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1.  IgG4-Related Disease: Baseline clinical and laboratory features in 125 patients with biopsy-proven disease 
Purpose
IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect nearly any organ. No detailed clinical and laboratory assessments have been reported in large numbers of patients with IgG4-RD diagnoses established by strict clinicopathological correlation.
Methods
We reviewed the baseline features of 125 patients with biopsy-proven disease. The diagnosis was confirmed by pathology review according to consensus diagnostic criteria. Disease activity and damage were assessed by the IgG4-RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts.
Results
Of the 125 patients, 103 had active disease and 86 were on no treatment. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher RI, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 (P<0.01 for all comparisons). The correlation between IgG4+ plasmablast level and RI (R=0.45, P=0.003) was stronger than that of total plasmablasts and RI. Seventy-six (61%) of the patients were male, but no significant differences according to gender were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Glucocorticoids failed to produce sustained remission in the majority of patients.
Conclusion
Nearly 50% of this patient cohort with biopsy-proven, clinically-active IgG4-RD had normal serum IgG4 concentrations. Serum IgG4 elevation identify a subset with more inflammatory features. IgG4+ plasmablasts correlate well with disease activity.
doi:10.1002/art.39205
PMCID: PMC4621270  PMID: 25988916
2.  Large vessel involvement by IgG4-related disease 
Medicine  2016;95(28):e3344.
Abstract
Objectives:
IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect multiple organs and lead to tumefactive, tissue-destructive lesions. Reports have described inflammatory aortitis and periaortitis, the latter in the setting of retroperitoneal fibrosis (RPF), but have not distinguished adequately between these 2 manifestations. The frequency, radiologic features, and response of vascular complications to B cell depletion remain poorly defined. We describe the clinical features, radiology findings, and treatment response in a cohort of 36 patients with IgG4-RD affecting large blood vessels.
Methods:
Clinical records of all patients diagnosed with IgG4-RD in our center were reviewed. All radiologic studies were reviewed. We distinguished between primary large blood vessel inflammation and secondary vascular involvement. Primary involvement was defined as inflammation in the blood vessel wall as a principal focus of disease. Secondary vascular involvement was defined as disease caused by the effects of adjacent inflammation on the blood vessel wall.
Results:
Of the 160 IgG4-RD patients in this cohort, 36 (22.5%) had large-vessel involvement. The mean age at disease onset of the patients with large-vessel IgG4-RD was 54.6 years. Twenty-eight patients (78%) were male and 8 (22%) were female. Thirteen patients (36%) had primary IgG4-related vasculitis and aortitis with aneurysm formation comprised the most common manifestation. This affected 5.6% of the entire IgG4-RD cohort and was observed in the thoracic aorta in 8 patients, the abdominal aorta in 4, and both the thoracic and abdominal aorta in 3. Three of these aneurysms were complicated by aortic dissection or contained perforation. Periaortitis secondary to RPF accounted for 27 of 29 patients (93%) of secondary vascular involvement by IgG4-RD. Only 5 patients demonstrated evidence of both primary and secondary blood vessel involvement. Of those treated with rituximab, a majority responded positively.
Conclusions:
IgG4-RD is a distinctive, unique, and treatable cause of large-vessel vasculitis. It can also involve blood vessels secondary to perivascular tumefactive lesions. The most common manifestation of IgG4-related vasculitis is aortitis with aneurysm formation. The most common secondary vascular manifestation is periaortitis with relative sparing of the aortic wall. Both primary vasculitis and secondary vascular involvement respond well to B cell depletion therapy.
doi:10.1097/MD.0000000000003344
PMCID: PMC4956774  PMID: 27428181
aortitis; coronary artery aneurysm; IgG4-related disease (IgG4-RD); inflammatory aortic aneurysm; large vessel vasculitis; periaortitis; pulmonary artery aneurysm; retroperitoneal fibrosis
3.  B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease 
Annals of the rheumatic diseases  2014;74(12):2236-2243.
Objectives
Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid.
Methods
Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab.
