Gastrointestinal and Extra-Intestinal Manifestations of IgG4-Related Disease.

IgG4-related disease (IgG4-RD) is a chronic relapsing multi-organ fibro-inflammatory syndrome of presumed autoimmune etiology. It is characterized by increased serum levels of IgG4 and tissue infiltration by IgG4+ cells. Increased titers of autoantibodies against a spectrum of self-antigens and response to steroids have led to its characterization as an autoimmune disease. However, the pathognomonic antigens probably differ among manifestations, and different antigens or autoantibodies produce similar immune reactions in different organs. Little is known about the pathogenic effects, if any, of serum IgG4 or IgG4+ plasma cells in tissues. Despite several animal models of the disease, none truly recapitulates human IgG4-RD. Histologic analyses of tissues from patients with IgG4-RD reveal a dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, although these features vary among organs. Typical presentation and imaging findings include mass-forming synchronous or metachronous lesions in almost any organ, but most commonly in the pancreas, bile duct, retroperitoneum, kidneys, lungs, salivary and lacrimal glands, orbit, and lymph nodes. In all organs, inflammation can be reduced by corticosteroids and drugs that deplete B cells, such as rituximab. Patients with IgG4-RD have relapses that respond to primary therapy. Intense fibrosis accompanies the inflammatory response, leading to permanent organ damage and insufficiency. Death from IgG4-RD is rare. IgG4-RD is a multi-organ disease with predominant pancreatico-biliary involvement. Despite its relapsing-remitting course, patients have an excellent prognosis.

Concomitant Disruption of CD4 and CD8 Genes Facilitates the Development of Double Negative αß TCR+ Peripheral T Cells That Respond Robustly to Staphylococcal Superantigen.

Mature peripheral double negative T (DNT) cells expressing αß TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated CD4 and CD8 genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3+ αß TCR+ thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3+ αß TCR+ cells and Foxp3+ T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.

A Central Role for HLA-DR3 in Anti-Smith Antibody Responses and Glomerulonephritis in a Transgenic Mouse Model of Spontaneous Lupus.

MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRß1*0301) and devoid of endogenous class II (both I-A and I-E genes, AE(0)) on a lupus-prone NZM2328 background (NZM2328.DR3(+)AE(0)). Both NZM2328 and NZM2328.DR3(+)AE(0) mice developed anti-dsDNA and glomerulonephritis, but anti-dsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328.DR3(+)AE(0) mice (7.2 ± 4.3 and 8.6 ± 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3(+)AE(0) mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p < 0.001). Periarterial lymphoid aggregates, classic wire loop lesions, and occasional crescents were seen only in kidneys from NZM2328.DR3(+)AE(0) mice. Interestingly, NZM2328.DR3(+)AE(0) mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3(+)AE(0) mice that were completely devoid of endogenous class II (AE(-/) (-)) but not in mice homozygous (AE(+/+)) or heterozygous (AE(+/-)) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4(+) T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background.

Cancer risk in cutaneous lupus erythematosus: a population-based cohort study.

OBJECTIVE: Immune dysregulation associated with chronic autoimmune diseases, such as SLE, has been associated with increased cancer risk. It is unclear whether isolated cutaneous lupus erythematosus (CLE) modifies cancer risk. We estimated the cumulative incidence of cancer in a population-based CLE cohort and compared the risk with a matched non-CLE cohort. METHODS: All incident cases of CLE in Olmsted County, MN, USA between 1965 and 2005 were identified and followed to December 2013. Estimates for the cumulative incidence of any cancer and skin cancer in patients with CLE were derived and compared with an age-, sex- and calendar-year-matched non-CLE cohort using Cox models. RESULTS: There were a total of 155 patients with CLE [age at diagnosis, 48 (sd 16) years; 65% females; BMI, 26.3 (sd 7.1) kg/m2; 40% smokers, 9% with diabetes]. During a median follow-up of 14.6 years, we observed 35 cases of incident cancer (including 10 cases of skin cancer). The cumulative 1-, 5- and 10-year incidence of any cancer after diagnosis of CLE was 1.4, 7.5 and 11.6%, respectively. Compared with matched non-CLE controls, the overall risk of malignancies was not increased in patients with CLE (smoking-adjusted hazard ratio = 1.29; 95% CI: 0.78, 2.13; P = 0.31). There was also no significant increase in risk of any skin cancer in patients with CLE (hazard ratio = 2.51; 95% CI: 0.91, 6.96; P = 0.16). CONCLUSION: CLE is not associated with an increased risk of any cancers, including skin cancers, compared with the general population. However, the number of events was small, limiting the power of the study.

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.

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 Vß8. 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.

High Systemic Type I Interferon Activity Is Associated With Active Class III/IV Lupus Nephritis.

OBJECTIVE: Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. METHODS: Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. RESULTS: Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. CONCLUSION: Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.

Baseline characteristics and long-term outcomes of eosinophilic fasciitis in 89 patients seen at a single center over 20 years.

