What investigations are needed to optimally monitor

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What investigations are needed to optimally monitor for malignancies in SLE? B Tessier-Cloutier1, AE Clarke2, CA Pineau3, S Keeling4, A Bissonauth4, R Ramsey-Goldman5, J Lee1 and S Bernatsky1 1 McGill University Health Centre, Division of Clinical Epidemiology, Montreal, Canada; 2University of Calgary, Division of Rheumatology, Calgary, Canada; 3Montreal General Hospital, Division of Rheumatology, Montreal, Canada; 4University of Alberta, Division of Rheumatology, Edmonton, Canada; and 5Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Objective: The overall cancer incidence risk in systemic lupus erythematosus (SLE) is approximately 15%–20% more than in the general population. Nevertheless, to date, the optimal malignancy screening measures in SLE remain undefined. Our objective is to determine what investigations are needed to optimally monitor for malignancies in SLE in order to inform upcoming Canadian Rheumatology Association recommendations. Methods: We conducted a systematic search looking at three scientific sources, Embase, Medline and Cochrane, in an attempt to identify cancer screening recommendations for patients with SLE. We used a filter for observational studies and included articles published in 2000 and onward. Results: The initial search strategy led to 986 records. After removal of duplicates and articles unrelated to SLE, we were left with 497 titles. From those, 79 research articles on cancer incidence in SLE were isolated and reviewed. Of the 79 original research papers, 25 offered screening recommendations, 14 suggested additional cancer screening whereas 11 studies simply promoted adherence to general population screening measures. The suggestions for more rigorous screening included recommending human papilloma virus testing in addition to routine cervical screening, and/or that cervical screening should be performed annually and/or suggested urine cancer screening in SLE patients with a history of cyclophosphamide exposure. Conclusions: We found no original research studies directly comparing cancer screening strategies in SLE. Generally, authors recommend adherence to general population screening measures, particularly cervical screening. This, possibly with adding targeted screening in special cases (e.g. annual urine cytology in patients with prior cyclophosphamide exposure, and considering existing lung cancer screening guidelines for past heavy smokers), may be a reasonable approach for cancer screening in SLE. Lupus (2015) 0, 1–7. Key words: Systematic lupus erythematosus; cancer; screening; screening guidelines; epidemiology; systematic review; DMARDs; primary care rheumatology

Introduction Systemic lupus erythematosus (SLE), an autoimmune disorder with complex environmental and genetic interactions, affects approximately one in 1000 women in North America.1 In the last five decades, advances in management have improved five-year survival to greater than 90%.2 The longer survival

Correspondence to: Sasha Bernatsky, Division of Clinical Epidemiology, Research Institute of the McGill University Health Centre, 687 Pine Avenue West, V-Building, Room V2.09, Montreal, Quebec H3A 1A1, Canada. Email: [email protected] Received 5 September 2014; accepted 5 February 2015

translates, in some cases, to considerable long-term morbidity, including distinct cancer profiles. The overall cancer incidence risk in SLE is approximately 15–20% more than in the general population.3,4 This risk profile includes a higher than expected risk for certain cancers, such as lymphoma, and lung cancer, as well as a lower than expected risk of breast and possibly other cancers.3 The underlying integral mechanism accounting for the disparity is yet to be elucidated, but is most likely multifactorial, featuring both intrinsic and iatrogenic elements. Recent research has looked at the role of the intrinsic altered immunity, iatrogenic immunosuppression, and genetic associations.5–7

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10.1177/0961203315575587


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What investigations are needed to optimally monitor for malignancies in SLE? B Tessier-Cloutier et al.

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Nevertheless, to date, despite strong evidence that SLE is an independent risk factor for developing a malignancy, the optimal cancer screening measures in SLE remain undefined. The current practice is to follow the same screening program as the general population. Our objective is to determine what investigations are needed to optimally monitor for malignancies in SLE in order to inform upcoming Canadian Rheumatology Association (CRA) recommendations related to the diagnosis and monitoring of SLE.

