Nodular regenerative hyperplasia in common variable immunodeficiency.

PURPOSE: Patients with Common Variable Immunodeficiency (CVID) are subject to the development of a liver disease syndrome known as nodular regenerative hyperplasia (NRH). The purpose of this study was to define the characteristics and course of this complication of CVID. METHODS: CVID patients were evaluated by retrospective and prospective clinical course review. Liver biopsy specimens were evaluated for evidence of NRH and studied via RT-PCR for cytokine analysis. RESULTS: NRH in our CVID patient population occurred in approximately 5 % of the 261 patients in our total CVID study group, initially presenting in most cases with an elevated alkaline phosphatase level. While in some patients the disease remained static, in a larger proportion a more severe disease developed characterized by portal hypertension, the latter leading to hypersplenism with neutropenia and thrombocytopenia and, in some cases, to ascites. In addition, a substantial proportion of patients either developed or presented initially with an autoimmune hepatitis-like (AIH-like) liver disease that resulted in severe liver dysfunction and, in most cases to death due to infections. The liver histologic findings in these AIH-like patients were characterized by underlying NRH pattern with superimposed interface hepatitis, lymphocytic infiltration and fibrosis. Immunologic studies of biopsies of NRH patients demonstrated the presence of infiltrating T cells producing IFN-γ, suggesting that the NRH is due to an autoimmune process. CONCLUSION: Overall, these studies provide evidence that NRH may not be benign but, can be a severe and potentially fatal disease complication of CVID that merits close monitoring and intervention.

Suppression of inflammation in ulcerative colitis by interferon-ß-1a is accompanied by inhibition of IL-13 production.

OBJECTIVE: Ulcerative colitis is associated with increased interleukin 13 (IL-13) production by natural killer T cells. Taking advantage of the inhibitory actions of interferon ß on IL-13 expression, this proof-of-concept study aimed to show that decreasing IL-13 production is associated with clinical improvement of ulcerative colitis symptoms. DESIGN: Open-label interventional drug trial. SETTING: Outpatient clinical research hospital. Patients Adult patients with active ulcerative colitis (Short Clinical Colitis Activity Index (SCCAI)≥ 5). Interventions Treatment with 30 µg IM interferon-ß-1a (Avonex) weekly for 12 weeks with 6 month follow-up. MAIN OUTCOME MEASURES: Clinical response was defined as ≥ 3 point drop in the SCCAI for at least two consecutive monitoring visits, and cytokine production was measured in cultured peripheral blood and lamina propria mononuclear cells (LPMC) before and after treatment. RESULTS: 11 of 16 patients were clinical responders, and 4 were in remission (SCCAI ≤ 2) at the end of treatment. Rectal bleeding subscores improved dramatically by week 4 (38% with frank bleeding vs 87% pretreatment). Increased IL-13 production by LPMC T cells fell significantly in clinical responders (690 ± 99 vs 297 ± 58 pg/ml p = 0.015) but was unchanged in non-responders (542 ± 83 vs 510 ± 39 pg/ml). In addition, non-responders had significantly higher production of IL-17 and IL-6 pre-treatment compared to responders. CONCLUSIONS: Interferon-ß-1a induces clinical response and remission in a large subset of patients with ulcerative colitis that is associated with significant inhibition of IL-13 production. In addition, increased IL-17 and IL-6 production is associated with no response to interferon-ß. These data provide a proof-of-concept that IL-13 is an effector cytokine in ulcerative colitis and should be a target for novel therapies.

Chronic granulomatous disease as a risk factor for autoimmune disease.

Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, suggesting that patients with CGD are at an elevated risk for development of autoimmune disorders. In this report, we describe antiphospholipid syndrome, recurrent pericardial effusion, juvenile idiopathic arthritis, IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pulmonary disease in the setting of CGD. The presence and type of autoimmune disease have important treatment implications for patients with CGD.

Determinants and prognostic implications of malignant ascites in metastatic papillary renal cancer.

