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Acta Derm Venereol 2016; 96: 530–534

CLINICAL REPORT

Risk of Acute Myocardial Infarction or Stroke in Patients with Mycosis
Fungoides and Parapsoriasis
Lise M. LINDAHL1, Uffe HEIDE-JØRGENSEN2, Lars PEDERSEN2, Henrik TOFT SØRENSEN2 and Lars IVERSEN1
Department of Dermatology, and 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
1

Mycosis fungoides (MF) and parapsoriasis display in- of acute myocardial infarction (AMI) in patients with
creased inflammation, which may be associated with in- severe disease (18). Furthermore, evidence is mounting
creased risk of arterial cardiovascular events. The aim that inflammation plays a key role in the pathogeneses of
of this Danish nationwide population-based cohort study atherosclerosis and that inflammation can elicit arterial
was to assess the relative risk (RR) of acute myocardial cardiovascular events (19).
infarction (AMI) or stroke in patients with MF and para­ We therefore hypothesized that both MF and parapso-
psoriasis. In patients with MF, the RR of AMI or stroke riasis are associated with an increased risk of arterial
was 1.0 (95% confidence interval (95% CI) 0.7–1.3). In cardiovascular events. Because of the implications for
the second half of the study period, the RR was 1.8 (95% clinical treatment of MF and parapsoriasis, it is important
CI 1.1–2.9) during the first 5 years of follow-up. In men to expand our sparse knowledge of arterial cardiovas-
with parapsoriasis, the RR of AMI or stroke was 1.7 cular events in these patients. The aim of this study was
(95% CI 1.1–2.7) within the first 5 years of follow-up, to conduct a nationwide population-based cohort study
whereas the RR of AMI during the first 5 years of follow- to assess the risk of AMI or stroke in patients with MF
up was 2.0 (95% CI 1.2–3.4). In conclusion, patients with and parapsoriasis, using data from the unique Danish
MF and parapsoriasis have an increased RR of AMI or medical and administrative registries.
stroke within the first 5 years of follow-up. Key words:
mycosis fungoides; parapsoriasis; cutaneous T-cell lymp-
homa; comorbidities; acute myocardial infarction; stroke. METHODS
The study was conducted using data from the Danish Cancer
Accepted Nov 16, 2015; Epub ahead of print Nov 18, 2015 Registry (DCR) and the Danish National Registry of Patients
(DNRP). The DCR has been recording data on the incidence
Acta Derm Venereol 2016; 96: 530–534. of cancer in Denmark since 1943. Diagnoses have been coded
according to the modified Danish version of the International
Lise M. Lindahl, Department of Dermatology, Aarhus Classification of Diseases, 10th revision (ICD-10), since 1978
University Hospital, P.P. Oerumsgade 11, DK-8000 Aarhus (20). Registration is based on notification forms from hospitals,
C, Denmark. E-mail: lise.lindahl@clin.au.dk including departments of pathology and forensic medicine, and
from practicing physicians (20). Comprehensive assessment
has shown that the DCR is 95–98% complete and valid (20).
Mycosis fungoides (MF) is an extranodal non-Hodgkin The DNRP was established in 1977 and records 99.4% of all
lymphoma with malignant proliferation of T lymphocytes discharges from Danish non-psychiatric acute-care hospitals (21).
Information in the DNRP includes dates of hospital admission
in the skin (1, 2). In early disease stages, MF presents and discharge, surgical procedures performed, and discharge
as erythematous skin patches and plaques, which may diagnoses classified according to the Danish version of the Inter-
progress to tumour formation, and may disseminate to national Classification of Diseases, 8th revision (ICD-8) until 31
lymph nodes and internal organs (1, 2). December 1993, and the 10th revision (ICD-10) thereafter (21).
