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2.  Rituximab Therapy for Primary Sjögren’s Syndrome: An Open-Label Clinical Trial and Mechanistic Analysis 
Arthritis and rheumatism  2013;65(4):1097-1106.
Objective
To study the safety and clinical efficacy of rituximab therapy for primary Sjögren’s syndrome, as well as investigate its mechanisms.
Methods
Patients with primary Sjögren’s syndrome were enrolled in an open-label trial and received rituximab (1 g) on days 1 and 15 and followed through week 52. The primary endpoint was safety, with secondary endpoints evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibodies and BAFF levels, and analysis of gene expression.
Results
Twelve female subjects with primary Sjögren’s syndrome were administered rituximab. They had a median (range) age of 51 (34–69) years and a median (range) disease duration of 8.0 (2–18) years. We observed no unexpected toxicities from rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-muscarinic receptor 3 autoantibodies or in the blood IFN signature.
Conclusion
In primary Sjögren’s syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells.
doi:10.1002/art.37850
PMCID: PMC3618621  PMID: 23334994
3.  Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren’s syndrome 
Introduction
Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab.
Methods
To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period.
Results
Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection.
Conclusions
For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means of measuring the chronicity and selection of expanded B-cell populations in humans.
doi:10.1186/ar4481
PMCID: PMC3978607  PMID: 24517398
4.  Association of Systemic Lupus Erythematosus with Angiographically-defined Coronary Artery Disease: A Retrospective Cohort Study 
Arthritis care & research  2013;65(2):266-273.
Objective
To determine if systemic lupus erythematosus (SLE) is associated with a higher prevalence of coronary artery disease (CAD) in selected patients undergoing coronary angiography, we compared the extent of angiographic abnormalities, CAD risk factors, and all-cause mortality in SLE patients with non-SLE controls.
Methods
We identified SLE patients (N=86) and controls matched by sex and year of cardiac catheterization (N=258) undergoing cardiac catheterization for the evaluation of CAD (median follow up of 4.3 years). Multivariable logistic regression was used to determine if SLE was associated with obstructive CAD defined as ≥ 70% stenosis in a major epicardial coronary artery. Risk adjusted survival differences between the two groups were assessed using Cox proportional hazards modeling.
Results
SLE patients (85% female) were younger than non-SLE patients (median age 49 years vs. 70 years, p<0.001) and were less likely to have diabetes and hyperlipidemia, but had similar rates of hypertension (70% vs.71%, p=0.892). In unadjusted analyses, SLE patients and non-SLE patients had similar rates of obstructive CAD by angiography (52% vs. 62% overall p=0.11). After adjustment for known CAD risk factors, SLE was associated with a significantly increased likelihood of CAD (OR 2.24, 95% CI: 1.08, 4.67). SLE was also associated with a non-significant increase in all-cause mortality (HR 1.683, 95% CI: 0.98, 2.89 p=0.060).
Conclusion
In this selected population, SLE was significantly associated with the presence of CAD as defined by coronary angiography, the gold standard for assessing flow-limiting lesions in this disease. The patients with SLE showed a similar severity of CAD as the controls despite having less than half the rate of diabetes and being 20 years younger.
doi:10.1002/acr.21782
PMCID: PMC3496832  PMID: 22745037
5.  Relationship Between Markers of Platelet Activation and Inflammation with Disease Activity in Wegener’s Granulomatosis 
The Journal of rheumatology  2011;38(6):1048-1054.
Objective
There remains a need for biomarkers to guide therapy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Our objective was to determine whether measures of platelet activation or inflammation are associated with disease activity in Wegener’s granulomatosis (WG).
Methods
Study subjects were participants in a clinical trial. Soluble CD40 ligand (sCD40L), C-reactive protein, interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), P-selectin, vascular endothelial growth factor, and proteinase 3 (PR3)-specific ANCA were measured by ELISA using plasma samples obtained at baseline (active disease), at remission, and prior to, during, and after first flares. Disease activity was assessed by the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Association of biomarkers with disease activity was determined with conditional logistic and linear regression.
