Unveiling Cancer Risk in ANCA-Associated Vasculitis: Result from the Turkish Vasculitis Study  Group (TRVaS)

Unveiling Cancer Risk in ANCA-Associated Vasculitis: Result from the Turkish Vasculitis Study Group (TRVaS) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Unveiling Cancer Risk in ANCA-Associated Vasculitis: Result from the Turkish Vasculitis Study Group (TRVaS) Emre Bilgin, Tuba Demirci Yıldırım, Bahar Özdemir Ulusoy, Tahir Saygın Öğüt, and 35 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3860558/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Mar, 2024 Read the published version in Internal and Emergency Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Aim: To investigate cancer incidence in patients with ANCA-associated vasculitides (AAV), compare it with the age/sex-spesific cancer risk of Turkish population, explore independent risk factors associated with cancer. Methods: This multicenter, incidence case-control study was conducted using TRVaS registry. AAV patients without cancer history before AAV diagnosis were included. Demographic and AAV-related data of patients with and without an incident cancer were compared. Standardized cancer incidence rates were calculated using age/sex-spesific 2017 Turkish National Cancer Registry data for cancers (excluding non-melanoma skin cancers). Cox regression was performed to find factors related to incident cancers in AAV patients. Results: Of 461 AAV patients (236[51.2%] male), 19 had incident cancers after 2022.8 patient-years follow-up. Median(IQR) disease duration was 3.4(5.5) years, and 58(12.6%) patients died [7 with cancer and 1 without cancer (log-rank,p=0.04)]. Cancer-diagnosed patients were older, mostly male, and more likely to have anti-PR3-ANCA positivity. The cumulative cyclophosphamide dose was similar in patients with and without cancer. Overall cancer risk in AAV was 2.1(SIR)(1.3-3.2),p=0.004); lung and head-neck [primary target sites for AAV] cancers were the most common. In Cox regression, male sex and ≥60 years of age at AAV diagnosis were associated with increased cancer risk, while receiving rituximab was associated with decreased cancer risk. Conclusions: Cancer risk was 2.1-times higher in AAV patients than the age/sex-spesific cancer risk of Turkish population, despite a high rate of rituximab use and lower dose of cyclophosphamide doses. Vigilance in cancer screening for AAV patients covering lung, genitourinary, and head-neck regions, particularly in males and the elderly, is vital. ANCA-associated vasculitis granulomatous polyangiitis cancer rituximab cyclophosphamide lung cancer head-neck cancers Figures Figure 1 Key Messages Cancer incidence was 2.1-fold higher in AAV patients compared to the age/sex-specific cancer incidence of the Turkish population. Clinicians should assess cancer risk more carefully, especially in male, elderly AAV patients. Rituximab was associated with lower cancer risk; the causality of this association needs further assessment. INTRODUCTION Anti-neutrophil Cytoplasmic Antibody (ANCA) associated vasculitides (AAV) is an umbrella term including Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA) ( 1 ). The incidence and prevalence of these diseases exhibit geographical variations ( 2 ). Depending on the subtype of AAV, there can be varying degrees of involvement in virtually any organ and tissue, predominantly the upper and lower respiratory tract, genitourinary system, and skin ( 1 ). The relationship between cancer and AAV has been investigated in patients from various geographical regions with distinct genetic backgrounds. A meta-analysis published in 2015 combining six studies examining cancer incidence in AAV patients has determined the overall cancer incidence to be (pooled SIR) 1.74 (1.37–2.21) ( 3 ) and revealed an increase in non-melanoma skin, leukemia, and bladder cancers. The increased risk of cancer in AAV patients has often been attributed to the use of high-dose cyclophosphamide in the literature ( 3 ). Considering the genetic complexity of cancer and AAV and their geographical differences, Data from different ethnicities and geographies is necessary. On the other hand, following the recent demonstrations of its efficacy and safety, rituximab-based therapies have emerged as game-changers in treatment practice. In this study, we aim to investigate the incidence of cancer in AAV patients from Turkey with no previous cancer before the AAV diagnosis in rituximab era, compare this incidence with the general Turkish population and assess factors associated with cancer development in Turkish AAV patients using the prospective Turkish Vasculitis Research Group (TrVAS) database. PATIENTS AND METHODS Study Design This incidence case-control study was conducted by the Turkish Vasculitis Study Group (TRVaS) registry ( 4 ). Data Source and Group of Interest TRVaS is a prospective, web-based registry of the Turkish Vasculitis Study Group established in 2020 ( 5 ). In general, data regarding all incidents and prevalent cases with all types of primary vasculitides are recorded in TRVaS. Regarding AAV, a baseline assessment form including patient and disease characteristics was recorded for all patients. For this current study, all participating centers were asked to complete the prespecified data form related to ‘’cancer’’ for patients diagnosed with any subtype of AAV by the end of July 2022. Patients with any subtype of AAV (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], eosinophilic granulomatosis with polyangiitis [EGPA] or unclassified AA-vasculitis) according to any of the followings: the treating physician, 1990 ACR Wegener or Churg-Strauss Classification Criteria, or EMA algorithm and complete prespecified data form related to ‘’cancer’’ were included in the current study. Among these patients, those with a history of malignancy before and at the time of AAV diagnosis and those with non-melanoma skin cancer or benign or non-invasive tumors (in the past or current) were excluded from the final analysis. Variables i. Related to Anca-Associated Vasculitis Date of birth, sex, date of AAV diagnosis, AAV subtype, ANCA status [Enzyme-linked immunoassay (ELISA) and indirect immunofluorescence assay (IIFA) ], sites of involvement, Birmingham Vasculitis Activity Score (v3) at baseline, revised five-factor score. Immunosuppressive treatments were recorded as ‘ever or never used’ for the time period between AAV diagnosis and cancer diagnosis in patients with cancer and between AAV diagnosis and the last visit in patients without cancer. ii. Related to cancer Date of cancer diagnosis, type, and extensity (local, locally advanced, or metastatic) of cancer, smoking status (ever or never), and survival status (date of death was recorded for deceased patients). Statistical analyses Statistical analysis was performed using the SPSS software (v25.0; IBM Corporation, Armonk, NY, USA). The descriptive analysis was expressed as either median, interquartile range (IQR) for quantitative variables, or number (percentage) for categorical variables. Distribution and univariable comparison of baseline demographic, disease characteristics and treatment options used during the disease course of AAV patients with or without cancer were explored via the Kaplan-Meier survival estimates and possible factors associated with cancer occurrence were investigated by using the log-rank test. The Mann-Whitney U test was used to compare the quantitative variables between the two groups. The factors identified in univariable analyses (p < 0.20, taking into account the correction for multiplicity and clinical relevance) were further entered into the Cox regression analysis, with the backward selection, to determine independent predictors of cancer occurrence. The proportional hazards assumption and model fit were assessed using residual (Schonfeld and Martingale) analysis. To compare cancer incidences, age and sex-spesific standardized incidence rates (SIR) for the overall group, according to sex and individual cancer types, were calculated. For each participant, patient-year follow-up duration was calculated: the starting from the date of AAV diagnosis, and to the date of cancer diagnosis, death, or last follow-up visit, whichever was the first. The observed number of cases is all individuals diagnosed with invasive cancer (except for non-melanoma skin cancer) on follow-up after the diagnosis of AAV. The expected number of cases is the total number of patients that would have been reported to the cancer registry within the same follow-up period and calculated from the 2017 Turkish National Cancer Registry (TNCR) data ( 6 ). To compare rates of cancers, incidence rates (IR)(per 1000 patient-years), and incidence rate ratios (IRR) for different subgroups (according to AAV subtype, ANCA status, renal and lung involvement, smoking status, age at diagnosis and immunosuppressive drugs ever being used) were calculated. For the calculation of the SIR, IR, IRR, and the 95% confidence interval (CI), OpenEpi v3.01 software was used. Type-1 error lower than 0.05 was considered statistically significant. Our study is compliant with the Helsinki Declaration and approved by the Hacettepe University ethical committee (Approval number: GO 19/1088). RESULTS A total of 476 AAV patients were included in the study. Fifteen patients were excluded from the final analysis (Eight had cancer before AAV diagnosis, three had colon cancer diagnosis during AAV work-up, three had basal cell carcinoma, and one had non-invasive cancer). The final data set comprised 461 AAV patients (19 with cancer). 312 (67.7%) patients had GPA, 76 (16.5%) had EGPA, 52 (11.3%) had MPA, and 21 (4.6%) had unclassified AAV. Median (IQR) disease duration was 3.4 (5.5) years; 6.4 (7.7) years in AAV patients with cancer, and 3.4 (5.3) years in those without cancer (p=0.013). The median (IQR) duration between AAV and cancer diagnosis was 46 (83) months. The total follow-up duration was 2022.8 patient-years. AAV patients with cancer were older at AAV diagnosis compared to those without cancer (median, IQR) (61.3 [28.2] vs. 49.7 [22.3], p=0.037). The male sex was predominant (94.7% vs. 49.3%, log-rank p<0.001) and smoking (ever) was also more prevalent in this group (70.6% vs. 39.4%, log-rank p=0.006). ( Table 1 ) ANCA serology (ELISA) differed between groups (PR3 and negative ANCA) were more prevalent in patients with cancer, whereas MPO ANCA was more prevalent in patients without cancer ( Table 1 ). Comorbidities (diabetes, hypertension, chronic kidney disease, chronic obstructive lung disease, and coronary artery disease) were similarly prevalent in both groups. Percentages of pulmonary involvement (83.3% vs. 78.4%, log-rank p=0.38) and renal involvement (68.4% vs. 55.1%, log-rank p=0.21) were similar in both groups. Other sites of involvement, disease activity, prognostic scores, and the need for dialysis and plasma exchange at baseline were also found to be similar between groups ( Table 1 ). 