Living with lupus: a prospective pan-Canadian study.

OBJECTIVE: To portray life with lupus for women affected by this disease and to identify predictors of fatigue, a common symptom that compromises patients' quality of life. METHODS: A sample of 120 female patients (mean age 42.5 yrs) with systemic lupus erythematosus (SLE) from 9 rheumatology clinics across Canada were followed prospectively for 15 months. Assessments of psychosocial functioning took place at baseline, and at 3, 9, and 15 months. Physician examinations were conducted at baseline and 15 months. RESULTS: Significant time effects were found for: global psychological distress (p < 0.001), stress (p < 0.01), emotion-oriented coping (p < 0.001), physical health status (p < 0.001), and fatigue (p < 0.001), indicating that patients improved from baseline to 15 months. Disease activity worsened for 40.3%, improved for 50.8%, and remained the same for 8.8% of the patients from baseline to 15 months. Controlling for baseline disease activity and fatigue, and considering sleep problems, decreases in stress and depression predicted less fatigue at 15 months (p < 0.001; adjusted R2 = 0.43). CONCLUSION: Despite fluctuations in disease activity, patients with SLE, as a group, cope adequately with their disease over time. There is, nonetheless, a subset of patients (about 40%) who remain distressed and who may benefit from psychosocial interventions.

Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a 3 year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study.

OBJECTIVE: To assess the longterm effect of delaying therapy with second-line agents in patients with early rheumatoid arthritis (RA). METHODS: One hundred nineteen patients who participated in a 9 month placebo controlled randomized trial of hydroxychloroquine sulfate (HCQ) were followed prospectively for an additional 3 years. Those randomized to HCQ are referred to as the early treatment group and those randomized to placebo as the delayed treatment group. Participants were assessed annually for pain [Arthritis Impact Measurement Scales (AIMS) and Stanford Health Assessment Questionnaire (HAQ)], physical disability (AIMS and HAQ), and the RA global well being scale (AIMS). Conversion of results into standard deviation (SD) units permitted defining a substantial difference as per Felson as > 0.30 SD units and a clinically indistinguishable difference as < or = 0.06 SD units. RESULTS: One hundred fifteen patients (97%) participated and complete data were available on 104 (87%). Compared to the early treatment group, the delayed group remained worse for both the pain and the physical disability outcomes over the additional 3 year followup. The difference in the RA global well being score became clinically indistinguishable for the early and delayed groups only after the 2 year post-trial assessment. The between-group differences were not explained by post-trial therapy with corticosteroids, other second-line agents, or nonsteroidal antiinflammatory drugs and analgesic preparations. CONCLUSION: These findings show that a delay in instituting therapy with second-line agents, even a 9 month delay in instituting a moderately powerful second-line agent such as HCQ, has significant effects on longterm patient outcome, and provides strong evidence in support of early therapy in RA.

36 month intermittent cyclical etidronate treatment in patients with established corticosteroid induced osteoporosis.

OBJECTIVE: To determine the longterm safety and efficacy of etidronate therapy in patients in whom corticosteroid induced bone loss has already occurred. METHODS: We performed a 36 month observational cohort study in which all data were obtained from Canadian Database of Osteoporosis and Osteopenia (CANDOO) patients. The etidronate group consisted of 24 patients who received 400 mg of etidronate disodium for 14 days, followed by 76 days of calcium carbonate (500 mg of elemental calcium), repeated every 3 mo; the control group included 37 patients who received calcium carbonate 500 to 1000 mg daily. Outcome measurements included changes within groups from baseline and differences between groups in the bone mineral density (BMD) of the lumbar spine, femoral neck, and trochanter at 12, 24, and 36 months. The incidence of vertebral fractures was also determined. RESULTS: Etidronate therapy resulted in a meaningful percentage increase from baseline in lumbar spine BMD, primarily during the first 24 months of treatment, and this increase was sustained for the remainder of the 36 month study period (5.2%; p = 0.016). Analysis of covariance revealed a significant percentage difference (SD) between groups in lumbar spine BMD at 12 [5.5 (13.5) percent; p = 0.003] and 24 months [6.0 (17.4) percent; p = 0.011] in favor of the etidronate group. After 3 years of therapy, one patient (4%) experienced one vertebral fracture in the etidronate group, whereas 3 patients (8%) experienced 5 vertebral fractures in the control group. CONCLUSION: Etidronate treatment administered for 36 months reversed lumbar spine bone loss, and appeared to be safe in patients with established corticosteroid induced osteoporosis.