AIM: Eosinophilic fasciitis (EF) is a rare, fibrosing disorder of skin and subcutaneous tissue. This study was undertaken to describe its clinical and laboratory features and identify prognostic factors associated with outcome. METHODS: We conducted a retrospective review of all EF patients evaluated at our institution from 1 January1997 to 30 December 2016. Kaplan-Meier methods were used to determine treatment response rates over time. Potential associations between baseline characteristics and complete response were examined using Cox models adjusted for age and sex. Time-dependent covariates were used to examine treatment effects. RESULTS: We identified 89 EF patients, with a female-to-male ratio of 1:1. Clinical features included groove sign in 26 (29%), peau d'orange/dimpling in 22 (25%), inflammatory arthritis in 9 (10%) and muscle weakness in 9 (10%). Aldolase was elevated in 11/36 (31%). Complete response rate was 60% (95% confidence interval [CI]: 35-75) at 3 years. Diagnostic delay was inversely associated with treatment response (hazards ratio: 0.84 per 1 month increase; 95% CI: 0.73-0.98). No baseline characteristics correlated with treatment response, but a trend toward positive association of elevated aldolase, hypergammaglobulinemia and presence of hematologic disorders was noted. Methotrexate was the most commonly used immunosuppressant in 79%, hydroxychloroquine in 45%, mycophenolate mofetil in 18% and azathioprine in 8%. No single immunosuppressant agent was associated with a superior response during treatment. CONCLUSIONS: EF is characterized by relatively high response rates. Consensus diagnostic criteria, standardized management algorithms, and large prospective multi-center cohorts are needed to develop an evidence-directed approach to this challenging condition.

Broad Concepts in Management of Systemic Lupus Erythematosus.

Systemic lupus erythematosus is a multisystem autoimmune disease with protean manifestation. Although commonly seen in young women, it can affect men as well as elderly patients. Approach to treatment is multidisciplinary, involves defining the extent of organ involvement, and distinguishing between active manifestations and damage. The mainstay of therapy is judicious use of immunosuppressive medications. Long-term follow-up to address morbidity arising from treatment complications, disease damage, and increased cardiovascular risk is essential.

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

OBJECTIVE: To characterize the epidemiology of mixed connective tissue disease (MCTD) from 1983 to 2014. METHODS: An inception cohort of patients with incident MCTD in 1985-2014 in Olmsted County, Minnesota was identified based on comprehensive individual medical record review. Diagnosis of MCTD required fulfillment of at least 1 of the 4 widely accepted diagnostic criteria without fulfillment of classification criteria for other connective tissue diseases. Data were collected on demographic characteristics, clinical presentation, laboratory investigations, and mortality. RESULTS: A total of 50 incident cases of MCTD were identified (mean age 48.1 years and 84% were female). The annual incidence of MCTD was 1.9 per 100,000 population. Raynaud's phenomenon was the most common initial symptoms (50%), followed by arthralgia (30%) and swollen hands (16%). The diagnosis was frequently delayed with the median time from first symptom to fulfillment of criteria of 3.6 years. At fulfillment of criteria, arthralgia was the most prevalent manifestation (86%), followed by Raynaud's phenomenon (80%), swollen hands (64%), leukopenia/lymphopenia (44%), and heartburn (38%). Evolution to other connective tissue occurred infrequently with a 10-year rate of evolution of 8.5% and 6.3% for systemic lupus erythematosus and systemic sclerosis, respectively. The overall mortality was not different from the general population with a standardized mortality ratio of 1.1 (95% confidence interval 0.4-2.6). CONCLUSION: This study was the first population-based study of MCTD to provide a complete picture of epidemiology and clinical characteristics of MCTD. MCTD occurred in about 2 persons per 100,000 per year. Evolution to other connective diseases occurred infrequently and the mortality was not affected.

Risk of Cerebrovascular Accidents and Ischemic Heart Disease in Cutaneous Lupus Erythematosus: A Population-Based Cohort Study.

OBJECTIVE: It is unclear whether isolated cutaneous lupus erythematosus (CLE) affects cardiovascular risk. We estimated the cumulative incidence and mortality of cardiovascular diseases in a population-based CLE cohort and compared the risk with a matched non-CLE cohort. METHODS: All incident cases of CLE in Olmsted County, Minnesota, between 1965 and 2005 were followed until December 2013. The cumulative incidence of cerebrovascular accidents (CVAs [including stroke and transient ischemic attack]), ischemic heart disease (IHD [including coronary artery disease, myocardial infarction, and angina pectoris]), heart failure, and peripheral arterial disease (PAD) was derived and compared to an age-, sex-, and calendar year-matched non-CLE cohort using Cox models. RESULTS: There were 155 patients with CLE (mean ± SD age at diagnosis 48 ± 16 years, 65% female, mean ± SD BMI 26.3 ± 7.1 kg/m2 , 40% smokers, 9% with diabetes mellitus). During a median followup of 14.6 years, 41 CLE patients had cardiovascular events (15 patients with CVAs, 32 patients with IHD), with a 20-year cumulative incidence of 31.6%. As compared to non-CLE subjects, the risk of CVAs (smoking-adjusted hazard ratio [HR] 2.97 [95% confidence interval (95% CI) 1.13-7.78]) and PAD (HR 2.06 [95% CI 0.99-4.32]) was increased in patients with CLE, but the risk of IHD was not increased (HR 0.94 [95% CI 0.57-1.54]). There was no increase in cardiovascular mortality (HR 1.68 [95% CI 0.76-3.75]). The magnitude of risk for any cardiovascular outcome was not significantly influenced by the extent of cutaneous involvement. CONCLUSION: CLE may be associated with an increased risk of CVAs and PAD, but not IHD. Factors contributing to increased CVA risk in patients with CLE merit evaluation.