Method We undertook a systematic review on the topic of cancer screening recommendations for patients with SLE. The search was conducted through three scientific sources, Embase, Medline and Cochrane. We used a filter for observational studies and included English articles published in 2000 and onward. Search terms included: SLE, systemic lupus, cancer, malignant and tumor. Study selection Three investigators (J.L., B.T.C. and S.B.) identified the potential studies and assessed them for eligibility using a three-step process (Figure 1). First,

986 Citations identified through database searching

489 Duplicated and irrelevant citations excluded on the basis of

497 Abstracts reviewed

title review

413 Irrelevant citations and five case reports excluded on the basis of title review 79 Full-text articles reviewed 54 Lacking recommendation, were excluded on the basis of 25 Studies included in

full-text review

the systematic review

Figure 1

Flow diagram of the systematic review process.

titles from the initial search were reviewed to broadly include potentially relevant studies and to exclude the duplicates. Second, titles and abstracts were reviewed to identify relevant studies and to exclude case reports and unrelated studies. Finally, full-text articles were reviewed to find recommendations on malignancy screening in SLE. Reviewers were not blinded to authors or journals. Data extraction and quality assessment Screening recommendations were extracted from every article (where applicable) as well as general information such as location of the study, type of study, type of population and first author. Synthesis of results Relevant data were extracted and presented in table format. Efforts were made to evaluate the evidence based on the future use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method.8 This methodology includes presenting the evidence while assessing its quality to judge the relative benefit versus harm in terms of the potential interventions being evaluated for recommendation (which in our case were cancer screening strategies in SLE).

Results The initial search strategy led to 986 records; after removal of duplicates, the titles were screened to remove those that were completely unrelated to SLE. This left us with 497 titles potentially related to cancer in SLE, of which five were excluded because they were case reports and 413 were excluded because they were unrelated to cancer in SLE. Seventy-eight original research articles on cancer incidence in SLE and one recommendation paper (European League Against Rheumatism (EULAR)) were retrieved and reviewed. Among these, no original research studies directly comparing new guidelines to the presently used cancer screening strategies in SLE were found. Of the 79 original research papers, 25 were selected for this review, including a recommendation paper (EULAR 2010), as they offered screening recommendations, all simply based on their cancer incidence rate results or reviews. Table 1 features the characteristics (location, type of study, number of patients and recommendation) of the studies that offered cancer screening recommendations. Among these studies, there were 25

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Table 1 Summary of the studies included in the systematic review. First author, year General Chang, 20129 Dreyer, 201110 Chen, 2010*11 Mosca, 201012 Tarr, 200713 Bernatsky, 200614 Bernatsky, 200215 Cervical dysplasia Liu, 201116 Dhar, 201117 Esmaeili, 201118 Tam, 201119 Dhar, 201020 Klumb, 201021 Klumb, 201022 Bernatsky, 2008*23 Ognenovski, 200424 Tam, 200425 Dhar, 200126 Bateman, 200027 Bladder cancer Kang, 201028 Bernatsky, 2008*23 Bongu, 200229 Hematologic cancer Chen, 2010*11 Sultan, 2000*30 Lung cancer Adzic´, 200831 Thyroid cancer Antonelli, 201032 Breast cancer Sultan, 2000*30 Prostate cancer Liang, 201233

Location

Study

SLE, N

Specific recommendations

Korea Denmark Taiwan European Union Hungarian Canada Canada

Cohort Cohort Cohort Review Cohort Cohort Review

N/A 576 11,763 N/A 860 165 N/A

Tailored surveillance to rheumatic disease Raise clinical alertness to oncogenic virus infections in SLE patients Continuous cancer screening for 8 years Follow general population cancer screening guidelines Focused patient exam and follow general population cancer screening guidelines Follow general population cancer screening guidelines Follow general population cancer screening guidelines

China US Iran China US Brazil Brazil Canada US China US US

Meta-analysis Case-control Case-control Cohort Cohort Cross-sectional Cross-sectional Case-cohort Cohort Cross-sectional Cohort Case-control

445 113 118 150 113 171 173 784 89 85 29 110

More stringent cervical cancer screening Annual Papanicolaou smear Papanicolaou smear screening Systematic HPV testing and more frequent Papanicolaou smear screening Annual Papanicolaou smear Annual Papanicolaou smear Follow a more stringent cervical cancer screening program Follow general population cervical cancer screening guidelines Highlight the importance of careful screening of women with lupus Systematic HPV testing Close gynecologic surveillance, possibly including HPV testing Papanicolaou smear prior to cyclophosphamide