Parapsoriasis is an inflammatory skin disorder, whose Diagnostic data from outpatient visits have been recorded since
1995 (21). Parapsoriasis is considered a non-malignant disease,
manifestations resemble the clinical and histopathologi- and it is most commonly treated in outpatient clinics. This diag-
cal findings in early MF. It has been regarded as a distinct nosis has therefore been registered in the DNRP only since 1995.
entity or an early form of MF, although this remains a Patients can be linked among Danish registries at the level of
matter of debate (3–12). the individual by means of the unique civil registration number
MF and parapsoriasis display increased low-grade (CRN) assigned to all Danish residents at birth. The CRN is
recorded in the Danish Civil Registration System (CRS), along
systemic inflammation (1, 13–15) similar to that observed with date of birth, residency status, and dates of immigration,
in patients with psoriasis (13) and other immune inflam- emigration and death (22).
matory diseases, that are associated with an increased risk We established a cohort of all patients with a first-time
of arterial cardiovascular events (16). The inflammation diagnosis of MF in the DCR between 1 January 1980 and 31
in psoriasis and other immune inflammatory diseases is December 2010, and a cohort of all patients with a first-time
diagnosis of parapsoriasis recorded in the DNRP from 1 January
regarded as a risk factor for arterial cardiovascular events 1995 to 31 December 2011. All MF and parapsoriasis patients
(16, 17). A correlation with the degree of inflammation were diagnosed by trained dermatologists and pathologists, and
has been indicated, as evidenced by a heightened risk were all treated at a department of dermatology. The criteria

Acta Derm Venereol 96 © 2016 The Authors. doi: 10.2340/00015555-2294
Journal Compilation © 2016 Acta Dermato-Venereologica. ISSN 0001-5555

the overall RR of AMI or stroke was 1. chronic heart failure. who progressed to MF (n = 19).1%). The mean age on the index date was 66 years (range 26–95 years) in patients with MF and 60 This nationwide cohort study investigates the risk years (25–100 years) in patients with parapsoriasis. 10 population comparison cohort members riasis cohort.9–1. of AMI or stroke in patients with MF and parapso- The youngest patient diagnosed with AMI was 63. years in the MF cohort and 40.7%) and their fidence intervals (95% CIs) as a measure of the relative risk population comparison cohort (15. and they were included in the MF group.199 person-years in MF and Statistical analysis 4.9).2 years in the MF cohort and patient.5%) in their population transient cerebral ischaemic attack. The overall RR of AMI or stroke separately for AMI and stroke.7. hypertension. 1-16-01-1-18). death. (cumulative incidence 8.6–1. 95% CI 1. 95% CI 1. but not in women (RR=1. we stratified the analysis analyses of the 2 endpoints. In the regression analysis.2–3. The female:male cohorts and their respective population comparison cohorts were ratio was 1:1. No further ethical approval (RR=1. 95% RESULTS CI 1.1–2. Cohort members were followed with parapsoriasis.6) (Table II). is needed for register-based studies in Denmark. The overall incidence rate of AMI or stroke was 12. analysis. As time from onset period.4 years in the parapsoriasis cohort. Characteristics of patients with mycosis fungoides (MF) erythematous patches combined with histopathological findings and parapsoriasis of a superficial lymphocytic infiltrate with pleomorphism. Patient characteristics for the remaining 439 MF patients and 570 parapsoriasis patients are shown DISCUSSION in Table I. Patient characteristics n = 439 n = 570 The CRS was used to link all patients to the DNRP in order to identify and exclude those with a previous diagnosis of AMI and/ Sex: F/M 161/278 264/306 or stroke. MF patients diagnosed in the second half 2010.6 per 1. Of was 1. 