The Impact of Global Collaboration on the Academic Focus of the West African College of Surgeons: Are Worldwide Efforts Aligning with Local Priorities?

BACKGROUND: Global collaboration has the potential to induce a shift in research focus away from the priorities of those in low- and low-middle-income countries (LICs and LMICs). This study quantified international collaboration among surgery publications by Fellows of the West African College of Surgeons (WACS) and investigated if collaboration with upper-middle-income and high-income countries (UMICs and HICs) decreases the homophily of research focus. METHODS: Publications by WACS surgery Fellows from 1960 to 2019 were characterized as local WACS publications, collaborative publications without UMIC/HIC participation, or collaborative publications with UMIC/HIC participation. Research topics were determined for each publication, and topic percentages were compared between collaboration groups. RESULTS: We analyzed 5065 publications. Most (3690 publications, 73%) were local WACS publications, while 742 (15%) were collaborative publications with UMIC/HIC participation and 633 (12%) were collaborative publications without UMIC/HIC participation. UMIC/HIC collaborations contributed to 49% of the increase (378 out of 766 publications) from 2000 to 2019. Topic homophily was significantly lower between local WACS publications and collaborations with UMIC/HIC participation (differed in nine research topics) than it was between local WACS publications and collaborations without UMIC/HIC participation (differed in two research topics). CONCLUSIONS: Publications without international collaboration comprise most WACS research, but the rate of UMIC/HIC collaborations is rapidly increasing. We found that UMIC/HIC collaborations decreased the homophily of topic focus in WACS publications, indicating that global collaborations need to have greater emphasis on the priorities of those in LICs and LMICs.

Surgical subspecialists in West Africa: Workforce size, training opportunities, and contributing factors.

BACKGROUND: The global burden of disease treatable by surgical subspecialists remains an outstanding area of need, and yet little is known about the subspecialist workforce worldwide, especially in sub-Saharan Africa. This study aims to quantify the subspecialty surgical workforce and number of subspecialty training programs in West Africa and to identify socioeconomic factors predicting the number of subspecialists in West African countries. METHODS: West African subspecialists and accredited fellowship training programs in 17 West African countries were quantified using membership data from the West African College of Surgeons and compared with publicly available workforce data from the United States, the United Kingdom, and East, Central, and Southern Africa. Spearman's coefficients were calculated to identify socioeconomic predictors of subspecialist surgical workforce. RESULTS: Of 2,181 surgeons, 712 (32.6%) were surgical subspecialists. Three (18%) of 17 West African countries had greater than 11 subspecialists. There were 174 subspecialty training programs in the region, though 13 countries (76%) had no programs. The number of subspecialists correlated most strongly with the number of subspecialty training programs (rS = 0.68, P = .003) but also correlated significantly with gross population and number of medical schools (rS = 0.50-0.52, P ≤ .05). CONCLUSION: Subspecialist surgeons represent one third of surgeons in West Africa, though most countries have fewer than 12 providers. The number of subspecialists is significantly correlated with the number of subspecialty training programs, and yet many West African countries lack accredited programs. These results suggest that investing in training programs is the most valuable potential strategy to address the shortage of surgical subspecialists in West Africa.

Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors. METHODS: VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV). RESULTS: VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P < 0.001) remained. CONCLUSION: Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

The Microbiome of Temporal Arteries.