Korea Canada US

Cohort Case-cohort Review

914 784 N/A

Urine cytology cancer screening in cyclophosphamide-exposed patients Lifelong urine cytology cancer screening in cyclophosphamide-exposed patients Urinalysis for bladder toxicities in cyclophosphamide-exposed patients

Taiwan England

Cohort Cohort

11,763 276

Hematologic cancer screen for 8years Focused patient exam for hematologic cancer

Serbia

Cohort

24

Chest imaging lung cancer screening

Italy

Cohort

153

Thyroid cancer screening: FT4, TSH, and AbTPO, ultrasonography

England

Cohort

276

Focused patient exam for breast cancer

Taiwan

Case-control

2150

More stringent follow-up and screening policies for prostate cancer in SLE

*Articles that appear twice offer recommendations in two screening categories. SLE: systemic lupus erythematosus; US: United States; HPV: human papillomavirus; FT4: free thyroxine; TSH: thyroid-stimulating hormone; AbTPO: anti-thyroid peroxidase antibodies.

original research studies, including 13 cohort studies, five case-control studies (including the case-cohort design variant), and three cross-sectional studies, three review papers as well as a meta-analysis. The studies came from North America (six from the United States (US) and four from Canada), Europe, and Asia. The studies involved from 24 to 11,763 SLE patients (median 165 patients). Recommendations were mainly regarding screening for cervical dysplasia, with 12 out of 25 providing some guidance. Some provided suggestions about screening for bladder, hematologic, lung, thyroid, breast and prostate cancers. Recommendations varied from adherence to current general population guidelines (11 studies) to enhanced screening measures specific for the SLE population (14 studies) (Table 2).

The suggestions for more rigorous screening included recommending human papilloma virus (HPV) testing in addition to routine cervical screening, and/or that cervical screening should be performed annually (as is performed in the high-risk human immunodeficiency virus (HIV) populations) and/or suggested regular urine cancer cytology screening in SLE patients with a history of cyclophosphamide exposure. Other recommendations included chest imagery for lung cancer as well as serum thyroid-stimulating hormone (TSH), T4 and anti-thyroglobulin antibodies (AbTPO) thyroid imaging for thyroid cancer. The EULAR recommendations suggested adherence to general population screening. However, despite not arguing for enhanced screening measures, they acknowledged the relevance of considering the development of Lupus



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Table 2 Frequency and type of recommendations for different malignancies Type of recommendation

Relevant cancer

Number of articles including the recommendation

Current guidelines Enhance guidelines Annual Pap testing HPV testing Chest imaging TSH, T3, T4 Thyroid imaging Urinalyses

All All Cervical Cervical Lung Thyroid Thyroid Bladder

11 14 6 2 1 1 1 3

Pap: Papanicolaou; HPV: human papillomavirus; TSH: thyroid-stimulating hormone.

SLE-specific guidelines based on epidemiologic and clinical data.34 The selected studies proposed screening measures based on their cancer incidence rate results or review of the literature. None offered a comparison between a more rigorous screening program and the general population screening recommendations for the lupus patients. Instead, they gave their expert opinion in light of the available cancer incidence data. No data were available to judge the relative benefit versus harm in terms of various cancer screening strategies.

Discussion This systematic review identified 25 articles suggesting malignancy screening guidelines in patients with lupus. Most of these were based on original observational studies of cohort (N ¼ 15) or case-control (N ¼ 7) design. Medical guidelines often suggest that an initial quality evaluation can be based on the type of experiment design being used. Among the papers we drew from, there were no randomized controlled trials; however, Petticrew and Roberts35 and others have suggested that design other than randomized controlled studies may be appropriate for addressing different types of questions. Since the articles represented SLE populations not only from North America but also from across Europe and Asia, we believe that our review is of use to a fairly general audience, representing not only North America but also Europe and Asia. Based on an increased rate of cancer incidence demonstrated in the cohort studies, the majority of these 25 articles suggested some cancer screening strategy for SLE patients. Despite a heterogeneous range of recommendations, 14 out of 25 authors proposed to enhance, at least to some degree,

