Patterns of medication use before, during and after pregnancy in women with systemic lupus erythematosus: a population-based cohort study.

OBJECTIVES: This study aimed to characterize the patterns of medication use before, during and after pregnancy in a population-based cohort of women with systemic lupus erythematosus (SLE). METHODS: Using population-based administrative data in British Columbia, Canada, with valid information on start date of pregnancy, we identified women with SLE who had singleton pregnancies ending in deliveries between January 1, 2002, and December 31, 2012. We assessed the proportion of SLE pregnancies exposed to SLE medications - namely antimalarials and immunosuppressants - as well as glucocorticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs) 24 months before pregnancy, each trimester of pregnancy, and 12 months postpregnancy. We also assessed discontinuation of antimalarials and immunosuppressants, defined as no prescriptions in a given window following a prescription in a preceding window. RESULTS: Of 376 pregnancies (284 women) with SLE, 24.2% had one or more dispensing for antimalarials, 8.2% for azathioprine, 19.7% for glucocorticosteroids and 4.8% for NSAIDs during pregnancy. We observed a 16.7% discontinuation of antimalarials in the year prior to pregnancy, 29.8% in the first trimester, 9.7% in the second trimester, and 26.0% in the third trimester. We also observed a 29.2% discontinuation of azathioprine in the first trimester, 8.0% in the second trimester, and 9.1% in the third trimester. CONCLUSIONS: These population-based data show frequent discontinuation of medications, particularly antimalarials, in SLE pregnancies. These findings suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy.

Incremental direct medical costs of systemic lupus erythematosus patients in the years preceding diagnosis: A general population-based study.

Objective We estimated the incremental (extra) direct medical costs of a population-based cohort of newly diagnosed systemic lupus erythematosus (SLE) for five years before and after diagnosis, and the impact of sex and socioeconomic status (SES) on pre-index costs for SLE. Methods We identified all adults newly diagnosed with SLE over 2001-2010 in British Columbia, Canada, and obtained a sample of non-SLE individuals from the general population, matched on sex, age, and calendar-year of study entry. We captured costs for all outpatient encounters, hospitalisations, and dispensed medications each year. Using generalised linear models, we estimated incremental costs of SLE each year before/after diagnosis (difference in costs between SLE and non-SLE, controlling for covariates). Similar models were used to examine the impact of sex and SES on costs within SLE. Results We included 3632 newly diagnosed SLE (86% female, mean age 49.6 ± 15.9) and 18,060 non-SLE individuals. Over the five years leading up to diagnosis, per-person healthcare costs for SLE patients increased year-over-year by 35%, on average, with the biggest increases in the final two years by 39% and 97%, respectively. Per-person all-cause medical costs for SLE the year after diagnosis (Year + 1) averaged C$12,019 (2013 Canadian) with 58% from hospitalisations, 24% outpatient, and 18% from prescription medications; Year + 1 costs for non-SLE averaged C$2412. Following adjustment for age, sex, urban/rural residence, socioeconomic status, and prior year's comorbidity score, SLE was associated with significantly greater hospitalisation, outpatient, and medication costs than non-SLE in each year of study. Altogether, adjusted incremental costs of SLE rose from C$1131 per person in Year -5 (fifth year before diagnosis) to C$2015 (Year -2), C$3473 (Year -1) and C$6474 (Year + 1). In Years -2, -1 and +1, SLE patients in the lowest SES group had significantly greater costs than the highest SES. Unlike the non-SLE cohort, male patients with SLE had higher costs than females. Annual incremental costs of SLE males (vs. SLE females) rose from C$540 per person in Year -2, to C$1385 in Year -1, and C$2288 in Year + 1. Conclusion Even years before diagnosis, SLE patients incur significantly elevated direct medical costs compared with the age- and sex-matched general population, for hospitalisations, outpatient care, and medications.

The needs of persons with lupus and health care providers: a qualitative study aimed toward the development of the Lupus Interactive Navigator™.