Results
The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R2=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition.
Conclusions
The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.
doi:10.1136/annrheumdis-2014-205799
PMCID: PMC4806785  PMID: 25143523
4.  Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis 
Annals of the rheumatic diseases  2012;72(8):1342-1350.
Objective
To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation.
Methods
Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6 months after treatment in a large clinical trial of AAV. Subjects (n=186) enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were available for comparison. The primary outcome was the ability of markers to distinguish severe AAV (Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG)≥3 at screening) from remission (BVAS/WG=0 at month 6), using areas under receiver operating characteristic (ROC) curve (AUC).
Results
All subjects had severe active vasculitis (median BVAS/WG=8) at screening. In the 137 subjects in remission at month 6, 24 of the 28 markers showed significant declines. ROC analysis indicated that levels of CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) best discriminated active AAV from remission (AUC>0.8) and from healthy controls (AUC>0.9). Correlations among these markers and with ESR or CRP were low.
Conclusions
Many markers are elevated in severe active AAV and decline with treatment, but CXCL13, MMP-3 and TIMP-1 distinguish active AAV from remission better than the other markers studied, including ESR and CRP. These proteins are particularly promising candidates for future studies to address unmet needs in the assessment of patients with AAV.
doi:10.1136/annrheumdis-2012-201981
PMCID: PMC4982463  PMID: 22975753
5.  Development and Implementation of a Double-Blind Corticosteroid-Tapering Regimen for a Clinical Trial 
We describe the design and operationalization of a blinded corticosteroid-tapering regimen for a randomized trial of tocilizumab in giant cell arteritis (GCA). To our knowledge, no clinical trial in any disease has ever employed a blinded corticosteroid-tapering regimen, but this was necessary to the design of our trial which is likely to be relevant to other investigations of steroid-sparing regimens. Two standardized corticosteroid-tapering regimens are required for this GCA trial: a 6-month regimen in 3 arms (taken with tocilizumab 162 mg subcutaneously weekly or every other week or with placebo) and a 12-month regimen with placebo (fourth arm). Investigators select initial prednisone doses, tapered in an open-label fashion until 20 mg/day. Doses <20 mg/day are blinded. At least 27 blinded blister packs are required to ensure blinding and encourage compliance. This permits all possible daily doses but requires ≤5 capsules/day. The number of capsules taken at any point during tapering is identical across groups. Our approach may be extrapolated to trials beyond GCA.
doi:10.1155/2015/589841
PMCID: PMC4387940  PMID: 25878667
6.  Neutrophil-Related Gene Expression And Low-Density Granulocytes Associated with Disease Activity and Response to Treatment in ANCA-Associated Vasculitis 
Objectives
To discover biomarkers involved in the pathophysiology of ANCA-associated vasculitis (AAV) and determine if low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.
Methods
The source of clinical data and linked biospecimens was a randomized controlled treatment trial in AAV. RNA-sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit (BL) and during remission 6 months later (6M). Gene expression was compared between patients who met versus did not meet the primary trial outcome of clinical remission at 6M (responders vs. nonresponders). Measurement of neutrophil-related gene expression was confirmed in PBMCs to validate findings in whole blood. A negative selection strategy isolated LDGs from PBMC fractions.
Results
Differential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at BL visit (p<0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multi-gene composite score was significantly higher in nonresponders than responders (p<0.01) and during active disease compared to remission (p<0.01). This signature strongly overlapped an LDG signature identified previously in lupus (FDRGSEA<0.01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response (p<0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO.
Conclusions
In AAV an increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.
doi:10.1002/art.39153
PMCID: PMC4485551  PMID: 25891759
vasculitis; antineutrophil cytoplasmic antibody (ANCA); proteinase 3; myeloperoxidase; biomarkers; low-density granulocyte (LDG); neutrophil extracellular traps (NETs); granulomatosis with polyangiitis (GPA; Wegener’s); microscopic polyangiitis (MPA)
7.  Therapeutic approach to IgG4-related disease 
Medicine  2016;95(26):e4002.