Quality of life in systemic lupus erythematosus patients during more and less active disease states: differential contributors to mental and physical health.

OBJECTIVE: To identify determinants of mental and physical health as a function of disease state in patients with systemic lupus erythematosus (SLE). METHODS: A sample of 129 SLE patients (mean age 42.01 years; SD 11.09) was recruited from 9 immunology/rheumatology clinics across Canada. Patients completed questionnaires assessing psychological distress, social support, coping, stress, and health-related quality of life. Physicians rated disease activity (using the revised Systemic Lupus Activity Measure; SLAM-R) and damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). Mental and physical health composite scores were derived from the Medical Outcomes Study Short Form 36. Patients were subdivided into more active (SLAM-R > or = 10; n = 38) or less active disease states (n = 91). RESULTS: Better mental health was predicted by more education and less emotion-oriented coping in the patients in a more active disease state (P = 0.0001; R2 = 0.46). Better mental health was predicted by less stress, less emotion-oriented coping and more task-oriented coping in patients during a less active disease state (P = 0.0001; R2 = 0.45). Better physical health was predicted by more emotion-oriented coping in patients in a more active disease state (P = 0.04; R2 = 0.11). Better physical health was predicted by less stress and younger age in patients during a less active disease state (P = 0.0001; R2 = 0.20). CONCLUSION: The positive association between emotion-oriented coping and better physical health in patients during a more active disease state suggests that this style of coping may be more adaptive in situations that are considered uncontrollable (e.g., SLE flare). Predictors of mental health were similar to those found in the literature, especially for SLE patients in a less active disease state.

A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group.

The ability of antimalarials to moderate severe disease activity in systemic lupus erythematosus (SLE) is plausible but undemonstrated. We evaluated the long-term effectiveness of maintaining treatment with hydroxychloroquine sulphate (HCQ) to prevent major flares in quiescent SLE. Forty-seven patients with quiescent SLE who had been randomized to take HCQ (n = 25) or placebo (n = 22) as part of a 24-week withdrawal trial were evaluated for an additional 3 years. The primary outcome was time to a major flare of SLE which resulted in either the institution of or an increase in the current dosage of prednisone of 10 mg/day or more, or institution of therapy with immunosuppressive agents. Secondary outcomes included the specific subtype of these major flares (glomerulonephritis, vasculitis or other) and hospitalization for an exacerbation of SLE. An intent-to-treat analysis was conducted. Over the 42 months of study, 11 of 22 (50%) patients randomized initially to placebo, and seven of 25 (28%) patients randomized to continue treatment experienced a major flare. The relative risk of major flare for those randomized to continue HCQ compared with controls was 0.43 (95% CI: 0.17, 1.12). The relative risks for subtypes of flares were 0.26 (95% CI: 0.03, 2.54) for nephritis, 0.51 (95% CI: 0.09, 3.08) for vasculitis and 0.65 (95% CI: 0.17, 2.41) for flares characterized by other symptoms. The relative risk of hospitalization for major flare for patients randomized to continue hydroxychloroquine was 0.58 (95% CI: 0.13, 2.60). While the results are not statistically significant, they are compatible with the clinical belief that HCQ has a long-term protective effect against major disease flares in SLE and suggest that on average, HCQ use reduces major flares by 57% (95% CI: 83% reduction to 12% increase).

Corticosteroid-induced osteoporosis.

Corticosteroid-induced osteoporosis is a serious disorder that results in significant morbidity. A summary of our understanding of the pathophysiology is provided and highlights some of the controversy the exists. Clinical trials for the prevention and treatment of corticosteroid-induced osteoporosis are reviewed.

Salmon calcitonin nasal spray in the prevention of corticosteroid-induced osteoporosis.

The objectives were to determine the efficacy and safety of nasal salmon calcitonin 200 IU daily in the prevention of corticosteroid-induced osteoporosis. A minimized, double-blind, placebo-controlled trial was carried out in corticosteroid-treated patients with polymyalgia rheumatica. The setting was a tertiary care university-affiliated hospital and a total of 31 patients were enrolled. The primary outcome measure was the percentage change in bone mineral density of the lumbar spine in the two treatment groups from baseline to 1 yr of follow-up. The mean +/- S.D. bone mineral density of the lumbar spine in the calcitonin-treated group decreased by 1.29 +/- 6.76% and in the placebo group by 4.95 +/- 3.50% after 12 months. The observed difference of 3.65 +/- 2.10% between groups is statistically significant (P < 0.05). Nasal salmon calcitonin prevented loss of bone in the lumbar spine as measured by dual-energy X-ray absorptiometry.