OBJECTIVE: Systemic lupus erythematosus is an inflammatory autoimmune disease associated with high morbidity and unacceptable mortality. A major challenge for persons with lupus is coping with their illness and complex care. Our objective was to identify the informational and resource needs of persons with lupus, rheumatologists, and allied health professionals treating lupus. Our findings will be applied toward the development of an innovative web-based technology, the Lupus Interactive Navigator (LIN™), to facilitate and support engagement and self-management for persons with lupus. METHODS: Eight focus groups were conducted: four groups of persons with lupus (n=29), three groups of rheumatologists (n=20), and one group of allied health professionals (n=8). The groups were held in British Columbia, Ontario, and Quebec. All sessions were audio-recorded and transcribed verbatim. Qualitative analysis was performed using grounded theory. The transcripts were reviewed independently and coded by the moderator and co-moderator using 1) qualitative data analysis software developed by Provalis Research, Montreal, Canada, and 2) manual coding. RESULTS: Four main themes emerged: 1) specific information and resource needs; 2) barriers to engagement in health care; 3) facilitators of engagement in health care; and 4) tools identified as helpful for the self-management of lupus. CONCLUSION: These findings will help guide the scope of LIN™ with relevant information topics and specific tools that will be most helpful to the diverse needs of persons with lupus and their health care providers.

IFN-alpha as induction and maintenance treatment of patients newly diagnosed with Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia is a rare malignant disorder of B lymphocytes. There are no studies on the use of interferon-alpha (IFN-alpha) as frontline therapy in this disease. Between April 1991 and September 2000, we treated 21 newly diagnosed patients using 8 mg/m(2) chlorambucil and 40 mg/m(2) prednisone p.o. daily for 10 days and 3 megaU/m(2) IFN-alpha three times a week. Patients who responded after induction continued receiving IFN until relapse or death. We found a high frequency of peripheral neuropathy (43%) and grade 3 diffuse marrow fibrosis (43%). Objective response was achieved in 12 (57%) patients, including 4 (19%) complete responders. Median time from treatment to response was 8 months (range 3-18). Median progression-free survival was 70 months (95% CI 47-93), and overall survival was 91 months (95% CI 50-132). Patients who achieved objective response lived longer (91 vs. 33 months, p < 0.03), as did patients who had lactic dehydrogenase (LDH) < 180 U/L (89 vs. 54 months, p < 0.01). Grade 3 hematologic toxicity was observed during induction in 5 patients. IFN-alpha is an effective agent for the induction and maintenance treatment of Waldenström's macroglobulinemia patients. LDH > 180 U/L and failure to respond are adverse prognostic factors.

Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial.

OBJECTIVE: To evaluate the efficacy of intravenous cyclophosphamide pulse therapy in patients with optic neuritis associated with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Ten consecutive patients with optic neuritis due to SLE whose condition was refractory to corticosteroids and oral immunosuppressants were treated with intravenous cyclophosphamide (0.5 to 1.0 g/m2) monthly for 6 months. RESULTS: All patients had bilateral eye involvement. One eye was legally blind, and 13 eyes could see only hand movements or count fingers. Six patients had evidence of the secondary antiphospholipid antibody syndrome. Complete recovery in visual acuity occurred in 10 eyes (50%), and a partial response occurred in six eyes (30%); four eyes (20%) had no response. Complete response in the field tests occurred in eight eyes (40%), with a partial response in nine eyes (45%); no improvement occurred in three eyes (15%). CONCLUSIONS: Intravenous cyclophosphamide pulse therapy seems to be an effective treatment for optic neuritis refractory to corticosteroids, oral immunosuppressants, or both. A randomized controlled trial will be necessary to confirm our results.

Reduction in hospitalization costs, morbidity, disability, and mortality in patients with aids treated with protease inhibitors.

