Long-Term Risk of Skin Cancer and Lymphoma in Users of Topical Tacrolimus and Pimecrolimus: Final Results from the Extension of the Cohort Study Protopic Joint European Longitudinal Lymphoma and Skin Cancer Evaluation (JOELLE)

Figures & data

Table 1 STROBE Statement for Cohort Studies with the RECORD Statement Extension—Checklist of Items That Should Be Included in Reports of Observational Studies Using Routinely Collected Health Data

	Item No^a	Recommendation	Corresponding Page(s)
Title and abstract	1	(a) Indicate the study’s design with a commonly used term in the title or the abstract	1
		(b) Provide in the abstract an informative and balanced summary of what was done and what was found	1
	R 1.1	The type of data used should be specified in the title or abstract. When possible, the name of the databases used should be included.	1, 2
	R 1.2	If applicable, the geographic region and timeframe within which the study took place should be reported in the title or abstract.	1, 2
	R 1.3	If linkage between databases was conducted for the study, this should be clearly stated in the title or abstract.	Not applicable
Introduction
Background/ rationale	2	Explain the scientific background and rationale for the investigation being reported	1, 2
Objectives	3	State specific objectives, including any prespecified hypotheses	2
Methods
Study design	4	Present key elements of study design early in the paper	2, 3
Setting	5	Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection	2, 3
Participants	6	(a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up	2, 3
		(b) For matched studies, give matching criteria and number of exposed and unexposed	2, 3, 4
	R 6.1	The methods of study population selection (such as codes or algorithms used to identify subjects) should be listed in detail. If this is not possible, an explanation should be provided.	2, 3
	R 6.2	Any validation studies of the codes or algorithms used to select the population should be referenced. If validation was conducted for this study and not published elsewhere, detailed methods and results should be provided.	2, 3
	R 6.3	If the study involved linkage of databases, consider use of a flow diagram or other graphical display to demonstrate the data linkage process, including the number of individuals with linked data at each stage.	Not applicable
Variables	7	Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable	Outcomes 3 Exposures 2 Confounders 3, Supplementary Materials
	R 7.1	A complete list of codes and algorithms used to classify exposures, outcomes, confounders, and effect modifiers should be provided. If these cannot be reported, an explanation should be provided.	Provided in study protocol that can be found in EUPAS registry.
Data sources/ measurement	8*	For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group	2, 3
Bias	9	Describe any efforts to address potential sources of bias	2, 3, 7–10
Study size	10	Explain how the study size was arrived at	2–4. All available users included
Quantitative variables	11	Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why	2, 3
Statistical methods	12	(a) Describe all statistical methods, including those used to control for confounding	3
		(b) Describe any methods used to examine subgroups and interactions	3
		(c) Explain how missing data were addressed	3. Protocol
		(d) If applicable, explain how loss to follow-up was addressed	Not applicable
		(e) Describe any sensitivity analyses	3, 9, 10
Data access and cleaning methods	R 12.1	Authors should describe the extent to which the investigators had access to the database population used to create the study population.	Full access
	R 12.2	Authors should provide information on the data cleaning methods used in the study.	Not included
Linkage	R 12.3	State whether the study included person level, institutional-level, or other data linkage across two or more databases. The methods of linkage and methods of linkage quality evaluation should be provided.	Stated in Protocol
Results
Participants	13*	(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed	Partial description page 3, 4, Supplementary Materials
		(b) Give reasons for non-participation at each stage	Not available
		(c) Consider use of a flow diagram	Not available
	R 13.1	Describe in detail the selection of the persons included in the study (ie, study population selection), including filtering based on data quality, data availability, and linkage. The selection of included persons can be described in the text and/or by means of the study flow diagram.	3, 4
Descriptive data	14*	(a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders	Page 3, 4, Table 2, Figure 1, Supplementary Materials
		(b) Indicate number of participants with missing data for each variable of interest	Patients with lack of recorded information on specific variables (eg, diagnosis of atopic dermatitis) were considered not to have such diagnoses.
		(c) Summarize follow-up time (eg, average and total amount)	Page 4. Supplementary Materials
Outcome data	15*	Report numbers of outcome events or summary measures over time	Partial Tables 3, 4, E2, E3
Main results	16	(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included	Page 4 Adjusted Tables 3, 4, E2, E3
		(b) Report category boundaries when continuous variables were categorized	Tables 3, 4, Supplementary Materials
		(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period
Other analyses	17	Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses	Page 4Tables 3, 4, E2, E3
Discussion
Key results	18	Summarize key results with reference to study objectives	4, 7–10
Limitations	19	Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias	7–10
	R 19.1	Discuss the implications of using data that were not created or collected to answer the specific research question(s). Include discussion of misclassification bias, unmeasured confounding, missing data, and changing eligibility over time, as they pertain to the study being reported.	7–10
Interpretation	20	Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence	7–10
Generalizability	21	Discuss the generalizability (external validity) of the study results	7–10
Other information
Funding	22	Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based	11
Accessibility of protocol, raw data, and programming code	R 22.1	Authors should provide information on how to access any supplemental information such as the study protocol, raw data, or programming code.	Provided in study protocol that can be found in EUPAS registry. Supplementary Materials