Fluoride therapy in prevention of rheumatoid arthritis induced bone loss.

OBJECTIVE: To determine the efficacy of sodium fluoride (40 mg/day) in preventing rheumatoid arthritis (RA) induced bone loss, which may lead to osteoporosis. METHODS: We conducted an 18 month, randomized, double blind, placebo controlled trial in 38 patients with RA. The primary outcome measure was the difference in the percentage change between groups in lumbar spine bone mineral density (BMD) from baseline values after 18 months of therapy. The secondary outcome measures were the differences in the percentage change between groups in femoral neck, Ward's triangle, trochanter, and total body BMD from baseline after 18 months of therapy. RESULTS: There was a significant percentage difference (SD) between groups of 6.2% (7.3%) (p = 0.0005) in lumbar spine BMD after 18 months of treatment in favor of the fluoride group. The fluoride group experienced a 5.2% (8.4%) (p = 0.0125) increase, whereas the placebo group showed a 1.0% (4.8%) (p = 0.8015) decrease in lumbar spine BMD after treatment. No significant differences were found for the femoral neck, Ward's triangle, trochanter, and total body BMD in terms of the percentage changes from baseline within each treatment group or in the differences in the degree of change between groups after therapy. Lumbar spine BMD increased in about 80% of patients treated with fluoride (responders) compared to 44% of patients treated with placebo. CONCLUSION: The results showed that fluoride therapy was well tolerated and increased vertebral bone mass in patients with RA.

Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada.

OBJECTIVE: To evaluate viscosupplementation with intraarticular hylan G-F 20 in current clinical practice. METHODS: A retrospective study of all patients with osteoarthritis of the knee treated with hylan by 5 Canadian clinicians over a period of 2.5 years. RESULTS: A total of 1537 injections were performed in 336 patients involving 458 knees. The overall response and the change of activity level were judged better or much better for 77 and 76% of the treated knees after the first course of treatment (3 weekly injections), and 87 and 84% after a 2nd course. The mean time elapsing between the first and 2nd course, 8.2 +/- 0.5 months, is an evaluation of the duration of benefits. Local adverse events were observed in 28 patients (32 knees), with an overall rate of 2.7% adverse events per injection, 7.0% per joint, and 8.3% per patient. No systemic adverse events were noted in any patient. The adverse events were characterized by pain and/or transient swelling of the injected joint, mostly mild or moderate in intensity, and 72% of the adverse events were considered to be possibly or probably related to the injection. The incidence of adverse events is significantly influenced by the injection technique: 5.2% adverse events per injection with a medial approach to a partially bent knee, and 2.4% (straight medial) and 1.5% (straight lateral). After an adverse event, clinical improvement still occurred in 69% of the affected knees. CONCLUSION: Hylan G-F 20 provided good clinical benefits and an acceptable safety profile in current clinical practice. The occurrence of adverse events after an intraarticular hylan injection is infrequent and unpredictable and is not necessarily hylan related, although injection related.

Vitamin D and calcium in the prevention of corticosteroid induced osteoporosis: a 3 year followup.

OBJECTIVE: To determine the efficacy and safety of vitamin D 50,000 units/week and calcium 1,000 mg/day in the prevention of corticosteroid induced osteoporosis. METHODS: A minimized double blind, placebo controlled trial in corticosteroid treated subjects in a tertiary care university affiliated hospital. The sample was 62 subjects with polymyalgia rheumatica, temporal arteritis, asthma, vasculitis, or systemic lupus erythematosus. The primary outcome measure was the percentage change in bone mineral density (BMD) of the lumbar spine in the 2 treatment groups from baseline to 36 mo followup. RESULTS: BMD of the lumbar spine in the vitamin D and calcium treated group decreased by a mean (SD) of 2.6% (4.1%) at 12 mo, 3.7% (4.5%) at 24 mo, and 2.2% (5.8%) at 36 mo. In the placebo group there was a decrease of 4.1% (4.1%) at 12 mo, 3.8% (5.6%) at 24 mo, and 1.5% (8.8%) at 36 mo. The observed differences between groups were not statistically significant. The difference at 36 mo was-0.693% (95% CI -5.34, 3.95). CONCLUSION: Vitamin D and calcium may help prevent the early loss of bone seen in the lumbar spine as measured by densitometry of the lumbar spine. Longterm vitamin D and calcium in those undergoing extended therapy with corticosteroids does not appear to be beneficial.