58 patients died during follow-up due to any cause; 7 (36.8%) in AAV patients with cancer and 51 (11.5%) in those without cancer (log-rank p = 0.04). Demographic and clinical characteristics of patients were shown in Table 1. Patients with cancer were less likely to be exposed to rituximab than those without cancer (21.1% vs. 58.8%, log-rank p<0.001). Both groups used other drugs in similar percentages ( Table 2 ). The cumulative cyclophosphamide dose [median (minimum-maximum)] dose was 5.4 (0.5-30.0) grams in AAV patients with cancer and 3.0 (1.5-7.0) grams in those without cancer (p=0.19). Of 19 patients, 18 (94.7%) were male. Overall cancer risk was higher in AAV patients compared to sex and age-specific cancer risk of general population (SIR 2.1 (1.3-3.2), p=0.004)). The distribution of cancers in the schematic figure is given in Figure 1 . As the male sex was predominant, analyses were stratified according to sex. In males: Cancer risk was higher than the age-specific cancer risk of male general population (SIR 3.1 (1.9-4.7), p<0.001). Lung cancer was the most common cancer type (6 patients, SIR 4.0 (1.6-8.3), p<0.001), followed by head-neck cancer (3 patients, SIR 27.3 (6.9-74.2), p<0.001). Details of the other types of cancers are given in Table 3 . According to age at AAV diagnosis, cancer SIRs were as follows; 2.3 (1.3-3.8, p=0.008) for ≥ 50 years,1.9 (0.95-3.3, p=0.07) for ≥ 55 years, 2.2 (1.1-3.9, p=0.03) for ≥ 60 years 1.7 (0.7-3.5, p=0.23) for ≥65 years and 1.2 (0.3-3.1, p=0.75) for ≥70 years. In females: Cancer risk was similar to the age-specific cancer risk of female general population (SIR 0.3 (0.1-1.5), p=0.20). There was one case with urinary bladder cancer ( Table 3 ). Among patient subgroups, each of the following subgroups had significantly higher cancer incidence rates than counterparts: male sex, age at ≥60 years at AAV diagnosis, and ever-smoked ( Table 4 ). Patients who received rituximab had a significantly lower cancer incidence rate than patients who did not receive rituximab (IRR 0.1 (0.03-0.4), p<0.001) (Table 4) . Results of the univariable comparisons and Cox regression models are given in Supplementary Table 1 . Due to the high rate of missing data, the ANCA ELISA variable was not included in the regression model. In the final model (results will be shown as Hazard ratio (HR) and 95% confidence interval (95% CI)): the male sex 22.3 (2.9-170.2, p=0.003), age ≥ 60 at AAV diagnosis 7.1 (2.5-20.1, p<0.001), receiving rituximab 0.06 (0.01-0.26, p<0.001) were independently associated with cancer risk. Individual characteristics of AAV patients with cancer are given in Supplementary Table 2 . DISCUSSION In this multicenter study investigating 461 patients diagnosed with ANCA-Associated Vasculitis (AAV), the cancer risk in AAV patients was found to be 2.1 times higher compared to the age and sex-spesific cancer risk of Turkish population. Lung cancer was the most frequently detected cancer type, while head and neck cancer incidence was also statistically significantly higher. Male sex and ≥ 60 years of age at AAV diagnosis were found to be associated with an increased risk of cancer. The cumulative dose of cyclophosphamide was similar in both groups, and no increased cancer risk was associated with using cyclophosphamide. However, using rituximab was associated with a decreased risk of cancer. We found a greater cancer risk in males, despite the overall similar cancer risk reported for both sexes in the literature ( 3 , 7 , 8 ) which may be due to the genetic, hormonal, or risky behavioral differences between sexes, or simply by detection bias. We found also higher cancer risk in AAV patients diagnosed at ≥ 60 years of age compared to younger patients, in addition to increased cancer risk in all age groups compared to the general population, especially in males. The late onset of AAV in cases with malignancy has been frequently reported in the literature ( 3 , 7 ). It is also plausible to speculate that patients diagnosed at an advanced age might be more susceptible to carcinogenesis that could develop due to the treatments they undergo, and their cumulative cancer risk might increase independently of AAV. Smoking is one of the most extensively studied and proven risk factors for cancer. However, data on smoking is lacking in many studies related to AAV and cancer. Although active or past smoking was more commonly found in cancer-diagnosed patients in our current study, it lost its significance in the multivariate model and we did not find any interactions between smoking and age. Nevertheless, due to the abundance of missing data and the lack of information on the quantity and frequency of smoking, making interpretations on this topic is challenging within the scope of this study. Aside from inflammation ( 9 , 10 ), another factor associated with cancer is the drugs used in AAV treatment, especially cyclophosphamide ( 3 , 11 ). In the current study, cyclophosphamide was not associated with increased cancer risk. In addition, as confirmatory data to the current understanding of no association in our study, no patient used oral cyclophosphamide; all patients had mesna, and more importantly, the cumulative cyclophosphamide dose was lower than the earlier studies. Methotrexate and azathioprine may also increase the risk of skin cancer ( 12 ). However, we excluded patients with skin cancer in our study. Regarding rituximab, recent data showed that the anti-tumor effect of rituximab is thought to originate from relatively increased anti-tumor cytotoxic T cells ( 13 ). In addition, recent solid data from the UK suggested a lower risk of cancer in rituximab-treated compared to cyclophosphamide-treated patients. The risk of cancer was comparable to the general population in rituximab-treated patients ( 14 , 15 ). Our results support the current literature about rituximab on cancer. However, we can not fully exclude the risk of selection bias regarding the use of rituximab as clinicians might have prescribed rituximab to patients with a high risk of developing cancer with ‘sense de clinique’. From a different perspective, despite the use of cyclophosphamide at a lower dose in accordance with current recommendations and the high rate of rituximab use in our cohort, the overall cancer risk was higher than in the general population. Bladder cancer, related to the disease and cyclophosphamide usage, has been highlighted in numerous studies in the literature for increased incidence with pooled SIR of 3.8 (2.7–5.4) ( 3 ). While the statistical significance of increased bladder cancer frequency based on sex stratification may not be apparent in our study, the presence of separately considered uroepithelial tumors can imply an elevated risk in genitourinary system cancers. However, the effect size of this risk is less substantial than in the literature, possibly due to the abovementioned reasons. In the literature, although most studies regarding lung cancer do not report a statistically significant increase in risk, the meta-analysis, as mentioned above, presents a SIR value of 1.67 (1.07–2.60) for lung cancer ( 3 ). Similarly, a large-scale population-based study conducted by Choi and colleagues utilizing propensity score matching has reported a significant increase in lung cancer risk ( 15 ). Regarding low hematologic malignancy incidence in our cohort, the relatively low cumulative cyclophosphamide dose and the administration of rituximab in more than half of the patients may be the underlying reason. As we excluded patients with non-melanoma skin cancers from the outset of our study, no inferences can be drawn from the current data regarding this matter. Increased genitourinary, lung, and head-neck cancer risk in our study may be attributable to the fact that these tissues are the primary target for AAV, especially PR3-positive AAVs. Nevertheless, especially in patients with lung and head-neck involvement, the routine performance of lung and head-neck imaging may result in the more frequent and earlier detection of cancerous lesions. Consequently, an increased incidence might be observed due to the lead-time bias. The multicenter nature, encompassing data from across the country, allowing for an exploration of the current short-to-medium-term safety profile of immunosuppressive treatment in AAV, can be counted as the strengths of our study. However, certain limitations must be acknowledged. The retrospective recording of some of the data from medical records introduces significant gaps, particularly in variables such as smoking, alcohol consumption, and environmental pollution, which could directly influence carcinogenesis. Moreover, notable deficiencies exist in the data regarding cumulative doses of cyclophosphamide and especially rituximab. Besides, we could not assess the cumulative dose of steroids and their effect on incident cancers. Although the distribution of major comorbidities was similar between the two groups, we can not precisely estimate the effect of comorbidities on cancer occurrence due to the lack of severity data about comorbidities. Since these patients are followed and investigated more closely, tumoral lesions that may have a variable effect on survival may be detected early, which may have caused us to find the incidence higher. So, the inability to address this lead-time bias risk is a noteworthy limitation in our study. It is known that cancer risk in rheumatic diseases is associated with increasing disease duration ( 16 ), and the cumulative follow-up period of the present study may be too short to reveal this relationship due to the small number of patients and the short follow-up period per person ( 17 ). Also, due to the low number of cases of cancer, SIR results should be interpreted cautiously. Lastly, quantitative data regarding the smoking history was not available; therefore, we were only able to categorize smoking status as ever vs. never. Considering that most cancers in the males were smoking-related cancers that were seen in the older ages, possible confounding