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John G Hanly

Publications and source records attributed to John G Hanly.

12 recordsLinked to original sources
PubMed2006

Meningeal involvement in Wegener's granulomatosis.

We describe a patient with Wegener's granulomatosis (WG) who developed neurological symptoms attributed to meningeal involvement. The diagnosis of WG was complicated by persistently negative antineutrophil cytoplasmic antibodies (ANCA) and lack of specificity in the histopathological findings from multiple anatomical sites. This rare neurological manifestation of WG was treated successfully with oral cyclophosphamide and the patient has continued remission for 3 years taking oral methotrexate.

Administration, Oral↗
PubMed2006

Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus.

OBJECTIVE: To determine the prevalence of circulating anti-NR2 antibodies and their association with neuropsychiatric systemic lupus erythematosus (NP-SLE), particularly cognitive function, in women with SLE. METHODS: Cognitive function was assessed in 65 consecutive women with SLE from a single referral center using standardized neuropsychological tests. These were selected subtests of the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale-Revised, and the California Verbal Learning Test, which provided information on 8 areas of cognitive function. After a mean followup of 64 (range 52-71) months, cognitive assessments were repeated. Global and domain-specific cognitive impairment was examined using predetermined decision rules, and the change in individual tests of cognitive performance over time was also examined. Overt NP-SLE was identified by clinical assessment and classified using the American College of Rheumatology nomenclature. Circulating IgG anti-NR2 and anti-dsDNA antibodies were determined by ELISA on up to 4 occasions over the study period. A positive result was defined as at least 3 standard deviations above the mean of healthy controls. RESULTS: At enrollment, 15/65 (23%) patients had cognitive impairment. This fell to 7/54 (13%) at followup. In addition 15/65 (23%) patients had a history of clinically overt NP-SLE. Twenty-three of 65 (35%) patients had anti-NR2 antibodies and 48/65 (74%) had anti-dsDNA antibodies. Anti-NR2 antibodies were present in 18/48 (38%) patients with anti-DNA antibodies, and 18/23 patients (78%) with anti-NR2 antibodies also had anti-dsDNA antibodies. There was no association between global cognitive impairment, domain-specific cognitive impairment, or a history of clinically overt NP-SLE and either the presence or amount of anti-NR2 or anti-dsDNA antibodies (p > 0.05). When change in cognitive performance or the occurrence of new NP-SLE events over the 5-year followup period was examined, there was no significant association with persistent elevation of either antibody (p > 0.05). Similarly there was no association between a rise in autoantibodies over time and the development of overt NP events or cognitive decline (p > 0.05). CONCLUSION: These results indicate that anti-NR2 antibodies occur in 35% of women with SLE and are infrequent in the absence of detectable anti-dsDNA antibodies. Their presence in the circulation is not associated with cognitive dysfunction at a single timepoint, and an increase in or persistently elevated antibody levels are not associated with a change in cognitive performance over time. There was no association with clinically overt NP-SLE. However, as our study did not examine cerebrospinal fluid samples, these results do not exclude a potential pathogenic role in selected patients for this group of autoantibodies should they penetrate the blood-brain barrier and thereby gain direct access to neuronal tissues.

Adult↗
PubMed2005

Management of neuropsychiatric lupus.

Nervous system disease in systemic lupus erythematosus (SLE) is manifested by a wide variety of clinical manifestations. Despite the development of a universal classification for neuropsychiatric (NP) lupus in 1999, there continues to be considerable variability in the reported prevalence of NP syndromes between different lupus cohorts. Due to the lack of specificity of individual NP manifestations, non-SLE causes such as complications of therapy and co-morbidities must be considered in advance of attributing the event to one or more primary immunopathogenic mechanisms. These include intracranial microangiopathy, autoantibodies to neuronal and non-neuronal antigens, and the generation of proinflammatory cytokines and mediators. The diagnosis of NP-SLE remains largely one of exclusion and is approached in individual patients by thorough clinical evaluation, supported when necessary by autoantibody profiles, diagnostic imaging, electrophysiologic studies and objective assessment of cognitive performance. Given the diversity in clinical manifestations, the management is tailored to the specific needs of individual patients. In the absence of controlled studies, the use of symptomatic therapies, immunosuppressives, anticoagulants and non-pharmacologic interventions is supported by case series and clinical experience.