cancer screening programs beyond the general population guidelines, which presumably form the basis of current screening for SLE patients. Furthermore, although 11 of 25 articles concluded that adherence to general population guidelines for screening was appropriate, they often did so by default, secondary to the absence of research studies directly comparing cancer screening strategies. Moreover, some of this same group that supports general guidelines recognize the suboptimal screening of the lupus population but, given that patients with lupus have been shown to have a much lower rate of adherence to preventive measures compared to the general population,36 they rather emphasize that the SLE population should initially be encouraged to follow a basic prevention program. Almost half (12/25) of all included studies discussed cervical dysplasia and cancer. Interestingly, although it has been suggested to be increased in patients with lupus,4 not all analyses to date have been definitive.37 Of note, there may be ascertainment issues in some cohort studies since cancer registries often do not record noninvasive malignancies, and cervical abnormality is increasingly identified and treated at a preinvasive state. It is unclear if the trend of increased incidence of cervical dysplasia is due to increased susceptibility or impaired clearance of HPV (the infection responsible for cervical cancer).37,39 This could be attributed to either intrinsic, extrinsic (especially cyclophosphamide, a commonly used immunemodulator in lupus) or multifactorial immune alterations. Hence, some studies advocate HPV typing, prior to introducing cyclophosphamide, in addition to yearly Papanicolaou testing. In this review, three articles commented on bladder cancer screening. One paper recommended urinalysis and two papers recommended periodic cytology in lupus patients previously exposed to cyclophosphamide. Although the most recent evidence does not support an increased bladder cancer incidence rate in SLE patients,40,41 cyclophosphamide is a well-known bladder carcinogen.42 Fewer data are available on SLE but many studies looking at other rheumatologic diseases (rheumatoid arthritis, Wegener’s granulomatosis and systemic sclerosis) demonstrated a significant association between cyclophosphamide and bladder cancer.42 Arguments can be made both for urinalysis and cytology for bladder cancer screening in lupus patients; however, in the case of urinalysis, the test should already be ordered at least annually to detect the presence of lupus glomerulonephritis.



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The evidence of a link between SLE and thyroid disease as well as the increased risk of thyroid cancer among patients with thyroid autoimmunity has been well documented.43,44 Therefore, it is not surprising that thyroid cancer was shown to be increased in lupus patients compared to the general population.3 According to Antonelli et al., the only study with a recommendation on thyroid cancer screening in this review, all patients with lupus should have free thyroxine (FT4), TSH and AbTPO testing as well as thyroid ultrasonography as part of their annual follow-up. AbTPO positivity and ultrasound findings were shown to be significantly correlated with thyroid autoimmunity, even with subclinical disease.43 Lung cancer also has a reported increased incidence (standardized incidence ratio (SIR) 1.30, 95% confidence interval (CI) 1.04–1.60)3,45 and mortality (standardized mortality ratio (SMR) 2.3, 95% CI 1.6–3.0)46 in SLE. The only article with a recommendation on lung cancer screening in SLE47 suggests considering regular follow-up and chest imaging. Interestingly, the US Preventive Services Task Force (USPSTF), although contested by the American Academy of Family Physicians (AAFP), now recommends annual low-dose computed tomography (CT) of the chest for adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years (Grade B).48 Furthermore, evidence suggests that women are more susceptible to the carcinogenic effects of smoking compared to men.49 Given that the lupus population is primarily composed of women and has a greater average number of packyears among smokers compared to the general population,50 it may be wise to consider implementing the USPSTF recommendations in patients with lupus who have the specified smoking history. Clearly, emphasizing the importance of smoking cessation is critical. Hematologic cancers (SIR 3.02, 95% CI 2.48–3.63), especially non-Hodgkin’s lymphoma (SIR 4.39, 95% CI 3.46–5.49), are the type of cancer most increased in SLE.3 Unfortunately, screening options for these malignancies are limited. They involve a focused history (inquiring about adenopathy, fever, night sweats, and weight loss), a physical exam for adenopathy, and blood tests (complete blood count and lactate dehydrogenase), which are generally performed during routine follow-up for lupus monitoring. In this context, the recommendations in this review rather stress the importance of performing these screening measures annually.