OBJECTIVE: A role for microorganisms in giant cell arteritis (GCA) has long been suspected. We describe the microbiomes of temporal arteries from patients with GCA and controls. METHODS: Temporal artery biopsies from patients suspected to have GCA were collected under aseptic conditions and snap-frozen. Fluorescence in situ hybridization (FISH) and long-read 16S rRNA-gene sequencing was used to examine microbiomes of temporal arteries. Taxonomic classification of bacterial sequences was performed to the genus level and relative abundances were calculated. Microbiome differential abundances were analyzed by principal coordinate analysis (PCoA) with comparative Unifrac distances and predicted functional profiling using PICRUSt. RESULTS: Forty-seven patients, including 9 with biopsy-positive GCA, 15 with biopsy-negative GCA and 23 controls without GCA, were enrolled. FISH for bacterial DNA revealed signal in the arterial media. Beta, but not alpha, diversity differed between GCA and control temporal arteries (P = 0.042). Importantly, there were no significant differences between biopsy-positive and biopsy-negative GCA (P > 0.99). The largest differential abundances seen between GCA and non-GCA temporal arteries included Proteobacteria (P), Bifidobacterium (g), Parasutterella (g), and Granulicatella (g) [Log 2-fold change ≥ 4]. CONCLUSION: Temporal arteries are not sterile, but rather are inhabited by a community of bacteria. We have demonstrated that there are microbiomic differences between GCA and non-GCA temporal arteries, but not between biopsy-positive and biopsy-negative GCA.

Microbiomes of Inflammatory Thoracic Aortic Aneurysms Due to Giant Cell Arteritis and Clinically Isolated Aortitis Differ From Those of Non-Inflammatory Aneurysms.

OBJECTIVE: We sought to characterize microbiomes of thoracic aortas from patients with non-infectious aortitis due to giant cell arteritis (GCA) and clinically isolated aortitis (CIA) and to compare them to non-inflammatory aorta aneurysm controls. We also compared microbiomes from concurrently processed and separately reported temporal arteries (TA) and aortas. METHODS: From 220 prospectively enrolled patients undergoing surgery for thoracic aorta aneurysm, 49 were selected. Inflammatory and non-inflammatory cases were selected based on ability to match for age (+/-10 years), gender, and race. Biopsies were collected under aseptic conditions and snap-frozen. Taxonomic classification of bacterial sequences was performed to the genus level and relative abundances were calculated. Microbiome differential abundances were analyzed by principal coordinates analysis. RESULTS: Forty-nine patients with thoracic aortic aneurysms (12 CIA, 14 GCA, 23 non-inflammatory aneurysms) were enrolled. Alpha (P=0.018) and beta (P=0.024) diversity differed between specimens from aortitis cases and controls. There were no significant differences between CIA and GCA (P>0.7). The largest differential abundances between non-infectious aortitis and non-inflammatory control samples included Enterobacteriaceae, Phascolarctobacterium, Acinetobactor, Klebsiella, and Prevotella. Functional metagenomic predictions with PICRUSt revealed enrichment of oxidative phosphorylation and porphyrin metabolism pathways and downregulation of transcription factor pathways in aortitis compared to controls. Microbiomes of aortic samples differed significantly from temporal artery samples from a companion study, in both control and GCA groups (P=0.0002). CONCLUSION: Thoracic aorta aneurysms, far from being sterile, contain unique microbiomes that differ from those found in temporal arteries. The aorta microbiomes are most similar between aneurysms that were associated with inflammation, GCA, and CIA, but differed from those associated with non-inflammatory etiologies. These findings are promising in that they indicate that microbes may play a role in the pathogenesis of aortitis-associated aneurysms or non-inflammatory aneurysms by promoting or protecting against inflammation. However, we cannot rule out that these changes are related to alterations in tissue substrate that favor secondary changes in microbial communities.

Outcomes Among 196 Patients With Noninfectious Proximal Aortitis.