Anticoagulants↗
PubMed2005

Neuropsychiatric lupus.

Nervous system disease in patients who have systemic lupus erythematosus (SLE) spans a wide spectrum of neurologic (N) and psychiatric (P) features that may be attributed to a primary manifestation of SLE, complications of the disease or its therapy, or a coincidental disease process. The etiology of primary NP disease is multifactorial and includes vascular injury of intracranial vessels, autoantibodies to neuronal antigens, ribosomes and phospholipid-associated proteins, and the intracranial generation of cytokines. In the absence of a diagnostic gold standard for most of the NP-SLE syndromes, a range of investigations are employed to support the clinical diagnosis and determine the severity of NP disease. Treatment remains largely empiric in the absence of controlled studies, and current strategies include the use of immunosuppressive therapies, appropriate symptomatic interventions, and the treatment of non-SLE factors.

Cognition Disorders↗
PubMed2005

Neuropsychiatric syndromes in patients with systemic lupus erythematosus and rheumatoid arthritis.

OBJECTIVE: The cause of neurologic (N) and psychiatric (P) syndromes in patients with systemic lupus erythematosus (SLE) is mutifactorial and includes primary immunopathogenic mechanisms, nonspecific sequelae of chronic disease, and concurrent illnesses. We compared the prevalence, diversity, and clinical significance of NP syndromes in patients with SLE and rheumatoid arthritis (RA). METHODS: Fifty-three patients with SLE were matched by age and sex to 53 patients with RA attending ambulatory clinics in a single academic medical center. All fulfilled the American College of Rheumatology (ACR) classification criteria for either SLE or RA. Cumulative NP manifestations were determined using the ACR nomenclature and case definitions for 19 NP syndromes. Depression and anxiety were measured by the Hospital Anxiety and Depression Scales (HADS) and symptoms of cognitive dysfunction were assessed by the Cognitive Symptoms Inventory (CSI). Health related quality of life (HRQOL) was evaluated by the SF-36 and fatigue by a 10 point Likert scale. RESULTS: The patients were well matched with regard to age, sex, disease duration, and years of education. There were no significant differences in self-reported HRQOL, fatigue, anxiety, depression, and cognitive symptoms between the 2 groups. The proportion of patients with cumulative NP events was higher in RA than in SLE patients (47% vs 28%; p = 0.045), and of these the occurrence of multiple NP events in individual patients was comparable in both groups (SLE 53%; RA 48%; p = 0.75). Fifty-five percent and 66% of NP events occurred prior to the diagnosis of SLE and RA, respectively. NP events common to both SLE and RA patients were headaches, mood disorders, acute confusional states, anxiety, cerebrovascular disease, and cognitive dysfunction. Seizures and demyelinating syndrome occurred only in SLE patients, but were rare. Depression scores (HADS) were significantly higher in SLE patients with a history of cumulative NP events compared to RA patients with NP events (p = 0.02). Similarly, symptoms of cognitive dysfunction (CSI) were more common in SLE patients with a history of NP manifestations (p = 0.02). However, there were no significant differences in SF-36 subscale or fatigue scores between SLE and RA patients with cumulative NP events. CONCLUSION: NP syndromes, regardless of etiology, are common in both SLE and RA patients. SLE patients with NP syndromes report more symptoms of depression and cognitive dysfunction compared to RA patients with NP syndromes, but do not report significantly poorer HRQOL. These results emphasize the presence of non-disease-specific causes of NP manifestations in SLE patients, which should be acknowledged in future studies of pathogenesis and treatment.