Results
Over a mean followup of 27 months, 180 subjects underwent 2044 visits; markers were measured in 563 samples. Longitudinally, all markers other than IL-6 were associated with disease activity. The strongest associations for active disease at baseline versus remission were observed for sCD40L (OR 4.72, 95% CI 2.47–9.03), P-selectin (OR 6.26, 95% CI 2.78–14.10), PR3-ANCA (OR 9.41, 4.03–21.99), and inversely for MCP-1 (OR 0.36, 95% CI 0.22–0.57). BVAS/WG increased by 0.80 (95% CI 0.44–1.16), 0.83 (95% CI 0.42–1.25), and 0.81 (95% CI 0.48–1.15) per unit-increase in PR3-ANCA, sCD40L, and P-selectin, respectively; and decreased by 1.54 (95% CI 0.96–2.12) per unit-increase in MCP-1.
Conclusion
Cytokines arising from within the circulation, including those of platelet activation, correlate with disease activity in WG.
doi:10.3899/jrheum.100735
PMCID: PMC3653633  PMID: 21411717
VASCULITIS; BIOMARKERS; DISEASE ACTIVITY; WEGENER’S GRANULOMATOSIS
6.  Gastric Antral Vascular Ectasia and Its Clinical Correlates in Patients with Early Diffuse Systemic Sclerosis in the SCOT Trial 
The Journal of rheumatology  2013;40(4):455-460.
Objective
To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; “watermelon stomach”) in early diffuse systemic sclerosis (SSc).
Methods
Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests.
Results
Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003).
Conclusion
Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.
doi:10.3899/jrheum.121087
PMCID: PMC3652008  PMID: 23418384
GASTRIC ANTRAL VASCULAR ECTASIA; GAVE; SYSTEMIC SCLEROSIS VASCULOPATHY; ENDOSCOPY
7.  Assessment of Health Related Quality of Life as an Outcome Measure in Granulomatosis with Polyangiitis (Wegener's) 
Arthritis care & research  2012;64(2):273-279.
Objective
Assess a generic measure of health-related quality of life (HRQOL) as an outcome measure in granulomatosis with polyangiitis (Wegener's, GPA)
Methods
Subjects were participants in the Wegener’s Granulomatosis Etanercept Trial (WGET) or the Vasculitis Clinical Research Consortium Longitudinal Study (VCRC-LS). HRQOL was assessed with the Short Form 36 Health Survey (SF-36) that includes physical and mental component summary scores (PCS and MCS). Disease activity was assessed with the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG).
Results
Data from 180 subjects in the WGET (median follow-up = 2.3 years, mean number of visits = 10) and 237 subjects in the VCRC-LS (median follow-up = 2.0 years, mean number of visits = 8) were analyzed. One unit increase in BVAS/WG corresponded to a 1.15 unit (95%CI: 1.02; 1.29) decrease in PCS and a 0.93 (95%CI: 0.78; 1.07) decrease in MCS in the WGET and by 1.16 for PCS (95%CI: 0.94; 1.39) and 0.79 for MCS (95%CI: 0.51; 1.39) in the VCRC-LS. In both arms of the WGET study, SF-36 measures improved rapidly during the first 6 weeks of treatment followed by gradual improvement among patients achieving sustained remission (0.5 improvement in PCS per three months), but worsened slightly (0.03 decrease in PCS per three months) among patients not achieving sustained remission (p = 0.005).
Conclusion
HRQOL, as measured by SF-36, is reduced among patients with GPA. SF-36 measures are modestly associated with other disease outcomes and discriminate between disease states of importance in GPA.
doi:10.1002/acr.20649
PMCID: PMC3250569  PMID: 21954229
vasculitis; health-related quality of life; outcome measures
8.  Circulating Markers of Vascular Injury and Angiogenesis in ANCA-Associated Vasculitis 
Arthritis and rheumatism  2011;63(12):3988-3997.
Objective
To identify biomarkers that distinguish between active ANCA-associated vasculitis (AAV) and remission in a manner superior or complementary to established markers of systemic inflammation.