Supplemental Digital Content is available in the text
Abstract
To review the reported evidence on the therapeutic management of IgG4-related disease (IgG4-RD) in clinical practice.
A systematic search of the literature was conducted. The primary outcome measured was the rate of efficacy of first-line therapeutic approaches. Secondary outcomes measured included the rate of disease relapse, the outcome of untreated patients, the rate of patients without drug therapy at the end of follow-up, the rate of side effects, and mortality. The MOOSE, AHRQ, STROBE, and GRACE recommendations/statements were followed.
The results of the systematic search strategy yielded 62 studies that included a total of 3034 patients. Complete information about first-line therapeutic regimens was detailed in 1952 patients, including glucocorticoid-based regimens in 1437 (74%), drug-free regimens in 213 (11%), and other therapies in 38 (2%). No therapy (wait and see management) was reported in 264 (13%) patients. The efficacy of monotherapy with glucocorticoids was specified in 1220 patients, of whom 97% had a therapeutic response. Relapses, however, were reported in 464/1395 (33%) patients despite typically short follow-up periods. Therapeutic efficacy was reported in 219/231 (95%) of relapses treated with glucocorticoids, 56/69 (81%) of those treated with azathioprine, 16/22 (72%) of those treated with other immunosuppressive agents, and in the 9 cases treated with rituximab (100%). In 14 studies, the authors detailed the outcome of 159/246 patients with wait-and-see management; spontaneous improvement or resolution was reported in 68 (43%) cases. Wide heterogeneity was observed with respect to the first-line therapeutic approaches used for the different organ-specific disease subsets, including significant differences in the mean dose of glucocorticoids used.
Nearly 70% of reported IgG4-RD patients are treated with oral glucocorticoids in monotherapy. However, the therapeutic management is heavily influenced by geographical, epidemiological, and clinical factors, especially with respect to the predominant organ affected. The frequency of glucocorticoid failure to induce sustained remissions both during and after treatment and the assessment of glucocorticoid toxicity in IgG4-RD require further study.
doi:10.1097/MD.0000000000004002
PMCID: PMC4937924  PMID: 27368010
autoimmune pancreatitis; glucocorticoids; IgG4; IgG4-related disease; rituximab
8.  Effects of Glucocorticoids on Weight Change During the Treatment of Wegener's Granulomatosis 
Arthritis and rheumatism  2008;59(5):746-753.
Objective
Weight gain is a side effect of glucocorticoid (GC) use, but the natural history and health implications of changes in weight that occur during the treatment of inflammatory disease are not understood.
Methods
We evaluated data from the Wegener's Granulomatosis Etanercept Trial. Patients were categorized according to clinical outcome at 1 year: remission (no disease flares), single flare, or multiple flares. Risk factors for gaining ≥10 kg were examined in multivariate models.
Results
Weights at baseline and 1 year were available for 157 (93%) of the 168 patients analyzed. During year 1, the mean cumulative prednisone dosage in the multiple flares subgroup was 7.9 gm, compared with 6.0 gm and 3.9 gm in the single flare and remission subgroups, respectively (P < 0.001). Patients in these subgroups gained an average of 2.6 kg, 4.1 kg, and 5.8 kg, respectively (P = 0.005). Weight gain did not correlate with cumulative GC dose (R = 0.10, P = 0.25). Thirty-five patients (22.3%) gained and maintained ≥10 kg in the first year. New diagnosis of Wegener's granulomatosis at baseline was an independent predictor of gaining ≥10 kg at 1 year (odds ratio 19.7, 95% confidence interval 2.4–162.6, P = 0.006). Among the 78 patients in the remission subgroup, 40 sustained remissions through the 2-year time point. For these 40 patients, the mean weight gained at year 1 did not regress by the end of year 2, despite the absence of continued GC use.
