Vaidehi R. Chowdhary

Liver Involvement in Systemic Lupus Erythematosus: Case Review of 40 Patients

Objective Subclinical liver involvement is frequent in systemic lupus erythematosus (SLE). We sought to determine the presence of endstage liver disease in patients with SLE. Methods We carried out a retrospective chart review of our cohort of patients with SLE. Endstage liver disease was defined as presence or development of cirrhosis, portal hypertension, or hepatic encephalopathy. Results Forty patients with liver enzyme abnormalities were identified. Major clinical diagnostic groups were drug-induced (n = 4), viral hepatitis (hepatitis B or C and cytomegalovirus; n = 8), non-alcoholic fatty liver disease (NAFLD; n = 8), autoimmune hepatitis (AIH; n = 6), primary biliary cirrhosis (PBC; n = 3), and miscellaneous [n = 11; liver involvement from infection (2), cryptogenic cirrhosis (2), lymphoma (1), and indeterminate (6)]. There were no differences in mean age, total and direct bilirubin, or aspartate aminotransferase and alkaline phosphatase levels. Alanine aminotransferase levels were higher in the miscellaneous group. Biopsies were performed in 20 patients and showed changes of NAFLD (n = 5), AIH (n = 4), PBC (n = 3), hepatitis C (n = 3), and cryptogenic cirrhosis (n = 2), and 1 each with phenytoin-induced liver injury, hepatic granulomas due to systemic candidiasis, and lymphomatous involvement of the liver. The median followup was 44 months (range 10–576). The estimated 5-year serious liver disease-free survival was 93% (95% confidence interval 84%–100%). Eight patients died. Mortality was not directly related to liver disease in any patient. Conclusion Complications of portal hypertension, cirrhosis, and hepatic encephalopathy are rare manifestations of SLE unless coexistent liver disease such as NAFLD, viral hepatitis, or AIH is present.

Noninfectious Ascending Aortitis: A Case Series of 64 Patients

Objective. To identify the clinical presentation and histopathologic characteristics of noninfectious ascending aortitis. Methods. A retrospective medical record and histopathology review was performed of patients with histologic evidence of active noninfectious aortitis who underwent ascending aortic aneurysm resection at Mayo Clinic between January 1, 2000, and February 28, 2006. Clinicopathologic features were recorded, including demographics, clinical presentation, laboratory, imaging findings, histopathology, complications, treatment, and outcome. Results. Sixty-four patients (50% women) were identified; the majority were Caucasian (83%) and elderly (mean age 69.1 yrs). Upon initial presentation, 45% had aneurysm-related symptoms, 33% were asymptomatic, 12.5% had constitutional symptoms, 4.7% had symptoms referable to cranial arteries, and 9.4% had polymyalgia rheumatica (PMR) symptoms. The majority (81%) were of “isolated” variant, with no rheumatologic history. Mean preoperative erythrocyte sedimentation rate was 16.2 ± 23.3 mm/h (n = 20). Additional vascular imaging abnormalities were present in 72% of patients, including stenoses and/or ectasia of major aortic branches and descending thoracic or abdominal aneurysms. Giant cells were seen in 71.9%. Median followup time was 15.4 months, during which 6 (9.4%) patients died. Only 22 (34%) patients received corticosteroids, with uncertain effect on development of recurrent aneurysms, rupture, or dissections. Conclusion. Noninfectious ascending aortitis frequently occurs even in the absence of history, symptoms, or signs of giant cell arteritis (GCA) or PMR. When discovered, such patients should be followed closely, as a majority have additional vascular abnormalities. More studies are needed to determine optimal strategies for surveillance, detection, and treatment of ascending aortitis, which may represent a clinical entity distinct from classical GCA.

Autoimmune Hepatitis: A Review of Current Diagnosis and Treatment

Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by periportal inflammation, elevated immunoglobulins, autoantibodies, and a dramatic response to immunosuppression. An environmental agent is hypothesized to trigger an immune-mediated attack directed against liver antigens in genetically predisposed individuals. A plethora of clinical presentations can be seen ranging from chronic indolent disease to fulminant hepatic failure, and diagnosis requires exclusion of other causes of liver disease. Corticosteroid therapy must be instituted early and modified in an individualized fashion. Treatment decisions are often complicated by the diverse clinical manifestations, uncertainty about natural history, evolving ideas about treatment end points, and a multitude of alternative immunosuppressive agents. Achieving normal liver tests and tissue is the ideal treatment end point, but needs to be weighed against the risk of side effects. Decompensated patients may benefit from early liver transplantation. Long-term prognosis is excellent with early and aggressive initiation of therapy. Our paper discusses AIH, giving a detailed overview of its clinical presentation, risk factors, immunopathogenesis, up-to-date diagnostic criteria, current updates in therapy with a brief discussion of AIH in pregnancy, and long-term implications for cirrhosis and hepatocellular carcinoma in AIH patients.

HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules

Abs to Ro/SSA Ags in the sera of patients with systemic lupus erythematosus and Sjögren’s syndrome are influenced by the HLA class II genes. To investigate the role of individual HLA class II genes in immune responses to human Ro60 (hRo60), mice lacking murine class II molecules and carrying either HLA genes DR2(DRB1*1502), DR3(DRB1*0301), DQ6(DQA1*0103/DQB1*0601), or DQ8(DQA1*0301/DQB1*0302), were immunized with rhRo60. The results show that hRo60 induces strong T and B cell responses in DR2, DR3, and DQ8 mice in comparison to weaker responses in DQ6 mice. In all mice, the majority of the dominant T cell epitopes were located in the amino portion (aa 61–185) and the carboxy portion (aa 381–525) of the hRo60 molecules. In contrast, the early dominant B cell epitopes were located in the middle and carboxy portion of the hRo60 molecule (aa 281–315 and 401–538). In DR2, DR3, and DQ8 mice, the B cell epitopes subsequently spread to the amino and carboxy portion of the hRo60 molecule but were limited to the middle and carboxy portion in DQ6 mice. The DR2 and DR3 mice produced the highest titers of immunoprecipitating Abs against hRo60 and native mouse Ro60. In addition, only DR2 mice exclusively produced immunoprecipitating Abs to native mouse Ro52 and Abs to mouse La by slot blot analysis, whereas in other strains of mice Abs to mouse La were cross-reactive with the immunogen. The results of the present study demonstrate the importance of HLA class II in controlling the immune responses to the Ro-ribonucleoprotein.

Increased Risk of Systemic Lupus Erythematosus in 29,000 Patients with Biopsy-verified Celiac Disease

Objective. To investigate a possible association between celiac disease (CD) and systemic lupus erythematosus (SLE). Case series have indicated a possible association, but population-based studies are lacking. Methods. We compared the risk of SLE in 29,048 individuals with biopsy-verified CD (villous atrophy, Marsh 3) from Sweden’s 28 pathology departments with that in 144,352 matched individuals from the general population identified through the Swedish Total Population Register. SLE was defined as having at least 2 records of SLE in the Swedish Patient Register. We used Cox regression to estimate hazard ratios (HR) for SLE. Results. During followup, 54 individuals with CD had an incident SLE. This corresponded to an HR of 3.49 (95% CI 2.48−4.90), with an absolute risk of 17/100,000 person-years and an excess risk of 12/100,000. Beyond 5 years of followup, the HR for SLE was 2.54 (95% CI 1.57−4.10). While SLE was predominantly female, we found similar risk estimates in men and women. When we restricted our outcome to individuals who also had a dispensation for a medication used in SLE, the HR was 2.43 (95% CI 1.22−4.87). The HR for having 2 records of SLE diagnoses, out of which at least 1 had occurred in a department of rheumatology, nephrology/dialysis, internal medicine, or pediatrics, was 2.87 (95% CI 1.97−4.17). Conclusion. Individuals with CD were at a 3-fold increased risk of SLE compared to the general population. Although this excess risk remained more than 5 years after CD diagnosis, absolute risks were low.

Chronic Exposure to Staphylococcal Superantigen Elicits a Systemic Inflammatory Disease Mimicking Lupus

Chronic nasal and skin colonization with superantigen (SAg)-producing Staphylococcus aureus is well documented in humans. Given that trans-mucosal and trans-cutaneous absorption of SAgs can occur, we determined whether chronic exposure to small amounts of SAg per se could activate autoreactive CD4+ and CD8+ T cells and precipitate any autoimmune disease without further external autoantigenic stimulation. Because HLA class II molecules present SAg more efficiently than do mouse MHC class II molecules, HLA-DQ8 transgenic mice were implanted s.c. with mini-osmotic pumps capable of continuously delivering the SAg, staphylococcal enterotoxin B (total of 10 μg/mouse), or PBS over 4 wk. Chronic exposure to staphylococcal enterotoxin B resulted in a multisystem autoimmune inflammatory disease with features similar to systemic lupus erythematosus. The disease was characterized by mononuclear cell infiltration of lungs, liver, and kidneys, accompanied by the production of anti-nuclear Abs and deposition of immune complexes in the renal glomeruli. The inflammatory infiltrates in various organs predominantly consisted of CD4+ T cells bearing TCR Vβ8. The extent of immunopathology was markedly reduced in mice lacking CD4+ T cells and CD28, indicating that the disease is CD4+ T cell mediated and CD28 dependent. The absence of disease in STAT4-deficient, as well as IFN-γ–deficient, HLA-DQ8 mice suggested the pathogenic role of Th1-type cytokines, IL-12 and IFN-γ. In conclusion, our study suggests that chronic exposure to extremely small amounts of bacterial SAg could be an etiological factor for systemic lupus erythematosus.