95% CI 0. and MF cohort Parapsoriasis cohort absence of Pautrier’s microabscesses and epidermotropism. The 2 patient 50. The results showed that. the RR of AMI or stroke was increased in men with parapsoriasis (RR=1. years (0–32 years) in patients with MF and 6.1 until the occurrence of a first hospitalization for AMI or stroke. whichever came first. and years (cumulative incidence 7. matched by sex and age on the index date. which would have excluded them from the study.9–2.3 years in the parapso- Utilizing the CRS. After stratifying these.6). arterial cardiovascular events before they had their MF diagno. The number of patients who had a first-time AMI and/or stroke The overall incidence rate of AMI or stroke was during the follow-up period were counted.2) (Table II). The regression analysis was stratified by sex and age below/ years.9) (Table III).010 person-years in parapsoriasis.2 years emigration.000 person- (RR) of AMI or stroke in patients with MF and parapsoriasis. endpoints were examined separately.4%) and 9.0. were censored from 1995–2010 234 – the parapsoriasis group at the time of progression.3) in patients with MF (Table II). 44 MF patients and 53 parapsoriasis patients by follow-up time.4 (95% CI 0.7 in patients with MF and 1:1. (0–17 years) in patients with parapsoriasis. During the study above 70 years.8.7–1. we found an increased RR of AMI were diagnosed with AMI or stroke before their index in patients with parapsoriasis during the first 5 years of date. Statistical analyses were carried was 1. the RR of AMI tients with incident parapsoriasis were identified.3. In an analysis in which the 2 A total of 483 patients with incident MF and 623 pa. The study was approved by the Danish Data Protection AMI or stroke was found in men with parapsoriasis Agency (record no.000 person-years in patients with parapsoriasis covariates: diabetes mellitus. RRs were also computed comparison cohort.9–1.9 per 1. we adjusted for the following per 1. Proportional hazards largely the same in patients with MF (14.2 in patients linked to the DNRP in order to identify all hospitalizations for AMI and stroke after the index date. The total follow-up time was 3. In separate time for patients with MF (24–26). Patients diagnosed in the first part of the study period of the study period (1995–2010) did have an increased could have been at a more advanced stage of their disease at RR of AMI or stroke within the first 5 years of follow- time of diagnosis. angina pectoris. However. For patients diagnosed with stroke.000 regression was used to compute hazard ratios and 95% con. 95% CI 0. Patients with Index year: 1980–1995 205 – parapsoriasis. within the first 5 Acta Derm Venereol 96 . The study period was therefore divided AMI or stroke was found in patients with MF (Table into 2 equal parts: the first part of the study period from 1980 to 1995 and the second part of the study period from 1995 to II). Notably. person-years. as previously used (10.0 sis.7) (Table III).2 (95% CI 0. no increased RR of either on time of diagnosis. cumulative incidence 15. and therefore more likely to have experienced up (RR=1.1 riasis. and they were therefore excluded from further follow-up (RR=2.2). 23).0 (95% of symptoms to diagnosis is thought to have decreased over CI 0. Risk of AMI or stroke in patients with mycosis fungoides and parapsoriasis 531 for the parapsoriasis diagnosis were clinical findings of scaly Table I.1–2.4) (Table III).7 per 1. or 31 December 2011.000 person- chronic ischaemic heart disease.0. A slightly elevated RR of out using SAS software (version 9. the were randomly selected from the general population for each youngest patient was 48. cumulative incidence 10. The median follow-up time was 5. The date of the first MF/parapsoriasis diagnosis was considered the index date. Patients under the age of 25 years were also excluded Age: < 70 years 257 399 because AMI and stroke are very rare in these patients and may > 70 years 182 171 be caused by other disposing risk factors than MF. within the first 5 years of follow-up.