Conclusion
Disease control was associated with lower cumulative GC doses but greater weight gain. More than one-fifth of patients gained >10 kg in the first year of treatment. The quantity of weight gained by patients during treatment has potential future health implications.
doi:10.1002/art.23561
PMCID: PMC4508273  PMID: 18438908
9.  A 44-Year-Old Man with Eye, Kidney, and Brain Dysfunction 
Annals of neurology  2016;79(4):507-519.
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of the three-prime repair exonuclease-1 (TREX1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient’s multisystem presentation, retinal involvement interpreted as “retinal vasculitis”, and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet’s disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy.
doi:10.1002/ana.24583
PMCID: PMC4858325  PMID: 26691497
retinal vasculopathy with cerebral leukodystrophy; cerebral calcifications; nephropathy
10.  Plasmablasts As A Biomarker For IgG4-Related Disease, Independent Of Serum IgG4 Concentrations 
Annals of the rheumatic diseases  2014;74(1):190-195.
Objectives
We examined the utility of circulating total and IgG4+ plasmablasts as biomarkers of diagnosis and disease activity in IgG4-related disease (IgG4-RD).
Materials & Methods
We evaluated patients with active, untreated, biopsy-proven IgG4-RD affecting an array of organs. Flow cytometry was used to measure total plasmablast and IgG4+ plasmablast counts by gating peripheral blood for CD19lowCD38+CD20−CD27+cells and CD19lowCD38+CD20−CD27+IgG4+cells. Serum IgG4 concentrations were measured by nephelometry. We compared 37 IgG4-RD patients to 35 controls, including healthy individuals (n=14) and patients with other inflammatory diseases prior to treatment (n=21).
Results
TheIgG4-RD patients’ mean age was 59, and 68% were male. Fourteen patients (38%) had three or more organs involved. The IgG4-RD patients had substantially elevated total plasmablast counts (median: 4,698/mL; range: 610–79,524/mL) compared to both untreated disease controls (median: 592/mL; range: 19–4,294/mL;P<0.001) and healthy controls (median: 94/mL; range: 1–653/mL; P<0.001).
Thirteen IgG4-RD patients (36%) had normal serum IgG4 concentrations (mean: 60 mg/dL; range: 5–123 mg/dL; normal: <135 mg/dL). However, the median plasmablast count was not significantly lower in that subset with normal serum IgG4 concentrations compared to those with elevated serum IgG4: 3,784/mL versus 5,155/mL, respectively (P=0.242). Among the 12 rituximab (RTX)-treated patients, the median plasmablast level during disease flare was 6,356/mL (range: 1,123–41,589/mL), declining to 1,419/ml (range: 386/mL–4,150/mL) during remission (P<0.01).
Conclusions
Circulating plasmablasts are elevated in active IgG4-RD, even in patients with normal serum IgG4 concentrations. Plasmablast counts are a potentially useful biomarker for diagnosis, assessing response to treatment, and determining the time to re-treat patients.
doi:10.1136/annrheumdis-2014-205233
PMCID: PMC4656194  PMID: 24817416
IgG4-Related Disease; IgG4; Plasmablast; Rituximab
11.  Prevalence of Atopy, Eosinophilia, and IgE Elevation in IgG4-Related Disease 
Allergy  2013;69(2):269-272.
IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that can affect virtually every organ system. T helper type 2 responses have been presumed to be pathogenic in this disease and a high proportion of IgG4-RD patients are reported to have longstanding allergies, peripheral blood eosinophilia, and serum IgE elevation. It has therefore been proposed that allergic mechanisms drive IgG4-RD. However, no epidemiological assessment of atopy, peripheral blood eosinophilia, serumIgEconcentrationshas ever been undertaken in IgG4-RD patients. In the present manuscript, we evaluated these parameters in a large cohort of IgG4-RD patients in whom a wide range of organs were affected by disease. Our results demonstrate that the majority of IgG4-RD patients are non-atopic. Nevertheless, a subset of non-atopic subjects exhibit peripheral blood eosinophilia and elevated IgE, suggesting that processes inherent to IgG4-RD itself rather than atopyper se contribute to the eosinophilia and IgE elevation observed in the absence of atopy.