due to smoking intensity could not be excluded. In conclusion, we found 2.1 times higher cancer risk in AAV patients compared to the age and sex-specific cancer risk of male Turkish population. Lung and head-and-neck cancers were the most frequently detected cancer types. While no relationship could be established between increased cancer risk and cyclophosphamide usage, an association was identified between reduced cancer risk and the utilization of rituximab. Greater attention should be given to cancer risks, and screening programs should be effectively employed in male AAV patients and AAV patients diagnosed at advanced age. A longer follow-up period for these patients has been planned. Furthermore, a global effort can be started under EUVAS and VCRC to better clarify this concept. Declarations Funding: TRVaS Turkish Vasculitis Study Group Prospective Database is a web-based registry supported by RedCaps and coordinated by the Hacettepe University Vasculitis Research Centre Steering committee consisting of Servet Akar, Cemal Bes, Haner Direskeneli, Ömer Karadağ, Fatoş Önen, Ahmet Omma, and Seza Özen. TRVaS is supported by Hacettepe University. There is no financial support for this database. https://redcap.huvac.hacettepe.edu.tr. No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article. Conflict of interest: Authors declare no conflict of interest. Correspondence Omer Karadag, MD, Professor of Rheumatology Hacettepe University Faculty of Medicine Department of Internal Medicine Division of Rheumatology e-mail: [email protected] , [email protected] Acknowledgment : None References Kitching AR, Anders HJ, Basu N, Brouwer E, Gordon J, Jayne DR, et al. ANCA-associated vasculitis. Nat Rev Dis Primers. 2020;6(1):71. Watts RA, Hatemi G, Burns JC, Mohammad AJ. Global epidemiology of vasculitis. Nat Rev Rheumatol. 2022;18(1):22-34. Shang W, Ning Y, Xu X, Li M, Guo S, Han M, et al. Incidence of Cancer in ANCA-Associated Vasculitis: A Meta-Analysis of Observational Studies. PLoS One. 2015;10(5):e0126016. Pearce N. Classification of epidemiological study designs. Int J Epidemiol. 2012;41(2):393-7. 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Distribution and time-dependent univariable comparison of demographic and disease characteristics of AAV patients with and without cancer Variable All patients (n=461) AAV Patients with Cancer (n=19) AAV Patients without Cancer (n=442) p-value Male, n(%) 236 (51.2) 18 (94.7) 218 (49.3) <0.001 Age at AAV diagnosis, years, median, (IQR) 49.8 (22.9) 61.3 (28.2) 49.7 (22.3) 0.037 ° AAV disease duration*, months, median (IQR) 3.4 (5.5) 6.4 (7.7) 3.4 (5.3) 0.013 ° Smoking (n=403) Never Ever 239 (59.3) 164 (40.7) 5 (29.4) 14 (70.6) 234 (60.6) 152 (39.4) 0.006 AAV subtype GPA EGPA MPA Unclassified 312 (67.7) 76 (16.5) 52 (11.3) 21 (4.6) 16 (84.2) 1 (5.3) 1 (5.3) 1 (5.3) 296 (67.0) 75 (17.0) 51 (11.5) 20 (4.5) 0.53 ANCA IFA cANCA pANCA Negative Unavailable 227 (49.2) 123 (26.7) 84 (18.2) 27 (5.9) 12 (63.2) 3 (15.8) 4 (21.2) 0 215 (48.6) 120 (27.1) 80 (18.1) 27 (6.1) 0.77** ANCA ELISA PR3 MPO Negative Unavailable 189 (41.0) 91 (19.7) 30 (6.5) 151 (32.8) 11 (63.6) 2 (9.1) 5 (22.7) 1 (4.5) 178 (40.3) 89 (20.1) 25 (5.7) 150 (33.9) 0.03** Comorbidities Diabetes Hypertension Chronic Kidney Disease Chronic Obstructive Lung Disease Coronary Artery Disease 68 (14.8) 132 (28.6) 38 (8.2) 7 (1.5) 36 (7.8) 1 (5.3) 4 (21.1) 2 (10.5) 0 2 (1.05) 67 (15.2) 128 (29.0) 36 (8.1) 7 (1.6) 34 (7.7) 0.34 0.53 0.55 0.70 0.25 Sites of involvement (ever) Constitutional (n=455) Mucocutaneous (n=453) Musculoskeletal (n=458) Ocular (n=456) Ear-nose-throat (n=457) Respiratory (n=461) Vascular (n=446) Gastrointestinal (n=455) Genitourinary (n=456) Central nervous system (n=456) Peripheral nervous system (n=445) 367 (81.2) 128 (28.4) 225 (49.5) 86 (19.0) 270 (59.5) 360 (78.6) 23 (5.2) 31 (6.9) 252 (55.6) 15 (3.3) 67 (15.2) 12 (72.2) 5 (29.4) 8 (44.4) 1 (5.9) 10 (58.8) 15 (83.3) 0 1 (5.6) 13 (68.4) 0 2 (11.1) 354 (81.6) 123 (28.4) 217 (49.7) 85 (19.5) 260 (59.5) 345 (78.4) 23 (5.4) 30 (6.9) 239 (55.1) 15 (3.4) 65 (15.3) 0.23 0.85 0.55 0.21 0.53 0.38 0.29 0.82 0.21 0.51 0.44 BVAS at baseline, median (IQR) 11 (11) 11 (15) 11 (11) 0.84 ° Revised Five-factor score ≥1 (n=314) 206 (65.6) 7 (58.3) 199 (65.9) 0.77 Dialysis at baseline 33 (7.2) 3 (15.8) 30 (6.8) 0.15 Plasma exchange at baseline 54 (11.7) 1 (5.3) 53 (12.0) 0.82 Mortality 58 (12.6) 7 (36.8) 51 (11.5) 0.04 *According to the last follow-up visit **p excluding the ‘’unavailable’’ strata °p values represent the result of the Mann-Whitney U test, all other p values represent the result of the log-rank test Table 2. Distribution and time-dependent univariable comparison of treatments ever used in AAV patients with and without cancer (upto time of cancer diagnosis or last follow-up visit) Treatments All patients (n=461) AAV Patients with Cancer (n=19) AAV Patients without Cancer (n=442) p-value ° Methotrexate 76 (16.5) 1 (5.3) 75 (17.0) 0.08 Mycophenolate mofetil 58 (12.6) 1 (5.3) 57 (12.9) 0.42 Azathioprine 261 (56.6) 14 (73.7) 247 (55.9) 0.99 Cyclophosphamide 270 (58.6) 10 (52.6) 260 (58.8) 0.14 Azathioprine+cyclophosphamide 167 (36.2) 7 (36.8) 160 (36.2) 0.11 Rituximab 264 (57.3) 4 (21.1) 260 (58.8) <0.001 Pulse steroid at baseline 198/453 (43.7) 5/18 (27.8) 193/435 (44.4) 0.46 Sequential cyclophosphamide and rituximab (or vice versa) 263 (58.8) 3 (15.8) 260 (58.8) <0.001 AAV: Anca-associated vasculitis °p values represent the result of the Mann-Whitney U test, all other p values represent the result of the log-rank test Table 3. Standardized incidence rates according to cancer types of AAV groups Subgroup Total (n,%) Observed cancer (n) Expected cancer (n) SIR Confidence interval (95%) p value Overall 461 (100) 19 9.2 2.1 1.3-3.2 0.004 Male Overall Lung Head-neck SCC* Urinary bladder Prostate Malign melanoma Stomach Non-Hodgkin Lymphoma Mesenchymal tumor Uroepithelial tumor ++ 236 (51.2) 18 6 3 2 1 1 1 1 1 2 5.9 1.5 0.11 0.56 1.03 0.04 0.4 0.15 0.04 NA 3.1 4 27.3 3.6 0.97 25 2.5 6.7 25 NA 1.9-4.7 1.6-8.3 6.9-74.2 0.6-11.8 0.05-4.78 1.2-123.3 0.1-12.3 0.3-32.9 1.2-123.3 NA <0.001 <0.001 <0.001 0.13 0.99 0.04 0.39 0.14 0.04 NA Female Overall Urinary bladder 225 (48.8) 1 1 3.3 0.06 0.3 16.6 0.1-1.5 0.8-82.2 0.20 0.06 *Head-neck SCC cases were considered different from skin SCC by oncologists in these cases. ++ SIR was not calculated as separate data was unavailable in the 2017 TNCR data for uroepithelial tumors SIR: Standardized incidence rate Table 4. Incidence rates and incidence rate ratios according to subgroups of AAV patients Subgroup Total (n,%) Observed cancer (n) Follow-up (patient-years) IR (95% CI) (per 1000 patient-years IRR (95% CI) p for IRR AAV Subtype GPA Non-GPA 312 (67.7) 149 (32.1) 16 3 1442.7 580.1 11.1 (6.8-18.1) 5.2 (1.6-16.0) 2.1 (0.6-11.5) Reference 0.22 ANCA Status PR3 MPO Negative 189 (61.0) 91 (29.4) 30 (9.6) 11 2 5 821.4 282.4 137.4 13.4 (7.5-24.1) 7.1 (1.8-28.2) 36.4 (15.4-86.0) 1.9 (0.4-17.6) Reference 5.1 (0.8-54.0) 0.43 0.07 Sex Male Female 236 (51.2) 225 (48.8) 18 1 977.3 1045.5 18.4 (11.7-29.1) 1.0 (0.1-6.8) 19.3 (3.0-802.3) Reference <0.001 Age at diagnosis <60 ≥60 337 (73.1) 124 (26.9) 8 11 1665.7 357.1 4.8 (2.4-9.6) 30.8 (17.2-55.1) Reference 6.4 (2.3-18.4) <0.001 Smoking history Never Ever 239 (59.3) 164 (40.7) 5 14 1102.1 688.9 4.5 (1.9-10.8) 20.3 (12.1-34.1) Reference 4.5 (1.5-15.9) 0.002 Pulmonary involvement Yes No 360 (78.6) 98 (21.4) 15 3 1511.7 483.8 9.9 (6.0-16.4) 6.2 (2.0-19.2) 1.6 (0.5-8.6) Reference 0.48 Genitourinary involvement Yes No 252 (55.7) 201 (44.3) 13 6 1068.4 919.0 12.2 (7.0-20.8) 6.5 (2.9-14.5) 1.9 (0.7-5.9) Reference 0.21 Immunosuppression, ever CYC, yes CYC, no AZA, yes AZA, no RTX, yes RTX, no MMF, yes MMF, no MTX, yes MTX, no 270 (58.6) 191 (41.4) 261 (56.6) 200 (43.4) 264 (57.3) 197 (42.7) 58 (12.6) 403 (87.4) 76 (16.5) 385 (83.5) 10 9 14 5 4 15 1 18 1 18 1349.3 673.5 1454.7 568.1 1324.1 698.7 239.2 1783.6 408.6 1614.3 7.4 (4.0-13.7) 13.3 (7.0-25.6) 9.6 (5.7-16.2) 8.8 (3.7-21.1) 3.0 (1.1-8.0) 21.5 (13.0-35.4) 4.2 (0.6-29.6) 10.0 (6.4-16.0) 2.4 (0.3-17.3) 11.1 (7.0-17.7) 0.6 (0.2-1.5) Reference 1.1 (0.4-3.9) Reference 0.1 (0.03-0.4) Reference 0.4 (0.01-2.6) Reference 0.2 (0.01-1.4) Reference 0.21 0.89 <0.001 0.42 0.10 AZA: Azathioprin, CYC: Cyclophosphamide, GPA: Granulomatosis polyangiitis, IR: Incidence rate, IRR: Incidence rate ratio, MTX: Methotrexate, MPO: Myeloperoxidase, MMF: Mycophenolate mofetil, PR3: Proteinase-3, RTX: Rituximab Supplementary Files SupplementaryTables.docx Cite Share Download PDF Status: Published Journal Publication published 28 Mar, 2024 Read the published version in Internal and Emergency Medicine → Version 1 posted Reviewers agreed at journal 18 Jan, 2024 Reviewers invited by journal 18 Jan, 2024 Editor assigned by journal 16 Jan, 2024 First submitted to journal 15 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1","display":"","copyAsset":false,"role":"figure","size":190409,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of cancer sites in AAV patients\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3860558/v1/dc303550c1e6b233cc53e77c.png"},{"id":53765046,"identity":"8a29a66a-52c2-43fb-8254-a7f3f0809e81","added_by":"auto","created_at":"2024-03-30 00:43:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":985004,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3860558/v1/06d99ecc-25d8-4846-914a-6d85f9c80754.pdf"},{"id":50044054,"identity":"3714393b-dae0-4a4e-81a2-02c3d7bb8480","added_by":"auto","created_at":"2024-01-23 15:51:14","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20188,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-3860558/v1/e2e65788424fd50194f2809d.docx"}],"financialInterests":"","formattedTitle":"Unveiling Cancer Risk in ANCA-Associated Vasculitis: Result from the Turkish Vasculitis Study Group (TRVaS)","fulltext":[{"header":"Key Messages","content":"\u003cul\u003e\n \u003cli\u003eCancer incidence was 2.1-fold higher in AAV patients compared to the age/sex-specific cancer incidence of the Turkish population.\u003c/li\u003e\n \u003cli\u003eClinicians should assess cancer risk more carefully, especially in male, elderly AAV patients.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRituximab was associated with lower cancer risk; the causality of this association needs further assessment.