Thomas J. A. Lehman

High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus.

Interferon α (IFN-α) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-α activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-α activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-α activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-α activity, concordance in affected sib pairs and frequent transmission of the high IFN-α activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN-α activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-α activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-α activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.

Intermittent intravenous cyclophosphamide arrests progression of the renal chronicity index in childhood systemic lupus erythematosus.

OBJECTIVE To assess prospectively the safety and efficacy of a 36-month course of systematic bolus intravenous cyclophosphamide therapy (IVCY) for children with lupus nephritis. STUDY DESIGN Sixteen children with lupus nephritis were treated with IVCY for 36 months. Renal biopsies performed before and after treatment were scored for activity and chronicity. SLEDAI scores, laboratory measures, and prednisone dosage were recorded at the time of each treatment. RESULTS After 36 months of IVCY therapy, the renal biopsy activity index decreased from 9 +/- 4 to 1 +/- 1 (P <.001) without a change in chronicity. The mean creatinine clearance increased from 90 +/- 23 to 107 +/- 23 mL/min/1.73 mol/L(2) (P <.01), and the mean 24-hour urine protein excretion decreased from 2.0 +/- 2.4 g/24 h to 0.5 +/- 0.7 g/24 h (P <.05). The mean SLEDAI score decreased from 19 +/- 5.2 to 2.9 +/- 3.1 (P <.001). The mean prednisone dosage decreased from 35.5 +/- 20 mg/d to 14.0 +/- 3 mg/d (P <.001). No significant complications occurred. CONCLUSIONS Thirty-six months of systematic IVCY therapy led to decreased renal biopsy activity without progression of chronicity, with excellent disease control and a greater than 50% reduction in mean corticosteroid dose.

Intermittent intravenous cyclophosphamide therapy for lupus nephritis

We carried out a preliminary study to determine whether intermittent intravenous cyclophosphamide therapy could be safely and effectively used in the treatment of childhood lupus nephritis. Sixteen children (4 to 18 years of age) with lupus nephritis were treated with cyclophosphamide monthly for 6 months and then every 3 months. Eight children were treated because of corticosteroid-unresponsive active lupus nephritis, with a fall in their creatinine clearance to less than 100 ml/min/1.75 m2, and eight children were treated because of corticosteroid-dependent nephrotic syndrome or active lupus nephritis with unacceptable corticosteroid-induced side effects. Cyclophosphamide treatment was associated with significant improvement at 1 year in mean levels of hemoglobin (11.3 +/- 0.5 to 13.1 +/- 0.3 gm/dl), C3 (52 +/- 5.9 to 108 +/- 13.7 mg/dl), and C4 (7.6 +/- 0.9 to 15.9 +/- 2.2 mg/dl) (all p less than 0.005), despite a significant reduction in mean prednisone dosage (31 +/- 5 to 14 +/- 2 mg/day; p less than 0.005). There was a decrease in 24-hour urine protein excretion from 3121 +/- 913 to 1016 +/- 364 mg/24 hours (p less than 0.05). For children whose initial creatinine clearance was less than 100 ml/min/1.75 m2, creatinine clearance also improved significantly (57.5 +/- 11 to 121 +/- 24.5 ml/min/1.75 m2; p less than 0.05). The long-term safety of intravenous cyclophosphamide therapy and its long-term efficacy in comparison with prednisone alone remain to be established. In the interim, intravenous cyclophosphamide therapy should be reserved for children with severe, unacceptable corticosteroid side effects or with corticosteroid-resistant and potentially life-threatening disease.

Age-and Sex-Related Patterns of Serum Interferon-α Activity in Lupus Families

OBJECTIVE Interferon-alpha (IFNalpha) levels are elevated in many patients with systemic lupus erythematosus (SLE) and may play a primary role in its pathogenesis. The purpose of this study was to determine whether serum IFNalpha activity in SLE patients and their healthy first-degree relatives is highest in early adulthood, when the incidence of SLE is greatest. METHODS Serum samples from 315 SLE patients, 359 healthy first-degree relatives, and 141 healthy unrelated donors were measured for IFNalpha activity using a functional reporter cell assay. IFNalpha activity was analyzed in relation to age, and subgroups with high levels of IFNalpha activity were identified within the large data sets using a Mann-Whitney sliding window segmentation algorithm. The significance of each subgrouping was ranked by Kruskal-Wallis testing. RESULTS Age was inversely correlated with IFNalpha activity in female SLE patients (r = -0.20, P = 0.001) as well as their healthy female first-degree relatives (r = -0.16, P = 0.02). In male patients and their healthy male first-degree relatives, there was no significant overall correlation between age and serum IFNalpha activity. The segmentation algorithm revealed significantly increased IFNalpha activity between the ages of 12 and 22 years in female SLE patients and between the ages of 16 and 29 years in male SLE patients. Both male and female healthy first-degree relatives had significantly decreased IFNalpha activity after the age of 50 years. CONCLUSION Serum IFNalpha activity is higher in younger individuals in the SLE family cohorts, and this tendency is accentuated in affected individuals. This age-related pattern of IFNalpha activity may contribute to the increased incidence of SLE in early adulthood, and interestingly, males and females had similar age-related patterns of IFNalpha activity.