doi:10.1111/all.12320
PMCID: PMC4638385  PMID: 24266692
Allergy; Atopy; Eosinophilia; IgG4-Related Disease; Th2 response
12.  IgG4-Related Midline Destructive Lesion 
Annals of the rheumatic diseases  2014;73(7):1434-1436.
doi:10.1136/annrheumdis-2014-205187
PMCID: PMC4625399  PMID: 24651619
IgG4-Related Disease; IgG4 - Midline destructive lesion
13.  De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease 
Background
IgG4-related disease (IgG4-RD) is a poorly understood, multi-organ, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis and the accumulation of IgG4-expressing plasma cells at disease sites.
Objective
The role of B cells and IgG4 antibodies in IgG4-RD pathogenesis is not well defined. We evaluated patients with IgG4-RD for activated B cells in disease lesions as well as peripheral blood and investigated their role in disease pathogenesis.
Methods
B cell populations were analyzed from the peripheral blood of 84 patients with active IgG4-RD using flow cytometry. The repertoire of B cell populations was analyzed in a subset of patients by Next-generation Sequencing. Fourteen of these patients, were longitudinally followed for 9-15 months after Rituximab therapy.
Results
CD19+CD27+CD20-CD38hi plasmablasts, which are largely IgG4+, are elevated in patients with active IgG4-RD. These expanded plasmablasts are oligoclonal, exhibit extensive somatic hypermutation and their numbers decline following rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of Ig heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG4 antibodies are self-reactive.
Conclusions
Clonally expanded CD19+CD27+CD20-CD38hi plasmablasts are a hallmark of active IgG4-RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones upon relapse indicate that the disease pathogenesis is linked to de novo recruitment of naïve B cells into T-dependent responses by CD4+ T cells, likely driving a self-reactive disease process.
doi:10.1016/j.jaci.2014.03.034
PMCID: PMC4149918  PMID: 24815737
IgG4-related disease; autoreactivity; rituximab; next-generation sequencing; somatic hypermutation; plasmablasts; IGHV repertoire; CDR3
14.  Peripheral CD5+ B Cells in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis 
Objective
CD5+ B cells have been conceptualized as a possible surrogate for Breg cells. The aim of the present study was to determine the utility of CD5+ B cells as biomarkers in antineutrophil cytoplasmic antibody–associated vasculitis (AAV).
Methods
The absolute and relative numbers (percentages) of CD5+ B cells (explanatory variables) were measured longitudinally during 18 months in 197 patients randomized to receive either rituximab (RTX) or cyclophosphamide (CYC) followed by azathioprine (AZA) for the treatment of AAV (Rituximab in ANCA-Associated Vasculitis [RAVE] trial). Outcome variables included disease activity (status of active disease versus complete remission), responsiveness to induction therapy, disease relapse, disease severity, and, in RTX-treated patients, relapse-free survival according to the percentage of CD5+ B cells detected upon B cell repopulation.
Results
CD5+ B cell numbers were comparable between the treatment groups at baseline. After an initial decline, absolute CD5+ B cell numbers progressively increased in patients in the RTX treatment arm, but remained low in CYC/AZA-treated patients. In both groups, the percentage of CD5+ B cells increased during remission induction and slowly declined thereafter. During relapse, the percentage of CD5+ B cells correlated inversely with disease activity in RTX-treated patients, but not in patients who received CYC/AZA. No significant association was observed between the numbers of CD5+ B cells and induction treatment failure or disease severity. The dynamics of the CD5+ B cell compartment did not anticipate disease relapse. Following B cell repopulation, the percentage of CD5+ B cells was not predictive of time to flare in RTX-treated patients.
