
==== Front
Clin Exp Med
Clin Exp Med
Clinical and Experimental Medicine
1591-8890
1591-9528
Springer International Publishing Cham

39230721
1475
10.1007/s10238-024-01475-0
Review
ANCA-associated vasculitis and lung cancer: an immunological perspective
http://orcid.org/0009-0008-2471-5939
Li Longzhao 12
Teng Jun 12
Kou Na 1
Yue Yuan 1
http://orcid.org/0000-0001-6401-977X
Wang HongWu wanghongwu2015@126.com

1
1 https://ror.org/05damtm70 grid.24695.3c 0000 0001 1431 9176 Respiratory Disease Center, Dongzhimen Hospital, Beijing University of Chinese Medicine, No.116 Cuiping West Road, Tongzhou District, 101121 Beijing China
2 grid.24695.3c 0000 0001 1431 9176 Beijing University of Traditional Chinese Medicine, Beijing, China
4 9 2024
4 9 2024
2024
24 1 20815 7 2024
20 8 2024
© The Author(s) 2024
2024
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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that often involves the upper and lower respiratory tracts. In recent years, numerous studies have found a significant increase in the incidence of cancer among AAV patients, but the association between lung cancer and AAV remains inconclusive, with relatively low clinical attention. This review summarizes the current literature on the risk of lung cancer in patients with ANCA-associated vasculitis (AAV), detailing the potential mechanisms by which AAV may contribute to lung cancer, and further elucidates the inherent carcinogenic risks of immunosuppressants.There is a correlation between AAV and lung cancer, which is related to T cell senescence and damage, as well as the abnormal expression of cytokines such as IL-6 and IL-10. In AAV patients, the use of cyclophosphamide and azathioprine (AZA) alone has a clear carcinogenic risk, with frequent use of CYC potentially posing a high risk for lung cancer. Although TNF inhibitors (TNFi) combined with CYC have carcinogenic risks, there is insufficient evidence to link them directly to an increased risk of lung cancer. For patients at high risk for lung cancer, the judicious use of immunosuppressants, timely computed tomography (CT), and lung cancer screening can reduce the risk of lung cancer in AAV patients.

Keywords

ANCA-associated vasculitis
Lung cancer
Risk
Immunosuppressive agents
issue-copyright-statement© Springer Nature Switzerland AG 2024
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pmcIntroduction

Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune vasculitis that mainly includes Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA). In recent years, multiple reports have shown a significant increase in the cancer risk associated with AAV [1, 2]. Most analyses suggest that non-melanoma skin cancer (NMSC), leukemia, and bladder cancer have a higher risk in AAV patients [3–5], with lung cancer not being among these. However, due to the fact that over 90% of AAV patients have upper airway abnormalities, 80%–85% of patients will develop pulmonary lesions, including lung nodules, bronchial damage, and vascular inflammatory infiltrates, which are risk factors for lung cancer [6, 7]. The risk of lung cancer is worth attention. Given that AAV is characterized by prolonged inflammatory responses, abnormal activation of the immune system, and the necessity for high doses of immunosuppressants during treatment, it is reasonable to explore the correlation between AAV and lung cancer from an immunological perspective. In this review, we will comprehensively analyze previous studies on the association between AAV and lung cancer, elucidate the role of immune responses and immunosuppressants, and propose potential clinical measures to reduce lung cancer risk in AAV patients.