unless otherwise specified.2 (0.8 (0.2–3.9) < 70 years 26 11. > 7 0 years 21 24.6–1.0) 1980–1995 27 14.0 (0.2 1. and transient cerebral ischaemic attack.3 (0.8 (0.6 465 18.5 1.7–1.8) 17 8.7–2.6 221 14.2 (0.0 (0.6) 0.000 crude adjusteda Cohort No.1 (0.0 (1.2 (0.5–1.5 (1. a Adjusted for diabetes mellitus.8) 1.6–1. Table II.390) person-years (95% CI) (95% CI) (n = 570) person-years cohort (n = 5.5–1.1 184 4.6–2.6 (0.8) L.7–1.7–1.0 (0.7–1.3 205 6. Relative risk of acute myocardial infarction (AMI) or stroke in patients with mycosis fungoides (MF) and parapsoriasis 532 Mycosis fungoides Parapsoriasis Population Relative risk Relative risk Population Relative risk Relative risk Cohort No.3 370 8.5–1.3 (0.4–1.1–1.3–1.7) 1.3 (0. angina pectoris.9) 0.8 223 21.9) 0.6–1.2) 27 21 219 209 1.8 (0.6) 6 11 85 89 0.0 (0.0 (0.7–1.0 (0.5 1. unless otherwise specified.2) Stroke 27 8.4 (0.3 (0.1 (0.5–1. and transient cerebral ischaemic attack.7–1.1) 1.7–1.5) Males 20 13 196 269 1.8 (0. .9–1.7–1.8) 0.5 1.000 crude adjusteda (n = 439) person-years cohort (n = 4.7) 1.4 314 25.2 1.6 (0.5 1. hypertension.5) – – – – – – 1995–2010 18 2 118 103 1.4 (0.0–2.4) 1.6–1.2 351 11.3 (0. angina pectoris.9) < 7 0 years 13 13 93 258 1.3) 1.7) Data are number of events.5 0. CI: confidence interval./ 1. hypertension.1 (0.0 (0. chronic heart failure.3) – – – – – – 1995–2010 20 15. M./1./1.3) 0.9 (0.7) 1.3) Data are number of events.6–1.8 (0.9) 0. chronic ischaemic heart disease.0 (0. Lindahl et al.8–1.0 (0.0 428 9.7–1.4) 21 10 134 120 1.0 (0.5 1.0) 1.9 (0.7–1.6) 1.0 (0.5) 12 13 129 111 1.0) Stroke 13 14 118 252 1.5–1.5) 1.6–1. chronic heart failure.3) 1.8–1.9–2.390) (95% Confidence interval) (n = 570) (n = 5.0) > 70 years 14 7 153 161 1.8) Females 7 7 50 150 1.4–1.000 comparison No. Adjusted relative risk of acute myocardial infarction (AMI) or stroke during follow-up of patients with mycosis fungoides (MF) and parapsoriasis MF population Parapsoriasis population comparison cohort Relative risk adjusteda Parapsoriasis cohort comparison cohort Relative risk adjusteda MF cohort (n = 439) (n = 4.1 240 5.9–1.3) 48 12.7) 1980–1995 9 18 128 316 0.7) 1.9 1.6–1.7–1.3) 1.3) 0.4) 1.9–2.1 (0.8) – – – – – – AMI 24 7.8) 1.3 (0.7 (0.3) 0.7–1.4–1.0 (0.5) 0.7 665 15.9–2.7–1.7) 16 9 133 90 1.9) 1.6–1.700) person-years (95% CI) (95% CI) Acta Derm Venereol 96 AMI or stroke 47 14.4 1.9 (0.2 444 16.6) Males 33 17.1 (0.1 (0.2 1.7–1. Table III.1 (0.0 (0.6) 16 9 86 98 2.6 200 11.1 (0.0 (0.0 (0.8 (1. chronic ischaemic heart disease.7) 1.3–1.9–2.7) 1.3 (0.8–2.5–2./1.6) 1.4 (0.7–2.3 313 7.8–2.2 (0.1 (0.000 comparison No.9) 0.7–2.0 (0.8 (0.7–3.3 (0.5) 25 6.3 (0.4 1.4 174 8.6 1.5) 1.9–1.1–2.5) 25 6.4 (0.8 1. a Adjusted for diabetes mellitus.4) 11 12 86 119 1.9–1.7 (0.5) 23 7.5–1.7–1.4 (0.3 (0.6–1.0 (0.9–2.7–2.7–2.9–1.1 1.7 (1.2 (0.4) 31 15.700) (95% Confidence interval) 0–5 years’ > 5 years’ 0–5 years’ > 5 years’ 0–5 years’ > 5 years’ 0–5 years’ > 5 years’ 0–5 years’ > 5 years’ 0–5 years’ > 5 years’ follow-up follow-up follow-up follow-up follow-up follow-up follow-up follow-up follow-up follow-up follow-up follow-up AMI or stroke 27 20 246 419 1.9 (0.1) – – – – – – AMI 14 10 124 189 1.6 254 11.7–1.6) Females 14 10.1–2.5) 1.7–1.5) 25 28.1 1.8) 1.