TLR2 and MyD88 Contribute to Lactobacillus casei Extract–Induced Focal Coronary Arteritis in a Mouse Model of Kawasaki Disease

Background— Kawasaki disease is the most common cause of acquired cardiac disease and acute vasculitis in children, targets the coronary arteries, and can occasionally be fatal. The pathogenesis and the molecular mechanisms remain unknown. After injection of Lactobacillus casei cell-wall extract (LCCWE), mice develop a focal coronary arteritis that histopathologically resembles Kawasaki disease, but the mechanism remains unclear. Here, we tested the hypothesis that signaling by Toll-like receptors (TLRs) through their key downstream adaptor molecule myeloid differentiation factor 88 (MyD88) is required for the cellular activation and coronary arteritis produced by LCCWE. Methods and Results— Bone marrow–derived macrophages from TLR2- or MyD88-deficient mice were unresponsive to LCCWE-induced stimulation. In contrast, macrophages obtained from TLR4-deficient mice produced the same amount of interleukin-6 as macrophages from wild-type mice after stimulation with LCCWE. Intraperitoneal injection of LCCWE produced severe focal coronary arteritis in TLR4−/− and C57BL/6 control mice but not in TLR2−/− or MyD88−/− mice. Collectively, these results indicate that LCCWE is a potent inducer of nuclear factor-&kgr;B via TLR2 but not TLR4 and that this activation proceeds via the MyD88-dependent signaling pathway. In vivo studies suggest that TLR2−/− mice are protected from LCCWE-induced coronary arteritis and that this protection is mediated through the adaptor molecule MyD88. Conclusions— Our results provide important insights into the molecular signaling in this mouse model of coronary arteritis. We show here that LCCWE-induced coronary arteritis is dependent on intact TLR2 and MyD88 signaling.

Involvement of Innate and Adaptive Immunity in a Murine Model of Coronary Arteritis Mimicking Kawasaki Disease

Kawasaki disease (KD) is the most common cause of acquired cardiac disease and acute vasculitis in children in the developed world. Injection of a cell wall extract isolated from Lactobacillus casei (LCCWE) into mice causes a focal coronary arteritis that histopathologically mimics the coronary lesions observed in KD patients. In this study we used this model to investigate the participation of T cells, B cells, and dendritic cells (DC) in the development of coronary arteritis. RAG1−/−, B cellnull, and wild-type (WT) mice were injected with a single dose of LCCWE (500 μg/mouse i.p.). None of the RAG1−/− mice developed coronary arteritis, whereas 70% of WT and 100% of B cellnull mice developed coronary lesions, indicating that T cells were required for lesion formation. When splenocytes isolated from LCCWE-treated mice were restimulated with LCCWE, we observed significant IFN-γ secretion in WT but not in RAG1−/− mice. Immunohistochemical staining showed F4/80+ macrophages, activated MIDC-8+ myeloid DCs (mDC), plasmacytoid DCs, and colocalization of CD3+ T cells with mDCs in coronary artery lesions, suggesting an Ag-driven process. T cells but not B cells are required for LCCWE-induced coronary arteritis. Similar to human lesions, the coronary lesions contain macrophages, activated mDCs, and plaslmacytoid DCs all in close proximity to T cells, further strengthening the relevance of this mouse model to the immunopathology of coronary disease in KD. These studies are consistent with the interpretation that macrophages and DCs may collaborate with T cells in the pathological mechanisms of coronary arteritis.