Incidence of lung cancer in ANCA-associated vasculitis

As of December 2023, clinical evidence supports an increased lung cancer risk in AAV patients compared to the general population (Table 1). In all studies involving AAV and lung cancer, the longest follow-up period reached up to 300 months, with a cancer incidence rate of 12.24% ± 0.1315. The risk of lung cancer in AAV patients was significantly increased [8–12], with an incidence rate of 1.61% ± 0.0156, accounting for 17.42% ± 0.1014 of all cancers, indicating a relatively high prevalence. These results are consistent with the findings of scholar Zaw Thet. The incidence of AAV-related tumors ranges from 10 to 26%, with lung cancer accounting for a relatively high proportion of AAV-related cancers [12]. Due to the influences of factors such as smoking and alcohol consumption brought about by differences in racial gene expression and geographical disparities, the three types of vasculitis in AAV exhibit demographic differences in gender and race [13, 14]. Differences in lung cancer incidence rates may also be related to this. Some studies have shown significant geographical and racial differences in cancer among AAV patients, with the prevalence of lung cancer also reflecting these demographic variations. For instance, AAV patients in East Asia are more likely to develop lung cancer [15]. Currently, no studies have systematically analyzed the demographic characteristics of AAV patients with lung cancer, including factors such as race, disease course, age, and smoking status. As future statistical analyses of the clinical distribution characteristics of AAV cancer patients become available, the impact of geographical location, race, and disease duration on the risk of lung cancer in AAV patients may be further elucidated. Table 1 Lung cancer in patients with ANCA-associated vasculitis

Author	Year	Country	Follow-up time	Study type and cases	Number of tumors/cancer incidence	Number of lung cancers/proportion of lung cancer in tumors	
Tatsis et al. [16]	Years: 1999	Country: Germany	Follow-up: 2 years

Mean follow-up:?

	Retrospective (N = 477)	N = 23/4.82%	N = 1/4.35%	
Knight et al. [17]	Years: 2002	Country: Sweden	Follow-up: 2 years

Mean follow-up:?

	Retrospective(N = 1065)	N = 110/10.33%	N = 8/7.27%	
Pagnoux et al. [18]	Years: 2008	Country: France and Belgium	Mean follow-up: 29 months	RCT (N = 126)	N = 3/2.38%	N = 1/33.33%	
Faurschou et al. [19]	Years: 2008	Country: Denmark	Median duration of follow-up: 72 months	Retrospective registry (N = 293)	N = 50/17.06%	N = 5/10.00% (Cancer of respiratory system, unknown location.)	
Stones et al. [20]	Years: 2010	Country: USA	Mean follow-up: 6 months	RCT (N = 197)	N = 9/4.57%	N = 2/22.22%	
Heijl et al. [5]	Years: 2011	Country: European countries	Mean follow-up: 58.8 months	Retrospective (N = 535)	N = 50/9.35%	N = 5/10.00%	
Holle et al. [21]	Years: 2011	Country: German	Follow-up: three periods (1966–1993,1994–1998, 1966–1993)	Retrospective (N = 445)	N = 18/4.04%	N = 2/11.11%	
Zycinska et al. [22]	Years:2013	Country: Poland	Median follow-up: 84 months	Retrospective (N = 117)	N = 15/12.82%	N = 2/13.33%	
Pendergraft et al. [23]	Years:2014	Country: USA	Median follow-up:25.2 months	Retrospective (N = 172)	N = 3/1.74%	N = 1/33.33%	
Faurschou et al. [24]	Years:2015	Country: Denmark	Median follow-up: 116.4 months	Retrospective (N = 293)	N = 73/24.91%	N = 5/6.85%	
Alberici et al. [25]	Years:2015	Country: UK	Median follow-up: 59.3 months	Retrospective (N = 69)	N = 4/5.80%	N = 1/25.00%	
Rahmattulla et al. [26]	Years:2015	Country: Netherlands	Mean follow-up: 120 months	Retrospective (N = 138)	N = 85/61.59%	N = 2/2.35%	
Sriskandarajah et al. [27]	Years: 2017	Country: Norway	Mean follow-up: 86.4 months	Retrospective (N = 419)	N = 46/10.98%	N = 8/17.39%	
van Daalen et al. [28]	Years:2017	Country: UK	Mean follow-up: 67.2 months	Retrospective (N = 323)	N = 45/13.93%	N = 4/8.89%	
Yoo et al. [29]	Years: 2018	Country: South Korea	Mean follow-up: 50.7 months	Retrospective (N = 150)	N = 4/2.67%	N = 1/25.00%	
McAdoo et al. [30]	Years:2019	Country: UK	Median follow-up: 56 months	Prospective longitudinal cohort (N = 66)	N = 6/9.09%	N = 1/16.67%	
Ahn et al. [15]	Years:2019	Country: South Korea	Follow-up: 96 months	Retrospective (N = 2097)	N = 114/5.44%	N = 19/16.67%	
Wallace et al. [31]	Years:2020	Country: USA	Mean follow-up: 84 months	Retrospective (N = 150)	N = 29/19.33%	N = 9/31.03%	
Choi s et al. [2]	Years:2021	Country: South Korea	Mean follow-up: 84 months	Retrospective (N = 1982)	N = 120/6.05%	N = 24/20.00%	
Tieu et al. [32]	Years: 2022	Country: Australia	Maximum follow-up: 300 months	Retrospective (N = 564)	N = 101/17.91%	N = 34/33.67%	

