Anne-Barbara Mongey

Disease outcomes and ovarian function of childhood-onset systemic lupus erythematosus:

The objective of this study was to determine the medical outcomes including the ovarian function childhood-onset SLE (cSLE). The medical records of all patients diagnosed with cSLE in the Greater Cincinnati area between 1981 and 2002 were reviewed. Patient interviews were performed to obtain additional information on current medication regimens, disease activity [SLE Disease Activity Index (SLEDAI-2k)], and damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)]. The occurence of premature ovarian failure (POF) and reduction of the ovarian reserve was assessed by timed gonadotropin levels. There were 77 patients (F: M = 70: 7, 53% Caucasian, 45% African-American and 2% Asian) with a mean age at diagnosis of 14.6 years. Nine patients died (88.3% survival) during the mean follow-up of 7.1 years (standard deviation [SD] 5.6) and 88% of the patients continued to have active disease (SLEDAI-2k mean/SD: 6.6/6.7), with 42% of them having disease damage (SDI mean/SD: 1.62/2.1); Non-Caucasian patients had higher disease activity (mean SLEDAI-2k: 10 versus 3.4; P < 0.0001) and more disease damage (mean SDI: 2.1 versus 1.2; P < 0.02) than Caucasian patients. Cyclophosphamide was given to 47% of the patients during the course of their disease and associated with the presence of significantly reduced ovarian reserve (RR = 2.8; 95% CI: 1.7-4.8; P = 0.026). Patient mortality and disease damage with cSLE continue to be high. Although overt POF with cyclophosphamide exposure is rare, it is a risk factor for significantly decreased ovarian reserve cSLE.

Adherence to medications in systemic lupus erythematosus.

Background:Lack of adherence is a ubiquitous problem which can be a hindrance in the treatment of chronic conditions like systemic lupus erythematosus (SLE). Objectives:A random sample of 63 SLE patients attending rheumatology clinics associated with University Medical Centers were surveyed to measure level of adherence to their SLE medications and to identify the risk factors that have been associated previously with nonadherence to these medications. Methods:Information on traditional SLE outcomes was obtained by face-to-face interviews and medical record review. Various patient proposed strategies were identified to improve adherence to these medications. Results:When considering adherence estimates of ≥80% as representing sufficient adherence for achieving a therapeutic response, adherence to medications was only modestly adherent, likely limiting the effectiveness of the prescribed medication regimens. Based on pharmacy refill information 61% of the patients were sufficiently adherent to prednisone, 49% to hydroxychloroquine, and 57% to other immunosuppressant medications. Significant risk factors of insufficient adherence included being single, low educational level, presence of other comorbidities, limited comprehension of physician explanations and instructions, and having to take the medication more than one daily. Based on subject reports, busy life styles were among the most important barriers to adherence whereas pillboxes were considered most helpful for helping with medication adherence. Conclusion:Although lack of sufficient adherence to medications appears to be a multifactorial problem, improved communication between the healthcare provider and the patient, and less complicated medication regimens, may be especially suitable interventions to improve adherence to medications.

Altered Dynamics of Kv1.3 Channel Compartmentalization in the Immunological Synapse in Systemic Lupus Erythematosus

Aberrant T cell responses during T cell activation and immunological synapse (IS) formation have been described in systemic lupus erythematosus (SLE). Kv1.3 potassium channels are expressed in T cells where they compartmentalize at the IS and play a key role in T cell activation by modulating Ca2+ influx. Although Kv1.3 channels have such an important role in T cell function, their potential involvement in the etiology and progression of SLE remains unknown. This study compares the K channel phenotype and the dynamics of Kv1.3 compartmentalization in the IS of normal and SLE human T cells. IS formation was induced by 1–30 min exposure to either anti-CD3/CD28 Ab-coated beads or EBV-infected B cells. We found that although the level of Kv1.3 channel expression and their activity in SLE T cells is similar to normal resting T cells, the kinetics of Kv1.3 compartmentalization in the IS are markedly different. In healthy resting T cells, Kv1.3 channels are progressively recruited and maintained in the IS for at least 30 min from synapse formation. In contrast, SLE, but not rheumatoid arthritis, T cells show faster kinetics with maximum Kv1.3 recruitment at 1 min and movement out of the IS by 15 min after activation. These kinetics resemble preactivated healthy T cells, but the K channel phenotype of SLE T cells is identical to resting T cells, where Kv1.3 constitutes the dominant K conductance. The defective temporal and spatial Kv1.3 distribution that we observed may contribute to the abnormal functions of SLE T cells.