Epidemiology of Mixed Connective Tissue Disease, 1985-2014: A Population-Based Study

To characterize the epidemiology of mixed connective tissue disease (MCTD) from 1983 to 2014.

Epidemiology of systemic lupus erythematosus and cutaneous lupus erythematosus in a predominantly white population in the United States

Epidemiologic studies comparing the incidence and prevalence of systemic lupus erythematosus (SLE) and isolated cutaneous lupus erythematosus (CLE) are few. Olmsted County, Minnesota provides a unique setting for such a study owing to resources of the Rochester Epidemiology Project. We sought to describe and compare the incidence and prevalence of SLE and CLE from 1993–2005.

Systemic Inflammatory Response Elicited by Superantigen Destabilizes T Regulatory Cells, Rendering Them Ineffective during Toxic Shock Syndrome

Life-threatening infections caused by Staphylococcus aureus, particularly the community-acquired methicillin-resistant strains of S. aureus, continue to pose serious problems. Greater virulence and increased pathogenicity of certain S. aureus strains are attributed to higher prevalence of exotoxins. Of these exotoxins, the superantigens (SAg) are likely most pathogenic because of their ability to rapidly and robustly activate the T cells even in extremely small quantities. Therefore, countering SAg-mediated T cell activation using T regulatory cells (Tregs) might be beneficial in diseases such as toxic shock syndrome (TSS). As the normal numbers of endogenous Tregs in a typical host are insufficient, we hypothesized that increasing the Treg numbers by administration of IL-2/anti–IL-2 Ab immune complexes (IL2C) or by adoptive transfer of ex vivo expanded Tregs might be more effective in countering SAg-mediated immune activation. HLA-DR3 transgenic mice that closely recapitulate human TSS were treated with IL2C to increase endogenous Tregs or received ex vivo expanded Tregs. Subsequently, they were challenged with SAg to induce TSS. Analyses of various parameters reflective of TSS (serum cytokine/chemokine levels, multiple organ pathology, and SAg-induced peripheral T cell expansion) indicated that increasing the Tregs failed to mitigate TSS. On the contrary, serum IFN-γ levels were increased in IL2C-treated mice. Exploration into the reasons behind the lack of protective effect of Tregs revealed IL-17 and IFN-γ–dependent loss of Tregs during TSS. In addition, significant upregulation of glucocorticoid-induced TNFR family-related receptor on conventional T cells during TSS could render them resistant to Treg-mediated suppression, contributing to failure of Treg-mediated immune regulation.

Pregnancy-related issues in women with systemic lupus erythematosus.

While fertility is preserved in females with systemic lupus erythematosus (SLE), it is well established that pregnancy in these patients is associated with adverse maternal and fetal outcomes, including pregnancy loss, pre‐eclampsia, preterm delivery and intrauterine growth retardation, as well as neonatal mortality. Mechanisms underlying these adverse outcomes are poorly understood, and better understanding of these would allow development of targeted and personalized treatment strategies. Established risk factors for adverse pregnancy outcomes include active disease within 6 months prior to conception and during pregnancy, active nephritis, maternal hypertension, antiphospholipid antibodies and hypocomplementemia. While intensive monitoring is recommended, the comparative effectiveness of appropriate management strategies is unclear. While current strategies are able to achieve live births in 85–90% of pregnancies, certain aspects such as prevention of preterm birth, treatment of congenital heart block due to neonatal lupus and recurrent pregnancy loss despite best management, remains challenging. Pregnancy is also associated with an increased risk of flare of lupus, particularly in patients with active disease at time of conception or within 6 months prior to conception. Pregnant patients with SLE should be followed in a high‐risk obstetric clinic, and care should be closely coordinated between the obstetrician and rheumatologist.