Anxiety↗
PubMed2004

Physician resources and postgraduate training in canadian academic rheumatology centers: a 5-year prospective study.

OBJECTIVE: To describe the trends in physician resources, changes in activity profiles, and the output of the postgraduate training programs in Canadian academic rheumatology centers from 1998-2002. METHODS: In 1998, the Canadian Council of Academic Rheumatologists (CCAR) established a prospective database to monitor physician resources, activity profiles, and recruitment within 15 academic rheumatology units in Canada. Information was also collected on residents pursuing subspeciality training in rheumatology. RESULTS: Over the 5 year period there was an increase in the number of rheumatologists from 157 to 168. The majority of this increase (91%) was attributable to changes in full-time staff. The mean age of rheumatologists increased from 47.9 to 48.9 years over the same period and the ratio of male to female rheumatologists decreased incrementally from 2.5:1 to 1.9:1. The overall allocation of time for clinical care (54-53%), teaching (17-16%), research (21-23%), and administration (7%) remained stable over time. Unfilled staff positions varied between 18-25 per year and were spread between 9-12 centers. The number of trainees in adult and pediatric rheumatology fell incrementally from 38 to 22 over the first 4 years of the study, with an increase to 30 in 2002. The majority of trainees were located at 2 centers and the number of active training programs varied between 6 and 12 per year. Funding for clinical fellowship training was provided by government (27-51%), the Arthritis Society (21-33%), and alternative sources (23-40%). CONCLUSION: These results indicate that rheumatology physician resources within Canadian academic units are inadequate to fulfill responsibilities in the delivery of clinical service and academic programs. Enrollment in rheumatology training programs is falling and is insufficient to meet the present and future needs for patients with rheumatic diseases in Canada.

Academic Medical Centers↗
PubMed2004

Neuropsychiatric events in systemic lupus erythematosus: attribution and clinical significance.

OBJECTIVE: To describe the range and attribution of neuropsychiatric (NP) disease in an unselected cohort of patients with systemic lupus erythematosus (SLE) and to examine the association with cumulative organ damage, medication use, and quality of life. METHODS: One hundred eleven patients with SLE in a single referral center were studied. NP syndromes were defined using the American College of Rheumatology (ACR) nomenclature and case definitions. Overall disease activity was measured by the SLE Disease Activity Index (SLEDAI); cumulative organ damage was determined by the ACR/SLICC damage index; and quality of life by the SF-36. RESULTS: Patients' mean age was 44.7 years, 87% were female, and 92% were Caucasian. The mean (+/- SE) disease duration was 10.1 +/- 0.7 years. A total of 74 NP events were identified in 41 of 111 (37%) patients. Thirteen of the 19 ACR NP syndromes were identified and 2 or more NP manifestations occurred in 56% of patients. Central nervous system manifestations accounted for 92% of the events compared to involvement of the peripheral nervous system in 8%. Thirty-five (47%) of these events were attributed entirely to SLE, 30 (41%) were attributed exclusively to non-SLE factors, and in the remaining 9 events (12%) both SLE and non-SLE factors were felt to be contributory. Cumulative organ damage was higher in patients with NP disease, although this was not statistically significant and they were more likely to have received prednisone or immunosuppressive drugs (p < 0.05). Patients with NP disease reported more fatigue (p < 0.05) and had significantly lower scores on 7 of 8 subscales of the SF-36 (p < 0.05). These associations were found regardless of the attribution of NP disease. In contrast, the occurrence of renal disease in the same cohort of patients was not associated with lower SF-36 scores or fatigue. CONCLUSION: In patients with SLE, NP disease has diverse manifestations and can be attributed to lupus in roughly half of the cases. The occurrence of NP disease is associated with more frequent use of corticosteroids and immunosuppressive drugs. In contrast to other serious manifestations of SLE, such as renal disease, NP disease is associated with a significant reduction in quality of life.