Intermittent cyclic therapy with etidronate in the prevention of corticosteroid induced bone loss.

OBJECTIVE: To assess the potential efficacy of intermittent cyclic therapy (ICT) with etidronate in the treatment of patients with corticosteroid induced osteoporosis. METHODS: Cohort study in a tertiary care university affiliated hospital in corticosteroid treated patients, with polymyalgia rheumatica, asthma, systemic lupus erythematosus, rheumatoid arthritis, or temporal arteritis, examining the effects of ICT etidronate. Patients were included if they were taking corticosteroids for a minimum of one year. Comparison patients were those who had been taking corticosteroids for a minimum of one year and who had not been treated with etidronate or other medication which might alter bone metabolism. A total of 68 patients were included from 253 considered. The mean (SD) dose of prednisone in the ICT etidronate treated patients was 9.3 (6.2) mg and in the comparison patients 9.4 (5.9) mg. The duration of prednisone therapy was 7.8 (5.8) years and 3.4 (4.2) years, respectively (p2 < 0.001). An analysis of covariance demonstrated that this difference did not alter our primary outcome measure. The primary outcome measure was the difference in the percentage change from baseline to one year of followup in bone mineral density (BMD) of the lumbar spine between treatment and comparison groups. RESULTS: ICT etidronate resulted in a statistically significant and clinically important increase in BMD. The BMD of the lumbar spine increased by 3.82% (0.65%), [95% confidence interval (CI), 2.51 to 5.14%] in the 35 ICT etidronate treated patients and decreased by 1.78% (0.76%), [95% CI, -3.34 to -0.23%] in the 33 comparison patients after 12 months (p2 < 0.0001). CONCLUSIONS: ICT etidronate prevented loss of vertebral bone density in patients with corticosteroid induced osteoporosis. Controlled, double blind, prospective trials with longer followup are needed to confirm these results and to demonstrate that increases in bone mass translate into decreased fracture rates.

Primary angiitis of the CNS diagnosed by angiography.

Sixteen patients (8 female, 8 male) with primary angiitis of the CNS (PACNS), were followed prospectively in a vasculitis clinic. Diagnosis was by angiography in patients without underlying disease. Median age at diagnosis was 36.5 years, and median duration of follow-up was 28 months. Onset was acute in 14 patients (88%), with 3.5 weeks (median) from onset symptoms to diagnosis. Three women developed symptoms within 3 weeks postpartum. The most frequent symptoms were severe headaches (12, 75%), stroke (6, 30%), transient ischaemic attack (TIA) (4, 28%), seizures (7, 44%), visual aberration (3, 19%), and cognitive impairment (5, 31%). Laboratory data included high ESR (2, 13%), leucocytosis (8, 80%), thrombocytosis (1, 6%), positive antinuclear antibody titre (3, 15%), and high levels of complement (5, 31%). Lumbar puncture was performed in 12 patients (75%). CSF analysis was abnormal in five patients (42%). EEG was abnormal in 5/9 patients. The major CT/MRI scan findings were cerebral haemorrhage (4, 25%), brain infarcts (5, 31%), brain atrophy (2, 13%) and non-specific lesions (2, 13%). Four patients had normal studies. All patients received corticosteroids (CS), and five were treated with oral cyclophosphamide. Two patients relapsed despite CS and cyclophosphamide therapy. All patients are alive, and at the last assessment, eight had a permanent neurological deficit, which included paresis (3, 19%), neurocognitive abnormalities (2, 13%), visual loss (2, 13%) and seizure activity (5, 31%). Our data suggest a non-progressive, non-fatal course in those PACNS patients diagnosed angiographically and treated with CS with or without cyclophosphamide.

Interrater reliability of the tender point criterion for fibromyalgia.

