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1.  Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide 
Annals of the Rheumatic Diseases  2004;63(10):1307-1311.
Objective: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis.
Methods: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969–95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated.
Results: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis.
Conclusion: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.
doi:10.1136/ard.2003.019125
PMCID: PMC1754772  PMID: 15130900
2.  Florid xanthelasmata (yellow lids) in orbital Wegener's granulomatosis. 
AIMS--A new sign of florid xanthelasmata is described in four male patients with orbital manifestations of Wegener's granulomatosis. METHODS--The case notes of four patients with Wegener's granulomatosis, with orbital involvement accompanied by yellow lid lesions, are reviewed. RESULTS--All the patients had active Wegener's granulomatosis at the time the lid lesions were most florid. The lesions gradually resolved as the inflammatory disease was controlled with immunosuppressive agents. The lesions displayed marked asymmetry and predominantly involved the side with the most severe inflammation. Abnormalities of lipid metabolism were not identified and it is believed that the lesions developed in a susceptible anatomical region affected by a vasculitic process. CONCLUSION--A 'yellow lid' associated with orbital inflammation and is a strong pointer to the clinical diagnosis of Wegener's granulomatosis.
Images
PMCID: PMC505134  PMID: 7612558
3.  A case of granulomatosis with polyangiitis complicated by cyclophosphamide toxicity and opportunistic infections: choosing between Scylla and Charybdis 
BMC Nephrology  2014;15:28.
Background
We report a case of progressive Granulomatosis with Polyangiitis (Wegener’s Granulomatosis) with life-threatening complications of both the underlying disease and induction immunosuppressive therapy. Here, for the first time, cyclophosphamide toxicity and severe opportunistic infections including pneumocystis jirovecii- pneumonia were found in one case in a close temporal relationship.
Case presentation
A 34-year-old male patient of Caucasian ethnicity presented with acute renal failure necessitating hemodialysis treatment due to Granulomatosis with Polyangiitis (Wegener’s Granulomatosis). Kidney disease progressed to end-stage renal disease shortly after first diagnosis. After the 2nd bolus of cyclophosphamide shortly, induction immunosuppression (glucocorticoid/cyclophosphamide) was interrupted for repeat infections and resumed 5 years later. By that time, the lungs developed large pulmonary cavernae most likely due to smoldering granuloma indicative for the failed goal of disease remission. Therefore, induction immunosuppression was resumed. Following two monthly boli of cyclophosphamide, the patient developed pericardial effusion and, consecutively, atrioventricular blockade most likely due to cyclophosphamide. After recovery, the patient was discharged without cotrimoxacole. 10 weeks after the last cyclophosphamide bolus and 6 weeks after cessation of cotrimoxacole, the patient was readmitted to the intensive-care unit with Pneumocystis jirovecii pneumonia, and died 6 months later or 74 months after first diagnosis of Granulomatosis with Polyangiitis.
Conclusions
This case illustrates both the need for adequate immunosuppressive therapy to reach disease remission and the limitations thereof in terms of complications including cardiotoxicity of cyclophosphamide and Pneumocystis jirovecii pneumonia. In line with current recommendations, the present case strongly encourages pneumocystis jirovecii- pneumonia chemoprophylaxis for at least 6 months following induction therapy in Granulomatosis with Polyangiitis.
doi:10.1186/1471-2369-15-28
PMCID: PMC3937139  PMID: 24495297
Cyclophosphamide toxicity; Granulomatosis with polyangiitis; Immunosuppression; Opportunistic infections
4.  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
5.  Genetically Distinct Subsets within ANCA-Associated Vasculitis 
The New England journal of medicine  2012;367(3):214-223.
BACKGROUND
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.
METHODS
A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria.
RESULTS
We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti–proteinase 3 ANCA was associated with HLA-DP and the genes encoding α1-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2×10−89, P = 5.6×10−12, and P = 2.6×10−7, respectively). Anti–myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1×10−8).