Methods
Markers of vascular injury and angiogenesis were measured before and after treatment in a large clinical trial in AAV. 163 subjects enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Serum levels of E-selectin, ICAM-3, MMP1, MMP3, MMP9, P-selectin, thrombomodulin, and VEGF were measured at study screening (time of active disease) and at month 6. ESR and CRP levels had been measured at the time of the clinical visit. The primary outcome was the difference in marker level between screening and month 6 among patients in remission (BVAS/WG score of 0) at month 6.
Results
All subjects had severe active vasculitis (mean BVAS/WG score 8.6 +/− 3.2 SD) at screening. Among the 123 subjects clinically in remission at month 6, levels of all markers except E-selectin showed significant declines. MMP3 levels were also higher among the 23 subjects with active disease at month 6 than among the 123 subjects in remission. MMP3 levels correlated weakly with ESR and CRP.
Conclusion
Many markers of vascular injury and angiogenesis are elevated in severe active AAV and decline with treatment, but MMP3 appears to distinguish active AAV from remission better than the other markers studied. Further study of MMP3 is warranted to determine its clinical utility in combination with conventional markers of inflammation and ANCA titers.
doi:10.1002/art.30615
PMCID: PMC3227746  PMID: 21953143
biomarkers; vasculitis; ANCA
9.  Oral Cyclophosphamide Therapy Diminishes Ovarian Reserve in Women with Granulomatosis with Polyangiitis 
Arthritis care & research  2011;63(12):1777-1781.
Objective
Standard treatment for severe granulomatosis with polyangiitis (GPA, previously Wegener’s granulomatosis) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX).
Methods
Patients in the Wegener’s Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women under 50, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti-Müllerian hormone (AMH) and follicle stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as AMH<1.0ng/ml.
Results
Of 42 women in this analysis (mean age 35), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6/8 who received CYC during the trial developed diminished ovarian reserve, compared to 0/4 who did not receive CYC (p<0.05). Changes in AMH correlated inversely with cumulative CYC dose (p=0.01), with a 0.74ng/ml decline in AMH for each 10g of CYC.
Conclusion
Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age.
doi:10.1002/acr.20605
PMCID: PMC3306000  PMID: 22127969
Granulomatosis with polyangiitis; fertility; cyclophosphamide; anti-Müllerian hormone; ovarian function
10.  Solid Malignancies Among Patients with Wegener’s Granulomatosis Treated with Etanercept: Long-term Follow-up of a Multicenter Longitudinal Cohort 
Arthritis and rheumatism  2011;63(8):2495-2503.
Purpose
An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener’s Granulomatosis Etanercept Trial (WGET). The present study was conducted to determine the malignancy risk beyond the exposure to study therapy.
Methods
The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic reports, and therapeutic interventions. The SEER database was used to estimate a standardized incidence rate (SIR) for solid malignancies.
Results
The median post-trial follow-up available for 153 patients (85% of the original cohort) was 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographics between etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept and 5 in the placebo group. The risk of solid malignancies in the etanercept group was increased compared to the general population (SIR=3.92; 95% CI 1.69–7.72), but not different from that of the placebo group (SIR=2.89; 95% CI 0.94–6.73, p=0.39). All solid malignancies occurred in patients exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial follow-up.
Conclusions
The incidence of solid malignancy remained increased during long-term follow-up of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with WG treated with cytotoxic therapy and should be avoided in such patients.
doi:10.1002/art.30394
PMCID: PMC3149780  PMID: 21484770
Wegener’s granulomatosis; vasculitis; etanercept; malignancy; cancer
11.  Challenges in the Pursuit of Immune Tolerance 
Immunological reviews  2011;241(1):49-62.