Adult↗
PubMed2003

Antiphospholipid syndrome: an overview.

Antiphospholipid antibodies are a heterogeneous group of autoantibodies that are detected by immunoassays and functional coagulation tests. The antigenic targets are negatively charged phospholipids and serum phospholipid-binding proteins. The latter antibodies are frequently associated with thrombosis, fetal loss and other clinical manifestations of the antiphospholipid syndrome. These antibodies are felt to be etiologically important in the syndrome, although the precise pathogenic mechanisms are still being determined. Proposed mechanisms include antibody-mediated interference with coagulation homeostasis, activation of platelets and endothelial cells and a T-cell immune response to serum phospholipid-binding proteins. The mainstay of therapy is anticoagulation, whereas immunosuppression is ineffective.

Abortion, Spontaneous↗
PubMed2003

Inhibition of annexin V binding to cardiolipin and thrombin generation in an unselected population with venous thrombosis.

OBJECTIVE: To examine the effect on annexin V binding to cardiolipin (CL) and in vitro thrombin generation by plasma samples from an unselected population of patients with confirmed venous thrombosis and matched controls. The prevalence of autoimmune antiphospholipid antibodies (aPL) was also determined. METHODS: A total of 111 patients who presented to a single emergency room with symptoms suggestive of venous thromboembolic (VTE) disease were studied. In 34 patients the diagnosis of lower limb deep venous thrombosis (DVT) and/or pulmonary embolus (PE) was confirmed (VTE+ group). In the remaining 77 patients the diagnostic workup was negative (VTE- group). Plasma samples were collected prior to the initiation of anticoagulation and examined for IgG anticardiolipin (aCL), IgG anti-beta2-glycoprotein I (GPI), and IgG anti-prothrombin (aPT antibodies) by ELISA. In addition, the effect of individual patient and control plasma samples on annexin V binding to CL and on in vitro thrombin generation was determined by a competitive ELISA and a chromogenic assay, respectively. RESULTS: The prevalence and levels of IgG aCL, anti-beta2-GPI, and aPT antibodies were similar in the VTE+ and VTE- groups. However, plasma samples from the VTE+ group caused a significant inhibition of in vitro thrombin generation (mean +/- SD Z score: -0.66 +/- 0.97 vs 0.26 +/- 1.46; p < 0.001) and a concurrent but less impressive inhibition of annexin V binding to CL (mean +/- SD Z score: -2.53 +/- 1.44 vs -2.05 +/- 1.61; p = 0.123). Upon analyzing a panel of clinical and laboratory variables, only age and inhibition of thrombin generation were significantly associated with VTE disease. CONCLUSION: Our findings suggest that subtle abnormalities in annexin V physiology may contribute to the procoagulant state in patients with idiopathic venous thrombosis.

Annexin A5↗
PubMed2002

Association of autoantibodies to nuclear lamin B1 with thromboprotection in systemic lupus erythematosus: lack of evidence for a direct role of lamin B1 in apoptotic blebs.