The mechanisms of ANCA-associated vasculitis in lung cancer

AAV patients face various carcinogenic risk factors throughout their clinical journey, including the use of immunosuppressants and dialysis [12]. However, previous studies have indicated that the intrinsic immune dysfunction brought about by the progression of AAV may be a risk factor for cancer [1]. Even with low cumulative doses of cyclophosphamide (an immunosuppressant associated with cancer) and without undergoing dialysis, patients have shown a high prevalence of cancer, including lung cancer, which is particularly notable [11]. The mechanisms linking AAV and lung cancer are very complex and may be related to the long-term inflammatory effects and immune system activation associated with AAV. AAV can induce a high level of inflammatory response, causing multiple pulmonary nodules and lung damage, and this prolonged inflammatory response has carcinogenic potential [33]. Compared to the clear mechanisms of inflammatory response, there is currently no systematic study on the immunological mechanisms linking AAV and lung cancer. Some studies have proposed that several cytokines with potential impact may influence cancer prevalence in AAV patients, and these cytokines and targeted mechanisms also apply to lung cancer.

Overexpression and failure of T cells

As an autoimmune disease, AAV leads to long-term immune activation, resulting in immune system damage and abnormal expression, with abnormal T cell activation being central to the development of AAV [34]. Some studies suggest that T cell damage causes abnormal expression of CTLA-4, CD28, CD25, and IL-10 in AAV patients, which may be related to the formation of lung cancer.

Under normal immune system activation, the expression of CD28 and CD25 increases, stimulating T cell activation and maintaining the active state of T cells, while CTLA-4 generally decreases, thereby reducing the inhibitory state of T cells. However, in AAV patients, both CTLA-4 [35] and CD25 [36] are significantly expressed, whereas CD28 is under-expressed [37], along with the release of a large amount of IFN-γ [38]. Previous studies have shown that high expression of CTLA-4 and low expression of CD28 are markers of early T cell aging and exhaustion [39]. These pieces of evidence suggest that T cells in AAV patients are highly activated and in a state of exhaustion. Some evidence also indicates that, in addition to exhaustion, T cells in AAV patients may experience damage. Research reports have confirmed that T cells in AAV patients show significantly reduced induction response to mitogens [35], and they exhibit high expression of defective CTLA-4 [35] and IFN-γ [36]. IL-10 secretion also appears abnormal. FACS analysis and cytokine staining demonstrate high expression of IL-10 in AAV patients [36], but compared to healthy individuals, AAV patients exhibit a weaker capacity to produce IL-10, with significantly decreased levels produced per T cell [40]. This evidence indicates severe damage to the activated T cells. Damaged and exhausted T cells have a reduced ability to respond to homologous antigens and cannot effectively recognize and eliminate lung cancer cells promptly, leading to immune escape [41]. Overall, the damage and exhaustion of T cells caused by AAV may be a significant reason for the formation of lung cancer.