BACKGROUND: The objective of this study was to analyze hospitalization costs, morbidity, disability, and mortality in patients with acquired immunodeficiency syndrome (AIDS) treated with protease inhibitors (PI). METHODS: This is a self-controlled, ambispective study of a total of 581 patients with human immunodeficiency virus (HIV)/AIDS seen at the Hospital de Infectología, Centro Médico La Raza, IMSS, in Mexico City during 1997. A total of 210 (36.14%) patients initiated protease inhibitor (PI) treatment at the onset of the study. Thirty-eight patients satisfied the inclusion criteria for this study and were analyzed retrospectively during the year prior to PI treatment, and then prospectively throughout the year on PI treatment. As concerns main outcome measures, financial costs, number of hospitalizations, number of infections, and productivity and laboratory parameters (CD4(+) counts and viral load) were analyzed during the year prior to PI treatment and then prospectively during the year on PI prescription. Our hypothesis was that the hospital costs, morbidity, disability, and mortality of patients with AIDS decreased while on PI treatment. RESULTS: During the year prior to PI prescription, the 38 patients enrolled in the study were admitted on a total of 59 occasions (1.55 hospitalizations/patient), whereas during the year on PI therapy, all 38 patients had only seven admissions (0.18 hospitalizations/patient). Hospitalization costs decreased 35% when annual PI costs for the 38 patients studied were taken into account. The number of microorganisms detected during hospitalization decreased from 24 prior to PI to five on PI. The number of disability days involved in patients on PI decreased significantly (p <0.0002). None of the 38 patients studied died during the year of follow-up under PI treatment. Mortality decreased significantly, from 116/481 (23.2%) in 1996, to 77/581 (13.2%) in 1997, to 40/740 (6.4%) in 1998. There were no deaths among the 38 patients studied during the 1-year follow-up period; when the observation period was extended 1 additional year, only one patient died (2.63%). Only six (3.48%) of the 172 PI-treated patients with AIDS not included in the study died during the same period. CD4(+) cell counts increased from 190.56 +/- 169.5 cells/mm(3) to 235.00 +/- 112.65 cells/mm(3) (p <0.05) after 12 months of PI treatment. Viral loads decreased from 5 logs to 2.4 logs at 12 months of PI treatment (p <0.001). CONCLUSIONS: Introduction of PI to antiretroviral treatment in patients with AIDS was associated with a lower rate of hospital admissions, lower costs, and a lesser number of infections/year, disabilities, and mortalities. Increase of CD4(+) cell counts and decrease in viral loads in the 38 patients were associated with decreased morbility and mortality.

Adverse drug reactions and debrisoquine/sparteine (P450IID6) polymorphism in patients with fibromyalgia.

OBJECTIVE: To assess the frequency of adverse drug reaction in patients with fibromyalgia in relation to medications prescribed for this condition. To evaluate the potential role of the P450IID6 phenotype in the pathogenesis of these adverse drug reactions. METHODS: Thirty-five patients with fibromyalgia were assessed using a structured questionnaire with demographic and clinical data and perceived adverse drug reactions. A sample of 60 patients with rheumatoid arthritis and 62 patients with localized back pain served as controls. The P450IID6 phenotype was determined for each of the fibromyalgia patients. RESULTS: Overall, 141 patients had used NSAID and 79 (56%) of them reported adverse effects. Antidepressant drugs were used by 68 patients and 35 (51%) patients had adverse effects. Muscle relaxant drugs were used by 48 patients and 15 (31%) of them reported side effects. Analgesics were used by 122 patients and 22 (18%) had experienced adverse effects. Statistical differences in the frequency of adverse effects were found with antidepressant drugs in the fibromyalgia group, compared with rheumatoid arthritis (p=0.01) and back pain (p=0.02). Four of the 35 patients (11.4%) had a metabolic ratio (M.R.) greater than 0.30 (log M.R.= -0.52) indicative of the poor metabolizers (PM) phenotype. M.R. varied from 0.005 (log M.R. = -2.30) to 4.99 (log M.R. = 0.70). CONCLUSIONS: The problem of adverse drug reactions in fibromyalgia patients does not appear to correlate with the PM phenotype of the P450IID6 oxidative enzyme. It also is unlikely that altered xenobiotic detoxification attributable to this PM phenotype would have a significant role in the development of fibromyalgia.

Rheumatic manifestations of neurologic and psychiatric diseases.

Rheumatic diseases have not proved to be more prevalent among neurologic or psychiatric patients than in the general population, except for osteoarthritis in some chronic disabling neurologic conditions (poliomyelitis, spinal cord injury). Some neurologic entities with relevant musculoskeletal manifestations are described here. The lower prevalence of rheumatoid arthritis in schizophrenia patients is mentioned, and a brief description is presented of somatoform disorders that may confound diagnosis with rheumatic diseases. Factitious disorders and malingering are frequently presented with rheumatic complaints such as low back pain and may have an important impact on the costs associated with the disease. Finally, some of the immune system abnormalities described in major depression and schizophrenia are mentioned with a clear reference to the growing field of psychoneuroimmunology. This paper will not address the issue of neurologic or psychiatric manifestations of rheumatic diseases.