CONCLUSIONS
This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA–associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA–associated vasculitis and myeloperoxidase ANCA–associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)
doi:10.1056/NEJMoa1108735
PMCID: PMC3773907  PMID: 22808956
6.  Wegener’s granulomatosis mimicking inflammatory bowel disease and presenting with chronic enteritis 
Wegener’s granulomatosis, also known as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, is a small vessel vasculitis with primarily pulmonary, renal, and sinus disease manifestations. The prevalence of Wegener’s granulomatosis is three cases per 100,000 patients. Cardiovascular, neurologic, cutaneous, and joint manifestations have been reported in many case reports and case series. Gastrointestinal manifestations are less noted in Wegener’s granulomatosis, although they have been previously reported in the form of intestinal perforation and intestinal ischemia. Additionally, there are characteristic findings of vasculitis that are noted with active Wegener’s granulomatosis of the small bowel. We report a case of an elderly patient who presented with weight loss, diarrhea, and hematochezia. His symptoms were chronic and had lasted for more than 1 year before diagnosis. Inflammatory bowel disease or chronic enteritis due to Salmonella arizonae because of reptile exposure originally were suspected as etiologies of his presentation. The findings of proteinuria, renal failure, and pauci-immune glomerulonephritis on renal biopsy, in conjunction with an elevated c-ANCA titer, confirmed the diagnosis of Wegener’s granulomatosis with associated intestinal vasculitis. This case demonstrates an atypical presentation of chronic duodenitis and jejunitis secondary to Wegener’s granulomatosis, which mimicked inflammatory bowel disease.
doi:10.2147/IMCRJ.S36546
PMCID: PMC3794984  PMID: 24124396
ANCA-associated vasculitis; Wegener’s syndrome; pauci-immune glomerulonephritis; Salmonella arizonae; inflammatory bowel disease
7.  Strawberry gums: a clinicopathological manifestation diagnostic of Wegener's granulomatosis? 
Journal of Clinical Pathology  1993;46(8):709-712.
AIMS--To highlight an uncommon but characteristic gingival lesion associated with Wegener's granulomatosis, emphasising the presence of pseudoepitheliomatous hyperplasia, microabscesses, and multinucleate giant cells; and the paucity of the currently accepted histopathological criteria of Wegener's granulomatosis--namely necrosis, vasculitis, and granulomata. METHODS--The histopathological features of a gingival biopsy specimen from a case of Wegener's granulomatosis limited to the upper aerodigestive tract in a 36 year old woman were compared with those of 14 similar reported cases. RESULTS--Pseudoepitheliomatous hyperplasia, microabscesses, and multinucleate giant cells were recorded as present in almost all cases of gingival Wegener's granulomatosis. Necrosis, vasculitis, and granuloma formation were present in only a few cases. CONCLUSIONS--The combination of pseudoepitheliomatous hyperplasia, microabscesses, and multinucleate giant cells in a gingival biopsy specimen from erythematous, swollen gums, clinically resembling over-ripe strawberries, in a patient with a severe systemic upset, is so typical of Wegener's granulomatosis as to be virtually diagnostic. Recognition of this characteristic lesion may aid early diagnosis and treatment in cases where other diagnostic variables are absent.
Images
PMCID: PMC501453  PMID: 8408694
8.  Cytomegalovirus retinitis presenting as vasculitis in a patient with Wegener’s granulomatosis 
Purpose
To present an unusual case of cytomegalovirus (CMV) retinitis in a patient with Wegener’s granulomatosis.
Results
A 54-year-old lady with Wegener’s granulomatosis presented with decreased vision in her left eye. Wegener’s retinal vasculitis was diagnosed initially and the patient received treatment with oral steroids. Three days later the patient developed typical CMV retinitis.
Conclusion
The likelihood of CMV retinitis in patients with Wegener’s granulomatosis should not be overlooked. Increased awareness in such cases is very important since CMV retinitis may present with less typical manifestations, which makes the correct diagnosis more challenging.