A variety of abnormal cytokines

AAV leads to the abnormal expression of various cytokines and receptors, which not only causes damage to the immune system but also directly affects the occurrence and metastasis of lung cancer. In patients with ANCA-associated vasculitis, the expression of PD-L1 in monocytes is significantly downregulated, mainly due to molecular defects in CMTM6 (a transmembrane protein that protects PD-L1) induced by AAV [42, 43]. This increases PD-L1 degradation, which is directly related to the recurrence of non-small cell lung cancer, particularly in patients with squamous cell carcinoma (P = 0.0155) [44]. This suggests that PD-L1 may be an intermediary link between AAV and lung cancer. IL-10 expression is abnormally elevated in AAV patients, promoting the production of TGF-β (a growth factor that promotes tumorigenesis) [45], downregulating the expression of MHC in antigen-presenting cells (APCs), thereby reducing or inhibiting antigen presentation. This is believed to contribute to immune suppression within the tumor microenvironment, promoting tumor escape [46]. Immune escape observed in lung cancer is also thought to be related to these mechanisms [47]. Additionally, increased IL-10 expression can promote the growth and migration of PC9 cells (human lung adenocarcinoma cells) [48], and synergistically with IFN-γ, which is highly expressed in AAV, induce immune suppressive polarization of monocytes and myeloid cells [49, 50]. This may be a significant reason for the high risk of lung cancer in AAV patients. Besides IL-10, IL-6 also increases during the active phase of MPO-ANCA-associated vasculitis [51]. IL-6 can induce IL-17 helper T cells (Th17), which in turn activate neutrophils [52, 53], playing an important role in the development and progression of AAV. Additionally, IL-6 can induce lung cancer growth and metastasis through the JAK/STAT, Ras/MAPK, and PI3K/AKT pathways [54], which may be directly related to the high risk of lung cancer. Overall, the abnormalities of cytokines and related receptors such as IL-6, IL-10, and PD-L1 may be important reasons for the high risk of lung cancer in AAV patients.

The relationship between immunosuppressive agents and cancer in AAV

The treatment of AAV relies on the use of glucocorticoids and immunosuppressants. Although some immunosuppressants are considered antitumor drugs, there is evidence that the use of these drugs in AAV patients increases the risk of cancer, including lung cancer. We have compiled reports on the lung cancer risk associated with immunosuppressants in AAV patients (Table 2). Most previous studies are retrospective cohort studies, often involving the combined use of immunosuppressants, making it difficult to assess the individual cancer risk of single drugs. Since there has been no drug risk assessment specifically for lung cancer, the risk assessment for lung cancer can only be inferred based on existing tumor risk data. Future research needs to prospectively evaluate the risk of single drugs and specific types of tumors based on established drug risks, providing ample evidence for clinical practice. Table 2 Lung cancer risk of commonly used drugs for ANCA-associated vasculitis

Author/Year/Country/Follow-up Time	Study type and cases	Immunosuppressants used/cases	Cross-use drugs	Number of tumors/cancer incidence	Number of lung cancers/propor-tion of lung cancer in tumors	
Knight et al. [17]

Years: 2002

Country: Sweden

follow-up: 2 years

Mean follow-up:?

	Retrospective (N = 1065)	Cyclophosphamide (N = 1065)	No	N = 110/10.33%	N = 8/7.27%	
Pagnoux et al. [18]

Years: 2008

Country: France and Belgium

Mean follow-up: 29 months

	RCT (N = 126)	Methotrexate (N = 35) versus azathioprine(N = 29)	All patients were treated with glucocorticoids and cyclophosphamide	N = 3/2.38%	N = 1/33.33%	
Faurschou et al. [19]

Years: 2008

Country: Denmark

median duration of follow-up:

72 months

	Retrospective (N = 293)	Cyclophosphamide (N = 171)	Drug cross-use azathioprine or methotrexate (N = 51)	N = 50/17.06%	N = 5/10.00%	
Stones et al. [20]

Years: 2010

Country: USA

Mean follow-up: 6 months

	Retrospective (N = 197)	Rituximab (N = 99) versus cyclophosphamide(98)	Some people in the CYC group used azathioprine	N = 9/4.57%	N = 2/22.22%	
Holle et al. [21]