OBJECTIVE: Noninfectious aortitis may occur in the context of a recognized systemic disease or as a topographically limited lesion without systemic features, which is called clinically isolated aortitis (CIA). This study was undertaken to better define and stress the limitations of this diagnostic category in a large population of patients in a single center dedicated to aortic diseases and to suggest recommendations for care. METHODS: Records of patients undergoing thoracic aortic surgery (1996-2012) at the Cleveland Clinic were reviewed to identify 196 patients with histopathologically proven aortitis. Clinical diagnoses (giant cell arteritis [GCA], Takayasu arteritis [TAK], CIA, or Other) were determined at the time of surgery. Clinical features, laboratory findings, and imaging results were recorded throughout the follow-up period. At least 6 months of follow-up data were available for 73 CIA patients. RESULTS: The mean age of the patients at time of surgery was 65.6 years (range 15-88 years); 67% of patients were female, and 90.3% were white. At the time of surgery, 129 patients (65.8%) met criteria for CIA, 42 (21.4%) for GCA, 14 (7.1%) for TAK, and 11 (5.6%) met criteria for other systemic inflammatory diseases. During a mean follow-up period of 56.2 months, 19% of CIA patients developed new symptoms, 45% developed new radiographic vascular lesions, 40% underwent additional vascular surgery, and 12% died (n = 9). Eleven of 73 patients (15%) initially classified as having CIA developed features of a systemic disease, most often GCA. CONCLUSION: The majority of patients (66%) with histopathologically proven aortitis have CIA at the time of surgery. CIA patients infrequently report new symptoms over time, but new vascular lesions requiring surgery commonly occur. Serial follow-up including large vessel imaging is strongly advised for all aortitis patients.

Face Transplantation for Granulomatosis With Polyangiitis (Wegener Granulomatosis): Technical Considerations, Immunological Aspects, and 3-Year Posttransplant Outcome.

BACKGROUND: We report new data for a rare face transplant performed 3 years ago. Granulomatosis with polyangiitis (GPA) (Wegener) is a severe autoimmune necrotizing vasculitis and parenchymal inflammatory disease that can affect any organ including those of the craniofacial region. Skin involvement manifests as malignant pyoderma. This account (1) highlights the technical details of face transplantation for this unique indication, (2) reports the 3-year posttransplant outcome, and (3) describes relevant immunological aspects. METHODS: A Le Fort III near-total face and near-total scalp transplant was performed after extensive trauma and subsequent bone and soft tissue infection in a patient with GPA. Incisions were planned along facial aesthetic subunits. The vascular pedicle comprised the facial and superficial temporal arteries bilaterally. The functioning left eye was preserved and fitted into the donor tissues. RESULTS: The procedure took 21 hours, and transfusion was limited to 4 units of packed red cells. Early medical and surgical complications were successfully treated. At 3 years, acceptable aesthetic outcome was achieved with adequate color match and scalp hair growth. The patient has recovered light touch, temperature, and 2-point discrimination and has evidence of symmetric cheek elevation albeit with limited eyelid and frontalis function. GPA relapse did not occur. Four acute rejections were fully reversed. CONCLUSIONS: This case represents a new underlying disease (trauma + GPA) leading to face transplantation and a unique clinical scenario where allografting was indicated for potentially life-threatening and sight-preserving reasons and not for mere functional and aesthetic concerns. Despite complexity, 3-year clinical outcome is encouraging, and the patient is no longer at risk for dural exposure, meningitis, and related morbidity.

Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis.

OBJECTIVE: To examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis. METHODS: The human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF -794 CATT5-8 promoter microsatellite (rs5844572). MIF promoter, CATT-length-dependent gene expression in response to ß-glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans ß-glucan into wild-type (WT) or Mif-knockout (Mif-KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung-Tg2.1). Mice were treated with a neutralizing anti-MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality. RESULTS: The percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung-Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif-KO mice. A significantly higher percentage of Mif lung-Tg2.1 mice, compared to Mif-KO or WT mice, died when injected with Candida albicans ß-glucan, and treatment of these mice with an anti-MIF monoclonal antibody protected against a lethal outcome. Levels of MIF-dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung-Tg2.1 mice. CONCLUSION: Patients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung-Tg2.1 mice, while anti-MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA.

Brief Report: Circulating Cytokine Profiles and Antineutrophil Cytoplasmic Antibody Specificity in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3-ANCA] versus myeloperoxidase ANCA [MPO-ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]). METHODS: A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest. RESULTS: Levels of 9 circulating cytokines (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-15, IL-18, CXCL8/IL-8, CCL-17/thymus and activation-regulated chemokine [TARC], IL-18 binding protein [IL-18 BP], soluble IL-2 receptor α [sIL-2Rα], and nerve growth factor ß [NGFß]) were significantly higher in PR3-AAV than MPO-AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase-associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM-1]) were higher in MPO-AAV than in PR3-AAV, 6 cytokines (IL-6, GM-CSF, IL-15, IL-18, sIL-2Rα, and NGFß) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3-AAV and MPO-AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL-15, IL-8, IL-18 BP, NGF-ß, sICAM-1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis. CONCLUSION: Distinct cytokine profiles were identified for PR3-AAV versus MPO-AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.