Conclusion
The percentage of peripheral CD5+ B cells might reflect disease activity in RTX-treated patients. However, sole staining for CD5 as a putative surrogate marker for Breg cells did not identify a subpopulation of B cells with clear potential for meaningful clinical use. Adequate phenotyping of Breg cells is required to further explore the value of these cells as biomarkers in AAV.
doi:10.1002/art.38916
PMCID: PMC4497572  PMID: 25332071
16.  IgG4-Related Disease 
doi:10.1155/2013/532612
PMCID: PMC3562585  PMID: 23401693
17.  A MODEL TO PREDICT CARDIOVASCULAR EVENTS IN PATIENTS WITH NEWLY DIAGNOSED WEGENER’S GRANULOMATOSIS AND MICROSCOPIC POLYANGIITIS 
Arthritis care & research  2011;63(4):588-596.
Objectives
To create a prognostic tool to quantify the 5 year cardiovascular (CV) risk in patients with newly diagnosed Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) without pre-morbid CV disease.
Methods
We reviewed CV outcomes during the long term follow up of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as: CV-death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener’s Granulomatosis Etanercept Trial (WGET) cohort.
Results
74/535 (13.8%) of the patients with 5 years of follow up from the EUVAS trials had at least one CV event: 33/281 (11.7%) WG vs. 41/254 (16%) MPA. The independent determinants of CV outcomes were; older age [OR 1.45 (95%CI 1.11 – 1.90)]; diastolic hypertension [OR 1.97 (95%CI 0.98 – 3.95)], and positive PR3 ANCA status [OR 0.39 (95%CI 0.20 – 0.74)]. The model was validated using the WGET cohort (Area under ROC curve = 0.80).
Conclusion
Within 5 years of diagnosis of WG or MPA, 14% of patients will have a cardiovascular event. We have constructed and validated a tool to quantify the risk of a cardiovascular event based on age, diastolic hypertension and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with reduced cardiovascular risk compared to MPO ANCA or negative ANCA status.
doi:10.1002/acr.20433
PMCID: PMC4511092  PMID: 21452269
Vasculitis; Cardiovascular; Wegener’s granulomatosis; microscopic polyangiitis; ANCA; myocardial infarction; stroke
18.  Association of Granulomatosis With Polyangiitis (Wegener’s) With HLA–DPB1*04 and SEMA6A Gene Variants Evidence From Genome-Wide Analysis 
Arthritis and rheumatism  2013;65(9):2457-2468.
Objective
To identify genetic determinants of granulomatosis with polyangiitis (Wegener’s) (GPA).
Methods
We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls.
Results
Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA–DPB1 and HLA–DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10−50 and 2.18 × 10−39, respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA–DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10−8).
Conclusion
We identified the SEMA6A and HLA–DP loci as significant contributors to risk for GPA, with the HLA–DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.
doi:10.1002/art.38036
PMCID: PMC4471994  PMID: 23740775
19.  IgG4-Related Disease and Hypertrophic Pachymeningitis 
Medicine  2013;92(4):206-216.
Abstract
Hypertrophic pachymeningitis (HP) is an inflammatory condition in which the dura mater of the cranium or spine becomes thickened, leading to symptoms that result from mass effect, nerve compression, or vascular compromise. The differential diagnosis of HP includes immune-mediated conditions such as rheumatoid arthritis and vasculitis, malignancies, and infections. Many times, no diagnosis is reached; in such cases, the disease has been described as idiopathic HP. IgG4-related disease (IgG4-RD) is a recently described inflammatory condition known to cause tumefactive lesions at myriad anatomical locations. Both IgG4-RD and idiopathic HP share similar demographics, histopathology, and natural history. We hypothesized that IgG4-RD is a common cause of idiopathic HP.
To investigate this hypothesis, we identified all pathology specimens diagnosed as noninfectious HP during 25 years at our institution. Fourteen cases had stained slides and paraffin blocks to permit review of the original hematoxylin and eosin stained slides as well as immunostaining of cell blocks. Recently published consensus guidelines describing characteristic histopathology and the necessary quantity of IgG4+ plasma cell infiltrate were used to diagnose IgG4-RD.
