Eliza F. Chakravarty

Pregnancy outcomes after maternal exposure to rituximab

Rituximab is a chimeric anti-CD20 monoclonal B cell-depleting antibody indicated for certain hematologic malignancies and active rheumatoid arthritis with inadequate response to tumor necrosis factor antagonists. Despite counseling to avoid pregnancy, women may inadvertently become pregnant during or after rituximab treatment. Using the rituximab global drug safety database, we identified 231 pregnancies associated with maternal rituximab exposure. Maternal indications included lymphoma, autoimmune cytopenias, and other autoimmune diseases. Most cases were confounded by concomitant use of potentially teratogenic medications and severe underlying disease. Of 153 pregnancies with known outcomes, 90 resulted in live births. Twenty-two infants were born prematurely; with one neonatal death at 6 weeks. Eleven neonates had hematologic abnormalities; none had corresponding infections. Four neonatal infections were reported (fever, bronchiolitis, cytomegalovirus hepatitis, and chorioamnionitis). Two congenital malformations were identified: clubfoot in one twin, and cardiac malformation in a singleton birth. One maternal death from pre-existing autoimmune thrombocytopenia occurred. Although few congenital malformations or neonatal infections were seen among exposed neonates, women should continue to be counseled to avoid pregnancy for ≤ 12 months after rituximab exposure; however, inadvertent pregnancy does occasionally occur. Practitioners are encouraged to report complete information to regulatory authorities for all pregnancies with suspected or known exposure to rituximab.

Reduced Disability and Mortality Among Aging Runners: A 21-Year Longitudinal Study

BACKGROUND Exercise has been shown to improve many health outcomes and well-being of people of all ages. Long-term studies in older adults are needed to confirm disability and survival benefits of exercise. METHODS Annual self-administered questionnaires were sent to 538 members of a nationwide running club and 423 healthy controls from northern California who were 50 years and older beginning in 1984. Data included running and exercise frequency, body mass index, and disability assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI; scored from 0 [no difficulty] to 3 [unable to perform]) through 2005. A total of 284 runners and 156 controls completed the 21-year follow-up. Causes of death through 2003 were ascertained using the National Death Index. Multivariate regression techniques compared groups on disability and mortality. RESULTS At baseline, runners were younger, leaner, and less likely to smoke compared with controls. The mean (SD) HAQ-DI score was higher for controls than for runners at all time points and increased with age in both groups, but to a lesser degree in runners (0.17 [0.34]) than in controls (0.36 [0.55]) (P < .001). Multivariate analyses showed that runners had a significantly lower risk of an HAQ-DI score of 0.5 (hazard ratio, 0.62; 95% confidence interval, 0.46-0.84). At 19 years, 15% of runners had died compared with 34% of controls. After adjustment for covariates, runners demonstrated a survival benefit (hazard ratio, 0.61; 95% confidence interval, 0.45-0.82). Disability and survival curves continued to diverge between groups after the 21-year follow-up as participants approached their ninth decade of life. CONCLUSION Vigorous exercise (running) at middle and older ages is associated with reduced disability in later life and a notable survival advantage.

Compression of morbidity 1980-2011: a focused review of paradigms and progress.

The Compression of Morbidity hypothesis—positing that the age of onset of chronic illness may be postponed more than the age at death and squeezing most of the morbidity in life into a shorter period with less lifetime disability—was introduced by our group in 1980. This paper is focused upon the evolution of the concept, the controversies and responses, the supportive multidisciplinary science, and the evolving lines of evidence that establish proof of concept. We summarize data from 20-year prospective longitudinal studies of lifestyle progression of disability, national population studies of trends in disability, and randomized controlled trials of risk factor reduction with life-style-based “healthy aging” interventions. From the perspective of this influential and broadly cited paradigm, we review its current history, the development of a theoretical structure for healthy aging, and the challenges to develop coherent health policies directed at reduction in morbidity.

Long Distance Running and Knee Osteoarthritis A Prospective Study

BACKGROUND Prior studies of the relationship of physical activity to osteoarthritis (OA) of the knee have shown mixed results. The objective of this study was to determine if differences in the progression of knee OA in middle- to older-aged runners exist when compared with healthy nonrunners over nearly 2 decades of serial radiographic observation. METHODS Forty-five long-distance runners and 53 controls with a mean age of 58 (range 50-72) years in 1984 were studied through 2002 with serial knee radiographs. Radiographic scores were two-reader averages for Total Knee Score (TKS) by modified Kellgren & Lawrence methods. TKS progression and the number of knees with severe OA were compared between runners and controls. Multivariate regression analyses were performed to assess the relationship between runner versus control status and radiographic outcomes using age, gender, BMI, education, and initial radiographic and disability scores among covariates. RESULTS Most subjects showed little initial radiographic OA (6.7% of runners and 0 controls); however, by the end of the study runners did not have more prevalent OA (20 vs 32%, p =0.25) nor more cases of severe OA (2.2% vs 9.4%, p=0.21) than did controls. Regression models found higher initial BMI, initial radiographic damage, and greater time from initial radiograph to be associated with worse radiographic OA at the final assessment; no significant associations were seen with gender, education, previous knee injury, or mean exercise time. CONCLUSIONS Long-distance running among healthy older individuals was not associated with accelerated radiographic OA. These data raise the possibility that severe OA may not be more common among runners.

