Andrea Braun

Lymphoid Neogenesis in Rheumatoid Synovitis

In rheumatoid arthritis (RA), tissue-infiltrating lymphocytes can be arranged in sophisticated organizations that resemble microstructures usually formed in secondary lymphoid organs. Molecular pathways and host risk factors involved in this process of lymphoid neogenesis remain to be defined. In a series of 64 synovial tissue biopsies, lymphoid follicles with germinal centers (GCs) were found in 23.4% of the patients. Follicular dendritic cells (FDCs) were exclusively present in tissues with GCs, suggesting that the recruitment or in situ maturation of FDCs is a critical factor for GC formation in the synovial membrane. Primary follicles were absent, emphasizing the role of Ag recognition in the generation of inflammation-associated lymphoid organogenesis. Multivariate logistic regression analysis of tissue cytokines and chemokines identified two parameters, in situ transcription of lymphotoxin (LT)-β and of B lymphocyte chemoattractant (BLC; BLC/CXCL13), that were predictors for FDC recruitment and synovial GC formation. LT-β and BLC/CXCL13 were found to be independent variables that could, in part, compensate for each other to facilitate GC formation. Prediction models incorporating in situ transcription of LT-β and BLC/CXCL13 had high negative yet moderate positive predictive values, suggesting that LT-β and BLC/CXCL13 are necessary but not sufficient. LT-β protein was detected on a subset of mantle zone and GC B cells, but also on T cells in follicular structures. BLC/CXCL13 was produced by FDCs in follicular centers, but was predominantly found in endothelial cells and synovial fibroblasts, suggesting heterotypic signaling between cells of the synovial membrane and infiltrating lymphocytes in regulating extranodal lymphoid neogenesis.

T Cell Activation in Rheumatoid Synovium Is B Cell Dependent

Rheumatoid arthritis results from a T cell-driven inflammation in the synovial membrane that is frequently associated with the formation of tertiary lymphoid structures. The significance of this extranodal lymphoid neogenesis is unknown. Microdissection was used to isolate CD4 T cells residing in synovial tissue T cell/B cell follicles. CD4 T cells with identical TCR sequences were represented in independent, nonadjacent follicles, suggesting recognition of the same Ag in different germinal centers. When adoptively transferred into rheumatoid arthritis synovium-SCID mouse chimeras, these CD4 T cell clones enhanced the production of IFN-γ, IL-1β, and TNF-α. In vivo activity of adoptively transferred CD4 T cells required matching of HLA-DRB1 alleles and also the presence of T cell/B cell follicles. HLA-DRB1-matched synovial tissues that were infiltrated by T cells, macrophages, and dendritic cells, but that lacked B cells, did not support the activation of adoptively transferred CD4 T cell clones, raising the possibility that B cells provided a critical function in T cell activation or harbored the relevant Ag. Dependence of T cell activation on B cells was confirmed in B cell depletion studies. Treatment of chimeric mice with anti-CD20 mAb inhibited the production of IFN-γ and IL-1β, indicating that APCs other than B cells could not substitute in maintaining T cell activation. The central role of B cells in synovial inflammation identifies them as excellent targets for immunosuppressive therapy.

Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill

Objective:We hypothesized that deficiency in 25-hydroxyvitamin D before hospital admission would be associated with all-cause mortality in the critically ill. Design:Multicenter observational study of patients treated in medical and surgical intensive care units. Setting:A total of 209 medical and surgical intensive care beds in two teaching hospitals in Boston, MA. Patients:A total of 2399 patients, age ≥18 yrs, in whom 25-hydroxyvitamin D was measured before hospitalization between 1998 and 2009. Interventions:None. Measurements and Main Results:Preadmission 25-hydroxyvitamin D was categorized as deficiency in 25-hydroxyvitamin D (≤15 ng/mL), insufficiency (16–29 ng/mL), and sufficiency (≥30 ng/mL). Logistic regression examined death by days 30, 90, and 365 post-intensive care unit admission, in-hospital mortality, and blood culture positivity. Adjusted odds ratios were estimated by multivariable logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive for short-term and long-term mortality. At 30 days following intensive care unit admission, patients with 25-hydroxyvitamin D deficiency have an odds ratio for mortality of 1.69 (95% confidence interval of 1.28–2.23, p < .0001) relative to patients with 25-hydroxyvitamin D sufficiency. 25-Hydroxyvitamin D deficiency remains a significant predictor of mortality at 30 days following intensive care unit admission following multivariable adjustment (adjusted odds ratio of 1.69, 95% confidence interval of 1.26–2.26, p < .0001). At 30 days following intensive care unit admission, patients with 25-hydroxyvitamin D insufficiency have an odds ratio of 1.32 (95% confidence interval of 1.02–1.72, p = .036) and an adjusted odds ratio of 1.36 (95% confidence interval of 1.03–1.79, p = .029) relative to patients with 25-hydroxyvitamin D sufficiency. Results were similar at 90 and 365 days following intensive care unit admission and for in-hospital mortality. In a subgroup analysis of patients who had blood cultures drawn (n = 1160), 25-hydroxyvitamin D deficiency was associated with increased risk of blood culture positivity. Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for blood culture positivity of 1.64 (95% confidence interval of 1.05–2.55, p = .03) relative to patients with 25-hydroxyvitamin D sufficiency, which remains significant following multivariable adjustment (odds ratio of 1.58, 95% confidence interval of 1.01–2.49, p = .048). Conclusion:Deficiency of 25-hydroxyvitamin D before hospital admission is a significant predictor of short- and long-term all-cause patient mortality and blood culture positivity in a critically ill patient population.

Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality

Objective:We hypothesized that deficiency in 25-hydroxyvitamin D at critical care initiation would be associated with all-cause mortalities. Design:Two-center observational study. Setting:Two teaching hospitals in Boston, MA. Patients:The study included 1,325 patients, age ≥18 yrs, in whom 25-hydroxyvitamin D was measured 7 days before or after critical care initiation between 1998 and 2009. Measurements:25-hydroxyvitamin D was categorized as deficiency in 25-hydroxyvitamin D (⩽15 ng/mL), insufficiency (16–29 ng/mL), and sufficiency (≥30 ng/mL). Logistic regression examined death by days 30, 90, and 365 postcritical care initiation and in-hospital mortality. Adjusted odds ratios were estimated by multivariable logistic regression models. Interventions:None. Key Results:25-hydroxyvitamin D deficiency is predictive for short-term and long-term mortality. Thirty days following critical care initiation, patients with 25-hydroxyvitamin D deficiency have an odds ratio for mortality of 1.85 (95% confidence interval 1.15–2.98; p = .01) relative to patients with 25-hydroxyvitamin D sufficiency. 25-hydroxyvitamin D deficiency remains a significant predictor of mortality at 30 days following critical care initiation following multivariable adjustment for age, gender, race, Deyo-Charlson index, sepsis, season, and surgical vs. medical patient type (adjusted odds ratio 1.94; 95% confidence interval 1.18–3.20; p = .01). Results were similarly significant at 90 and 365 days following critical care initiation and for in-hospital mortality. The association between vitamin D and mortality was not modified by sepsis, race, or neighborhood poverty rate, a proxy for socioeconomic status. Conclusion:Deficiency of 25-hydroxyvitamin D at the time of critical care initiation is a significant predictor of all-cause patient mortality in a critically ill patient population.

Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill*

Objective:Given the importance of inflammation in acute kidney injury and the relationship between vitamin D and inflammation, we sought to elucidate the effect of vitamin D on acute kidney injury. We hypothesized that deficiency in 25-hydroxyvitamin D prior to hospital admission would be associated with acute kidney injury in the critically ill. Design:Two-center observational study of patients treated in medical and surgical intensive care units. Setting:Two hundred nine medical and surgical intensive care beds in two teaching hospitals in Boston, Massachusetts. Patients:Two thousand seventy-five patients, aged ≥18 yrs, in whom serum 25-hydroxyvitamin D was measured prior to hospitalization between 1998 and 2009. Interventions:None. Measurements and Main Results:The exposure of interest was preadmission serum 25-hydroxyvitamin D and categorized a priori as deficiency (25-hydroxyvitamin D <15 ng/mL), insufficiency (25-hydroxyvitamin D 15–30 ng/mL), or sufficiency (25-hydroxyvitamin D ≥30 ng/mL). The primary outcome was acute kidney injury defined as meeting Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) Injury or Failure criteria. Logistic regression examined the RIFLE criteria outcome. Adjusted odds ratios were estimated by multivariate logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive of acute kidney injury. Patients with 25-hydroxyvitamin D deficiency have an odds ratio for acute kidney injury of 1.73 (95% confidence interval 1.30–2.30; p < .0001) relative to patients with 25-hydroxyvitamin D sufficiency. 25-Hydroxyvitamin D deficiency remains a significant predictor of acute kidney injury following multivariable adjustment (adjusted odds ratio 1.50; 95% confidence interval 1.42–2.24; p < .0001). Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for acute kidney injury of 1.49 (95% confidence interval 1.15–1.94; p = .003) and an adjusted odds ratio of 1.23 (95% confidence interval 1.12–1.72; p = .003) relative to patients with 25-hydroxyvitamin D sufficiency. In addition, preadmission 25-hydroxyvitamin D deficiency is predictive of mortality. Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for 30-day mortality of 1.60 (95% confidence interval 1.18–2.17; p = .003) and an adjusted odds ratio of 1.61 (95% confidence interval 1.06–1.57; p = .004) relative to patients with 25-hydroxyvitamin D sufficiency. Conclusion:Deficiency of 25-hydroxyvitamin D prior to hospital admission is a significant predictor of acute kidney injury and mortality in a critically ill patient population.