Drug insight: autoimmune effects of medications-what's new?

Autoantibodies and lupus-like syndromes can develop following the use of certain medications; however, although many patients develop autoantibodies, only a minority develop clinical features. Although these autoantibodies primarily consist of antinuclear and antihistone antibodies, additional types of antibody, such as antineutrophil cytoplasmic antibodies and anti-double-stranded DNA antibodies, have been reported in association with minocycline and tumor necrosis factor inhibitor therapy. Clinical features of drug-related lupus usually consist of constitutional symptoms, arthralgias, arthritis, myalgias and serositis, although cutaneous manifestations have been reported in association with the use of tumor necrosis factor inhibitors. Typically, clinical features resolve with discontinuation of the medication, although antibodies can persist for months or years. Arthralgias and inflammatory arthritis have also been reported in association with the use of aromatase inhibitors and other biologic agents such as interleukins and interferons.

Differential calcium signaling and Kv1.3 trafficking to the immunological synapse in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) T cells exhibit several activation signaling anomalies including defective Ca(2+) response and increased NF-AT nuclear translocation. The duration of the Ca(2+) signal is critical in the activation of specific transcription factors and a sustained Ca(2+) response activates NF-AT. Yet, the distribution of Ca(2+) responses in SLE T cells is not known. Furthermore, the mechanisms responsible for Ca(2+) alterations are not fully understood. Kv1.3 channels control Ca(2+) homeostasis in T cells. We reported a defect in Kv1.3 trafficking to the immunological synapse (IS) of SLE T cells that might contribute to the Ca(2+) defect. The present study compares single T cell quantitative Ca(2+) responses upon formation of the IS in SLE, normal, and rheumatoid arthritis (RA) donors. Also, we correlated cytosolic Ca(2+) concentrations and Kv1.3 trafficking in the IS by two-photon microscopy. We found that sustained [Ca(2+)](i) elevations constitute the predominant response to antigen stimulation of SLE T cells. This defect is selective to SLE as it was not observed in RA T cells. Further, we observed that in normal T cells termination of Ca(2+) influx is accompanied by Kv1.3 permanence in the IS, while Kv1.3 premature exit from the IS correlates with sustained Ca(2+) responses in SLE T cells. Thus, we propose that Kv1.3 trafficking abnormalities contribute to the altered distribution in Ca(2+) signaling in SLE T cells. Overall these defects may explain in part the T cell hyperactivity and dysfunction documented in SLE patients.

Risk Factors for the Development of Osteoporosis and Osteoporotic Fractures Among Older Men

Objective. Osteoporotic fractures are associated with significant morbidity and mortality particularly among older men. However, there is little information regarding risk factors among this population. The aims of our study were to determine risk factors for osteoporosis and fragility fractures and the predictive value of bone mineral density (BMD) measurements for development of fragility fractures in a cohort of elderly Caucasian and African American men. Methods. We evaluated 257 men aged 70 years or older for risk factors for osteoporosis and fragility fractures using a detailed questionnaire and BMD assessment. Exclusion criteria included conditions known to cause osteoporosis such as hypogonadism and chronic steroid use, current treatment with bisphosphonates, bilateral hip arthroplasties, and inability to ambulate independently. Results. Age, weight, weight loss, androgen deprivation treatment, duration of use of dairy products, exercise, and fracture within 10 years prior to study entry were associated with osteoporosis (p ≤ 0.05). Fragility fractures were associated with duration of use of dairy products, androgen deprivation treatment, osteoporosis, and history of fracture within 10 years prior to BMD assessment (p ≤ 0.05). There were some differences in risk factors between the Caucasian and African American populations, suggesting that risk factors may vary between ethnic groups. Conclusion. Although men with osteoporosis had a higher rate of fractures, the majority of fractures occurred in men with T-scores > −2.5 standard deviations below the mean, suggesting that factors other than BMD are also important in determining risk.

