Effects of obesity on health-related quality of life in juvenile-onset systemic lupus erythematosus.

OBJECTIVE: This study evaluated the effects of obesity on health-related quality of life (HRQOL) measures in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: Obesity was defined as a body mass index (BMI) ≥ 95 th percentile according to the Sex-specific Center for Disease Control BMI-For-Age Charts and determined in a multicenter cohort of jSLE patients. In this secondary analysis, the domain and summary scores of the Pediatric Quality of Life (PedsQL) Inventory and the Child Health Questionnaire (CHQ) of obese jSLE patients were compared to those of non-obese jSLE patients as well as historical obese and non-obese healthy controls. Mixed-effects modeling was performed to evaluate the relationship between obesity and HRQOL measures. RESULTS: Among the 202 jSLE patients, 25% (n = 51) were obese. Obesity had a significant negative impact on HRQOL in jSLE, even after adjusting for differences in current corticosteroid use, disease activity, disease damage, gender and race between groups. Obese jSLE patients had lower physical functioning compared to non-obese jSLE patients, and to non-obese and obese healthy controls. Compared to their non-obese counterparts, obese jSLE patients also had worse school functioning, more pain, worse social functioning and emotional functioning. Parents of obese jSLE patients worry more. The CHQ scores for obese jSLE patients were also worse compared to non-obese jSLE patients in several other domains. CONCLUSION: Our study demonstrates the detrimental effects of obesity on patient-reported outcomes in jSLE. This supports the importance of weight management for the therapeutic plan of jSLE.

Use of atorvastatin in systemic lupus erythematosus in children and adolescents.

OBJECTIVE: Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. METHODS: A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. RESULTS: Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. CONCLUSION: Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS: Patients ages 2-18 years with rheumatoid factor (RF)-positive or RF-negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (> or =10 mg/m(2)/week [ approximately 0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open-label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment. RESULTS: A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure-adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient-years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient-years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study. CONCLUSION: These data confirm the findings of other long-term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.

Rasmussen syndrome and CNS granulomatous disease with NOD2/CARD15 mutations.

Rasmussen syndrome (RS) is a clinical diagnosis characterized by persistent focal seizures in a previously healthy child. Occasionally, the typical features of RS may be followed by another diagnosis. We discuss the course of a 12-year-old girl who presented with RS but was later diagnosed with CNS granulomatous disease and NOD2/CARD15 mutations. Her response to infliximab suggests that it should be included in immune-modulatory therapies used to treat these refractory disorders.

Evidence for the expression of a second CD6 ligand by synovial fibroblasts.

OBJECTIVE: CD6, a cell surface glycoprotein expressed primarily on T cells, may function as a costimulatory molecule and may play a role in autoreactive immune responses. Recently, a CD6 ligand termed CD166 (previously known as activated leukocyte cell adhesion molecule [ALCAM]) has been identified and shown to be expressed on activated T cells, B cells, thymic epithelium, keratinocytes, and in rheumatoid arthritis synovial tissue. However, the results of functional studies have suggested the existence of a second CD6 ligand. The present study was undertaken to seek evidence for a second CD6 ligand on cultured synovial fibroblasts. METHODS: Flow cytometric and biochemical techniques were applied, using anti-CD166 monoclonal antibody (mAb) and a recombinant CD6 fusion protein, to determine whether cultured synovial fibroblasts and other cell types expressed a non-ALCAM CD6 ligand. RESULTS: CD14- fibroblastic synoviocytes showed greater binding of a recombinant CD6 fusion protein than of anti-ALCAM mAb. With interferon-gamma treatment of synovial fibroblasts, binding of both reagents increased, but this was more marked for binding of CD6 fusion protein. Exposure of synovial fibroblasts to other cytokines or to the superantigen staphylococcal enterotoxin A also regulated binding of CD6 fusion protein and anti-ALCAM mAb in a discordant manner. Immunoprecipitation of proteins from membrane extracts of synovial fibroblasts with a CD6-Ig fusion protein revealed a novel 130-kd band distinct from CD166; an identical molecule was also precipitated from membranes of HBL-100 tumor cells. CONCLUSION: Taken together with previous data regarding CD6 and CD166 function, the present findings strongly suggest the existence of a second CD6 ligand distinct from CD166, which can be expressed by synovial fibroblasts as well as other cells.