Years: 2011

Country: German

Follow-up: three periods

(1966–1993,1994–1998, 1966–1993)

	Retrospective (N = 445)	Standardized treatment plan	Drug cross-use Unknown specific drugs	N = 18/4.04%	N = 2/11.11%	
Heijl et al. [5]

Years: 2011

Country: European countries

Mean follow-up: 58.8 months

	Retrospective (N = 535)	Unknown	Drug cross-use cyclophosphamide(438)/Methotrexate (N = 331)	N = 50/9.35%	N = 5/10.00%	
Zycinska et al. [22]

Years:2013

Country: Poland

Median follow-up: 84 months

	Retrospective (N = 117)	Unknown	Drug cross-use cyclophosphamide(117)/prednisolone (N = 90)/Methylprednisolone (N = 20)/Azathioprine and methotrexate (N = 7)	N = 15/12.82%	N = 2/13.33%	
Pendergraft et al. [23]

Years:2014

Country: USA

Median follow-up:25.2 months

	Retrospective (N = 172)	Rituximab (N = 172)	Unknown	N = 3/1.74%	N = 1/33.33%	
Faurschou et al. [24]

Years:2015

Country: Denmark

Median follow-up: 116.4 months

	Retrospective (N = 293)	Cyclophosphamide(208)	No	N = 73/24.91%	N = 5/6.85%	
Alberici et al. [25]

Years:2015

Country: UK

Median follow-up: 59.3 months

	Retrospective (N = 69)	Rituximab (N = 69)	Unknown	N = 4/5.80%	N = 1/25.00%	
Rahmattulla et al. [26]

Years:2015

Country: Netherlands

Mean follow-up: 120 months

	Retrospective(N = 138)	Unknown	Drug cross-use All the people accepted Prednisolone, cyclophosphamide(110)/Azathioprine(N = 62)/Mycophenolate mofetil(N = 24)	N = 85/61.59%	N = 2/2.35%	
van Daalen et al. [28]

Years:2017

Country: UK

Mean follow-up: 67.2 months

	Retrospective (N = 323)	cyclophosphamide(233)versus Rituximab(N = 155)	Drug cross-use

Cyclophosphamide AND Rituximab(N = 114)/Azathioprine(N = 218) Mycophenolate mofetil (N = 154)Methotrexate (N = 39)

	N=45/13.93%	N = 4/8.89%	
Yoo et al. [29]

Years: 2018

Country: South Korea

Mean follow-up: 50.7 months

	Retrospective (N = 150)	Unknown	Drug cross-use

Glucocorticoids (N = 129)

Cyclophospha (N = 63)/Azathioprine(N = 41)

	N = 4/2.67%	N = 1/25.00%	
McAdoo et al. [30]

Years:2019

Country: UK

Median follow-up: 56 months

	Prospective longitudinal cohort (N = 66)	Unknown	Drug cross-use

All the people received glucocorticoids, cyclophosphamide, and rituximab

	N = 6/9.09%	N = 1/16.67%	
Ahn et al. [15]

Years:2019

Country: South Korea

follow-up: 96 months

	Retrospective (N = 2097)	Unknown	Drug cross-use

cyclophosphamide(N = 1022)/Rituximab(N = 250)/Azathioprine(N = 835)

Glucocorticoid steroid usage ≥ 1 year(N = 1037)

	N=114/5.44%	N = 19/16.67%	
Choi s et al. [2]

Years:2021

Country: South Korea

Mean follow-up: 84 months

	Retrospective (N = 1982)	Unknown	Drug cross-use

Cyclophosphamide(N = 1078)/Rituximab(N = 210)

	N = 120/6.05%	N = 24/20.00%	

Cyclophosphamide

Although cyclophosphamide (CYC) is commonly used in cancer treatment, early studies suggest that cyclophosphamide may be a factor in increased cancer risk. Bladder cancer [55], skin cancer, and malignant hematologic diseases are the most frequently reported [19, 56].