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eAnti-neutrophil Cytoplasmic Antibody (ANCA) associated vasculitides (AAV) is an umbrella term including Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The incidence and prevalence of these diseases exhibit geographical variations (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Depending on the subtype of AAV, there can be varying degrees of involvement in virtually any organ and tissue, predominantly the upper and lower respiratory tract, genitourinary system, and skin (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe relationship between cancer and AAV has been investigated in patients from various geographical regions with distinct genetic backgrounds. A meta-analysis published in 2015 combining six studies examining cancer incidence in AAV patients has determined the overall cancer incidence to be (pooled SIR) 1.74 (1.37\u0026ndash;2.21) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) and revealed an increase in non-melanoma skin, leukemia, and bladder cancers. The increased risk of cancer in AAV patients has often been attributed to the use of high-dose cyclophosphamide in the literature (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Considering the genetic complexity of cancer and AAV and their geographical differences, Data from different ethnicities and geographies is necessary. On the other hand, following the recent demonstrations of its efficacy and safety, rituximab-based therapies have emerged as game-changers in treatment practice.\u003c/p\u003e \u003cp\u003eIn this study, we aim to investigate the incidence of cancer in AAV patients from Turkey with no previous cancer before the AAV diagnosis in rituximab era, compare this incidence with the general Turkish population and assess factors associated with cancer development in Turkish AAV patients using the prospective Turkish Vasculitis Research Group (TrVAS) database.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis incidence case-control study was conducted by the Turkish Vasculitis Study Group (TRVaS) registry (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData Source and Group of Interest\u003c/h2\u003e \u003cp\u003eTRVaS is a prospective, web-based registry of the Turkish Vasculitis Study Group established in 2020 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In general, data regarding all incidents and prevalent cases with all types of primary vasculitides are recorded in TRVaS. Regarding AAV, a baseline assessment form including patient and disease characteristics was recorded for all patients. For this current study, all participating centers were asked to complete the prespecified data form related to \u0026lsquo;\u0026rsquo;cancer\u0026rsquo;\u0026rsquo; for patients diagnosed with any subtype of AAV by the end of July 2022.\u003c/p\u003e \u003cp\u003ePatients with any subtype of AAV (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], eosinophilic granulomatosis with polyangiitis [EGPA] or unclassified AA-vasculitis) according to any of the followings: the treating physician, 1990 ACR Wegener or Churg-Strauss Classification Criteria, or EMA algorithm and complete prespecified data form related to \u0026lsquo;\u0026rsquo;cancer\u0026rsquo;\u0026rsquo; were included in the current study. Among these patients, those with a history of malignancy before and at the time of AAV diagnosis and those with non-melanoma skin cancer or benign or non-invasive tumors (in the past or current) were excluded from the final analysis.\u003c/p\u003e \u003cp\u003e \u003cb\u003eVariables\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ei. Related to Anca-Associated Vasculitis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eDate of birth, sex, date of AAV diagnosis, AAV subtype, ANCA status [Enzyme-linked immunoassay (ELISA) and indirect immunofluorescence assay (IIFA) ], sites of involvement, Birmingham Vasculitis Activity Score (v3) at baseline, revised five-factor score. Immunosuppressive treatments were recorded as \u0026lsquo;ever or never used\u0026rsquo; for the time period between AAV diagnosis and cancer diagnosis in patients with cancer and between AAV diagnosis and the last visit in patients without cancer.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eii. Related to cancer\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eDate of cancer diagnosis, type, and extensity (local, locally advanced, or metastatic) of cancer, smoking status (ever or never), and survival status (date of death was recorded for deceased patients).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using the SPSS software (v25.0; IBM Corporation, Armonk, NY, USA). The descriptive analysis was expressed as either median, interquartile range (IQR) for quantitative variables, or number (percentage) for categorical variables.\u003c/p\u003e \u003cp\u003eDistribution and univariable comparison of baseline demographic, disease characteristics and treatment options used during the disease course of AAV patients with or without cancer were explored via the Kaplan-Meier survival estimates and possible factors associated with cancer occurrence were investigated by using the log-rank test. The Mann-Whitney U test was used to compare the quantitative variables between the two groups. The factors identified in univariable analyses (p\u0026thinsp;\u0026lt;\u0026thinsp;0.20, taking into account the correction for multiplicity and clinical relevance) were further entered into the Cox regression analysis, with the backward selection, to determine independent predictors of cancer occurrence. The proportional hazards assumption and model fit were assessed using residual (Schonfeld and Martingale) analysis. To compare cancer incidences, age and sex-spesific standardized incidence rates (SIR) for the overall group, according to sex and individual cancer types, were calculated. For each participant, patient-year follow-up duration was calculated: the starting from the date of AAV diagnosis, and to the date of cancer diagnosis, death, or last follow-up visit, whichever was the first. The observed number of cases is all individuals diagnosed with invasive cancer (except for non-melanoma skin cancer) on follow-up after the diagnosis of AAV. The expected number of cases is the total number of patients that would have been reported to the cancer registry within the same follow-up period and calculated from the 2017 Turkish National Cancer Registry (TNCR) data (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). To compare rates of cancers, incidence rates (IR)(per 1000 patient-years), and incidence rate ratios (IRR) for different subgroups (according to AAV subtype, ANCA status, renal and lung involvement, smoking status, age at diagnosis and immunosuppressive drugs ever being used) were calculated. For the calculation of the SIR, IR, IRR, and the 95% confidence interval (CI), OpenEpi v3.01 software was used. Type-1 error lower than 0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003e Our study is compliant with the Helsinki Declaration and approved by the Hacettepe University ethical committee (Approval number: GO 19/1088).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 476 AAV patients were included in the study. Fifteen patients were excluded from the final analysis (Eight had cancer before AAV diagnosis, three had colon cancer diagnosis during AAV work-up, three had basal cell carcinoma, and one had non-invasive cancer). The final data set comprised 461 AAV patients (19 with cancer).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e312 (67.7%) patients had GPA, 76 (16.5%) had EGPA, 52 (11.3%) had MPA, and 21 (4.6%) had unclassified AAV. Median (IQR) disease duration was 3.4 (5.5) years; 6.4 (7.7) years in AAV patients with cancer, and 3.4 (5.3) years in those without cancer (p=0.013). The median (IQR) duration between AAV and cancer diagnosis was 46 (83) months. The total follow-up duration was 2022.8 patient-years. AAV patients with cancer were older at AAV diagnosis compared to those without cancer (median, IQR) (61.3 [28.2] vs. 49.7 [22.3], p=0.037). The male sex was predominant \u0026nbsp;(94.7% vs. 49.3%, log-rank p\u0026lt;0.001) and smoking (ever) was also more prevalent in this group (70.6% vs. 39.4%, log-rank p=0.006). (\u003cstrong\u003eTable 1\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003eANCA serology (ELISA) differed between groups (PR3 and negative ANCA) were more prevalent in patients with cancer, whereas MPO ANCA was more prevalent in patients without cancer (\u003cstrong\u003eTable 1\u003c/strong\u003e). Comorbidities (diabetes, hypertension, chronic kidney disease, chronic obstructive lung disease, and coronary artery disease) were similarly prevalent in both groups. Percentages of pulmonary involvement (83.3% vs. 78.4%, log-rank p=0.38) and renal involvement (68.4% vs. 55.1%, log-rank p=0.21) were similar in both groups. Other sites of involvement, disease activity, prognostic scores, and the need for dialysis and plasma exchange at baseline were also found to be similar between groups (\u003cstrong\u003eTable 1\u003c/strong\u003e). 58 patients died during follow-up due to any cause; 7 (36.8%) in AAV patients with cancer and 51 (11.5%) in \u0026nbsp;those without cancer (log-rank p = 0.04). Demographic and clinical characteristics of patients were shown in Table 1.\u003c/p\u003e\n\u003cp\u003ePatients with cancer were less likely to be exposed to rituximab than those without cancer (21.1% vs. 58.8%, log-rank p\u0026lt;0.001). Both groups used other drugs in similar percentages (\u003cstrong\u003eTable 2\u003c/strong\u003e). \u0026nbsp;The cumulative cyclophosphamide dose [median (minimum-maximum)] dose was 5.4 (0.5-30.0) grams in AAV patients with cancer and 3.0 (1.5-7.0) grams in those without cancer (p=0.19).\u003c/p\u003e\n\u003cp\u003eOf 19 patients, 18 (94.7%) were male. Overall cancer risk was higher in AAV patients compared to sex and age-specific cancer risk of general population (SIR 2.1 (1.3-3.2), p=0.004)). The distribution of cancers in the schematic figure is given in \u003cstrong\u003eFigure 1\u003c/strong\u003e. As the male sex was predominant, analyses were stratified according to sex.\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;In males:\u003c/em\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eCancer risk was higher than the age-specific cancer risk of male general population (SIR 3.1 (1.9-4.7), p\u0026lt;0.001). Lung cancer was the most common cancer type (6 patients, SIR 4.0 (1.6-8.3), p\u0026lt;0.001), followed by head-neck cancer (3 patients, SIR 27.3 (6.9-74.2), p\u0026lt;0.001). Details of the other types of cancers are given in \u003cstrong\u003eTable 3\u003c/strong\u003e. According to age at AAV diagnosis, cancer SIRs were as follows; \u0026nbsp;2.3 (1.3-3.8, p=0.008) for ≥ 50 years,1.9 (0.95-3.3, p=0.07) for ≥ 55 years, 2.2 (1.1-3.9, p=0.03) for ≥ 60 years 1.7 (0.7-3.5, p=0.23) for ≥65 years and 1.2 (0.3-3.1, p=0.75) for ≥70 years.