PMCID: PMC2699776  PMID: 19668453
cytomegalovirus retinitis; Wegener’s granulomatosis; ganciclovir
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.  Alpha-1-Antitrypsin Deficiency in Serbian Adults with Lung Diseases 
Aim: Alpha-1-antitrypsin (A1AT) is the main inhibitor of neutrophil elastase, and severe alpha-1-antitrypsin deficiency (A1ATD) is a genetic risk factor for early-onset emphysema. Despite the relatively high prevalence of A1ATD, this condition is frequently underdiagnosed. Our aim was to determine the distribution of the A1ATD phenotypes/alleles in patients with lung diseases as well as in the Serbian population. Methods: The study included the adults with chronic obstructive pulmonary disease (COPD) (n=348), asthma (n=71), and bronchiectasis (n=35); the control was 1435 healthy blood donors. The A1ATD variants were identified by isoelectric focusing or polymerase chain reaction-mediated site-directed mutagenesis. Results: PiMZ heterozygotes, PiZZ homozygotes, and Z allele carriers are associated with significantly higher risk of developing COPD than healthy individuals (odds ratios 3.43, 42.42, and 5.49 respectively). The calculated prevalence of PiZZ, PiMZ, and PiSZ was higher in patients with COPD (1:202, 1:8, and 1:1243) than in the Serbian population (1:5519, 1:38, and 1:5519). Conclusion: The high prevalence of A1ATD phenotypes/allele in our population has confirmed the necessity of screening for A1ATD in patients with COPD. On the other hand, on the basis of the estimated number of those with A1ATD among the COPD patients, it is possible to assess the diagnostic efficiency of A1ATD in the Serbian population.
doi:10.1089/gtmb.2012.0152
PMCID: PMC3483045  PMID: 22971141
11.  Distinct tumour necrosis factor α, interferon γ, interleukin 10, and cytotoxic T cell antigen 4 gene polymorphisms in disease occurrence and end stage renal disease in Wegener's granulomatosis 
Annals of the Rheumatic Diseases  2005;64(3):457-461.
Background: Cytokines and T cell regulatory proteins play an important role in the pathogenesis of Wegener's granulomatosis (WG).
Objective: To investigate cytokine and cytotoxic T cell antigen-4 (CTLA4) gene polymorphisms and HLA class II alleles in generalised WG.
Methods: The distribution of cytokine and cytotoxic T cell antigen 4 (CTLA4) gene polymorphisms and HLA class II alleles was analysed in 32 patients with generalised WG and 91 healthy controls. Genotyping was carried out for HLA-DRB1 and HLA-DQB1 and for polymorphism of the genes encoding TNFα (–238, –308, –376), TGFß (codon 10 and 25), IFNγ (+874), IL6 (–174), IL10 (–592, –819, –1082), CTLA4 (–318, +49), and the (AT)n repeats of the CTLA4 gene. In addition, stratification analysis was carried out according to the presence (n = 15) or absence (n = 17) of end stage renal disease.
Results: An increase in the IFNγ +874 T/T (odds ratio (OR) = 3.14) and TNFα –238 G/A (OR = 5.01) genotypes was found in WG patients. When ESRD positive and negative patients were compared, the IFNγ +874 A/A and the CTLA4 –318 C/C genotypes were found more often in the ESRD subgroup (OR = 10.6 and OR = 2.25). WG patients without ESRD had a higher frequency of the IL10 GCC/ACC promotor genotype (OR = 0.13) and long CTLA4 (AT)n repeats (OR = 0.4). No effect was seen for HLA-DR and –DQ markers.
Conclusions: Disease susceptibility and clinical course in WG may be associated with distinct polymorphisms of cytokine and CTLA4 genes.
doi:10.1136/ard.2004.025809
PMCID: PMC1755422  PMID: 15708894
12.  Granulomatosis with polyangiitis (Wegener’s) presenting as the right ventricular masses: A case report and review of the literature. 
Journal of Nephropathology  2012;1(1):49-56.