Rheumatic manifestations of hematologic disorders.

A review of the literature during the past year on rheumatic manifestations in hematologic diseases supports the idea that 80% of the hemorrhage in hemophilia occurs within the joints, with knees, elbows, and ankles being the most affected joints in adults. In contrast, the ankle is the target joint in children. Septic arthritis in hemophilic patients is becoming more important due to the advent of HIV infection. Radioactive synoviorthesis in hemarthrosis has the same rate of success as surgical synovectomy, but with far lower costs. A new study documents the association of arthritis and vasculitis in patients with myelodysplasic syndromes and lymphoproliferative disorders. An increased incidence of scoliosis in patients with beta-thalassemia has been noted. Finally, the effects of bone marrow transplantation in patients with previous autoimmune diseases is reviewed. Progression of rheumatoid arthritis after bone marrow transplantation is documented in a patient with 13 years of follow-up. Hematologic disorders in rheumatic diseases are not the topic of this review.

Incidence of myopathy in patients treated with antimalarials. A report of three cases and a review of the literature.

A retrospective review of 4405 patients' charts identified 214 patients who initiated antimalarial therapy between January 1987 and April 1993 for different rheumatic disorders (mean duration of therapy of 17 months). From these, three patients with myopathy were found for a total of 303 patient-years of therapy, for an incidence of 1 in 100 patient-years (95%, confidence interval 0.2-3). All three patients had rheumatoid arthritis and had received chloroquine for between 12 and 18 months with a maximum dose of 250 mg/daily. All had a muscle biopsy, but only one showed the classical rimmed vacuoles. All patients improved within 2 months after the drug was stopped. A review of the literature was carried out with special reference to the significance of clinical myopathy with a negative biopsy. We found that positive biopsies are usual only if the duration of symptoms have been allowed to persist for more than 6 months.

Rheumatic manifestations of malignancy.

Rheumatic manifestations of malignancy include a wide spectrum of osteoarticular, muscular, glandular, endocrinologic, and systemic features, posing a therapeutic challenge. The clinician should be aware that Sjögren's syndrome, polymyositisdermatomyositis, rheumatoid and rheumatoid-like arthritis, polymyalgia rheumatica and temporal arteritis, and diverse osteomuscular conditions may be the immunopathogenic features of a neoplasm, the direct consequence of osteomuscular tumors, the effect of tumor-associated hormones, or the consequence of cancer therapy. The principal articles that have appeared in the past year on these associations are discussed. We also review the association of x-ray irradiation and cancer in patients with ankylosing spondylitis.

Disappointing longterm results with disease modifying antirheumatic drugs. A practice based study.

OBJECTIVE: To evaluate the longterm effectiveness of disease modifying antirheumatic drugs (DMARD) in an inception cohort of patients with rheumatoid arthritis (RA) seen by rheumatologists. METHODS: We performed a retrospective audit of the records of patients with onset of RA between January 1985 and June 1994. Charts were reviewed from the time of diagnosis to the last consult. Survival analysis was performed using Kaplan-Meier and Cox proportional hazard regression to adjust for potential confounders. RESULTS: A total of 2296 DMARD therapies were analyzed. Roughly half were started within 2 years of disease onset. By 16 months, 50% of the DMARD therapy courses had been discontinued, and after 4.5 years 75% had been discontinued. Over all, methotrexate (MTX) had the highest probability of continuation. After roughly 3 years 50% of patients were still receiving MTX, compared to one-third of patients who received antimalarials or intramuscular gold, 30% D-penicillamine, 25% sulfasalazine, and 18% oral gold. After 6 years, when considering all DMARD together, only 20% of the therapies had not been discontinued, with no substantial differences between drugs. Toxicity from gold compounds occurred within the first 18 months of therapy and stabilized thereafter. For MTX, withdrawals due to toxicity continued throughout therapy. CONCLUSION: This is the largest observational study examining the longterm termination rates of DMARD in patients followed from the time of their initial consult. Our results confirm previous reports of short therapeutic times, even for patients treated early in the course of their disease. MTX appears to be the best drug within the first 5 years of disease. These differences, however, decrease in the longer term. It is unclear whether the results observed for MTX within the first years of therapy translate to better health status in the longer term when compared to other DMARD.