The Utility of Urinalysis in Determining the Risk of Renal Relapse in ANCA-Associated Vasculitis.

BACKGROUND AND OBJECTIVES: The significance of persistent hematuria or proteinuria in patients with ANCA-associated vasculitis who are otherwise in clinical remission is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis was conducted using participants enrolled in two randomized, placebo-controlled clinical trials who had active GN due to ANCA-associated vasculitis, had positive ANCA, and achieved remission by month 6. Dipstick and microscopic urinalyses were performed at each visit. Persistent hematuria or proteinuria for at least 6 months and the cumulative duration of hematuria were examined. Renal relapse was defined as new or worsening red blood cell casts and/or worsening kidney function according to the Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis. RESULTS: There were 149 patients included in this study: 42% had persistent hematuria, and 43% had persistent proteinuria beyond 6 months. Persistent hematuria was associated with a significantly higher risk of relapse, even after adjusting for potential confounders (subdistribution hazard ratio, 3.99; 95% confidence interval, 1.20 to 13.25; P=0.02); persistent proteinuria was not associated with renal relapse (subdistribution hazard ratio, 1.44; 95% confidence interval, 0.47 to 4.42; P=0.53). Furthermore, greater cumulative duration of hematuria was significantly associated with a higher risk of renal relapse (adjusted subdistribution hazard ratio, 1.08 per each month; 95% confidence interval, 1.03 to 1.12; P<0.01). The median time to renal relapse was 22 months. CONCLUSIONS: In patients with ANCA-associated vasculitis and kidney involvement who achieve remission after induction therapy, the presence of persistent hematuria, but not proteinuria, is a significant predictor of future renal relapse.

Interstitial Immunostaining and Renal Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis.

BACKGROUND: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed therapy. METHODS: Renal biopsies from 33 patients treated with cyclophosphamide (CYC; n = 17) or rituximab (RTX; n = 16) in the RTX in ANCA-associated vasculitis (RAVE) trial were classified according to the new ANCA GN classification. T- and B-cell infiltration in the interstitium was assessed by immunostaining for CD3 and CD20. Correlations of clinical and histologic parameters with renal function at set time points were examined. RESULTS: The mean (SD) baseline estimated glomerular filtration rate was 36 (20) mL/min/1.73 m2. ANCA GN class distribution was 46% focal, 33% mixed, 12% sclerotic and 9% crescentic. The interstitial infiltrate consisted of >50% CD3 positive cells in 69% of biopsies, but >50% CD20 positive cells only in 8% of biopsies. In a multiple linear regression model, only baseline glomerular filtration rate (GFR) correlated with GFR at 6, 12, and 18 months. Interstitial B- and T-cell infiltrates had no significant impact on long-term prognosis, independent of the treatment limb. A differential effect was noted only at 6 months, where a dense CD3 positive infiltrate predicted lower GFR in the RTX group and a CD20 positive infiltrate predicted higher GFR in the CYC group. CONCLUSIONS: In ANCA-associated GN, the interstitial infiltrate contains mainly T lymphocytes. However, it is neither reflecting baseline renal function nor predictive of response to treatment, regardless of the immunosuppression regimen employed.