\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cem\u003eIn females:\u003c/em\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eCancer risk was similar to the age-specific cancer risk of female general population (SIR 0.3 (0.1-1.5), p=0.20). There was one case with urinary bladder cancer (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong patient subgroups, each of the following subgroups had significantly higher cancer incidence rates than counterparts: male sex, age at ≥60 years at AAV diagnosis, and ever-smoked (\u003cstrong\u003eTable 4\u003c/strong\u003e). Patients who received rituximab had a significantly lower cancer incidence rate than patients who did not receive rituximab (IRR 0.1 (0.03-0.4), p\u0026lt;0.001) \u003cstrong\u003e(Table 4)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eResults of the univariable comparisons and Cox regression models are given in \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e. Due to the high rate of missing data, the ANCA ELISA variable was not included in the regression model. In the final model (results will be shown as Hazard ratio (HR) and 95% confidence interval (95% CI)): \u003cstrong\u003e\u003cem\u003ethe male sex\u003c/em\u003e\u003c/strong\u003e 22.3 (2.9-170.2, p=0.003), \u003cstrong\u003e\u003cem\u003eage ≥ 60 at AAV diagnosis\u003c/em\u003e\u003c/strong\u003e7.1 (2.5-20.1, p\u0026lt;0.001), \u003cstrong\u003e\u003cem\u003ereceiving rituximab\u003c/em\u003e\u003c/strong\u003e0.06 (0.01-0.26, p\u0026lt;0.001) were independently associated with cancer risk.\u003c/p\u003e\n\u003cp\u003eIndividual characteristics of AAV patients with cancer are given in \u003cstrong\u003eSupplementary Table 2\u003c/strong\u003e.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this multicenter study investigating 461 patients diagnosed with ANCA-Associated Vasculitis (AAV), the cancer risk in AAV patients was found to be 2.1 times higher compared to the age and sex-spesific cancer risk of Turkish population. Lung cancer was the most frequently detected cancer type, while head and neck cancer incidence was also statistically significantly higher. Male sex and \u0026ge;\u0026thinsp;60 years of age at AAV diagnosis were found to be associated with an increased risk of cancer. The cumulative dose of cyclophosphamide was similar in both groups, and no increased cancer risk was associated with using cyclophosphamide. However, using rituximab was associated with a decreased risk of cancer.\u003c/p\u003e \u003cp\u003eWe found a greater cancer risk in males, despite the overall similar cancer risk reported for both sexes in the literature (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) which may be due to the genetic, hormonal, or risky behavioral differences between sexes, or simply by detection bias. We found also higher cancer risk in AAV patients diagnosed at \u0026ge;\u0026thinsp;60 years of age compared to younger patients, in addition to increased cancer risk in all age groups compared to the general population, especially in males. The late onset of AAV in cases with malignancy has been frequently reported in the literature (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). It is also plausible to speculate that patients diagnosed at an advanced age might be more susceptible to carcinogenesis that could develop due to the treatments they undergo, and their cumulative cancer risk might increase independently of AAV. Smoking is one of the most extensively studied and proven risk factors for cancer. However, data on smoking is lacking in many studies related to AAV and cancer. Although active or past smoking was more commonly found in cancer-diagnosed patients in our current study, it lost its significance in the multivariate model and we did not find any interactions between smoking and age. Nevertheless, due to the abundance of missing data and the lack of information on the quantity and frequency of smoking, making interpretations on this topic is challenging within the scope of this study.\u003c/p\u003e \u003cp\u003eAside from inflammation (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), another factor associated with cancer is the drugs used in AAV treatment, especially cyclophosphamide (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In the current study, cyclophosphamide was not associated with increased cancer risk. In addition, as confirmatory data to the current understanding of no association in our study, no patient used oral cyclophosphamide; all patients had mesna, and more importantly, the cumulative cyclophosphamide dose was lower than the earlier studies. Methotrexate and azathioprine may also increase the risk of skin cancer (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, we excluded patients with skin cancer in our study. Regarding rituximab, recent data showed that the anti-tumor effect of rituximab is thought to originate from relatively increased anti-tumor cytotoxic T cells (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In addition, recent solid data from the UK suggested a lower risk of cancer in rituximab-treated compared to cyclophosphamide-treated patients. The risk of cancer was comparable to the general population in rituximab-treated patients (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Our results support the current literature about rituximab on cancer. However, we can not fully exclude the risk of selection bias regarding the use of rituximab as clinicians might have prescribed rituximab to patients with a high risk of developing cancer with \u0026lsquo;sense de clinique\u0026rsquo;. From a different perspective, despite the use of cyclophosphamide at a lower dose in accordance with current recommendations and the high rate of rituximab use in our cohort, the overall cancer risk was higher than in the general population.\u003c/p\u003e \u003cp\u003eBladder cancer, related to the disease and cyclophosphamide usage, has been highlighted in numerous studies in the literature for increased incidence with pooled SIR of 3.8 (2.7\u0026ndash;5.4) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). While the statistical significance of increased bladder cancer frequency based on sex stratification may not be apparent in our study, the presence of separately considered uroepithelial tumors can imply an elevated risk in genitourinary system cancers. However, the effect size of this risk is less substantial than in the literature, possibly due to the abovementioned reasons. In the literature, although most studies regarding lung cancer do not report a statistically significant increase in risk, the meta-analysis, as mentioned above, presents a SIR value of 1.67 (1.07\u0026ndash;2.60) for lung cancer (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Similarly, a large-scale population-based study conducted by Choi and colleagues utilizing propensity score matching has reported a significant increase in lung cancer risk (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Regarding low hematologic malignancy incidence in our cohort, the relatively low cumulative cyclophosphamide dose and the administration of rituximab in more than half of the patients may be the underlying reason. As we excluded patients with non-melanoma skin cancers from the outset of our study, no inferences can be drawn from the current data regarding this matter. Increased genitourinary, lung, and head-neck cancer risk in our study may be attributable to the fact that these tissues are the primary target for AAV, especially PR3-positive AAVs. Nevertheless, especially in patients with lung and head-neck involvement, the routine performance of lung and head-neck imaging may result in the more frequent and earlier detection of cancerous lesions. Consequently, an increased incidence might be observed due to the lead-time bias.\u003c/p\u003e \u003cp\u003eThe multicenter nature, encompassing data from across the country, allowing for an exploration of the current short-to-medium-term safety profile of immunosuppressive treatment in AAV, can be counted as the strengths of our study. However, certain limitations must be acknowledged. The retrospective recording of some of the data from medical records introduces significant gaps, particularly in variables such as smoking, alcohol consumption, and environmental pollution, which could directly influence carcinogenesis. Moreover, notable deficiencies exist in the data regarding cumulative doses of cyclophosphamide and especially rituximab. Besides, we could not assess the cumulative dose of steroids and their effect on incident cancers. Although the distribution of major comorbidities was similar between the two groups, we can not precisely estimate the effect of comorbidities on cancer occurrence due to the lack of severity data about comorbidities. Since these patients are followed and investigated more closely, tumoral lesions that may have a variable effect on survival may be detected early, which may have caused us to find the incidence higher. So, the inability to address this lead-time bias risk is a noteworthy limitation in our study. It is known that cancer risk in rheumatic diseases is associated with increasing disease duration (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), and the cumulative follow-up period of the present study may be too short to reveal this relationship due to the small number of patients and the short follow-up period per person (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Also, due to the low number of cases of cancer, SIR results should be interpreted cautiously. Lastly, quantitative data regarding the smoking history was not available; therefore, we were only able to categorize smoking status as ever vs. never. Considering that most cancers in the males were smoking-related cancers that were seen in the older ages, possible confounding due to smoking intensity could not be excluded.