Clinical evaluation of various selected ELISA kits for the detection of anti-DNA antibodies.

Fifty four coded sera, 38 from eight patients with systemic lupus erythematosus (SLE), four from one patient with systemic vasculitis, one from one patient with polyarthritis and 11 normal controls were tested for anti-dsDNA antibodies using seven commercial enzyme linked immunosorbent assays (ELISA) and the radioimmunoassay method (RIA) routinely used in our unit. Sensitivity, specificity and predictive values were tested for both SLE diagnosis and disease activity. Using anti-dsDNA antibodies as a diagnostic test for SLE there were differences in sensitivity (from 66% to 95%), specificity (from 75% to 100%), predictive positive values (from 89% to 100%) and predictive negative values (from 50% to 87%) among ELISA kits. The RIA method was either more specific or equal to ELISA kits. Using 'equivocal' values as positive values an increase in sensitivity was observed but at the expense of specificity. Similar differences and trends were observed when the results were used as a measure for disease activity. This suggests that there are differences in sensitivity, specificity and predictive values among ELISA kits both in the diagnosis of SLE as well as in the determination of disease activity.

Long-term effectiveness of antimalarial drugs in rheumatic diseases.

OBJECTIVE: The purpose of this study was to compare the long-term effectiveness between chloroquine (CQ) and hydroxychloroquine (HCQ). METHODS: Medical charts of all patients seen by eight rheumatologists practising in two tertiary care centres and starting antimalarial treatment between January 1985 and December 1993 were reviewed. Patient characteristics, disease, and treatment information were collected. The main outcome measures were the cause of and the time to the discontinuation of antimalarial drugs resulting from all causes, principally toxicity or inefficacy, or both. Bivariate analysis including t tests and chi 2 tests were used to assess differences between means and proportions respectively. Survival curves were evaluated using the Kaplan-Meier method. Multivariate analysis (Cox regression) was used to adjust for potential confounders. RESULTS: After all medical records were reviewed, 1042 eligible cases were identified. From these, 940 (90%) had usable information and they represent the cohort. Five hundred and fifty eight had rheumatoid arthritis, 178 had systemic lupus erythematosus, 127 had palindromic arthritis, and 77 had other diagnoses. Fifty seven per cent of the patients received CQ and 43% HCQ. The proportion of patients with side effects taking HCQ and CQ was 15% and 28% respectively (p = 0.001). Using Cox regression model to adjust for age at the onset of antimalarial treatment, physician differences, sex, disease type, disease duration before treatment, and rank selection, there were no differences in the hazard ratio (HR) for overall discontinuations between CQ and HCQ. While the HR for discontinuations because of toxicity was lower for HCQ (HR = 0.6, 95% CI 0.4, 0.9), the HR for discontinuations because of inefficacy was significantly higher for HCQ (HR = 1.4, 95% CI 1.1, 1.9). CONCLUSIONS: After adjusting for time and several confounders HCQ was less toxic but less effective than CQ. Only one case of probable/possible retinopathy was found. Therefore, we propose a careful baseline ophthalmological evaluation by an expert and then one or every two years if proper doses are used.

Long-term effectiveness of danazol corticosteroids and cytotoxic drugs in the treatment of hematologic manifestations of systemic lupus erythematosus.