Background
Granulomatosis with polyangiitis (Wegener’s) is a systemic necrotizing vasculitis. Cardiac involvement in Wegener’s has rarely been reported. In this study the echocardiographic findings of granulomatosis with polyangiitis (GPA) in a patient is described.
Case Presentation
The case was a 45 years old man admitted to the hospital with a 3 months history of persistent fever and sinusitis. Mild left and right ventricular enlargements as well as three small masses in the right ventricular cavity were identified in echocardiography. One mass was attached to the tricuspid valve and the other two masses were attached to the right septum. Pulmonary artery hypertension (45mmHg) was also reported. The masses responded dramatically to plasma exchanges in combination with steroid therapy, followed by oral cyclophosphamid and low-dose steroid therapy. In the kidney biopsy, 8 out of 11 golomeruli contained fibrous crescents along with sclerotic lesions. Spleen has 140 mm diameter with multiple echo-free lesions and coarse parenchyma in abdominal ultrasound. Serum C-ANCA=671, P-ANCA=1.7 (normal= up to 15U/mL). The diagnosis of granulomatosis with polyangiitis (Wegener’s) was established.
Conclusions
Presence of three small masses in right ventricular cavity and pulmonary artery hypertension in association with the spleen lesions were an uncommon presentation of GPA. GPA should be considered in the differential diagnosis of any nonspecific illnesses with cardiac involvement.
doi:10.5812/jnp.9
PMCID: PMC3886160  PMID: 24475386
Granulomatosis; Polyangiitis; Wegener’s; Vasculitis; Ventricular mass
13.  Wegener's Granulomatosis presenting with an abscess in the parotid gland: a case report 
Introduction
Wegener's Granulomatosis is a vasculitis of uncertain aetiology. Affected patients usually present with disease of the respiratory and renal tracts. Classic symptoms and clinical findings, together with serology titres positive for anti-neutrophil cytolplasmic antibody against proteinase 3 confirm the diagnosis. Wegener's Granulomatosis can occasionally involve other organs, but solitary parotid gland disease is uncommon; patients generally also have systemic disease.
Case Presentation
We report a case of Wegener's Granulomatosis in a 69-year-old Caucasian female presenting initially with an isolated parotid abscess and only subsequently developing nasal, paranasal sinus and respiratory symptoms. We describe the clinical course, diagnostic difficulties, imaging and histopathology of this case.
Conclusion
Major salivary gland infection is not an uncommon ENT disorder, but the clinician should be wary of the patient who fails to respond appropriately to adequate therapy. In such cases a differential diagnosis of Wegener's Granulomatosis should be considered, as early recognition and treatment of this potentially fatal disease is paramount.
doi:10.1186/1752-1947-3-19
PMCID: PMC2635375  PMID: 19166579
14.  Hepatic involvement in Wegener's granulomatosis: a case report 
Introduction
We report the case of a 58-year-old Caucasian Greek man who presented with dry cough, fever, bilateral alveolar infiltrates and acute hepatitis.
Case presentation
After a lung biopsy, the patient was diagnosed with Wegener's granulomatosis. The diagnosis was supported by the presence of anti-proteinase-3 anti-neutrophil cytoplasmic antibodies. A liver biopsy demonstrated the presence of mild non-specific lobular hepatitis and periodic acid-Schiff positive Lafora-like inclusions in a large number of his liver cells. The patient was treated with prednisone and cyclophosphamide, which was followed by subsequent remissions of chest X-ray findings and liver function studies.
Conclusion
What makes this case worth reporting is the coexistence of liver inflammation with a biochemical profile of severe anicteric non-viral, non-drug induced hepatitis coinciding with the diagnosis of Wegener's granulomatosis. Our paper may be the first report of hepatic involvement in a patient diagnosed with Wegener's granulomatosis. The aetiological link between the two diseases is supported by the reversion of hepatitis after the immunosuppression of Wegener's granulomatosis. We favor the hypothesis that hepatic vasculitis may be the cause of acute hepatocellular necrosis.
doi:10.1186/1752-1947-4-9
PMCID: PMC2821396  PMID: 20157433
15.  The upper thoracic spinal cord compression as the initial manifestation of Wegener’s granulomatosis: a case report 
European Spine Journal  2007;16(Suppl 3):296-300.