Four cases (66.6%) that had been regarded previously as representing idiopathic HP were diagnosed as IgG4-RD; of all the reviewed cases, IgG4-RD represented 29% of cases. Of the remaining cases, 3 cases were associated with granulomatosis with polyangiitis (GPA), 2 with lymphoma, and 1 each with rheumatoid arthritis, giant cell arteritis, and sarcoidosis. Two of the cases could not be diagnosed more precisely and were classified as undifferentiated HP. Clinical history, serologic tests, cerebrospinal fluid studies, and radiology alone could not identify the cause of HP. Rather, biopsy with histopathology and immunostaining was necessary to reach an accurate diagnosis. Significant IgG4+ plasma cell infiltrates were observed in rheumatoid arthritis, granulomatosis with polyangiitis, and lymphoma, underscoring the importance of histopathology in making the diagnosis of IgG4-RD.
This case series demonstrates that IgG4-RD may be the most common etiology of noninfectious HP and highlights the necessity of biopsy for accurate diagnosis.
doi:10.1097/MD.0b013e31829cce35
PMCID: PMC4553969  PMID: 23793110
ANCA = antineutrophil cytoplasmic antibodies; CNS = central nervous system; CSF = cerebrospinal fluid; CT = computed tomography; GPA = granulomatosis with polyangiitis; HP = hypertrophic pachymeningitis; HPF = high-power field; IgG4-RD = IgG4-related disease; MRI = magnetic resonance imaging; WBC = white blood cell
20.  Current therapy of granulomatosis with polyangiitis and microscopic polyangiitis: the role of rituximab 
Journal of Nephrology  2014;28:17-27.
Granulomatosis with polyangiitis and microscopic polyangiitis are anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs) that are prone to cycles of remission and relapse. The introduction of cytotoxic therapy has changed the prognosis for these diseases from typically fatal to manageable chronic illnesses with a relapsing course. Despite improvements in outcomes, recurrence of disease and drug-related toxicity continue to produce significant morbidity and mortality. Better understanding of the pathogenesis of AAV and the mechanism of action of cyclophosphamide has led to investigation of therapies that target B cells. Two randomized controlled trials have shown that rituximab is not inferior to cyclophosphamide for induction of remission in severe AAV, with no significant difference in the incidence of overall adverse events in rituximab- versus cyclophosphamide-treated patients. Data from ongoing clinical trials will determine the role of rituximab in the maintenance of remission.
doi:10.1007/s40620-014-0135-3
PMCID: PMC4322237  PMID: 25185728
Anti-neutrophil cytoplasmic antibody; Renal; Rituximab; Vasculitis
21.  IgG4-Related Disease Is Not Associated with Antibody to the Phospholipase A2 Receptor 
Patients with IgG4-related disease (IgG4-RD) share histopathological characteristics that are similar across affected organs. The finding of infiltration with IgG4+ plasma cells in the proper clinical and histopathological contexts connects a large number of clinical entities that were viewed previously as separate conditions. The renal involvement in IgG4-RD is usually characterized by tubulointerstitial nephritis, but membranous nephropathy has also been reported to be one of the renal complications of IgG4-RD. The recent discovery that a high proportion of patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies to the M-type phospholipase A2 receptor (PLA2R) in the circulation and glomerular immune deposits, together with the profound IgG4 hypergammaglobulinemia and occasional reports of membranous nephropathy in IgG4-RD, raised the question of a common antigen. To assess the presence of anti-PLA2R antibody in patients with IgG4-RD, we screened sera from 28 IgG4-RD patients by immunoblot. None of the patients in this cohort had detectable circulating anti-PLA2R antibodies. This study suggests that despite some clinical and serological overlaps between IgG4-RD and IMN,anti-PLA2R antibodies do not play a role in the pathogenesis of IgG4-RD. Additional studies of IgG4-RD with evidence of membranous nephropathy are important to exclude any definite relationship.