OBJECTIVE: To describe the incidence of ascites in metastatic papillary renal cell cancer (pRCC), identify the factors associated with its development and evaluate its prognostic effect on the survival of these patients. METHODS: A retrospective evaluation of the medical records of patients with metastatic pRCC seen at National Cancer Institute (2000-2014) was undertaken. Logistic regression to identify predictors of the development of malignant ascites and Kaplan-Meier analysis to estimate survival was done. RESULTS: Overall, 106 consecutive patients with metastatic pRCC were identified; sufficient data were available in 100 patients to enable assessment of ascites. Further, 20% had evidence of malignant ascites. Median age at diagnosis of ascites was 48.0 years (26.1-76.6 years) and median time to development of ascites from initial diagnosis of metastatic disease was 16.0 (0-73.3) months. There was no significant difference in the incidence of ascites between patients with hereditary and sporadic pRCC (P = 0.803) or among patients with different subtypes of pRCC (P = 0.456). Elevated platelet-lymphocyte ratio predicted development of malignant ascites in our cohort (P = 0.009). Median overall survival was shorter for patients who developed ascites [25.0 (10.2-39.8) months] compared with patients who did not develop this complication [42.5 (30.5-54.4) months, P = 0.041]. CONCLUSION: To our knowledge, this is the first systematic evaluation of the incidence, predictors, and prognostic effect of ascites in metastatic pRCC. Malignant ascites is a common manifestation of metastatic pRCC and is associated with a shorter overall survival. An elevated platelet-lymphocyte ratio predicts a higher risk of developing malignant ascites.

Targeting the mTOR pathway in Chromophobe Kidney Cancer.

Chromophobe kidney cancer accounts for approximately 5% of cases of renal cell carcinoma (RCC). While the genetics of clear cell RCC has been a major focus of research, little is known about the biology of chromophobe tumors. There is ample preclinical rationale for the use of targeted therapy in clear cell tumors, and agents targeting the VHL/HIF pathway are now widely used in clinical practice. However, there is limited experience with targeted agents in non-clear cell tumors. Recently, a few case reports have emerged which report the use of mTOR inhibitors in chromophobe tumors. Here, we report our experience with targeted therapy in a patient with advanced chromophobe RCC who had a durable partial response to temsirolimus. We also include a literature review summarizing the published experience with targeted therapeutic approaches in chromophobe RCC. Additionally, the preclinical rationale for the use of mTOR inhibitors in this population based on our characterization of the hereditary form of chromophobe kidney cancer, Birt-Hogg-Dube syndrome, is discussed.

Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency.

BACKGROUND & AIMS: Common variable immunodeficiency (CVID) patients can develop an idiopathic inflammatory bowel disease resulting in chronic diarrhea and life-threatening malabsorption. This study was designed to assess the status of the gastrointestinal tract and to define the mucosal immune abnormalities in patients with and without symptomatic gut inflammatory disease. METHODS: CVID patients underwent tests of gut absorption, peripheral blood mononuclear cell phenotyping, and upper and lower endoscopy for histology and lamina propria mononuclear cell (LPMC) cytokine production. RESULTS: CVID patients with gastrointestinal symptoms differed from asymptomatic CVID patients by having significantly longer duration of disease and lower body mass index, D-xylose absorption, serum albumin, CD4/CD45RA cells, CD3/CD25 cells, and natural killer cells. Symptomatic CVID patients showed diffuse histologic inflammatory changes in the duodenal and colonic mucosa including villus blunting, increased lamina propria and intraepithelial lymphocytes, and epithelial apoptosis, less frequently seen in asymptomatic patients. LPMCs from symptomatic CVID patients produced significantly higher T-helper (Th) 1 cytokines, interleukin-12, and interferon-gamma. Compared with the Th1 cytokines produced by LPMCs from Crohn's disease, CVID patients did not produce excess amounts of interleukin-23, interleukin-17, or tumor necrosis factor-alpha. CONCLUSIONS: The idiopathic inflammatory bowel disease associated with gastrointestinal symptoms in CVID is a unique combination of diverse histologic findings accompanied by excessive Th1 cytokine production, distinct from that in Crohn's disease. These data show that human gut mucosal inflammatory disease can occur with excess interleukin-12 and interferon-gamma production alone and provide a rationale for developing targeted therapies for this complication of CVID.

Sarcoidosis in chronic granulomatous disease.

In addition to increased susceptibility to infections in patients with chronic granulomatous disease (CGD), a higher incidence of sterile inflammatory disorders in these patients has been noted. However, sarcoidosis has not been reported previously in CGD. In this report, we describe two patients who have CGD and a disorder consistent with sarcoidosis on the basis of unequivocal clinical-radiographic presentations, their responses to treatment, and serum angiotensin-converting enzyme levels. Serum angiotensin-converting enzyme levels were measured in 26 other patients with CGD to establish an appropriate reference range. A possible relationship between CGD and sarcoidosis is discussed.