There are only a few reported cases about spinal cord involvement with Wegener’s granulomatosis (WG) in the literature. In these cases, the spinal cord is usually indented or compressed by dural and meningeal masses which are characterized by necrotizing granuloma formation and vasculitis. And, it usually cannot be correctly diagnosed. A 53-year-old woman suffered from Wegener’s granulomatosis, in whom the upper thoracic spinal cord compression is the initial manifestation. The surgical biopsy and thoracic laminectomy were performed and the histologic examination was done. This patient was finally diagnosed as WG when the pathologic examination revealed as Wegener’s granulomatosis and the serum antineutrophil cytoplasmic antibodies (ANCA) were reported positive; titers of antimyeloperoxidase (MPO) antibodies were markedly elevated. After treatment with cyclophosphamide and corticosteroids this patient partially recovered from neurological involvement. In a case such as this, careful monitoring of clinical parameters is essential for assessing disease activity with repeated MRI if neurologic status changes. Serial measurement of ANCA titers may also be helpful to establish the diagnosis. Cyclophosphamide and corticosteroids are the agents of choice for induction of remission of WG.
doi:10.1007/s00586-007-0318-x
PMCID: PMC2148087  PMID: 17294055
Spinal cord; Wegener’s granulomatosis; Vasculitis
16.  Cytomegalovirus retinitis treated with valganciclovir in Wegener’s granulomatosis 
A case of cytomegalovirus (CMV) retinitis in a patient with Wegener’s granulomatosis treated with oral valganciclovir as maintenance therapy is reported. A 68-year-old male patient with anti-proteinase-3 ANCA-positive Wegener’s granulomatosis who was receiving immunosuppressive therapy with methylprednisolone, cyclophosphamide, and azathioprine developed CMV retinitis. The patient received intravenous ganciclovir as induction therapy and oral valganciclovir as maintenance therapy. The patient responded to treatment and showed no recurrence for 8 months. There were no serious adverse effects associated with oral valganciclovir. Oral valganciclovir is convenient and effective for the management of CMV retinitis in the patient with Wegener’s granulomatosis.
doi:10.2147/OPTH.S31130
PMCID: PMC3334207  PMID: 22536046
cytomegalovirus retinitis; Wegener’s granulomatosis; valganciclovir; ganciclovir; maintenance therapy
17.  Diagnostic Consideration for Sinonasal Wegener's Granulomatosis Clinically Mistaken for Carcinoma 
Case Reports in Otolaryngology  2013;2013:839451.
We report a case of Wegener's granulomatosis clinically mistaken for carcinoma in a 21-year-old girl presenting with an ulcerated mass of the nasopharynx associated with enlarged laterocervical nodes. The lesion was clinically suspected as malignant on the basis of clinical and radiological findings (namely, computed tomography scan and positron emission tomography). However, multiple biopsies were not conclusive for malignancy showing histological change suggestive of Wegener's granulomatosis. A serum determination of cANCA supported the diagnosis of Wegener's granulomatosis. Clinical findings and image studies suggested an erroneous diagnosis of malignancy whereas a definitive diagnosis of Wegener's granulomatosis was achieved only after repeated biopsies thus leading to a correct therapeutic approach. The Wegener granulomatosis must be added to the list of the differential diagnoses of the masses of the nasopharynx associated with or without enlarged laterocervical nodes.