Update on the pathogenesis and treatment of systemic onset juvenile rheumatoid arthritis

Purpose of reviewAlthough systemic onset juvenile rheumatoid arthritis accounts for only about 20% of most reported series, children with systemic onset juvenile rheumatoid arthritis are often the most difficult to treat. Many children with persistent systemic onset juvenile rheumatoid arthritis have marked physical and emotional disability as a result of both disease and treatment-related morbidities. This review highlights recent studies that better elucidate the etiopathogenesis of systemic onset juvenile rheumatoid arthritis. New therapies derived from better understanding of cytokines, cytokine gene expression, and their complex interactions, which result in inflammation, are improving our ability to control active disease while reducing or reliance on corticosteroids. Recent findingsRecent advances in our understanding of the etiopathogenesis of systemic onset juvenile rheumatoid arthritis have led to therapies that specifically target the cytokines found in abnormal quantities in children with active disease. Biologic agents that directly target interleukin-1a, interleukin-6, and tumor necrosis factor α are currently in use, and additional agents that modulate interleukin-18, myeloid-related proteins 8 and 14, natural killer cell function, and macrophage migration inhibitory factor production are under investigation. SummaryAnakinra, monoclonal antibody to interleukin-6 receptor, and thalidomide each have led to significant clinical improvement with fewer side effects than resulted when corticosteroids were the mainstay of therapy.

Diagnosis of the mucopolysaccharidoses

The mucopolysaccharidoses (MPSs) often present a diagnostic challenge, particularly for patients who have more slowly progressive disease phenotypes, as early disease manifestations can be subtle or non-specific. However, certain types of bone and joint involvement should always prompt consideration of an MPS diagnosis, such as early joint involvement without classic inflammatory features or erosive bone lesions, claw hand, spinal deformities or dysostosis multiplex. All such patients should be referred to a geneticist or metabolic specialist for diagnostic evaluation. The earlier the diagnosis is made, the better the potential outcome of treatment. Each type of MPS is associated both with deficient activity of a specific lysosomal enzyme that degrades specific glycosaminoglycans (GAGs) and with abnormalities in urinary GAG excretion. MPS patients usually excrete excess GAG in urine and/or have different relative proportions of types of GAG in urine as compared with age-matched normal subjects. Although urinary GAG analyses (both quantitative and qualitative) can suggest the most likely type of MPS, diagnosis must be confirmed by enzyme assay. Multiple assays may be necessary to identify the disease subtype. Correct identification of the MPS type is essential to guide treatment and management decisions.

Neutral lipid storage disease with subclinical myopathy due to a retrotransposal insertion in the PNPLA2 gene

An 18-year-old girl referred to a rheumatologist with malar flush and Gottran papules was found to have a markedly elevated serum CK. She was a good student and an avid ballet dancer. A muscle biopsy showed massive triglyceride storage, which was also found in peripheral blood granulocytes (Jordan anomaly) and cultured skin fibroblasts. Assessment using computerized dynamometry and cycle ergometry showed normal strength and muscle energetics, but proton spectroscopy revealed severe triglyceride accumulation in both skeletal and cardiac muscle. Sequencing of PNPLA2, the gene responsible for neutral lipid storage disease with myopathy (NLSDM), revealed a retrotransposal insertion of about 1.8kb in exon 3 that abrogates transcription of PNPLA2. The sequences of CGI-58, the gene responsible for Chanarin-Dorfman syndrome (CDS), another multisystem triglyceride storage disease, and of two genes encoding lipid droplets-associated proteins, perilipin A and adipophilin, were normal. This case shows that NLSDM can be a transposon-associated disease and that massive lipid storage in muscle can present as asymptomatic hyperCKemia.

Systemic lupus erythematosus and related disorders of childhood.

Systemic lupus erythematosus (SLE) remains a challenging autoimmune disease in term of its etiology, pathogenesis, and management. Much progress has been made in the past year in searching for the SLE susceptibility genes, particularly by several genome-wide screening groups. Cumulative evidence about the association of infections and hormones with SLE has been gathered. Researchers believe that childhood SLE involves more severe organ involvement than adult SLE. Central nervous system complicated lupus continues to be problematic because functional imaging can be abnormal in otherwise asymptomatic lupus individuals. Whether these abnormalities result from subclinical central nervous system involvement or from false positives remains to be determined. With the wide use of corticosteroids as a cornerstone therapy for major organ involvement in childhood SLE, potential complications, especially those involving the growing bone or osteoporosis, are a cause of concern. Evidence suggests that regular exercise, as well as calcium and vitamin D supplementation, may help alleviate bone complications. Researchers have also updated information about pediatric antiphospholipid antibody syndrome. Follow-up studies on neonatal lupus and its pathogenesis have progressed, leading to a better understanding of its natural history and, in turn, to proper counseling of mothers of infants with neonatal lupus and of women with positive anti-Ro or anti-La antibodies. Drug-induced lupus in children is not uncommon. Minocycline and zafirlukast have been increasingly used, and were reported to induce lupus in children.