IgA antibodies to myeloperoxidase in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

OBJECTIVES: To determine the prevalence of anti-myeloperoxidase (MPO) antibodies of IgA (IgA anti-MPO) isotype in patients with eosinophilic granulomatosis with polyangiitis (EGPA), and the association of the IgA antibodies with IgG anti-MPO and with disease activity. METHODS: Serum samples from patients with EGPA followed in a multicenter longitudinal cohort were tested by ELISA for the presence of IgA anti-MPO and IgG anti-MPO antibodies. Sera from 87 healthy controls were used to define a positive test. Sera from 168 patients with EGPA (298 samples) were tested. Frequencies of positive testing for IgA anti-MPO were compared between patients with active EGPA, patients in remission, and controls. RESULTS: IgA anti-MPO was detected in 10 of 168 (6%) patients with EGPA (11 of 298 serum samples) compared to 1 of 87 (1%) healthy controls (p=0.10). All 11 samples testing positive for IgA anti-MPO also tested positive for IgG anti-MPO. Ninety samples tested positive for IgG anti-MPO but negative for IgA. Samples taken during active EGPA were positive for IgA anti-MPO in 6/72 cases (8%), compared to 5/226 (2%) during remission (p=0.03). Among samples taken during moderate or high disease activity, 5/41 were positive (12%, p=0.01 compared to remission). CONCLUSIONS: Although IgA anti-MPO antibodies are detectable in some patients with EGPA and may be detectable more frequently during active disease, their presence seems unlikely to provide information beyond what is obtained from conventional IgG anti-MPO.

The Pharmacogenomic Association of Fcγ Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively. METHODS: Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests. RESULTS: No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission (P = 0.01). The 519AA genotype predicted complete remission (P = 0.006) and a shorter time to complete remission (P < 0.001). CONCLUSION: The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy.

Effect of Disease Activity, Glucocorticoid Exposure, and Rituximab on Body Composition During Induction Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: We investigated the relationships between glucocorticoid use, disease activity, and changes in body mass index (BMI) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We analyzed AAV patients enrolled in the Rituximab in AAV trial. Glucocorticoid use, BMI, and disease activity were measured regularly during the trial period. We performed mixed-effects regressions to examine the associations of time-dependent cumulative average glucocorticoid use and disease activity with changes in BMI over time, while adjusting for potential confounders. RESULTS: The mean ± SD baseline BMI of the 197 patients enrolled was 28.8 ± 6.3 kg/m2 . Patients with newly diagnosed AAV tended to have a lower mean ± SD BMI than those with relapsing disease (28.0 ± 5.7 kg/m2 versus 29.6 ± 6.8 kg/m2 ) and higher disease activity (mean ± SD Birmingham Vasculitis Activity Score for Wegener's Granulomatosis 8.7 ± 3.3 versus 7.4 ± 2.7). The most significant change in BMI occurred during the first 6 months of the trial (mean ± SD increase of 1.1 ± 2.2 kg/m2 ; P < 0.0001). Disease activity improvement, glucocorticoid exposure, and randomization to rituximab were each independently associated with an increase in BMI (P < 0.001 for all analyses). CONCLUSION: Our findings suggest that changes in BMI, as well as glucocorticoid exposure, are independently associated with improvements in disease activity in AAV. Rituximab may also have effects on BMI independent of its impact on disease activity.

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

OBJECTIVE: To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. RESULTS: Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA-DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)-reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. CONCLUSION: This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive and ANCA-Negative Patients With Granulomatosis With Polyangiitis (Wegener's): Distinct Patient Subsets.

OBJECTIVE: To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). RESULTS: Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P = 0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P < 0.01), primarily because of a lower prevalence of renal involvement. CONCLUSION: We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV.

Malignant Pyoderma Associated with Granulomatosis with Polyangiitis (Wegener Granulomatosis) as a Unique Indication for Facial Vascularized Composite Allotransplantation: Part I.