The diagnosis fibromyalgia (FS) requires the existence of tender points, routinely identified by clinical examination. We evaluated the interrater reliability of digital (thumb) examination for tender points by comparison with dolorimeter examination, a procedure considered to measure accurately muscle tenderness. Subjects were 15 patients with varying rheumatological diagnoses and anatomically widespread pain. In a physician blinded procedure, 2 rheumatologists determined the tender point count by digital examination at 18 points, and the tender point threshold by dolorimeter at 12 points. A pain threshold of 4 kg/1.77 cm2 or less defined the presence of tender points under both methods. Results indicate (1) classification as FS vs other diagnosis using pain complaint and digital examination for tender points, was moderately reliable (kappa = 0.74, p < 0.005); (2) interrater agreement about presence/absence of tenderness at individual points was not significantly lowered by digital examination (kappa = 0.51, p < 0.0001) relative to dolorimetry (kappa = 0.62, p < 0.0001); however, (3) analyses on the 12 anatomical points that were common to both methods indicated that digital examination resulted in significantly more anatomical points being considered tender relative to dolorimetry. Our findings indicate that digital and dolorimeter measures are equally reliable, but have poor concurrent validity for defining tender points in FS. Implications of these findings for the classification of fibromyalgia are discussed.

Relationship of antiphospholipid antibodies to pregnancy loss in patients with systemic lupus erythematosus: a cross-sectional study.

To determine whether an association exists between the presence of antiphospholipid antibodies and pregnancy loss, a cross-sectional study was performed. Consecutive women who were referred to three outpatient rheumatology clinics and who had systemic lupus erythematosus (SLE) and a history of one or more pregnancies were evaluated. Patients were interviewed to determine outcomes of all previous pregnancies. Blood was taken on two separate occasions at least 3 months apart to test for the presence of the lupus anticoagulant and anticardiolipin antibodies; on both occasions, five tests of the lupus anticoagulant, with well-defined normal ranges, and an enzyme-linked immunosorbent assay to measure IgG anticardiolipin antibodies were performed. Patients were considered to be positive for the lupus anticoagulant if one or more tests was abnormal on both occasions and positive for anticardiolipin antibodies if the test was abnormal on both occasions. Forty-two women were studied. Statistically significant associations were shown between lupus anticoagulant positivity and previous pregnancy loss (odds ratio [OR], 4.8; 95% confidence intervals [CI], 1.0 to 23.6; P = .05) and between anticardiolipin antibody positivity and previous pregnancy loss (OR, 20.0; 95% CI, 1.3 to 97.0; P = .01). All seven women with multiple episodes of pregnancy loss were lupus anticoagulant positive and four of these were also anticardiolipin antibody positive. If patients who are transiently positive for lupus anticoagulant and/or anticardiolipin antibodies are considered to be test positive, the associations with pregnancy loss are no longer statistically significant. Within the group of lupus anticoagulant-positive patients, we observed stronger associations between the presence of six or more positive tests and pregnancy loss than between the presence of two to five positive tests and pregnancy loss. No single test for the lupus anticoagulant provides a statistically significant association with pregnancy loss. The results of our study show that by performing multiple lupus anticoagulant tests and by repeating testing for lupus anticoagulant and anticardiolipin antibodies on more than one occasion, significant associations between the presence of antiphospholipid antibodies and previous pregnancy loss can be shown in patients with SLE.

The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus: a cross-sectional study.

In order to determine whether an association exists between antiphospholipid antibodies (APLA) and thromboembolic events in patients with systemic lupus erythematosus (SLE), we performed a cross-sectional study of consecutive unselected SLE patients. The occurrence of previous thromboembolic events was determined by investigators blinded to the APLA status of the patients by critical review of objective tests that had been performed at the time of symptomatic presentation and by performing venous Doppler ultrasound of the legs to elicit venous reflux as an indication of previous venous thrombosis. The presence of APLA was determined by coagulation assays for the lupus anticoagulant (LA) using five tests with well-defined control ranges and by ELISA assay for anticardiolipin antibodies (ACLA). These tests were measured on two separate occasions. The results of the study demonstrate a statistically significant association between persistently abnormal ACLA assays and thromboembolic events and a non-significant trend between persistently abnormal LA and thromboembolic events. Transient abnormalities of LA and ACLA were less strongly associated with thromboembolic events. We conclude that in patients with SLE, there is a significant association between thromboembolism and APLA.

Gold induced thrombocytopenia: 12 cases and a review of the literature.

Gold induced thrombocytopenia is immune mediated, with the production of platelet associated IgG leading to peripheral platelet destruction. An association with HLA-DR3 has been demonstrated. Corticosteroid therapy is effective in treatment, although other modes of therapy may be as efficacious.