The purpose of this study was to compare the long-term effectiveness among danazol, corticosteroids, cytotoxics, and dapsone in the treatment of hematological manifestations of systemic lupus erythematosus (SLE). Medical charts of all patients seen at the Rheumatic Disease Unit from January to December of 1998 were reviewed. Patient characteristics, disease and treatment information were collected. The main outcome measures were the cause of and time to discontinuation of drugs used to treat hematological manifestations of SLE resulting from all causes, mainly toxicity and inefficacy or both. Bivariate analysis including one-way ANOVA and chi2 tests were used to compare differences between means and proportions, respectively. Survival curves among the different drugs were evaluated using the Kaplan-Meier method. Multivariate analysis (Cox-regression) was used to adjust for potential confounders. After all medical records were reviewed 41 cases were eligible. Two cases had hemolytic anemia, 34 had thrombocytopenia, and five had both. These cases had received a total of 121 cycles of treatment at different times and they represent the study population (corticosteroids n = 37, danazol n = 51, citotoxic drugs n = 29, and dapsone n = 4). Crude rates of discontinuations due to any cause, toxicity and inefficacy werenot statistically significant among the drugs. However, the Kaplan-Meier curves showed statistically significant difference for discontinuations due to all causes as well as inefficacy. Prednisone and cytotoxic drugs had the lowest probability of continuation. In contrast, there were not statistically significant differences among the drugs with respect to first relapse. This is the first study examining the long-term termination rates of several drugs used to treat hematological manifestations of SLE. Using rates of discontinuation adjusted for time there were statistically significant differences among the drugs. Danazol had the highest probability of continuation.

Variations and trends in the prescription of initial second line therapy for patients with rheumatoid arthritis.

OBJECTIVE: To evaluate practice variation and time trends in the initial prescription of second line drugs for the treatment of rheumatoid arthritis (RA) by a group of selected rheumatologists. METHODS: We retrospectively reviewed medical charts of all patients with a diagnosis of RA, initially seen between January 1, 1985, and June 30, 1994, by rheumatologists from a tertiary center and a rheumatology referral clinic in Edmonton. RESULTS: 1427 patients initially seen between 1985 and 1994 were included in the study. Of these, 1244 (87%) received a second line drug, 71% within 1.5 years after the disease onset. Overall, antimalarials and parenteral gold were the most frequently prescribed. Statistically significant trends were observed for the years under study. From 1985 to 1987, the most frequently prescribed initial second line drug was parenteral gold, between 1988 to 1990, sulfasalazine, and after 1991, antimalarials. Methotrexate was rarely used as a first choice. Marked variability was observed among rheumatologists in the use of initial second line drugs. In general, year of prescription and prescribing rheumatologist were significantly associated with the selection of all second line drugs but methotrexate. In addition, disease duration and residence (urban or rural) were associated with the selection of antimalarials and parenteral gold. CONCLUSION: Most patients were treated early with second line drugs. Initial prescription patterns varied among rheumatologists. These patterns have changed over the last 10 years. An increasing trend in the use of antimalarials was noted, and unlike prescription patterns in the US, methotrexate was rarely used as the first second line drug.

Donor lymphocyte infusions for relapse of chronic myeloid leukemia after allogeneic stem cell transplantation: prognostic significance of the dose of CD3(+) and CD4(+) lymphocytes.

Between December 1993 and November 2001, 30 patients with chronic myeloid leukemia who relapsed after stem cell transplantation were studied. Seventeen patients were not treated before donor lymphocyte infusion (DLI), eight patients received interferon-alpha (IFN-alpha), and five underwent chemotherapy. The method of DLI was the bulk dose regimen. The median time between DLIs was 6 weeks. The median number of infusions was three; the median time from transplant to relapse was 17 months and from relapse to DLI 2 months. Eleven patients (37%) were in molecular/cytogenetic relapse, 14 (47%) in chronic phase, and five (16%) in accelerated or blastic phase. Seventeen patients (57%) developed acute graft-versus-host disease (GVHD). Chronic GVHD was observed in 15 of 24 (62%) patients. Four (13%) patients developed cytopenia after a median of 30 days. Nineteen (63%) patients achieved response, 15 of them developed GVHD. The response rate according to the disease phase was molecular or cytogenetic relapse: 91%, chronic phase: 57%, and accelerated or blastic phase: 20%. The median time to response was 6 months. Patients treated with IFN-alpha or no treatment as well as those who were in molecular/cytogenetic relapse and those who received a CD3(+) cell dose <1 x 10(8)/kg and CD4(+) <8 x 10(7)/kg had better survival. We conclude that patients who receive lower doses of lymphocytes have better survival. In some patients IFN-alpha seems to be a good choice to potentiate the graft-versus-leukemia (GVL) effect.