\u003c/p\u003e \u003cp\u003eIn conclusion, we found 2.1 times higher cancer risk in AAV patients compared to the age and sex-specific cancer risk of male Turkish population. Lung and head-and-neck cancers were the most frequently detected cancer types. While no relationship could be established between increased cancer risk and cyclophosphamide usage, an association was identified between reduced cancer risk and the utilization of rituximab. Greater attention should be given to cancer risks, and screening programs should be effectively employed in male AAV patients and AAV patients diagnosed at advanced age. A longer follow-up period for these patients has been planned. Furthermore, a global effort can be started under EUVAS and VCRC to better clarify this concept.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eTRVaS Turkish Vasculitis Study Group Prospective Database is a web-based registry supported by RedCaps and coordinated by the Hacettepe University Vasculitis Research Centre Steering committee consisting of Servet Akar, Cemal Bes, Haner Direskeneli, \u0026Ouml;mer Karadağ, Fatoş \u0026Ouml;nen, Ahmet Omma, and Seza \u0026Ouml;zen. TRVaS is supported by Hacettepe University. There is no financial support for this database. https://redcap.huvac.hacettepe.edu.tr.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e Authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOmer Karadag, MD, Professor of Rheumatology\u003c/p\u003e\n\u003cp\u003eHacettepe University Faculty of Medicine\u003c/p\u003e\n\u003cp\u003eDepartment of Internal Medicine\u003c/p\u003e\n\u003cp\u003eDivision of Rheumatology\u003c/p\u003e\n\u003cp\u003ee-mail: [email protected], [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e: None\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKitching AR, Anders HJ, Basu N, Brouwer E, Gordon J, Jayne DR, et al. 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Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials. Ann Rheum Dis. 2011;70(8):1415-21.\u003c/li\u003e\n\u003cli\u003eHolle JU, Gross WL, Latza U, N\u0026ouml;lle B, Ambrosch P, Heller M, et al. Improved outcome in 445 patients with Wegener\u0026apos;s granulomatosis in a German vasculitis center over four decades. Arthritis Rheum. 2011;63(1):257-66.\u003c/li\u003e\n\u003cli\u003eWei X, Xie F, Zhou X, Wu Y, Yan H, Liu T, et al. Role of pyroptosis in inflammation and cancer. Cell Mol Immunol. 2022;19(9):971-92.\u003c/li\u003e\n\u003cli\u003eGrulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59-67.\u003c/li\u003e\n\u003cli\u003eKnight A, Askling J, Granath F, Sparen P, Ekbom A. Urinary bladder cancer in Wegener\u0026apos;s granulomatosis: risks and relation to cyclophosphamide. Ann Rheum Dis. 2004;63(10):1307-11.\u003c/li\u003e\n\u003cli\u003eLafarge A, Joseph A, Pagnoux C, Puechal X, Cohen P, Samson M, et al. Risk of malignancy in patients treated for systemic necrotising vasculitis. Ann Rheum Dis. 2020;79(3):431-3.\u003c/li\u003e\n\u003cli\u003eBalkwill F, Montfort A, Capasso M. B regulatory cells in cancer. Trends Immunol. 2013;34(4):169-73.\u003c/li\u003e\n\u003cli\u003evan Daalen EE, Rizzo R, Kronbichler A, Wolterbeek R, Bruijn JA, Jayne DR, et al. Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis. Ann Rheum Dis. 2017;76(6):1064-9.\u003c/li\u003e\n\u003cli\u003eChoi ST, Ahn SV, Lee PH, Moon CM. The cancer risk according to three subtypes of ANCA-associated vasculitis: A propensity score-matched analysis of a nationwide study. Semin Arthritis Rheum. 2021;51(4):692-9.\u003c/li\u003e\n\u003cli\u003eTreppo E, Toffolutti F, Manfr\u0026egrave; V, Taborelli M, De Marchi G, De Vita S, et al. Risk of Cancer in Connective Tissue Diseases in Northeastern Italy over 15 Years. J Clin Med. 2022;11(15).\u003c/li\u003e\n\u003cli\u003eHe M-m, Lo C-H, Wang K, Polychronidis G, Wang L, Zhong R, et al. Immune-Mediated Diseases Associated With Cancer Risks. JAMA Oncology. 2022;8(2):209-19.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. Distribution and time-dependent univariable comparison of demographic and disease characteristics of AAV patients with and without cancer\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"728\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll patients\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=461)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAV Patients with Cancer\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=19)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAV Patients without Cancer\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=442)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale, n(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e236 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e18 (94.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e218 (49.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at AAV diagnosis, years, median, (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e49.8 (22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e61.3 (28.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e49.7 (22.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.037\u003cstrong\u003e\u0026deg;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAV disease duration*, months, median (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e3.4 (5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e6.4 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e3.4 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.013\u003cstrong\u003e\u0026deg;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking (n=403)\u003c/strong\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eNever\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eEver\u003c/strong\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e239 (59.3)\u003c/p\u003e\n \u003cp\u003e164 (40.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (29.4)\u003c/p\u003e\n \u003cp\u003e14 (70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e234 (60.6)\u003c/p\u003e\n \u003cp\u003e152 (39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAV subtype\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGPA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEGPA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMPA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUnclassified\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e312 (67.7)\u003c/p\u003e\n \u003cp\u003e76 (16.5)\u003c/p\u003e\n \u003cp\u003e52 (11.3)\u003c/p\u003e\n \u003cp\u003e21 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (84.2)\u003c/p\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e296 (67.0)\u003c/p\u003e\n \u003cp\u003e75 (17.0)\u003c/p\u003e\n \u003cp\u003e51 (11.5)\u003c/p\u003e\n \u003cp\u003e20 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eANCA IFA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ecANCA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003epANCA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNegative\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUnavailable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e227 (49.2)\u003c/p\u003e\n \u003cp\u003e123 (26.7)\u003c/p\u003e\n \u003cp\u003e84 (18.2)\u003c/p\u003e\n \u003cp\u003e27 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (63.2)\u003c/p\u003e\n \u003cp\u003e3 (15.8)\u003c/p\u003e\n \u003cp\u003e4 (21.2)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e215 (48.6)\u003c/p\u003e\n \u003cp\u003e120 (27.1)\u003c/p\u003e\n \u003cp\u003e80 (18.1)\u003c/p\u003e\n \u003cp\u003e27 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.77**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eANCA ELISA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePR3\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMPO\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNegative\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUnavailable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e189 (41.0)\u003c/p\u003e\n \u003cp\u003e91 (19.7)\u003c/p\u003e\n \u003cp\u003e30 (6.5)\u003c/p\u003e\n \u003cp\u003e151 (32.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (63.6)\u003c/p\u003e\n \u003cp\u003e2 (9.1)\u003c/p\u003e\n \u003cp\u003e5 (22.7)\u003c/p\u003e\n \u003cp\u003e1 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e178 (40.3)\u003c/p\u003e\n \u003cp\u003e89 (20.1)\u003c/p\u003e\n \u003cp\u003e25 (5.7)\u003c/p\u003e\n \u003cp\u003e150 (33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.03**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDiabetes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHypertension\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eChronic Kidney Disease\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eChronic Obstructive Lung Disease\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCoronary Artery Disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e68 (14.8)\u003c/p\u003e\n \u003cp\u003e132 (28.6)\u003c/p\u003e\n \u003cp\u003e38 (8.2)\u003c/p\u003e\n \u003cp\u003e7 (1.5)\u003c/p\u003e\n \u003cp\u003e36 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003cp\u003e4 (21.1)\u003c/p\u003e\n \u003cp\u003e2 (10.5)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e2 (1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e67 (15.2)\u003c/p\u003e\n \u003cp\u003e128 (29.0)\u003c/p\u003e\n \u003cp\u003e36 (8.1)\u003c/p\u003e\n \u003cp\u003e7 (1.6)\u003c/p\u003e\n \u003cp\u003e34 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSites of involvement (ever)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eConstitutional (n=455)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMucocutaneous (n=453)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMusculoskeletal (n=458)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOcular (n=456)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEar-nose-throat (n=457)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRespiratory (n=461)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eVascular (n=446)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGastrointestinal (n=455)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGenitourinary (n=456)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCentral nervous system (n=456)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePeripheral nervous system (n=445)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e367 (81.2)\u003c/p\u003e\n \u003cp\u003e128 (28.4)\u003c/p\u003e\n \u003cp\u003e225 (49.5)\u003c/p\u003e\n \u003cp\u003e86 (19.0)\u003c/p\u003e\n \u003cp\u003e270 (59.5)\u003c/p\u003e\n \u003cp\u003e360 (78.6)\u003c/p\u003e\n \u003cp\u003e23 (5.2)\u003c/p\u003e\n \u003cp\u003e31 (6.9)\u003c/p\u003e\n \u003cp\u003e252 (55.6)\u003c/p\u003e\n \u003cp\u003e15 (3.3)\u003c/p\u003e\n \u003cp\u003e67 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (72.2)\u003c/p\u003e\n \u003cp\u003e5 (29.4)\u003c/p\u003e\n \u003cp\u003e8 (44.4)\u003c/p\u003e\n \u003cp\u003e1 (5.9)\u003c/p\u003e\n \u003cp\u003e10 (58.8)\u003c/p\u003e\n \u003cp\u003e15 (83.3)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1 (5.6)\u003c/p\u003e\n \u003cp\u003e13 (68.4)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e354 (81.6)\u003c/p\u003e\n \u003cp\u003e123 (28.4)\u003c/p\u003e\n \u003cp\u003e217 (49.7)\u003c/p\u003e\n \u003cp\u003e85 (19.5)\u003c/p\u003e\n \u003cp\u003e260 (59.5)\u003c/p\u003e\n \u003cp\u003e345 (78.4)\u003c/p\u003e\n \u003cp\u003e23 (5.4)\u003c/p\u003e\n \u003cp\u003e30 (6.9)\u003c/p\u003e\n \u003cp\u003e239 (55.1)\u003c/p\u003e\n \u003cp\u003e15 (3.4)\u003c/p\u003e\n \u003cp\u003e65 (15.