OBJECTIVE: To demonstrate the association between autoantibodies to nuclear lamin B1 (aLB1) and protection against thrombosis ("thromboprotection") in patients with systemic lupus erythematosus (SLE), and to elucidate the mechanism by which aLB1 cause thromboprotection in vivo. Since a number of autoantigens in SLE have been localized specifically to the external surface of apoptotic blebs, it was hypothesized that circulating aLB1 may block the procoagulant effect of apoptotic blebs by binding to LB1 displayed at the external bleb surface. METHODS: A cross-sectional study was performed using serum samples obtained at first evaluation of 259 English Canadian and French Canadian patients from SLE registries at 3 hospitals. A case-control study was performed to analyze the relationship between aLB1 and lupus anticoagulant (LAC) status and thrombotic manifestations between onset of disease and last followup. Reactivity of aLB1 with Jurkat or endothelial cells, which had been induced to undergo apoptosis, was determined by indirect immunofluorescence. Localization of LB1 in apoptotic cells and blebs was analyzed by confocal microscopy and surface labeling of cell membrane proteins. RESULTS: High-titer aLB1 was restricted to a subset of SLE patients (46 patients), with an overall frequency of 17.8% (range 11.6-24.3% in the 3 centers). LB1 antibodies were significantly associated with LAC but not with antibodies to cardiolipin (aCL) or beta(2)-glycoprotein I (anti-beta(2)GPI). The frequency of thrombosis differed markedly depending on aLB1 and LAC status, as follows: presence of LAC and absence of aLB1 50%, presence of both LAC and aLB1 22.7%, absence of both LAC and aLB1 25.5%, absence of LAC and presence of aLB1, 20.8%. Further subclassification of patients based on aCL and anti-beta(2)GPI status revealed that, in the presence of LAC but in the absence of aCL, anti-beta(2)GPI, and aLB1, the frequency of thrombosis was 40%, whereas in the presence of aLB1, it decreased strikingly, to 9.1%. LB1 was found to be translocated into surface membrane blebs during apoptosis and to be entirely enclosed within the apoptotic bleb plasma membrane of Jurkat and endothelial cells. CONCLUSION: The presence of aLB1 in SLE patients with LAC essentially nullifies the strong prothrombotic risk associated with LAC. Hence, aLB1 is associated with thromboprotection. Reactivity of aLB1 with apoptotic blebs does not seem to play a direct role in mediating this protection, since LB1 is buried within apoptotic blebs and inaccessible to circulating aLB1. The mechanism by which aLB1 confers thromboprotection in SLE remains to be elucidated.

Adult↗
PubMed2002

Factor V Leiden, prothrombin gene mutation, and thrombosis risk in patients with antiphospholipid antibodies.

OBJECTIVE: To determine if the prevalence of 2 prothrombotic genetic factors, factor V Leiden and prothrombin gene mutation, is increased in patients with antiphospholipid (aPL) antibodies with a history of venous/arterial thrombosis compared to patients with aPL antibodies with no history of thrombosis. METHODS: One hundred fifty-seven patients with aPL antibodies were studied. The occurrence of venous and arterial thrombotic events since the time of antibody detection was determined retrospectively, using appropriate clinical and diagnostic criteria. Clinical risk factors for thrombosis were documented and included hypertension, hyperlipidemia, cigarette smoking, diabetes, positive family history, use of oral contraceptive, pregnancy, trauma, hospitalization, varicose veins, and malignancy. Genomic DNA was extracted from blood cells for determination of factor V Leiden mutation G1691 --> A and prothrombin mutation G20210 --> A by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Of 157 patients, 69 had a history of thrombosis (venous 37, arterial 32); 147 (94%) patients had anticardiolipin (aCL) antibodies; 69 (45%) had lupus anticoagulant (LAC). The prevalence of factor V Leiden in patients with thrombosis was 13% compared to 4.6% in patients without thrombosis (OR 3.11, CI 0.92-10.6). In patients with aCL antibodies, 15% of patients with arterial thrombosis had factor V mutation compared to 3.5% of patients without thrombosis (OR 4.9, CI 1.2-19.3). The prothrombin gene mutation was identified in 5 patients, none of whom had thrombosis. Stepwise logistic regression analysis indicated that LAC (p = 0.005), male sex (p = 0.04), and hypertension (p = 0.03) were the strongest risk factors for developing thrombosis and that no additional risk was conferred by factor V Leiden (p = 0.13) and prothrombin gene mutation. CONCLUSION: Although the prevalence of factor V Leiden is modestly increased in patients with autoimmune aPL antibodies and thrombosis, these results suggest that its detection does not significantly increase the risk of a thrombotic event, once other clinical risk factors have been considered. Prothrombin gene mutation is not associated with thrombosis in patients with aPL antibodies.

Adult↗