Notes: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at http://www.strobe-statement.org. ^aItems numbers starting with an “R” correspond to items of the RECORD extension. *Give information separately for exposed and unexposed groups. Adapted from von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–349.²²

Table 2 Distribution of Users by Study Cohort and Population

Study Database	Topical Tacrolimus, n (%)	Topical Corticosteroids, n (%)	Topical Pimecrolimus, n (%)	Topical Corticosteroids, n (%)	Untreated Cohort, n (%)^a	Topical Corticosteroids, n (%)
Children aged 0 to < 18 years
UK-CPRD	3895 (11.9)	15,253 (13.0)	2752 (9.8)	11,008 (9.9)	61,001 (16.9)	15,253 (13.0)
Denmark	11,417 (35.0)	43,673 (37.1)	20,343 (72.8)	81,140 (73.1)	158,089 (43.7)	43,673 (37.1)
NL-PHARMO	5197 (15.9)	14,904 (12.7)	3189 (11.4)	12,168 (11.0)	58,424 (16.2)	14,904 (12.7)
Sweden	12,096 (37.1)	43,762 (37.2)	1677 (6.0)	6708 (6.0)	84,070 (23.3)	43,762 (37.2)
Total	32,605 (100)	117,592 (100)	27,961 (100)	111,024 (100)	361,584 (100)	117,592 (100)
Adults aged ≥ 18 years
UK-CPRD	12,705 (10.0)	50,822 (11.2)	5124 (8.3)	20,496 (8.4)	202,459 (15.7)	50,822 (11.2)
Denmark	40,710 (32.1)	149,242 (32.9)	43,042 (69.6)	169,559 (69.3)	484,789 (37.6)	149,242 (32.9)
NL-PHARMO	21,037 (16.6)	67,293 (14.9)	8506 (13.8)	33,841 (13.9)	264,378 (20.5)	67,293 (14.9)
Sweden	52,456 (41.4)	185,639 (41.4)	5169 (8.4)	20,676 (8.5)	339,416 (26.3)	185,639 (41.4)
Total	126,908 (100)	452,996 (100)	61,841 (100)	244,572 (100)	1,291,042 (100)	452,996 (100)

Notes: ^aUntreated cohort members were matched 4:1 to corticosteroid users on year of birth, sex, and general practice/geographic region. In Sweden, the matching ratio was of approximately 2:1; however, in UK-CPRD and Denmark, age at cohort entry date (defined as date of first qualifying corticosteroid prescription) was estimated from the year and month of birth, where possible). This resulted in a small number of matches being split across age bands.

Abbreviations: NL-PHARMO, PHARMO Database Network (the Netherlands); UK-CPRD, Clinical Practice Research Database (United Kingdom).

Figure 1 Summary results for tacrolimus and pimecrolimus in children and adults combined.

Abbreviations: CI, confidence interval; CTCL, cutaneous T-cell lymphoma; HL, Hodgkin lymphoma; M, Melanoma; NHL, non-Hodgkin lymphoma; NMSC, nonmelanoma skin cancer.