doi:10.1155/2012/139409
PMCID: PMC3357948  PMID: 22654915
22.  Development of an IgG4-RD Responder Index 
IgG4-related disease (IgG4-RD) is a multiorgan inflammatory disease in which diverse organ manifestations are linked by common histopathological and immunohistochemical features. Prospective studies of IgG4-RD patients are required to clarify the natural history, long-term prognosis, and treatment approaches in this recently recognized condition. Patients with IgG4-RD have different organ manifestations and are followed by multiple specialties. Divergent approaches to the assessment of patients can complicate the interpretation of studies, emphasizing the critical need for validated outcome measures, particularly assessments of disease activity and response to treatment. We developed a prototype IgG4-RD Responder Index (IgG4-RD RI) based on the approach used in the development of the Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG). The IgG4-RD RI was refined by members of the International IgG4-RD Symposium Organizing Committee in a paper case exercise. The revised instrument was applied retrospectively to fifteen IgG4-RD patients at our institution. Those scores were compared to physician's global assessment scale for the same visits. This paper describes the philosophy and goals of the IgG4-RD RI, the steps in the development of this instrument to date, and future plans for validation of this instrument as an outcome measure.
doi:10.1155/2012/259408
PMCID: PMC3348627  PMID: 22611406
23.  B-cell-depleting Therapy in Systemic Lupus Erythematosus 
The American journal of medicine  2012;125(4):327-336.
The emergence of a new class of agents (B-cell-depleting therapies) has opened a new era in the therapeutic approach to systemic lupus erythematosus, with belimumab being the first drug licensed for use in systemic lupus erythematosus in more than 50 years. Four agents deserve specific mention: rituximab, ocrelizumab, epratuzumab, and belimumab. Controlled trials have shown negative results for rituximab, promising results for epratuzumab, and positive results for belimumab. Despite these negative results, rituximab is the most-used agent in patients who do not respond or are intolerant to standard therapy and those with life-threatening presentations. B-cell-depleting agents should not be used in patients with mild disease and should be tailored according to individual patient characteristics, including ethnicity, organ involvement, and the immunological profile. Forthcoming studies of B-cell-directed strategies, particularly data from investigations of off-label rituximab use and postmarketing studies of belimumab, will provide new insights into the utility of these treatments in the routine management of patients with systemic lupus erythematosus.
doi:10.1016/j.amjmed.2011.09.010
PMCID: PMC3925418  PMID: 22444096
Belimumab; Epratuzumab; Ocrelizumab; Rituximab; Systemic lupus erythematosus
24.  Meta-analysis in granulomatosis with polyangiitis reveals shared susceptibility loci with rheumatoid arthritis 
Arthritis and rheumatism  2012;64(10):3463-3471.
Objectives
To examine the association of previously identified autoimmune disease susceptibility loci with granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), and determine whether genetic susceptibility profiles of other autoimmune diseases are associated with GPA
Methods
Genetic data from two cohorts were meta-analyzed. Genotypes for 168 previously identified single nucleotide polymorphisms (SNPs) associated with susceptibility to different autoimmune diseases were ascertained for a total of 880 GPA cases and 1969 controls of European descent. Single marker associations were identified using additive logistic regression models. Multi-SNP associations with GPA were assessed using genetic risk scores based on susceptibility loci for Crohn’s disease, type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, celiac disease, and ulcerative colitis. Adjustment for population substructure was performed in all analyses using ancestry informative markers and principal components analysis.
Results
Genetic polymorphisms in CTLA4 were significantly associated with GPA in the single-marker meta-analysis (OR 0.79. 95% CI 0.70–0.89, p=9.8×10−5). A genetic risk score based on rheumatoid arthritis susceptibility markers was significantly associated with GPA (OR 1.05 per 1-unit increase in genetic risk score, 95% CI 1.02–1.08, p=5.1×10−5).
Conclusions
Rheumatoid arthritis and GPA may arise from a similar genetic predisposition. Aside from CTLA4, other loci previously found to be associated with common autoimmune diseases were not statistically associated with GPA in this study.
doi:10.1002/art.34496
PMCID: PMC3425721  PMID: 22508400
genetics; vasculitis; granulomatosis with polyangiitis; rheumatoid arthritis; CTLA4
25.  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

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