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBVAS at baseline, median (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e11 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e11 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e11 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.84\u003cstrong\u003e\u0026deg;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRevised Five-factor score \u0026ge;1 (n=314)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e206 (65.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e7 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e199 (65.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDialysis at baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e33 (7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e3 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e30 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlasma exchange at baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e54 (11.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e53 (12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.23076923076923%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMortality\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\"\u003e\n \u003cp\u003e58 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.521978021978022%\" valign=\"top\"\u003e\n \u003cp\u003e7 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.75824175824176%\" valign=\"top\"\u003e\n \u003cp\u003e51 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.203296703296703%\" valign=\"top\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*According to the last follow-up visit\u003c/p\u003e\n\u003cp\u003e**p excluding the \u0026lsquo;\u0026rsquo;unavailable\u0026rsquo;\u0026rsquo; strata\u003c/p\u003e\n\u003cp\u003e\u0026deg;p values represent the result of the Mann-Whitney U test, all other p values represent the result of the log-rank test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Distribution and time-dependent univariable comparison of treatments ever used in AAV patients with and without cancer (upto time of cancer diagnosis or last follow-up visit)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"709\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatments\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll patients\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=461)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAV Patients with Cancer\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=19)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAV Patients without Cancer\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=442)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003cstrong\u003e\u0026deg;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMethotrexate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e76 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e75 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMycophenolate mofetil\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e58 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e57 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAzathioprine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e261 (56.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e14 (73.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e247 (55.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCyclophosphamide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e270 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e10 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e260 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAzathioprine+cyclophosphamide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e167 (36.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e7 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e160 (36.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRituximab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e264 (57.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e4 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e260 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePulse steroid at baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e198/453 (43.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e5/18 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e193/435 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.99153737658674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSequential cyclophosphamide and rituximab (or vice versa)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.643159379407617%\" valign=\"top\"\u003e\n \u003cp\u003e263 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.668547249647391%\" valign=\"top\"\u003e\n \u003cp\u003e3 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.143864598025388%\" valign=\"top\"\u003e\n \u003cp\u003e260 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.552891396332862%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAAV: Anca-associated vasculitis\u003c/p\u003e\n\u003cp\u003e\u0026deg;p values represent the result of the Mann-Whitney U test, all other p values represent the result of the log-rank test\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Standardized incidence rates according to cancer types of AAV groups\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"728\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.46217331499312%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubgroup\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (n,%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eObserved cancer (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eExpected cancer (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8404401650618984%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSIR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.543328748280604%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eConfidence interval (95%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07840440165062%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.46217331499312%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e461 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e9.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8404401650618984%\" valign=\"top\"\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.543328748280604%\" valign=\"top\"\u003e\n \u003cp\u003e1.3-3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07840440165062%\" valign=\"top\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.46217331499312%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLung\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHead-neck SCC*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUrinary bladder\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eProstate\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMalign melanoma\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStomach\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNon-Hodgkin Lymphoma\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMesenchymal tumor\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUroepithelial tumor\u003csup\u003e++\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e236 (51.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5.9\u003c/p\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8404401650618984%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.1\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e27.3\u003c/p\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.543328748280604%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.9-4.7\u003c/p\u003e\n \u003cp\u003e1.6-8.3\u003c/p\u003e\n \u003cp\u003e6.9-74.2\u003c/p\u003e\n \u003cp\u003e0.6-11.8\u003c/p\u003e\n \u003cp\u003e0.05-4.78\u003c/p\u003e\n \u003cp\u003e1.2-123.3\u003c/p\u003e\n \u003cp\u003e0.1-12.3\u003c/p\u003e\n \u003cp\u003e0.3-32.9\u003c/p\u003e\n \u003cp\u003e1.2-123.3\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07840440165062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.46217331499312%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUrinary bladder\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e225 (48.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.691884456671252%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8404401650618984%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e16.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.543328748280604%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.1-1.5\u003c/p\u003e\n \u003cp\u003e0.8-82.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07840440165062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Head-neck SCC cases were considered different from skin SCC by oncologists in these cases.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e++\u003c/sup\u003e SIR was not calculated as separate data was unavailable in the 2017 TNCR data for uroepithelial tumors\u003c/p\u003e\n\u003cp\u003eSIR: Standardized incidence rate\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Incidence rates and incidence rate ratios according to subgroups of AAV patients\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"756\" style=\"margin-right: calc(-1%); width: 101%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubgroup\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (n,%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObserved cancer (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up (patient-years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIR (95% CI) (per 1000 patient-years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIRR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep for IRR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAV Subtype\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGPA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNon-GPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e312 (67.7)\u003c/p\u003e\n \u003cp\u003e149 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1442.7\u003c/p\u003e\n \u003cp\u003e580.