The increased risk of bladder cancer is primarily attributed to the toxic metabolite acrolein produced after the breakdown of CYC, which can accumulate highly in urine and is highly carcinogenic. The risk of other cancers remains unclear. Due to the potent effects of cyclophosphamide on multiple organs in the human body, it is suggested that it may have a broader carcinogenic potential.

The carcinogenicity of cyclophosphamide may be related to long-term use and dosage. Lower doses of cyclophosphamide are considered safer, with relatively lower carcinogenicity [57]. A retrospective cohort study indicated that when the cumulative dose of CYC is ≤ 36 g, the risk of malignancies, except for non-melanoma skin cancer (NMSC), does not increase. In contrast, when the cumulative dose exceeds 36 g, the risk of acute myeloid leukemia (SIR 59.0, 95% CI 12–172) and bladder cancer (SIR 9.5, 95% CI 2.6–24) increases significantly [19]. This cumulative risk is also related to the duration of treatment. Treatment exceeding one year increases the risk of bladder cancer eightfold (OR = 7.7, 95% CI 0.9–69) and the risk of cancer tenfold (OR = 2.0, 95% CI 0.8–4.9). Early studies also demonstrated the cumulative dose-time-risk relationship between cyclophosphamide and cancer [58]. In addition, because the cumulative dose of intravenous administration in the body may be lower than oral administration [59], switching from oral to intravenous administration can reduce the risk of cancer occurrence [60]. Due to the complexity of cancer mechanisms, the precise safety threshold and duration of safe use for cyclophosphamide remain unclear.

For the risk of lung cancer, it is clinically important to note that high cumulative doses of CYC may be related to the occurrence of lung cancer in AAV patients. Although there is a lack of direct mechanistic studies, the existing cases are sufficient to warrant clinical attention [5, 17, 22, 24, 26].

Tumor necrosis factor inhibitors

Tumor Necrosis Factor Inhibitors (TNFi) exert a similar effect to cyclophosphamide in AAV [20]. Represented by drugs like infliximab and adalimumab, existing clinical evidence demonstrates the efficacy of these medications in managing AAV [61, 62]. However, from the perspective of the mechanism of TNFi, the use of these drugs in AAV has raised significant concerns about tumor development. TNFi may lead to the emergence of new tumors and accelerate the growth of existing tumors.

In a randomized trial, it was found that among patients (N = 89) treated with infliximab, there were 6 cases of cancer (SIR: 3.12, 95% CI 1.15–6.80; P = 0.014). No tumors were observed in patients who did not receive TNFi treatment. All patients received cyclophosphamide treatment, suggesting that the combined use of cyclophosphamide and TNFi or the use of TNFi alone may increase cancer risk [63]. Similar results were observed during a median follow-up of 43 months, showing that patients receiving etanercept treatment had a cancer risk similar to that associated with cyclophosphamide exposure [64]. For infliximab, there have been no reports on its cancer risk, mainly because the emergence of rituximab has significantly reduced the enthusiasm for using TNFi, and related safety studies are few.

The U.S. Food and Drug Administration (FDA) has issued warnings pointing out the potential cancer risk associated with various TNF inhibitors [65]. Interestingly, this risk varies by disease. In conditions like rheumatoid arthritis (RA), long-term exposure to TNF drugs may not increase cancer risk [66, 67]. Even in AAV, some reports suggest that TNF drugs might help reduce the cancer risk in AAV patients [28]. These differences may be attributed to the varying mechanisms of different tumor necrosis factor inhibitors and their interactions with other medications. The complex mechanisms involved make it challenging to determine whether tumor necrosis factor inhibitors independently pose a cancer risk for AAV. There are currently no separate studies on the incidence of lung cancer in AAV patients receiving TNF therapy. However, based on existing evidence, AAV patients undergoing long-term cyclophosphamide treatment should exercise caution when considering high-dose TNFi.

Rituximab

Compared to the high side effects of tumor necrosis factor inhibitors, the advent of rituximab has provided a more promising drug for controlling refractory AAV [68]. Existing evidence indicates that rituximab has good efficacy and safety, although a few studies suggest that rituximab may have a cancer risk.