Receipt of Disease-Modifying Antirheumatic Drugs Among Patients With Rheumatoid Arthritis in Medicare Managed Care Plans

CONTEXT In 2005, the Healthcare Effectiveness Data and Information Set (HEDIS) introduced a quality measure to assess the receipt of disease-modifying antirheumatic drugs (DMARDs) among patients with rheumatoid arthritis (RA). OBJECTIVE To identify sociodemographic, community, and health plan factors associated with DMARD receipt among Medicare managed care enrollees. DESIGN, SETTING, AND PARTICIPANTS We analyzed individual-level HEDIS data for 93,143 patients who were at least 65 years old with at least 2 diagnoses of RA within a measurement year (during 2005-2008). Logistic regression models with generalized estimating equations were used to determine factors associated with DMARD receipt and logistic regression was used to adjust health plan performance for case mix. MAIN OUTCOME MEASURES Receipt or nonreceipt of DMARD. RESULTS The mean age of patients was 74 years; 75% were women and 82% were white. Overall performance on the HEDIS measure for RA was 59% in 2005, increasing to 67% in 2008 (P for trend <.001). The largest difference in performance was based on age: patients aged 85 years and older had a 30 percentage point lower rate of DMARD receipt (95% confidence interval [CI], -29 to -32 points; P < .001), compared with patients 65 to 69 years of age, even after adjusting for other factors. Lower percentage point rates were also found for patients who were men (-3 points; 95% CI, -5 to -2 points; P < .001), of black race (-4 points; 95% CI, -6 to -2 points; P < .001), with low personal income (-6 points; 95% CI, -8 to -5 points; P < .001), with the lowest zip code-based socioeconomic status (-4 points; 95% CI, -6 to 2 points; P < .001), or enrolled in for-profit health plans (-4 points; 95% CI, -7 to 0 points; P < .001); and in the Middle Atlantic region (-7 points; 95% CI, -13 to -2 points; P < .001) and South Atlantic regions (-11 points; 95% CI, -20 to -3 points; P < .001) as compared with the Pacific region. Performance varied widely by health plan, ranging from 16% to 87%. CONCLUSIONS Among Medicare managed care enrollees carrying a diagnosis of RA between 2005 and 2008, 63% received a DMARD. Receipt of DMARDs varied based on demographic factors, socioeconomic status, geographic location, and health plan.

Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension, and sickle cell disease.

OBJECTIVE: Systemic sclerosis, primary pulmonary hypertension, and sickle cell disease are uncommon vasculopathic diseases affecting women. We estimated the nationwide occurrence of pregnancies in women with these conditions and compared pregnancy outcomes to the general obstetric population. METHODS: We studied the 2002–2004 Nationwide Inpatient Sample, of the Healthcare Cost and Utilization Project to estimate the number of obstetric hospitalizations and deliveries among women with systemic sclerosis, primary pulmonary hypertension, sickle cell disease, and women in the general population. Pregnancy outcomes included length of hospital stay, hypertensive disorders including preeclampsia, intrauterine growth restriction (IUGR), and cesarean delivery. Multivariable regression analyses were performed using maternal age, race or ethnicity, antiphospholipid antibody syndrome, diabetes mellitus, and renal failure as covariates. RESULTS: Of an estimated 11.2 million deliveries, 504 occurred in women with systemic sclerosis, 182 with primary pulmonary hypertension, and 4,352 with sickle cell disease. Systemic sclerosis, was associated with an increased risk of hypertensive disorders including preeclampsia (odds ratio [OR] 3.71, 95% confidence interval [CI] 2.25–6.15), IUGR (OR 3.74, 95% CI 1.51–9.28), and increased length of hospital stay. Primary pulmonary hypertension was associated with an increase in the odds of antenatal hospitalization (OR 4.67, 95% CI 2.88–7.57), hypertensive disorders including preeclampsia (OR 5.62, 95% CI 2.60–12.15) and a substantial increase in length of hospital stay. Sickle cell disease was associated with an increased odds of antenatal hospitalization (OR 5.56 95% CI 5.08–6.09), hypertensive disorders including preeclampsia (OR 1.78, 95% CI 1.48–2.14), and IUGR (OR 2.91, 95% CI 2.16–3.93), with a modest increase in length of hospital stay. CONCLUSION: Women with systemic sclerosis, primary pulmonary hypertension, and sickle cell disease have significantly increased rates of adverse pregnancy outcomes, requiring extensive preconceptional counseling about the risks of pregnancy. LEVEL OF EVIDENCE: II