doi:10.1155/2013/839451
PMCID: PMC3782763  PMID: 24106630
18.  A Rare Case of Nasal Septal Perforation Due to Purpureocillium lilacinum: Case Report and Review 
Perforations of nasal septum are fairly frequent with an incidence of about 0.9 % and may lead to morbidity than mortality. Common causes are trauma (iatrogenic occasionally nose picking), malignancy, inflammations and infections such as tuberculosis, syphilis, Wegener’s granulomatosis, sarcoidosis and fungal infections. Paranasal fungal sinusitis is frequently encountered in clinical practice in both immunocompromised and immunocompetent individuals. Nasal septal perforations caused by species of Aspergillus and Fusarium have been documented. We report a case of nasal septal perforation in a 35-years-old immunocompetent male patient due to Purpureocillium lilacinum, a soil and environmental fungus and an emerging pathogen, which is known to cause various infections in humans with normal and deficient immune system. Fungal aetiology was diagnosed by histopathology and direct smear examination and confirmed by culture. Patient was treated with voriconozole, following Antifungal susceptibility testing (AFST), to which the patient is responding.
doi:10.1007/s12070-012-0570-1
PMCID: PMC3649030  PMID: 24427563
Purpureocillium lilacinum; Nasal septal perforation; Immunocompetent
19.  Lacrimal drainage surgery in Wegener's granulomatosis 
AIM—To examine the results of open lacrimal surgery in patients with Wegener's granulomatosis.
METHODS—A retrospective review of patients with Wegener's granulomatosis who underwent lacrimal surgery over a 17 year period.
RESULTS—11 patients were identified and a total of 14 primary dacryocystorhinostomies (DCR) and one revisional DCR were performed; symptomatic relief was achieved in 13/14 operations and one patient required revisional surgery for persistent symptoms. There were no intraoperative and few postoperative complications.
CONCLUSIONS—In contrast with some previous reports, open DCR appears to be a safe procedure and it is recommended as a treatment for lacrimal obstruction in patients with Wegener's granulomatosis, but an increase of perioperative immunosuppression is recommended in certain cases.


doi:10.1136/bjo.84.3.329
PMCID: PMC1723393  PMID: 10684848
20.  Low Serum Alpha-1 Antitrypsin (AAT) in Family Members of Individuals with Autism Correlates with PiMZ Genotype 
Biomarker Insights  2009;4:45-56.
Aim
Deficiency of Alpha-1-antitrypsin (AAT) can be a genetic condition that increases the risk of developing liver, lung and possibly gastrointestinal disease. Since many autistic children also have gastrointestinal disorders, this study was designed to measure serum concentration of AAT and establish AAT genotypes in autistic children, age and gender matched non-autistic siblings, parents and controls.
Subjects and Methods
We used an indirect ELISA with monoclonal IgG to AAT to measure AAT serum concentrations in 71 members from 16 families of individuals with autism and 18 controls (no family history of autism). We used a duplex polymerase chain reaction to detect M, S and Z alleles for alpha-1 antitrypsin expression in 52 members of 12 of the above families.
Results
A significantly high number of autistic family members had lower than normal serum levels of AAT when compared to controls. Autistic children with regressive onset had significantly lower levels of AAT compared to controls, and a significant number of autistic children with low serum AAT also had hyperbilirubinemia, gastrointestinal disease and respiratory problems. We also found that a significantly high number of these individuals had the PiMZ genotype and correspondingly low levels of serum alpha-1 antitrypsin.
Discussion
Knowing that low levels of alpha-1 antitrypsin may be inherited, and that low levels of AAT may be associated with GI disease in autistic children, genotyping autistic children may help identify individuals susceptible to developing digestive problems.
PMCID: PMC2716675  PMID: 19652762
alpha-1 antitrypsin; autism; gastrointestinal disease
21.  Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies 
Annals of the Rheumatic Diseases  2006;66(2):222-227.
Background
The classification of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN) for epidemiology studies is confusing. The existing schemes such as American College of Rheumatology (ACR) criteria, Chapel Hill Consensus Conference (CHCC) definitions and Lanham criteria produce overlapping and conflicting classifications, making it difficult to compare incidence figures.
Aim
To develop a consensus method of using these criteria and definitions for epidemiological studies to permit comparison without confounding by classification.