Similarly the recommendations for prostate and breast cancers remained general, promoting a targeted physical exam for breast malignancies and asking for an enhanced follow-up and screening for prostate cancer. The sole article discussing prostate cancer screening guidelines51 bases its argument on only one cohort suggesting an increased incidence of prostate cancer in SLE compared to the general population. However, the latter is debated and more evidence seems to argue for the opposite, a decreased incidence of prostate cancer in lupus compared to the general population, similarly to breast cancer.3,41 Thus, we would recommend that lupus patients continue to adhere to general population screening guidelines for these cancers. The papers included in this review were subject to limitations. Most important, the studies based their recommendations on the cancer incidence rate difference between SLE patients and the general population, not on studies comparing screening methods. Although identifying SLE or its treatment as an independent risk factor for the development of certain cancers should alert physicians to the importance of screening, it is difficult to establish new guidelines without validating their superiority over those currently in use. This lack of tangible evidence could explain the vague or weak recommendations often observed in the selected papers. Currently the only available evidence relies on expert opinions mainly based on cancer incidence rate. The EULAR recommendations,9 released in 2010, also relied on similar evidence to establish their recommendations on cancer screening in SLE. One study critically appraised guidelines for cancer screening in the renal transplant and general populations.52 Like our situation, recommendations for cancer screening in renal transplant recipients were entirely extrapolated from data in the general population but for increased cancer risk for certain types (as well, they argue, as competing risks for deaths from causes and reduced overall life expectancies), the authors state that validity of their recommendations in renal transplant patients is uncertain. The paper did note that the American and European transplantation organizations recommend skin cancer screening in renal transplant individuals using monthly self-skin examination and six- to 12-monthly total body skin examination by expert physicians and dermatologists. However, at present there is no evidence to verify that total body skin cancer examination (in any population) reduces skin cancer mortality. Lupus



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In conclusion, we found no original research studies directly comparing cancer screening strategies in SLE, and thus there is no way to objectively judge the relative benefit versus harm in terms of various cancer screening strategies. False-positive results from any cancer screening can generate anxiety and unnecessary biopsies and procedures, hence the rationale for weighing the risk and benefit ratio. Hence, the strength of any future meaningful recommendations regarding cancer screening strategies for SLE as per the GRADE criteria will be largely influenced by other domains such as the balance of benefits versus harms versus burdens, values and preferences and resource implications. Regardless, among the studies on cancer incidence in SLE, several offered screening recommendations. These mostly argue for rigorous cervical screening strategies, and/or suggested urine cancer screening in SLE patients with a history of cyclophosphamide exposure, which are strategies that many centers already endorse. Many authors recommend following general population screening measures; there is evidence that there is suboptimal adherence to even this level of cancer guidelines in SLE. Thus, even if SLE patients follow current general population guidelines for cancer screening (according to the jurisdiction in which they live), that would likely already improve the current quality of cancer screening in SLE.

Conclusions We found no original research studies directly comparing cancer screening strategies in SLE. Generally, authors recommend adherence to general population screening measures, particularly cervical screening. This, possibly with adding targeted screening in special cases (e.g. annual urine cytology in patients with prior cyclophosphamide exposure, and considering existing lung cancer screening guidelines for past heavy smokers), may be a reasonable approach for cancer screening in SLE.

Key points . Results found no original research studies directly comparing cancer screening strategies in systemic lupus erythematosus (SLE). . Expert opinions argue for enhanced cervical and bladder cancer screening strategies in SLE patients with a history of cyclophosphamide exposure.

. Most of the reviewed articles agree that cancer screening in lupus patients is currently suboptimal.

Acknowledgement The authors would like to thank McGill librarian Genevieve Gore for her assistance with the literature review. The Canadian SLE Working Group is developing recommendations for the diagnosis and monitoring of SLE.

Funding This work was supported by Canadian Institutes of Health Research (CIHR) funds held by Dr Keeling.

Conflict of interest statement The authors have no conflicts of interest to declare.

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