Obstetric outcomes in women with multiple sclerosis and epilepsy

Objective: To estimate the national occurrence of pregnancies in women with multiple sclerosis (MS) and epilepsy and to compare these pregnancy outcomes cross-sectionally with those in women with pregestational diabetes mellitus (DM) and the general obstetric population. Methods: We studied the 2003–2006 Nationwide Inpatient Sample, of the Healthcare Cost and Utilization Project, to estimate the number of deliveries in women with MS, epilepsy, DM, and the general obstetric population. Pregnancy outcomes included length of hospital stay, hypertensive disorders including preeclampsia (HTN), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), and cesarean delivery. Multivariable regression analyses used maternal age and race/ethnicity as covariates. Results: Of an estimated 18.8 million deliveries, 10,055 occurred in women with MS, 4,730 with epilepsy, and 187,239 with DM. MS was associated with mildly increased odds of antenatal hospitalization (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.2–1.5), IUGR (OR 1.7, 95% CI 1.2–2.4), and cesarean delivery (OR 1.3, 95% CI 1.1–1.4). Similarly, epilepsy was associated with increased rates of antenatal hospitalization (OR 3.0, 95% CI 2.6–3.5), IUGR (OR 1.9, 95% CI 1.2–3.3), and cesarean delivery (OR 1.5, 95% CI 1.3–1.9). HTN and PROM were not increased in either group. DM was associated with an increased risk of all adverse outcomes. Length of stay was modestly increased in all groups compared with controls. Conclusion: In this large national database study of pregnancy outcomes in women with multiple sclerosis and epilepsy, rates of intrauterine growth restriction and cesarean delivery were only marginally higher than the general obstetric population without increases in other adverse outcomes.

Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus

Women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have fewer children on average than other women. We sought to determine the roles of infertility, pregnancy loss, and personal choice on family size in women with these diseases.

Lifestyle risk factors predict disability and death in healthy aging adults.

BACKGROUND Associations between modifiable health risk factors during middle age with disability and mortality in later life are critical to maximizing longevity while preserving function. Positive health effects of maintenance of normal weight, routine exercise, and nonsmoking are known for the short and intermediate term. We studied the effects of these risk factors into advanced age. METHODS A cohort of 2327 college alumnae aged 60 years or more was followed annually (1986-2005) by questionnaires addressing health risk factors, history, and Health Assessment Questionnaire disability. Mortality data were ascertained from the National Death Index. Low-, medium-, and high-risk groups were created on the basis of the number (0, 1, ≥2) of health risk factors (overweight, smoking, inactivity) at baseline. Disability and mortality for each group were estimated from unadjusted data and regression analyses. Multivariable survival analyses estimated time to disability or death. RESULTS The medium- and high-risk groups had higher disability than the low-risk group throughout the study (P<.001). Low-risk subjects had onset of moderate disability delayed 8.3 years compared with high-risk subjects. Mortality rates were higher in the high-risk group (384 vs 247 per 10,000 person-years). Multivariable survival analyses showed the number of risk factors to be associated with cumulative disability and increased mortality. CONCLUSION Seniors with fewer behavioral risk factors during middle age have lower disability and improved survival. These data document that the associations of lifestyle risk factors on health continue into the ninth decade.

Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus

Autoantibodies against cytokines, chemokines, and growth factors inhibit normal immunity and are implicated in inflammatory autoimmune disease and diseases of immune deficiency. In an effort to evaluate serum from autoimmune and immunodeficient patients for Abs against cytokines, chemokines, and growth factors in a high-throughput and unbiased manner, we constructed a multiplex protein microarray for detection of serum factor-binding Abs and used the microarray to detect autoantibody targets in SLE. We designed a nitrocellulose-surface microarray containing human cytokines, chemokines, and other circulating proteins and demonstrated that the array permitted specific detection of serum factor-binding probes. We used the arrays to detect previously described autoantibodies against cytokines in samples from individuals with autoimmune polyendocrine syndrome type 1 and chronic mycobacterial infection. Serum profiling from individuals with SLE revealed that among several targets, elevated IgG autoantibody reactivity to B cell-activating factor (BAFF) was associated with SLE compared with control samples. BAFF reactivity correlated with the severity of disease-associated features, including IFN-α-driven SLE pathology. Our results showed that serum factor protein microarrays facilitate detection of autoantibody reactivity to serum factors in human samples and that BAFF-reactive autoantibodies may be associated with an elevated inflammatory disease state within the spectrum of SLE.