Prevention of infectious complications in rheumatic disease patients: immunization, Pneumocystis carinii prophylaxis, and screening for latent infections.

Most rheumatology textbooks lack adequate recommendations for specific immunization of patients with rheumatic diseases, especially those treated with immunosuppressive medications. The authors wish to alert clinicians to issues pertinent to immunization of immunosuppressed rheumatology patients. By elucidating deficiencies in the current literature, the authors hope to identify future directions for clinical investigation and to increase the rates of effective immunization against vaccine preventable diseases. In addition to focusing on immunizations, this article also discusses Pneumocystis carinii prophylaxis in immunosuppressed patients with rheumatic diseases and screening that clinicians should consider before beginning administration of immunosuppressive agents.

Update on immunosuppressive therapy.

In this review we summarize selected articles that have been published about immunosuppressive agents in the past year. These studies fall into three major categories: 1) use of pulse cyclophosphamide in autoimmune diseases other than systemic lupus erythematosus; 2) use of newer immunosuppressive agents such as cyclosporine and FK506 in a variety of rheumatic diseases; and 3) toxicity.

Differential regulation of translation and eIF4E phosphorylation during human thymocyte maturation.

Activation of peripheral blood T cells by cross-linking of CD3 results in a rapid and substantial rise in translation rates and proliferation, which coincides with an increase in the cap-binding protein, eIF4E activity. In contrast, immature CD4+ CD8+ double-positive (DP) thymocytes undergo apoptosis in response to anti-CD3 mAb. We have investigated translation initiation in the response of immature thymocytes to activating signals. Activation by anti-CD3 + anti-CD4 of immature CD4+ CD8+ DP thymocytes results in a rapid decrease in protein synthesis. In contrast, similar treatment of CD4+ or CD8+ single-positive (SP) thymocytes results in an increase in protein synthesis. The rate of protein synthesis is linked to the phosphorylation status of eIF4E. Following anti-CD3 + anti-CD4 stimulation, eIF4E phosphorylation strongly decreases in immature DP thymocytes, whereas it increases in mature SP thymocytes. The expression of 4E-BP2, a specific repressor of eIF4E function, is high in DP cells but decreases during maturation, raising the possibility of a role for 4E-BP2 in repressing eIF4E phosphorylation. These data provide evidence for differential regulation of the translational machinery during T cell development.

CD6 dependent interactions of T cells and keratinocytes: functional evidence for a second CD6 ligand on gamma-interferon activated keratinocytes.

The CD6 glycoprotein is expressed by T lymphocytes and is hypothesized to interact with one or more ligands expressed on antigen presenting cells (APCs). We show that CD6 mediates binding of the transformed CD4+ T cell line Hut 78 to gamma-interferon activated keratinocytes (KCs). A recombinant CD6-Ig fusion protein has been reported to bind to a CD6 ligand ALCAM, but this is the first demonstration that cell-cell adhesion of human T lymphocytes can be CD6 dependent. The known CD6 ligand ALCAM (CD166) is expressed on cultured KCs but does not appear to mediate KC-Hut 78 binding, suggesting the existence of additional CD6 ligands expressed on KCs. In functional studies using autologous KCs as APCs for tetanus toxoid specific T cell clones, KCs +/- gamma-interferon are unable to stimulate autologous T cells with recall antigen. Therefore interaction of T cell CD6 with CD6 ligands on KCs does not provide sufficient co-stimulation of primed T cells to support responses to nominal antigen.

Immunosuppressive drug treatment.

Use of the immunosuppressive agents in patients with rheumatic diseases is becoming increasingly common as our experience using these agents increases. This year's review of recent reports on immunosuppressive drugs for rheumatic diseases focuses on recent contributions to the literature regarding individual agents. Additionally, we review recommendations regarding immunization of immunosuppressed patients and exposure of such patients to common communicable illnesses to which they may be inadvertently exposed.