Neighborhood Poverty Rate and Mortality in Patients Receiving Critical Care in the Academic Medical Center Setting

BACKGROUND Poverty is associated with increased risk of chronic illness but its contribution to critical care outcome is not well defined. METHODS We performed a multicenter observational study of 38,917 patients, aged ≥ 18 years, who received critical care between 1997 and 2007. The patients were treated in two academic medical centers in Boston, Massachusetts. Data sources included 1990 US census and hospital administrative data. The exposure of interest was neighborhood poverty rate, categorized as < 5%, 5% to 10%, 10% to 20%, 20% to 40% and > 40%. Neighborhood poverty rate is the percentage of residents below the federal poverty line. Census tracts were used as the geographic units of analysis. Logistic regression examined death by days 30, 90, and 365 post-critical care initiation and in-hospital mortality. Adjusted ORs were estimated by multivariable logistic regression models. Sensitivity analysis was performed for 1-year postdischarge mortality among patients discharged to home. RESULTS Following multivariable adjustment, neighborhood poverty rate was not associated with all-cause 30-day mortality: 5% to 10% OR, 1.05 (95% CI, 0.98-1.14; P = .2); 10% to 20% OR, 0.96 (95% CI, 0.87-1.06; P = .5); 20% to 40% OR, 1.08 (95% CI, 0.96-1.22; P = .2); > 40% OR, 1.20 (95% CI, 0.90-1.60; P = .2); referent in each is < 5%. Similar nonsignificant associations were noted at 90-day and 365-day mortality post-critical care initiation and in-hospital mortality. Among patients discharged to home, neighborhood poverty rate was not associated with 1-year-postdischarge mortality. CONCLUSIONS Our study suggests that there is no relationship between the neighborhood poverty rate and mortality up to 1 year following critical care at academic medical centers.

Anti‐chromatin and anti‐C1q antibodies in systemic lupus erythematosus compared to other systemic autoimmune diseases

Objective: To evaluate the prevalence, sensitivity, and specificity of anti‐chromatin and anti‐C1q antibodies in systemic lupus erythematosus (SLE) and lupus nephritis compared to small vessel vasculitis and other connective tissue diseases. To provide long‐term follow‐up data for anti‐chromatin antibodies in lupus nephritis. Methods: We determined the significance of anti‐nuclear antibodies (ANA), anti‐ double‐stranded DNA (anti‐dsDNA), anti‐chromatin, and anti‐C1q antibodies, as well as complement factors C3 and C4, in relation to disease activity in SLE patients with (n = 47; long‐term follow‐up data for 33 patients) and without (n = 31) biopsy‐confirmed lupus nephritis, microscopic polyangiitis (n = 37), Wegeners granulomatosis (n = 66), primary Sjögrens syndrome (n = 17), limited scleroderma (CREST syndrome) (n = 6), and progressive systemic scleroderma (PSS) (n = 11). Results: Anti‐chromatin antibodies were more specific and sensitive than anti‐C1q antibodies in distinguishing SLE patients from those with other systemic autoimmune diseases [anti‐chromatin: sensitivity 64.1%, specificity 99.2%, odds ratio (OR) 219.6; anti‐C1q: sensitivity 50%, specificity 72.6%, OR 2.65]. Anti‐C1q antibodies were present in 75% of patients with Sjögrens syndrome and 35.1% of patients with microscopic polyangiitis. Anti‐chromatin antibodies could identify SLE in patients with positive ANA but negative anti‐dsDNA antibodies. Persisting anti‐chromatin antibodies indicated SLE disease activity, even if anti‐dsDNA antibodies had become negative. In long‐term follow‐up, those SLE patients with negative anti‐dsDNA antibodies but persisting ANA and anti‐chromatin antibodies relapsed if immunosuppression had been tapered. Anti‐chromatin antibodies correlated with the SLE disease activity index (SLEDAI) as a marker of disease activity. Conclusions: The measurement of anti‐chromatin, but not anti‐C1q, antibodies in patients with systemic autoimmune diseases increases diagnostic sensitivity and specificity for SLE and assists in treatment decisions in anti‐dsDNA‐negative patients.