BACKGROUND: Granulomatosis with polyangiitis (Wegener granulomatosis) is a rare disease that commonly starts in the craniofacial region and can lead to considerable facial disfigurement. Granulomas and vasculitis, however, can involve many other tissues (especially pulmonary and renal). Dermatologic and subcutaneous components can lead to malignant pyoderma. METHODS: The authors describe a unique pathologic condition, where significant Le Fort type trauma was associated with subsequent development of granulomatosis with polyangiitis and malignant pyoderma. Successive operations to excise necrotic tissue and reconstruct the defects were followed by worsening inflammation and tissue erosions. Trauma and surgery in proximity to the eye and sinuses masked the initial clinical presentation and led to delay in diagnosis and disease progression. The resultant facial disfigurement and tissue loss were substantial. RESULTS: Despite multiple confounding factors, accurate diagnosis was eventually established. This was based on persistence of sinus inflammations in the absence of infective agents, proven sterility of lung lesions, and antineutrophil cytoplasmic antibody positivity with proteinase 3 specificity. Skin lesion biopsy specimens were identified as pyoderma gangrenosum and later as malignant pyoderma. Institution of immunosuppressive therapy allowed successful control of the disease and wound healing. The resulting craniofacial destruction, however, necessitated facial vascularized composite allotransplantation. CONCLUSION: Recognition of this rare pathologic association is essential, to prevent delays in diagnosis and treatment that can lead to major craniofacial tissue loss. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type.

OBJECTIVE: To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. METHODS: Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper. RESULTS: PR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis. CONCLUSIONS: Patients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV. TRIAL REGISTRATION NUMBER: NCT00104299; post-results.

Vasculitis in patients with inflammatory bowel diseases: A study of 32 patients and systematic review of the literature.

BACKGROUND: Published small case series suggest that inflammatory bowel disease [IBD; Crohn's disease (CD) or ulcerative colitis (UC)] and vasculitis co-occur more frequently than would be expected by chance. OBJECTIVES: To describe this association by an analysis of a large cohort of carefully studied patients and through a systematic literature review. METHODS: Patients with both IBD and vasculitis enrolled in the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Studies, followed in Canadian Vasculitis research network (CanVasc) centers and/or in the University of Toronto's IBD clinic were included in this case series. A systematic literature review of patients with IBD and vasculitis involved a PubMed search through February 2014. The main characteristics of patients with Takayasu arteritis (TAK) and IBD were compared to those in patients with TAK without IBD followed in the VCRC. RESULTS: The study identified 32 patients with IBD and vasculitis: 13 with large-vessel vasculitis [LVV; 12 with TAK, 1 with giant cell arteritis (GCA); 8 with CD, 5 with UC]; 8 with ANCA-associated vasculitis [AAV; 6 granulomatosis with polyangiitis (GPA), 2 with eosinophilic granulomatosis with polyangiitis (EGPA)]; 5 with isolated cutaneous vasculitis; and 6 with other vasculitides. Patients with LVV and AAV were mostly female (18/21). The diagnosis of IBD preceded that of vasculitis in 12/13 patients with LVV and 8/8 patients with AAV. The review of the literature identified 306 patients with IBD and vasculitis: 144 with LVV (133 TAK; 87 with IBD preceding LVV), 19 with AAV [14 GPA, 1 EGPA, 4 microscopic polyangiitis (MPA)], 66 with isolated cutaneous vasculitis, and 77 with other vasculitides. Patients with IBD and TAK were younger and had more frequent headaches, constitutional symptoms, or gastrointestinal symptoms compared to those patients in the VCRC who had TAK without IBD. CONCLUSIONS: These findings highlight the risk of vasculitis, especially TAK, in patients with IBD (both CD and UC).

Cardiac Involvement in Granulomatosis with Polyangiitis.

OBJECTIVE: To determine frequency and outcomes of granulomatosis with polyangiitis (GPA)-related cardiac disease in a North American GPA cohort. METHODS: Analysis was done of all patients in the Vasculitis Clinical Research Consortium Longitudinal Study of GPA. Demographic and clinical characteristics of patients with and without GPA-related cardiac involvement were compared. RESULTS: Of 517 patients with GPA, 3.3% had cardiac involvement. No differences were observed between patients with or without cardiac involvement in terms of demographics, antineutrophil cytoplasmic antibody positivity, or relapse rate. CONCLUSION: Cardiac involvement in GPA is rare and heterogeneous. In this cohort, cardiac involvement was not associated with a higher rate of relapse or premature death.