In a follow-up study of 7 patients over an average of 62.9 months, patients who received long-term rituximab treatment experienced various adverse reactions such as sepsis and cytomegalovirus infection, along with 2 cases of cancer [69, 70]. A larger-scale cohort study showed that within a 6-month follow-up period, there was 1 case of cancer in both the rituximab group (N = 99) and the cyclophosphamide group (N = 98) [20]. However, several retrospective cohort studies have not demonstrated an increased risk of tumors with rituximab [20, 23, 28]. While the latest systematic review suggests a need to reassess the adverse effects of rituximab in AAV patients [70], the current evidence does not indicate that rituximab carries a high tumor risk. Although lung cancer has been observed in AAV patients treated with rituximab, there is still insufficient evidence to establish a direct relationship between rituximab and lung cancer.

Azathioprine

Azathioprine is a first-line drug for many immune-related diseases, recommended by guidelines as an alternative to long-term use of cyclophosphamide [56]. In clinical practice, azathioprine is rarely used alone, making it challenging to independently assess its safety.

Some clinical evidence suggests a close association between azathioprine and an increased risk of various cancers [71]. Basic experiments have found that azathioprine can significantly induce DNA damage and exhibit skin toxicity, potentially increasing the risk of skin cancer [72]. An early study indicated that the risk of skin cancer significantly increased after more than one year of azathioprine use [4]. Compared to cyclophosphamide, azathioprine (N = 6, 8%) and cyclophosphamide (N = 11, 15%) have similar tumor risks (P = 0.3) [73]. A study from Europe found that after using azathioprine for 6–60 months, the incidence of cancer was between 9 and 11% (N = 380) [74]. However, since patients were also taking other medications, it is difficult to determine whether this risk is solely attributable to azathioprine.

Existing evidence suggests that azathioprine may have a carcinogenic risk similar to cyclophosphamide. However, because azathioprine is rarely used alone to treat AAV, the relationship between this cancer risk and azathioprine dosage and duration remains unclear. Additionally, there is insufficient evidence to suggest that azathioprine significantly increases the risk of lung cancer.

Methotrexate

The potential cancer risk of methotrexate in treating AAV is unknown. Compared to commonly used cyclophosphamide or rituximab, methotrexate has a relatively lower usage rate in AAV. Only a few studies suggest that methotrexate may induce lymphoma in patients with rheumatoid arthritis [75], but there is insufficient research evidence to prove methotrexate's carcinogenic effect in AAV.

Discussion

Preliminary evidence indicates a significantly increased incidence of lung cancer in AAV patients, with variations in risk observed across different geographical regions and genetic backgrounds (Unveiling cancer risk in ANCA-associated vasculitis: result from the Turkish Vasculitis Study Group). This variability may be a major factor contributing to the mixed results regarding lung cancer risk. Considering the complexity of AAV and cancer, current evidence suggests that the higher incidence of lung cancer in AAV is likely associated with both the mechanisms of AAV itself and the use of immunosuppressants. However, there is currently no clear research on the mechanisms by which AAV affects lung cancer development. Based on the abnormal immune changes induced by AAV, several intermediary pathways that may influence lung cancer have been identified, including damaged T cells, aberrant expression of cytokines, and target interactions. For immunosuppressants, the risk association with tumors is well-established. Preliminary evidence indicates significant carcinogenic risks associated with cyclophosphamide and azathioprine, with cyclophosphamide showing clear dose and cumulative time effects. Regarding azathioprine, existing evidence cannot assess the correlation between dose, time, and tumor risk. Combination therapy with tumor necrosis factor antagonists and cyclophosphamide carries a high carcinogenic risk, but it is difficult to evaluate the carcinogenicity of tumor necrosis factor alone in AAV. Current evidence suggests that rituximab is relatively safe and does not pose a high carcinogenic risk, while studies on methotrexate are limited, making its risk assessment inconclusive.