The Difference Between Critical Care Initiation Anion Gap and Prehospital Admission Anion Gap is Predictive of Mortality in Critical Illness

Objective:We hypothesized that the delta anion gap defined as difference between critical care initiation standard anion gap and prehospital admission standard anion gap is associated with all cause mortality in the critically ill. Design:Observational cohort study. Setting:Two hundred nine medical and surgical intensive care beds in two hospitals in Boston, MA. Patients:Eighteen thousand nine hundred eighty-five patients, age ≥18 yrs, who received critical care between 1997 and 2007. Measurements:The exposure of interest was delta anion gap and categorized a priori as <0, 0–5, 5–10, and >10 mEq/L. Logistic regression examined death by days 30, 90, and 365 postcritical care initiation and in-hospital mortality. Adjusted odds ratios were estimated by multivariable logistic regression models. The discrimination of delta anion gap for 30-day mortality was evaluated using receiver operator characteristic curves performed for a subset of patients with all laboratory data required to analyze the data via physical chemical principles (n = 664). Interventions:None. Results:Delta anion gap was a particularly strong predictor of 30-day mortality with a significant risk gradient across delta anion gap quartiles following multivariable adjustment: delta anion gap <0 mEq/L odds ratio 0.75 (95% confidence interval 0.67–0.81; p < 0.0001); delta anion gap 5–10 mEq/L odds ratio 1.56 (95% confidence interval 1.35–1.81; p < 0.0001); delta anion gap >10 mEq/L odds ratio 2.18 (95% confidence interval 1.76–2.71; p < 0.0001); and all relative to patients with delta anion gap 0–5 mEq/L. Similar significant robust associations post multivariable adjustments are seen with death by days 90 and 365 as well as in-hospital mortality. Correcting for albumin or limiting the cohort to patients with standard anion gap at critical care initiation of 10–18 mEq/L did not materially change the delta anion gap–mortality association. Delta anion gap has similarly moderate discriminative ability for 30-day mortality in comparison to standard base excess and strong ion gap. Conclusion:An increase in standard anion gap at critical care initiation relative to prehospital admission standard anion gap is a predictor of the risk of all cause patient mortality in the critically ill.

Vitamin D in Acute Kidney Injury

Vitamin D deficiency is common in critically ill patients and associated with increased mortality, as well as an increased risk of acute kidney injury. The occurrence of acute kidney injury by itself substantially increases critical care mortality. In addition to regulating calcium and phosphorus homeostasis and bone metabolism, vitamin D has pleotropic effects on the immune response. Potential mechanisms of how a deficiency in vitamin D could predispose individuals to increased risk of acute renal failure include dysregulation of the immune system, predisposing patients to sepsis, endothelial dysfunction and prevention of healing of renal ischemia-reperfusion injury. Toll-like receptors, NF-κB and the renin-angiotensin-aldosterone system are mediators of vitamin D effects.

Rheumatoid Arthritis and the Kidney: Uneasy Companions

Accessible online at: www.karger.com/nec Mortality in patients with rheumatoid arthritis (RA) is higher compared to the general population, although the exact percentage of excess mortality attributable to RA depends on various factors [1, 4]. Hospital-based studies tend to render higher mortality rates than communitybased surveys, as well as studies focusing on older RA patients or patients with long-standing disease before study entry. In recent years, the focus in such analyses has mainly been on cardiovascular disease as the most common cause of death, both in the general and even more so in the RA population [1, 2]. Seropositive female RA patients have twice the expected cardiovascular mortality compared to the general population [3]. This may reflect an increased inflammatory disease burden promoting atherosclerosis. Another important cause of excess deaths in RA is infection, which seems to rise with disease duration [1]. Various renal complications adding to morbidity and mortality may also be seen in RA (table 1), many occurring simultaneously [2]. The precise contribution of renal disease to increased mortality is still vigorously debated, since former studies described no excess fatalities attributable to renal disease [4], or a death rate 20 times that of control populations [5]. It remains unclear if the excess mortality in RA patients with renal disease is based on the higher incidence of amyloidosis in this population alone, or if other renal disease entities confer an increased death rate as well. In order to address this question, Sihvonen et al. [6], in this issue of Nephron Clinical Practice, report on a prospective case-control study of Finnish RA patients with renal disease followed for 10 years. They found a significantly increased mortality in all RA patients (26 compared to 16% in the control group), with a hazard ratio of 1.78, which is in line with most other studies on the topic. Interestingly, the hazard ratio was not significantly increased if one took only the male RA population into