Methods
A stepwise algorithm was developed by consensus between a group of doctors interested in the epidemiology of vasculitis. The aim was to categorise patients with Wegener's granulomatosis, microscopic polyangiitis (MPA), Churg–Strauss syndrome (CSS) and PAN into single clinically relevant categories. The ACR and Lanham criteria for CSS, and ACR criteria for Wegener's granulomatosis were applied first, as these were considered to be the most specific. Surrogate markers for Wegener's granulomatosis were included to distinguish Wegener's granulomatosis from MPA. MPA was classified using the CHCC definition and surrogate markers for renal vasculitis. Finally, PAN was classified using the CHCC definition. The algorithm was validated by application to 20 cases from each centre and 99 from a single centre, followed by a paper case exercise.
Results
A four-step algorithm was devised. It successfully categorises patients into a single classification. There was good correlation between observers in the paper case exercise (91.5%; unweighted κ = 0.886).
Conclusion
The algorithm achieves its aim of reliably classifying patients into a single category. The use of the algorithm in epidemiology studies should permit comparison between geographical areas.
doi:10.1136/ard.2006.054593
PMCID: PMC1798520  PMID: 16901958
22.  Alpha1-Antitrypsin Deficiency Carriers, Tobacco Smoke, Chronic Obstructive Pulmonary Disease, and Lung Cancer Risk 
Archives of internal medicine  2008;168(10):1097-1103.
Background
Genetic susceptibility in lung cancer risk has long been recognized but remains ill defined, as does the role of tobacco smoke exposure and chronic obstructive pulmonary disease (COPD).
Methods
Using a dual case-control design, we tested whether alpha1-antitrypsin deficiency (α1ATD) carriers are predisposed to a higher risk of lung cancer, adjusting for the effects of tobacco smoke exposure and COPD. A total of 1856 patients with incident lung cancer were included in the study; 1585 community residents served as controls. A second control group was composed of 902 full siblings of the patients. We first modeled 1585 case-control pairs without the α1ATD variable using multiple logistic regression analysis and then modeled the α1 ATD allele type in the presence of other known risk factors of lung cancer.
Results
We found a significantly increased lung cancer risk among α1ATD carriers from 2 parallel case-control comparisons: when patients were compared with unrelated controls, α1ATD carriers had a 70% higher risk of developing lung cancer than noncarriers (odds ratio, 1.7; 95% confidence interval, 1.2–2.4). In a further comparison of patients with their cancer-free siblings, we found a 2-fold increased lung cancer risk in α1ATD carriers (95% confidence interval, 1.4–2.7). Stratified analysis by tumor histologic subtypes showed a significant increase for adenocarcinoma and squamous cell carcinoma among α1ATD carriers.
Conclusion
Our results suggest that α1ATD carriers are at a 70% to 100% increased risk of lung cancer and may account for 11% to 12% of the patients with lung cancer in our study.
doi:10.1001/archinte.168.10.1097
PMCID: PMC2562773  PMID: 18504338
23.  Histopathological features predictive of a clinical diagnosis of ophthalmic granulomatosis with polyangiitis (GPA) 
Background
The limited form of Granulomatosis with Polyangiitis (GPA), formerly known as Wegener’s Granulomatosis (WG) primarily involves the head and neck region, including the orbit, but is often a diagnostic challenge, particularly as it commonly lacks positive anti-neutrophil cytoplasm antibody (ANCA) titres or classical features on diagnostic orbital biopsies. The purpose of this study was to relate biopsy findings with clinical outcome and to determine which histopathological features are predictive of a clinical diagnosis of GPA.
Methods
Retrospective case series of 234 patients identified from the database of the UCL Institute of Ophthalmology Department of Eye Pathology as having had orbital biopsies of orbital inflammatory disorders performed between 1988 and 2009. Clinical records were obtained for the patients and analysed to see whether patients had GPA or not, according to a standard set of diagnostic criteria (excluding any histopathological findings). Biopsy features were then correlated with the clinical diagnosis in univariate and multivariate analyses to determine factors predictive of GPA.