Summary
Strategies for inducing immune tolerance are fundamentally similar across a spectrum of immune-mediated disorders, including allergic disease, autoimmunity, and rejection of allografts. In each case, the objective of establishing an immunoregulatory balance is challenged by variable upswings in effector cell populations and proinflammatory mediators of immunity, requiring careful and innovative therapeutic intervention to restore stability. The Immune Tolerance Network, an international consortium sponsored by the National Institutes of Health, seeks to advance both the scientific understanding and the clinical success of immune therapies for these disorders, through an innovative and collaborative effort involving clinical trials and mechanistic studies. Over the last decade, scientists have evaluated cell-based ablation and deviation strategies in trials using lymphocyte-specific targeting, induction of host-donor hematopoietic chimerism, induction of antigen-specific immune regulation, and a variety of antigen desensitization approaches. In this article, we review some of the highlights of this experience and discuss the potential for progress, utilizing new insights into regulatory mechanisms and biomarker signatures of tolerance.
doi:10.1111/j.1600-065X.2011.01003.x
PMCID: PMC3092524  PMID: 21488889
immune-mediated disease; tolerance; immunosuppression; transplantation; allergy; autoimmunity
12.  Circulating Angiopoietin-2 as a Biomarker in ANCA-Associated Vasculitis 
PLoS ONE  2012;7(1):e30197.
The endothelial-specific Angiopoietin-Tie2 ligand-receptor system is an important regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to Tie2 receptor renders the endothelial barrier responsive to pro-inflammatory cytokines. We previously showed that circulating Ang-2 correlated with disease severity in a small cohort of critically ill patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The current study reassessed Ang-2 as a biomarker of disease activity and relapse in AAV. Circulating Ang-2 was measured in 162 patients with severe AAV (BVAS/WG≥3, with or without glomerulonephritis) in a clinical trial. Ang-2 levels during active AAV were compared to levels in the same patients during remission (BVAS/WG = 0). Levels in clinical subsets of AAV were compared, and association with future disease course was assessed. Ang-2 levels were elevated in severe disease (median 3.0 ng/ml, interquartile range 1.9–4.4) compared to healthy controls (1.2, 0.9–1.5). However, they did not reliably decline with successful treatment (median 2.6 ng/ml, interquartile range 1.9–3.8, median change −0.1). Ang-2 correlated weakly with BVAS/WG score (r = 0.17), moderately with markers of systemic inflammation (r = 0.25–0.41), and inversely with renal function (r = −0.36). Levels were higher in patients with glomerulonephritis, but levels adjusted for renal dysfunction were no different in patients with or without glomerulonephritis. Levels were higher in patients with newly diagnosed AAV and lower in patients in whom treatment had recently been started. Ang-2 levels during active disease did not predict response to treatment, and Ang-2 levels in remission did not predict time to flare. Thus, Ang-2 appears to have limited practical value in AAV as a biomarker of disease activity at time of measurement or for predicting future activity.
doi:10.1371/journal.pone.0030197
PMCID: PMC3261176  PMID: 22279570
13.  Alpha1-Antitrypsin Deficiency–Related Alleles Z and S and the Risk of Wegener’s Granulomatosis 
Arthritis and rheumatism  2010;62(12):3760-3767.
Objective
Deficiency of α1-antitrypsin (α1AT) may be a determinant of susceptibility to Wegener’s granulomatosis (WG). Several previous, mainly small, case–control studies have shown that 5–27% of patients with WG carried the α1AT deficiency Z allele. It is not clear whether the S allele, the other major α1AT deficiency variant, is associated with WG. This study investigated the relationship of the α1AT deficiency Z and S alleles with the risk of developing WG in a large cohort.
Methods
We studied the distribution of the α1AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay. Results were compared between cases and controls using exact statistical methods.
Results
Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2-parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98–2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33–∞). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying ≥1 Z or ≥1 S allele.
Conclusion
Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between α1AT deficiency and susceptibility to WG.
doi:10.1002/art.27742
PMCID: PMC3123032  PMID: 20827781
14.  Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis 
The New England journal of medicine  2010;363(3):221-232.
BACKGROUND
Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen.
METHODS
We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months.
RESULTS
Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.
CONCLUSIONS
Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)
doi:10.1056/NEJMoa0909905
PMCID: PMC3137658  PMID: 20647199
15.  Good and Bad Memories Following Rituximab Therapy 
Arthritis and rheumatism  2010;62(1):1-5.
doi:10.1002/art.25039
PMCID: PMC2806494  PMID: 20039422
16.  Novel Targeted Therapies for Autoimmunity 
Current opinion in immunology  2009;21(6):648-657.