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.

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

OBJECTIVE: 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. METHODS: SLE cases were identified from review of medical records and fulfilled the 1982 American College of Rheumatology classification criteria. CLE cases included patients with classic discoid lupus erythematosus, subacute CLE, lupus panniculitis, and bullous lupus erythematosus. Age- and sex-adjusted incidence and prevalence were standardized to the 2000 US white population. RESULTS: The age- and sex-adjusted incidence of SLE (2.9 per 100,000; 95% confidence interval [95% CI] 2.0-3.7) was similar to that of CLE (4.2 per 100,000; 95% CI 3.1-5.2, P = 0.10). However, the incidence of CLE was 3 times higher than SLE in men (2.4 versus 0.8 per 100,000; P = 0.009). The age- and sex-adjusted prevalence of CLE on January 1, 2006 was higher than that of SLE (70.4 versus 30.5 per 100,000; P < 0.001). The prevalences of CLE and SLE in women were similar, but the prevalence of CLE was higher in men than in women (56.9 versus 1.6 per 100,000; P < 0.001). The incidence of CLE rose steadily with age and peaked at 60-69 years. CONCLUSION: The incidences of CLE and SLE are similar, but CLE is more common than SLE in men and in older adults. These findings may reflect differences in genetic or environmental etiology of CLE.

Superantigens produced by catheter-associated Staphylococcus aureus elicit systemic inflammatory disease in the absence of bacteremia.

SAgs, produced by Staphylococcus aureus, play a major role in the pathogenesis of invasive staphylococcal diseases by inducing potent activation of the immune system. However, the role of SAgs, produced by S. aureus, associated with indwelling devices or tissues, are not known. Given the prevalence of device-associated infection with toxigenic S. aureus in clinical settings and the potency of SAgs, we hypothesized that continuous exposure to SAgs produced by catheter-associated S. aureus could have systemic consequences. To investigate these effects, we established a murine in vivo catheter colonization model. One centimeter long intravenous catheters were colonized with a clinical S. aureus isolate producing SAgs or isogenic S. aureus strains, capable or incapable of producing SAg. Catheters were subcutaneously implanted in age-matched HLA-DR3, B6, and AE(o) mice lacking MHC class II molecules and euthanized 7 d later. There was no evidence of systemic infection. However, in HLA-DR3 transgenic mice, which respond robustly to SSAgs, the SSAg-producing, but not the nonproducing strains, caused a transient increase in serum cytokine levels and a protracted expansion of splenic CD4(+) T cells expressing SSAg-reactive TCR Vß8. Lungs, livers, and kidneys from these mice showed infiltration with CD4(+) and CD11b(+) cells. These findings were absent in B6 and AE(o) mice, which are known to respond poorly to SSAgs. Overall, our novel findings suggest that systemic immune activation elicited by SAgs, produced by S. aureus colonizing foreign bodies, could have clinical consequences in humans.

CT angiographic imaging characteristics of thoracic idiopathic aortitis.

BACKGROUND: Idiopathic aortitis (IA) is characterized by giant cell or lymphoplasmacytic inflammation of aorta without a secondary cause. OBJECTIVE: We undertook a retrospective case-control study to identify characteristic CT angiographic findings in these patients and to correlate them with known atherosclerotic risk factors. METHODS: IA cases and controls with noninflammatory aneurysm (control group I) and patients with secondary aortitis (control group II) were identified with a pathology database. Preoperative CT angiographic images of thoracic aorta were reviewed. Diameter of thoracic aorta, wall thickness, and calcification were measured at various sites. Traditional atherosclerotic risk factors were identified from case records and included hypertension, hyperlipidemia, diabetes mellitus, and smoking. RESULTS: Twenty-two idiopathic aortitis cases were compared with 18 patients in control group I and 16 patients in control group II. No differences were found in prevalence of hypertension and diabetes, but hyperlipidemia was more prevalent in the control group I than in cases (72% vs 36%; P = .03). Current smoking was more prevalent in cases (24%) than for patients in control group I (6%) and group II (19%) but not statistically significant (P = .18 and .69, respectively). Thoracic aortic diameters at various points were significantly larger in cases than for patients in control group I. Calcification was more frequent in cases than for patients in control group II. No differences in wall thickness were found. No meaningful correlation was observed between atherosclerotic risk factors and aortic diameter and calcification scores. CONCLUSIONS: Patients with IA have significantly larger and more diffuse dilatation of the thoracic aorta than patients with noninflammatory aneurysms.

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.