referral and as well as patients with parapsoriasis have an increased diagnostic biases are also largely avoided. The validity mortality within the first 5 years of follow-up (10). These of our data depends mainly on the accuracy of the coding findings indicate that a particular subgroup of MF and of MF and parapsoriasis and the endpoint diagnoses. dolent clinical cause of their disease and a lower degree 37). Nordborg. with newly diagnosed MF and parapsoriasis. The of disease severity for the risk of arterial cardiovascular inflammatory process therefore exerts its effects on the events. believed to cause cardiovascular events. Furthermore. However. such as psoriasis and therapies (e. which may avoid or postpone occurrence of arterial the study period (1995–2010). In MF patients diagnosed in the second part of mia. these patients have a higher Systemic retinoids used in treatment of MF may induce RR of AMI or stroke than a matched general population dyslipidaemia and therefore increase the risk of arterial cohort after adjustment for potential confounders. nitrogen mustard. Earlier recognition of MF could have reduced the risk of exclusion from the study due to AMI or stroke before the MF diagnosis was established. which increases their ensure a high validity of the parapsoriasis diagnosis. To respond with severe inflammation. time from exposure of AMI was 2-fold increased in patients with parapsoriasis of increased blood lipids to development of arterial car- during the first 5 years of follow-up. As we lacked data on disease stage of MF. we The time elapsed from symptom onset to diagnosis of could draw no conclusions as to the relative importance MF and parapsoriasis is usually several years (29). the Danish Cancer Society (R73-A4284-13-S17).g. Thus. of arterial cardiovascular events in MF and parapsoriasis Discharge diagnoses have been documented to have patients within the first 5 years of follow-up (10). which is a study limitation. with complete long-term follow-up. A of follow-up. the RR of AMI or stroke cardiovascular events. and the predictive value is slightly lower for stroke (36. 17. without selection bias. rheumatoid arthritis (16. 28). the clinical treatment of MF and parapsoriasis properties in psoriasis and rheumatoid arthritis essentially patients is not believed to influence the risk of subsequent resemble those of MF and parapsoriasis with increased arterial cardiovascular events. early diagnosis. thus systemic retinoids are not was increased by 80% during the first 5 years of follow-up. that patients with MF Service provides free access to healthcare. Thus. which may explain that they would have biased the relative risk estimates towards have no increased risk of arterial cardiovascular events. 27. In these diseases. mechanisms underlying arterial cardiovascular events The most prominent finding of the present study is long before a firm diagnosis of MF or parapsoriasis is that both patients with MF and parapsoriasis have an established. 13–15). and parapsoriasis. 32). 33). a limited specificity of these diagnoses of systemic inflammation. Furthermore. and described for psoriasis and rheumatoid arthritis. these previous the cohort was restricted to patients treated at hospital data accord with the present findings of an increased risk departments of dermatology. Aarhus University Research Foundation and from the Program Acta Derm Venereol 96 . AMI or stroke often occurs increased risk of AMI or stroke within the first 5 years shortly after the MF or parapsoriasis diagnosis is made. Risk of AMI or stroke in patients with mycosis fungoides and parapsoriasis 533 years of being diagnosed. Consequently. This subgroup of patients may diagnoses with high classification specificity (20). 35). growing awareness and better intervention against cardiovascular risk factors should tools for diagnosis of patients with MF may have shortened be emphasized in the clinical management of patients the time from symptom onset to diagnosis of MF (24–26). period than during the first half of the study period. which cardiovascular events has been observed in persons shortly emphasizes the importance of adequate treatment of MF after they were diagnosed with rheumatoid arthritis (30). Since the Danish National Health It has been reported previously. the null. Th1 inflammation (1. treatment and Over the study period. The study was supported by unrestricted grants from LINAK cular events were recorded in the second half of the study A/S. and it is therefore plausible A strength of the study is its population-based cohort that they induce the same pro-atherogenic effects as those study design. psoralen plus ultraviolet A irradiation (PUVA). which have to formation of atherosclerosis and the increased risk of no known adverse cardiovascular effects (23. especially not An increased risk of arterial cardiovascular events has within the first 5 years of follow-up (31. Patients previously been described in patients with other chronic with parapsoriasis are primarily treated with skin-directed immune inflammatory diseases. 28). This argument is consistent ACKNOWLEDGEMENTS with the finding that more MF-related arterial cardiovas. risk of arterial cardiovascular events. It is plausible that the excess cardiovas- similar pattern of immediate increase in the RR of arterial cular risk is mediated by chronic inflammation. The inflammatory lectively. The RR cardiovascular disease. combined RR of AMI and stroke was increased by 70% systemic retinoid treatment is always accompanied by in male parapsoriasis patients during the first 5 years of monitoring of blood lipids and treatment of dyslipidae- follow-up. However. topical corticosteroids. and the inflammatory Th1/Th2 imbalance has been related narrow-band ultraviolet B irradiation) (11). Col- arterial cardiovascular events (17. the diovascular events may last several years. Patients a positive predictive value of 90% for AMI (34. with more than 5 years follow-up may have a more in. parapsoriasis patients harbour a clinically aggressive The Danish registries have a high validity for cancer form of their disease (10).

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