Table 3 Pooled Adjusted Incidence Rate Ratios in Users of Topical Tacrolimus and Topical Pimecrolimus Compared with Users of Topical Corticosteroids—Adults

Exposure	Adjusted^a Incidence Rate Ratios (95% CI)
	Malignant Melanoma	Nonmelanoma Skin Cancer	Non-Hodgkin Lymphoma	Hodgkin Lymphoma	Cutaneous T-cell Lymphoma
Topical tacrolimus
Single use	1.00 (0.88–1.14)	1.04 (1.00–1.09)	0.96 (0.80–1.14)	0.89 (0.58–1.35)	1.80 (1.25–2.58)
Cumulative dose (grams)^b
≤ 0.05	1.01 (0.87–1.18)	1.03 (0.98–1.09)	0.93 (0.75–1.15)	0.85 (0.52–1.41)	0.81 (0.45–1.47)
> 0.05 to 0.1	0.92 (0.71–1.20)	1.00 (0.91–1.09)	0.86 (0.60–1.25)	0.66 (0.25–1.79)	2.11 (1.13–3.95)
> 0.1	1.09 (0.82–1.45)	1.12 (1.02–1.24)	1.18 (0.82–1.69)	1.48 (0.65–3.38)	5.25 (3.21–8.56)
Topical pimecrolimus
Single use	1.21 (1.03–1.41)	1.28 (1.20–1.35)	1.01 (0.79–1.28)	0.81 (0.47–1.38)	0.57 (0.25–1.33)
Cumulative dose (grams)^b
≤ 0.5	1.15 (0.95–1.38)	1.23 (1.15–1.32)	0.85 (0.63–1.15)	0.56 (0.27–1.16)	0.40 (0.12–1.29)
> 0.5 to 1.0	1.04 (0.68–1.60)	1.32 (1.15–1.52)	1.41 (0.85–2.33)	2.42 (1.04–5.64)	0.00 (0.00-N/E)
> 1.0	1.59 (1.14–2.22)	1.43 (1.26–1.62)	1.39 (0.83–2.32)	0.72 (0.18–2.78)	2.11 (0.66–6.71)

Notes: ^aAdjusted by study database, deciles of propensity scores, and sex; and, in Denmark, NL-PHARMO, and Sweden, by type of prescriber (dermatologist, non-dermatologist) of the first prescription. ^bGrams of active substance.

Abbreviations: CI, confidence interval; N/E, not estimable.

Table 4 Sensitivity Analysis by Time Since Start of Exposure, by Each Type of Malignancy: Adjusted Incidence Rate Ratios in Users of Topical Tacrolimus Compared with Users of Topical Corticosteroids—Adults

Exposure Category by Outcome	Topical Tacrolimus (Single Use) Adjusted IRR^a (95% CI)	Topical Pimecrolimus (Single Use) Adjusted IRR^a (95% CI)
Malignant melanoma
Main analysis	1.00 (0.88–1.14)	1.21 (1.03–1.41)
Time since exposure
< 6 months	0.90 (0.64–1.27)	1.38 (0.84–2.25)
6–24 months	1.07 (0.83–1.38)	0.70 (0.47–1.04)
2–5 years	1.03 (0.84–1.25)	1.60 (1.24–2.07)
≥ 5 years	0.91 (0.73–1.14)	1.18 (0.94–1.49)
Nonmelanoma skin cancer
Main analysis	1.04 (1.00–1.09)	1.28 (1.20–1.35)
Time since exposure
< 6 months	0.99 (0.88–1.11)	1.29 (1.08–1.54)
6–24 months	1.09 (1.00–1.19)	1.31 (1.15–1.48)
2–5 years	1.05 (0.98–1.13)	1.28 (1.16–1.42)
≥ 5 years	1.00 (0.92–1.08)	1.25 (1.15–1.36)
Cutaneous T-cell lymphoma
Main analysis	1.80 (1.25–2.58)	0.57 (0.25–1.33)
Time since exposure
< 6 months	1.34 (0.64–2.80)	0.28 (0.03–2.33)
6–24 months	2.07 (1.18–3.61)	0.96 (0.28–3.35)
2–5 years	2.09 (1.25–3.48)	0.21 (0.03–1.56)
≥ 5 years	0.25 (0.03–1.87)	1.33 (0.43–4.07)

Notes: ^aAdjusted by study database, deciles of propensity scores, and sex; and, in Denmark, NL-PHARMO, and Sweden, by type of prescriber (dermatologist, non-dermatologist) of the first prescription.

Abbreviations: CI, confidence interval; IRR, incidence rate ratio.

Figure 2 Summary results: untreated adults.

Abbreviations: CI, confidence interval; CTCL, cutaneous T-cell lymphoma; HL, Hodgkin lymphoma; M, Melanoma; NHL, non-Hodgkin lymphoma; NMSC, nonmelanoma skin cancer.

von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–349.18313558

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