Results
Of the 234 patients, 36 were diagnosed with GPA and 198 with other orbital pathologies. The majority of biopsies were from orbital masses (47%). Histology showed a range of acute and chronic inflammatory pictures in all biopsies, but the presence of neutrophils (P<0.001), vasculitis (P<0.001), necrosis (P<0.001), eosinophils (P<0.02) and macrophages (P=0.05) were significantly associated with a later clinical diagnosis of GPA. In a multivariate analysis, only tissue neutrophils (OR=3.6, P=0.01) and vasculitis (OR=2.6, P=0.02) were independently associated with GPA, in contrast to previous reports associating eosinophils and necrosis with the diagnosis.
Conclusions
Neutrophil, eosinophil and macrophage infiltration of orbital tissues, together with vasculitis and necrosis, are all associated with a clinical diagnosis of GPA, but only neutrophil infiltration and vasculitis are independently associated with this diagnosis. These features may assist in the establishing the diagnosis of limited GPA among patients with early orbital disease, particularly in the absence of positive serum ANCA titres.
PMCID: PMC3438764  PMID: 22977665
Granulomatosis with polyangiitis; histopathology; eosinophils; nuclear dust
24.  PR3-ANCA in Wegener's granulomatosis prime human mononuclear cells for enhanced activation via TLRs and NOD1/2 
Diagnostic Pathology  2009;4:23.
Background
Anti-neutrophil cytoplasmic antibodies (ANCA) is autoantibodies characteristic of vasculitis diseases. A connection between ANCA and Wegener's granulomatosis was well established. The interaction of both ANCA phenotypes (PR3-ANCA and MPO-ANCA) with leukocytes provoked cell activation, which might be involved in the pathogenesis of ANCA-related Wegener's granulomatosis.
Methods
In this study, we examined whether PR3-ANCA sera and purified immunoglobulins from patients with Wegener's granulomatosis prime human monocytic cells for enhanced responses to microbial components in terms of production of proinflammatory cytokines.
Results
Flow cytometry demonstrated that stimulation with antibodies to proteinase 3 enhanced the expression of TLR2, 3, 4, 7, and 9, NOD1, and NOD2 in human mononuclear cells. The sera and purified immunoglobulins significantly primed human mononuclear cells to secrete interleukin-8 in response to microbial components via TLRs and NODs. Priming effects were also observed for the production of interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α. On the other hand, PR3-ANCA-negative sera from patients with polyarteritis nodosa which possibly related to MPO-ANCA and aortitis syndrome as well as control sera from a healthy volunteer did not have any priming effects on PBMCs.
Conclusion
In conclusion, PR3-ANCA prime human mononuclear cells to produce cytokines upon stimulation with various microbial components by up-regulating the TLR and NOD signaling pathway, and these mechanisms may partially participate in the inflammatory process in Wegener's granulomatosis.
doi:10.1186/1746-1596-4-23
PMCID: PMC2717921  PMID: 19594951
25.  Intestinal perforation as an early complication in Wegener’s granulomatosis 
We present the case of a young man with involvement of the gastrointestinal tract in the early phase of Wegener’s granulomatosis. The patient presented at the emergency department with sudden onset of abdominal pain, nausea and vomiting. Radiography work up was negative for free air although ultrasound examination showed extraluminal intra-abdominal fluid. Exploratory laparotomy showed perforation of the jejunum. The bowel was vital except for this small segment of jejunum. A 5-cm long segment of jejunum was resected which revealed ulcerative inflammation accompanied by occluded arteries of the small intestine. Although intestinal perforation in Wegener’s granulomatosis is uncommon, several cases have been previously reported. Intestinal involvement in the early phase of the disease is even more uncommon. This case combined with previously reported cases emphasizes the possibility of gastrointestinal manifestation early in Wegener’s disease.
doi:10.4240/wjgs.v2.i5.169
PMCID: PMC2999230  PMID: 21160868
Wegener’s granulomatosis; Intestinal tract; Perforation

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