CONCLUSIONS: Calcitonin in a dose of 50 to 100 IU daily, given subcutaneously or intranasally, should be offered to all patients with serious pain related to acute vertebral fractures for symptom relief and to facilitate mobilization.

Acute Disease↗
PubMed1997

Osteoporosis.

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Bone Density↗