Summary
The emergence of new targeted therapies is rapidly improving the treatment of autoimmune disease. These drugs have been variably designed to deplete specific T and B cell subsets, interrupt receptor-ligand interactions, and inhibit the activity of inflammatory mediators relevant to immune function. Abatacept, a costimulatory blocker, and rituximab, a B cell depleting antibody are among the approved therapies seeking new indications, while the newer therapies include Fc receptor-non-binding CD3-specific antibodies, IL-12/23 antibodies, an IL-6 receptor antagonist, a sphingosine-1-phosphate agonist, and small molecule inhibitors of intracellular protein kinases. Antigen-specific therapies are in their infancy, but the latest results administering glutamic acid dehydrogenase peptide to type 1 diabetics are promising. In the future, treatment strategies may increasingly explore the use of drug combinations acting at multiple sites of aberrant immunoregulation to achieve disease quiescence and immune tolerance.
doi:10.1016/j.coi.2009.09.008
PMCID: PMC2792714  PMID: 19828300
18.  The calm after the cytokine storm: lessons from the TGN1412 trial 
The Journal of Clinical Investigation  2008;118(4):1344-1347.
In March 2006, a phase I study of the superagonistic anti-CD28 antibody TGN1412 caused a massive cytokine storm and multiorgan failure in six healthy human volunteers. Such a profound impact on the immune system was not predicted by preclinical animal studies. In a study from this issue of the JCI, Müller et al. treated rats with the superagonistic anti-CD28 antibody JJ316 and found that it rapidly induced a marked T cell lymphopenia by trapping T cells in the spleen and lymph nodes (see the related article beginning on page 1405). This dramatic redistribution of T cells simulated the profound T cell lymphopenia observed in human recipients of TGN1412. In contrast, JJ316 treatment in the rats did not reproduce the massive cytokine storm observed following TGN1412 administration to the human volunteers. These results point to similarities as well as differences between rodents and humans in the immunological effects of superagonistic anti-CD28 antibody treatment and raise further questions about how best to design preclinical studies that can better predict the risks of novel immunotherapeutics in humans.
doi:10.1172/JCI35382
PMCID: PMC2269728  PMID: 18357347
19.  Serum, urinary, and salivary nitric oxide in rheumatoid arthritis: complexities of interpreting nitric oxide measures 
Nitric oxide (NO) may play important roles in rheumatoid arthritis (RA). RA is an inflammatory disease involving joints and other systems including salivary glands. To assess NO production in RA patients, we compared levels of serum, urine, and salivary nitrite and nitrate (NOx) in patients with RA and normal subjects, and we examined the relationships of these measures to disease activity. Serum, urine, and NOx levels as well as renal creatinine, NOx clearance and fractional excretion rates were compared in 25 RA patients and 20 age- and gender-matched healthy controls. Subjects were hospitalized for 3 days and placed on a NOxrestricted diet. NOx was assayed using nitrate reductase and the Griess reagent. RA activity was assessed using standard clinical and laboratory measures. While consuming a restricted diet for 3 days to eliminate the effects of oral intake of NOx, 24 hour urinary NOx excretion decreased in both RA patients and healthy controls. Urine NOx levels at all time points were not significantly different between RA patients and normal subjects. Serum NOx levels also decreased during the 3 days of NOx restriction, but RA patients had higher serum NOx levels at all time points compared with the control group. Likewise, serum NOx/creatinine ratios were higher in RA patients than in controls. Although basal salivary flow rate and tear flow were lower in RA patients, salivary NOx levels did not differ between normal and RA subjects. While renal creatinine clearance was not different between the two groups, we found that RA patients had lower renal NOx clearance and lower renal NOx fractional excretion. After correction of p values for multiple comparisons, there were no significant relationships for the RA group between measures of disease activity and the urinary NOx, serum NOx, or urinary NOx clearance. Despite interest in the use of NO as a marker of disease activity, alterations in renal NOx clearance and fractional excretion in RA make it difficult to assess in vivo NO production even with strict dietary restriction of NOx intake.
doi:10.1186/ar2030
PMCID: PMC1779437  PMID: 16907988

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