Role of the CD6 glycoprotein in antigen-specific and autoreactive responses of cloned human T lymphocytes.

CD6 is a 130 000 MW T-cell surface glycoprotein that can deliver coactivating signals to mature T lymphocytes. Studies using monoclonal antibodies (mAb) have defined at least four epitopes on CD6, and distinct functional responses are elicited by mAb to the different epitopes. The function of CD6 is unknown. Multiple CD6 ligands are predicted, based on data that a soluble CD6 fusion protein precipitates at least three peptides. A cDNA clone for one of these ligands, termed activated leucocyte-cell adhesion molecule (ALCAM) has recently been isolated. In order to further characterize the role of CD6 in cell-cell interactions, we have examined the role of CD6 in a variety of responses by tetanus toxoid (TT) specific human T-cell clones. Anti-CD6 mAb UMCD6 (epitope 3) inhibits antigen-specific responses of such clones to TT, but not to the superantigen SEA. Responses of clones to nominal antigen are CD6-dependent using either peripheral blood mononuclear cells (PBMC) or macrophage-depleted E rosette negative cells as the antigen-presenting cell (APC) population. Furthermore, these clones made autoreactive with DNA methyltransferase inhibitors express increased CD6, and autoreactivity is inhibited by UMCD6. Taken together, the data suggests the existence of a functional CD6 ligand in peripheral blood which is expressed by APC, including cells other than macrophages. Interactions between CD6 and CD6 ligands may regulate both antigen specific and autoreactive responses of human T lymphocytes.

Responsiveness of human T lymphocytes to bacterial superantigens presented by cultured rheumatoid arthritis synoviocytes.

OBJECTIVE: Type B fibroblastic synoviocytes are abundant in inflamed joints of patients with rheumatoid arthritis (RA), and can secrete cytokines and other mediators of inflammation. The aim of this study was to determine whether cell lines derived from RA type B synoviocytes could also serve as accessory cells for T lymphocyte activation. METHODS: Cells from RA synoviocyte lines, with or without preculture in interferon-gamma (IFN gamma), were cultured with purified peripheral blood T cells, in the presence or absence of superantigens or other accessory cell-dependent T cell mitogens. T cell proliferation was measured by thymidine incorporation, and synoviocyte surface markers were analyzed by flow cytometry. RESULTS: RA type B synoviocyte lines were potent accessory cells for T cell responses to bacterial superantigens or lectins, and direct cell-cell contact was required. Preculture in IFN gamma augmented synoviocyte expression of major histocompatibility complex (MHC) class II molecules and of ligands for some T cell costimulatory receptors, but synoviocyte accessory cell function was evident even in the absence of IFN gamma. Blocking studies using monoclonal antibodies supported the notion of a role CD2, CD11a/CD18 and MHC class II molecules in synoviocyte-dependent T cell activation. Monoclonal antibodies against IFN gamma, interleukin-1 beta (IL-1 beta), IL-6, IL-8, and tumor necrosis factor alpha failed to block the T cell proliferative responses, but anti-IL-2 was strongly inhibitory. CONCLUSION: Cultured RA and type B synoviocytes can perform some of the functions of professional antigen-presenting cells. If such cells have similar properties in vivo, they may be important participants in activation of immune responses, in addition to their previously described synthetic and proinflammatory roles. If RA synovial tissue T cells, like normal peripheral blood T cells, can respond to superantigens presented by synoviocytes, this interaction could be important in the pathogenesis of RA.

Neurobehavioral functioning in a nonconfounded group of asymptomatic HIV-seropositive homosexual men.

Neurobehavioral functioning was tested in 34 asymptomatic HIV-seropositive and 43 HIV-seronegative male homosexual subjects without substance abuse and CNS disorders. The HIV-positive subjects exhibited mild motor slowing compared to the seronegative subjects. These differences remained after controlling for potential cofactors. Early neurobehavioral impairment in HIV infection seems limited to subclinical motor deficits and attributable to HIV rather than possible confounding factors.