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11.1 (6.8-18.1)\u003c/p\u003e\n \u003cp\u003e5.2 (1.6-16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.1 (0.6-11.5)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eANCA Status\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePR3\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMPO\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNegative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e189 (61.0)\u003c/p\u003e\n \u003cp\u003e91 (29.4)\u003c/p\u003e\n \u003cp\u003e30 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e821.4\u003c/p\u003e\n \u003cp\u003e282.4\u003c/p\u003e\n \u003cp\u003e137.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13.4 (7.5-24.1)\u003c/p\u003e\n \u003cp\u003e7.1 (1.8-28.2)\u003c/p\u003e\n \u003cp\u003e36.4 (15.4-86.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.9 (0.4-17.6)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e5.1 (0.8-54.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e236 (51.2)\u003c/p\u003e\n \u003cp\u003e225 (48.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e977.3\u003c/p\u003e\n \u003cp\u003e1045.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18.4 (11.7-29.1)\u003c/p\u003e\n \u003cp\u003e1.0 (0.1-6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e19.3 (3.0-802.3)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;60\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;60\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e337 (73.1)\u003c/p\u003e\n \u003cp\u003e124 (26.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1665.7\u003c/p\u003e\n \u003cp\u003e357.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4.8 (2.4-9.6)\u003c/p\u003e\n \u003cp\u003e30.8 (17.2-55.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e6.4 (2.3-18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking history\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNever\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEver\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e239 (59.3)\u003c/p\u003e\n \u003cp\u003e164 (40.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1102.1\u003c/p\u003e\n \u003cp\u003e688.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4.5 (1.9-10.8)\u003c/p\u003e\n \u003cp\u003e20.3 (12.1-34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e4.5 (1.5-15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePulmonary involvement\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e360 (78.6)\u003c/p\u003e\n \u003cp\u003e98 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1511.7\u003c/p\u003e\n \u003cp\u003e483.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9.9 (6.0-16.4)\u003c/p\u003e\n \u003cp\u003e6.2 (2.0-19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.6 (0.5-8.6)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGenitourinary involvement\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e252 (55.7)\u003c/p\u003e\n \u003cp\u003e201 (44.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1068.4\u003c/p\u003e\n \u003cp\u003e919.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12.2 (7.0-20.8)\u003c/p\u003e\n \u003cp\u003e6.5 (2.9-14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.9 (0.7-5.9)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.155878467635404%\" valign=\"top\" style=\"width: 25.0645%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunosuppression, ever\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCYC, yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCYC, no\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAZA, yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAZA, no\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRTX, yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRTX, no\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMMF, yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMMF, no\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMTX, yes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMTX, no\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.096433289299869%\" valign=\"top\" style=\"width: 16.0195%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e270 (58.6)\u003c/p\u003e\n \u003cp\u003e191 (41.4)\u003c/p\u003e\n \u003cp\u003e261 (56.6)\u003c/p\u003e\n \u003cp\u003e200 (43.4)\u003c/p\u003e\n \u003cp\u003e264 (57.3)\u003c/p\u003e\n \u003cp\u003e197 (42.7)\u003c/p\u003e\n \u003cp\u003e58 (12.6)\u003c/p\u003e\n \u003cp\u003e403 (87.4)\u003c/p\u003e\n \u003cp\u003e76 (16.5)\u003c/p\u003e\n \u003cp\u003e385 (83.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.303830911492735%\" valign=\"top\" style=\"width: 8.3555%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.228533685601057%\" valign=\"top\" style=\"width: 10.9375%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1349.3\u003c/p\u003e\n \u003cp\u003e673.5\u003c/p\u003e\n \u003cp\u003e1454.7\u003c/p\u003e\n \u003cp\u003e568.1\u003c/p\u003e\n \u003cp\u003e1324.1\u003c/p\u003e\n \u003cp\u003e698.7\u003c/p\u003e\n \u003cp\u003e239.2\u003c/p\u003e\n \u003cp\u003e1783.6\u003c/p\u003e\n \u003cp\u003e408.6\u003c/p\u003e\n \u003cp\u003e1614.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.305151915455745%\" valign=\"top\" style=\"width: 18.1914%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7.4 (4.0-13.7)\u003c/p\u003e\n \u003cp\u003e13.3 (7.0-25.6)\u003c/p\u003e\n \u003cp\u003e9.6 (5.7-16.2)\u003c/p\u003e\n \u003cp\u003e8.8 (3.7-21.1)\u003c/p\u003e\n \u003cp\u003e3.0 (1.1-8.0)\u003c/p\u003e\n \u003cp\u003e21.5 (13.0-35.4)\u003c/p\u003e\n \u003cp\u003e4.2 (0.6-29.6)\u003c/p\u003e\n \u003cp\u003e10.0 (6.4-16.0)\u003c/p\u003e\n \u003cp\u003e2.4 (0.3-17.3)\u003c/p\u003e\n \u003cp\u003e11.1 (7.0-17.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.116248348745046%\" valign=\"top\" style=\"width: 15.3652%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.6 (0.2-1.5)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e1.1 (0.4-3.9)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.1 (0.03-0.4)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.4 (0.01-2.6)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003cp\u003e0.2 (0.01-1.4)\u003c/p\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.793923381770146%\" valign=\"top\" style=\"width: 5.9687%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAZA: Azathioprin, CYC: Cyclophosphamide, GPA: Granulomatosis polyangiitis, IR: Incidence rate, IRR: Incidence rate ratio, MTX: Methotrexate, MPO: Myeloperoxidase, MMF: Mycophenolate mofetil, PR3: Proteinase-3, RTX: Rituximab\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"ANCA-associated vasculitis, granulomatous polyangiitis, cancer, rituximab, cyclophosphamide, lung cancer, head-neck cancers","lastPublishedDoi":"10.21203/rs.3.rs-3860558/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3860558/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eAim:\u003c/strong\u003eTo investigate cancer incidence in patients with ANCA-associated vasculitides (AAV), compare it with the age/sex-spesific cancer risk of Turkish population, explore independent risk factors associated with cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eThis multicenter, incidence case-control study was conducted using TRVaS registry. AAV patients without cancer history before AAV diagnosis were included. Demographic and AAV-related data of patients with and without an incident cancer were compared. Standardized cancer incidence rates were calculated using age/sex-spesific 2017 Turkish National Cancer Registry data for cancers (excluding non-melanoma skin cancers). Cox regression was performed to find factors related to incident cancers in AAV patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003eOf 461 AAV patients (236[51.2%] male), 19 had incident cancers after 2022.8 patient-years follow-up. Median(IQR) disease duration was 3.4(5.5) years, and 58(12.6%) patients died [7 with cancer and 1 without cancer (log-rank,p=0.04)]. Cancer-diagnosed patients were older, mostly male, and more likely to have anti-PR3-ANCA positivity. The cumulative cyclophosphamide dose was similar in patients with and without cancer. Overall cancer risk in AAV was 2.1(SIR)(1.3-3.2),p=0.004); lung and head-neck [primary target sites for AAV] cancers were the most common. In Cox regression, male sex and ≥60 years of age at AAV diagnosis were associated with increased cancer risk, while receiving rituximab was associated with decreased cancer risk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003eCancer risk was 2.1-times higher in AAV patients than the age/sex-spesific cancer risk of Turkish population, despite a high rate of rituximab use and lower dose of cyclophosphamide doses. Vigilance in cancer screening for AAV patients covering lung, genitourinary, and head-neck regions, particularly in males and the elderly, is vital.\u003c/p\u003e","manuscriptTitle":"Unveiling Cancer Risk in ANCA-Associated Vasculitis: Result from the Turkish Vasculitis Study Group (TRVaS)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-23 15:51:09","doi":"10.21203/rs.3.rs-3860558/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-01-19T02:03:53+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-18T17:57:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-16T17:44:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Internal and Emergency Medicine","date":"2024-01-15T06:30:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ac9ba115-a009-4f7e-9fcd-6b92f179a65b","owner":[],"postedDate":"January 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-30T00:43:26+00:00","versionOfRecord":{"articleIdentity":"rs-3860558","link":"https://doi.org/10.1007/s11739-024-03577-9","journal":{"identity":"internal-and-emergency-medicine","isVorOnly":false,"title":"Internal and Emergency Medicine"},"publishedOn":"2024-03-29 00:43:26","publishedOnDateReadable":"March 29th, 2024"},"versionCreatedAt":"2024-01-23 15:51:09","video":"","vorDoi":"10.1007/s11739-024-03577-9","vorDoiUrl":"https://doi.org/10.1007/s11739-024-03577-9","workflowStages":[]},"version":"v1","identity":"rs-3860558","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3860558","identity":"rs-3860558","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}