Existing studies cannot determine the exact risk magnitude and specific safety thresholds for each immunosuppressant. This is mainly because most of the current studies are retrospective, and patients often use multiple drugs in combination. For a complex disease like AAV, conducting a prospective evaluation of a single medication is often unethical, making it difficult to rule out interactions between drugs. Regarding lung cancer, only cyclophosphamide has relatively sufficient clinical evidence. The combination of TNFi and cyclophosphamide may increase the risk of lung cancer, while the risks associated with other immunosuppressants cannot be accurately determined. This is primarily due to the lack of studies on the risk between AAV and individual cancer types, and the related impact of multiple cancers is more complex.

For treatment recommendations, we suggest personalized risk assessment for the use of different immunosuppressants. For the use of cyclophosphamide, intravenous administration should be preferred over oral administration in AAV patients whenever tolerated by the body. When the cumulative dose of cyclophosphamide exceeds 36 g or the duration of use exceeds one year, close monitoring of cancer risk is recommended. Regarding potential tumor risks associated with TNFi, caution is advised for AAV patients with a history of malignancy or hereditary tumor diseases who have received long-term cyclophosphamide treatment, possibly avoiding or cautiously using TNFi. For azathioprine, increased attention to the risk of skin cancer is recommended. For overall AAV treatment, it is advisable to minimize the duration and dosage of cyclophosphamide when used in combination therapy. Compared to other immunosuppressants, rituximab use may be safer.

There is currently no consensus on lung cancer screening for AAV patients. Due to the lack of quantitative studies (comparing the incidence of lung tumors with the use of individual drugs), we tend to refer to the risk medication recommendations for tumors in AAV patients to propose opinions on lung cancer. Among all immunosuppressants, cyclophosphamide is likely the most associated with the risk of lung cancer in AAV patients. It is recommended to conduct regular CT scans when using cyclophosphamide long-term for AAV treatment. For AAV patients who are high-risk adults for lung cancer aged 55–79, current smokers, or those who have quit smoking for less than 15 years, and have a smoking history of 30 pack-years, regular CT scans are recommended if long-term use of immunosuppressants is necessary [12].

Conclusion

This study focuses on the relationship between AAV, lung cancer, and immunosuppressants. It introduces literature reports on AAV and lung cancer, as well as the tumor and lung cancer risks associated with the use of immunosuppressants. It briefly discusses possible intermediate mechanisms between AAV and lung cancer. The literature review supports the occurrence and metastasis of lung cancer caused by AAV, which is related to T-cell senescence damage, abnormal expression of cytokines, and targets induced by AAV, although the detailed mechanisms remain unclear. Careful selection of the type, dosage, and duration of immunosuppressants, along with regular tumor screening, is crucial in reducing the tumor risk in AAV patients. For high-risk populations of lung cancer who need long-term use of immunosuppressants, especially cyclophosphamide, regular CT scans are recommended. Although the risk of lung cancer in the context of AAV has received some clinical attention, the specific mechanisms of lung cancer have not been systematically elucidated. Further research is needed to clarify the specific mechanisms between AAV and lung cancer, the distribution of risk factors for AAV-associated lung cancer, conduct safety assessments of AAV medication concerning lung cancer, determine the safety thresholds of drugs, and further optimize pharmacological treatment measures.

Author contributions

Long-zhao LI arranged all the documents and prepared the first draft. Jun Teng collated all the documents and materials and made vital revisions. Na KOU and Yuan YUE is responsible for consulting the literature, revising the article format, and giving suggestions for modifying the article. Hong-wu WANG was responsible for data supervision, agreed to take responsibility for all aspects of the manuscript, guided on matters related to the manuscript, and was ultimately responsible for the review and approval of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

Not funded by any specific project.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Conflict of interest

The authors declare no conflicts of interest.

Consent for publication

All authors agree to the publication of this article. The manuscript is unique and has not been published in part or whole in any form, nor has it been considered by any other source.

Ethical standards

This study does not involve human trials.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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