Is the development of drug-related lupus a contraindication for switching from one TNF alpha inhibitor to another?

The use of TNF alpha (TNFα) inhibitors has made a strong impact on the management of rheumatoid and psoriatic arthritis, ankylosing spondylitis and Crohn disease. Side effects of these agents include the development of autoantibodies and a lupus-like syndrome (drug-related lupus, DRL). Here, a case of a patient who developed DRL while receiving infliximab therapy which resolved spontaneously upon discontinuation of the agent and did not recur with subsequent institution of adalimumab is described. A discussion on the possible pathogenic mechanisms involved in the development of drug-related autoimmunity and differences between the agents is also included.

Genetic, Immunologic and Biotransformation Studies of Patients on Procainamide

This report represents follow-up observations of a unique long-term study of patients on procainamide (PA) for various cardiac arrhythmias. Serologic and clinical evaluations associated with drug-related autoimmunity were assessed and patients were characterized for factors postulated to influence susceptibility to autoimmunity, including acetylator phenotype, oxidative metabolism of PA, HLA class profile, and production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Fifty-two percent had IgM and 70% IgG antibodies to total histones; 67% had IgG antibodies to histone H2A/H2B. Patients were equally divided between fast and slow acetylators. N-oxidative metabolism of PA was indicated by the presence of urinary nitroprocainamide, which correlated with elevated titers of antihistone antibodies. There was a significant incidence of the DQw7 split of DQw3 in PA patients when compared to controls, and the frequency of antibodies to total histones and H2A/H2B was significantly increased in the DQw7 patients. C4A*QO and C4B*QO alleles were more frequent in the PA patients than in controls. IL-1 and TNF production was not different in patients compared to controls. These data suggest that certain genetic factors may serve as markers for PA-related autoimmunity.

Role of genetic factors in drug-related autoimmunity.

Although there is evidence to suggest that genetic factors play a major role in the pathogenesis of many of the rheumatic diseases, far less is known of their role in the induction and expression of human autoimmunity resulting from long-term exposure to drugs, chemicals and environmental agents. Pharmacogenetic factors represent an important source of interindividual variation in response to drugs; most research to date has focused on genetic polymorphism of drug metabolism via N-acetylation, S-methylation or cytochrome P-450-catalyzed oxidation. In drug-related autoimmunity, there is limited evidence that the hosts genetic background plays a major role beyond the expression of autoantibodies. More recent prospective studies have concentrated on the association of MHC-genes in the expression of autoimmunity and the susceptibility of patients to develop drug-related clinical syndromes.

Drug-related lupus

All physicians should be alerted to the many drugs and other agents that are associated with drug-related lupus, as there is an increasing number of such drugs. A wide range of immune responses and antibodies are being reported with this syndrome. A new concern is the perceived ability of new biologic treatments to induce these autoimmune phenomena. More in-depth studies of various environmental factors are providing new insights into possible mechanisms. These include the immune responses to the drugs, their metabolites, and drug-altered conjugates; bioactivation mechanisms of drug protein conjugation; the role of macrophages in antigen recognition and processing; and lastly, the important role of the acetylation of various drugs and the relationship to immunogenetic factors. Continued study of this human experimental model of lupus will help to clarify the etiology and mechanisms of systemic lupus erythematosus itself.