Association between atopic dermatitis and autoimmune diseases: a population-based case-control study.

BACKGROUND: Atopic dermatitis (AD) is a common chronic skin disorder and is well known to be associated with other atopic conditions. There is increasing evidence for an association also with nonatopic conditions, including autoimmune diseases, but data are limited about several autoimmune diagnoses. OBJECTIVES: To investigate the association between AD and autoimmune diseases. METHODS: This case-control study used Swedish national healthcare registers. The source population comprised the entire Swedish population aged ≥ 15 years from 1968 to 2016. Cases, including all those with an inpatient diagnosis of AD (from 1968) and/or a specialist outpatient diagnosis of AD (from 2001), were matched by sex and age to healthy controls (104 832 cases of AD, 1 022 435 controls). RESULTS: AD was significantly associated with one or more autoimmune diseases compared with controls - adjusted odds ratio (aOR) 1·97, 95% confidence interval (CI) 1·93-2·01 - and this association was significantly stronger in the presence of multiple autoimmune diseases compared with only one. The association was strongest for autoimmune disorders involving the skin (aOR 3·10, 95% CI 3·02-3·18), the gastrointestinal tract (aOR 1·75, 95% CI 1·69-1·82) or connective tissue (aOR 1·50, 95% CI 1·42-1·58). In the overall analysis, men with AD had a stronger association with rheumatoid arthritis and coeliac disease than did women with AD. In subanalyses, the findings remained stable in multivariable analyses after adjustment for smoking and parental autoimmune disease. CONCLUSIONS: This large population-based study indicates significant autoimmune comorbidity of adults with AD, especially between AD and autoimmune dermatological, gastrointestinal and rheumatological diseases. Having multiple autoimmune diseases resulted in a stronger association with AD than having only one autoimmune disease.

Merkel cell carcinoma incidence is increasing in Sweden.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare aggressive neuroectodermal skin cancer with a high recurrence rate and a high mortality rate. Risk factors for MCC are reported to include high age, UV exposure, Caucasian skin type and immunosuppression. The incidence is reported to be increasing. OBJECTIVE: The purpose of this study was to describe a Swedish cohort and calculate incidence. METHODS: The study design is a retrospective cohort study of population-based data for MCC collected by the Swedish Cancer Registry to determine the incidence of MCC in Sweden and the clinical characteristics of these tumours including demographics, TNM classification, body part distribution and overall survival after diagnosis. De-identified data were collected from 1993 to 2012. RESULTS: A total of 606 cases of MCC were identified during the study period. The median age was 81 years (range 21-99) and a majority, 54.4% were women but age-adjusted incidence is higher in men. The incidence (per 100,000) of MCC in Sweden in 1993-2012 increased from 0.09 to 0.20 for men and 0.12-0.17 for women, adjusted for age to the world standard population. For the both sexes, the increase was from 0.11 to 0.19 per 100 000, an increase of 73%. The most common site of the primary tumour was the head and neck, with 51.8% of the cases. The size of the tumour was <5 cm in 82.1% of the cases. The majority of the tumours (90.7%) had no known lymphatic spread and only a few patients had confirmed distant metastases (2.9%) when diagnosed. CONCLUSIONS: MCC is a rare disease in Sweden, but the incidence is increasing. This study supports the finding that high age, male sex and UV exposure are risk factors for MCCs. Interventions are required to increase awareness of MCC among clinicians and the public.

End-of-life care for hospitalized patients with metastatic melanoma in France: a nationwide, register-based study.

BACKGROUND: Although the aggressiveness of end-of-life cancer care has come under great scrutiny over the past two decades, little is known about the intensity of care and treatments in the last months of life of patients with metastatic melanoma. OBJECTIVES: To measure the prevalence of aggressive cancer care use, and to assess the frequency of palliative care referral over the course of the last 3 months of life of hospitalized patients who died from metastatic melanoma. METHODS: A nationwide register-based study in France was carried out, including all hospitalized adults aged ≥ 20 years who died from metastatic melanoma in metropolitan France between 2010 and 2013. RESULTS: Of 3889 patients who died from metastatic melanoma, 51·9% received chemotherapy in the last 3 months before death, 25·9% in the last month, 12·9% in the last 2 weeks and 7·6% in the last week. On average, patients were hospitalized for 31·7 days over the course of their last 3 months of life. During the final month before death, 12·0% of patients received radiation therapy, 14·0% received blood transfusion, 12·1% were transferred into an intensive care unit and 19·7% remained hospitalized continuously. Palliative care needs were identified in 78·4% of patients, with variations according to the type of facility. In total 17% of all patients died in palliative care inpatient units. CONCLUSIONS: Treatment intensity near the end of life of patients with metastatic melanoma raises concerns for the quality of care. There is a need for clinical guidelines and adequate support to facilitate patient-physician communication and to improve access to palliative care services.

Risk of basal cell carcinoma in Swedish organ transplant recipients: a population-based study.

BACKGROUND: Risk of basal cell carcinoma (BCC) has been reported to be several-fold increased among organ transplant recipients (OTRs). However, due to lack of reliable BCC registration, population-based risk estimates are scarce. OBJECTIVES: To characterize risk of BCC among OTRs compared with the general population, and contrast with risk of cutaneous squamous cell carcinoma (SCC). SUBJECTS AND METHODS: OTRs transplanted during 2004-2011 were identified through national healthcare registers and linked with the nationwide Swedish BCC Register initialized in 2004. Relative risk of BCC was expressed as standardized incidence ratios (SIR) with 95% confidence intervals (CI). RESULTS: Altogether, 4023 transplanted patients developed 341 BCCs during follow-up. Compared with the general population, the relative risk of BCC was increased sixfold (SIR 6·1, 95% CI 5·4-6·9). The risk was higher in kidney and heart/lung than in liver recipients (SIRkidney 7·2, 6·3-8·3; SIRheart/lung 5·8, 4·0-8·2; SIRliver 2·6, 1·7-4·0), and risk increased with time since transplantation (Ptrend < 0·01). The SCC to BCC ratio was 1 : 1·7 and BCC developed earlier after transplantation than SCC. Distribution of anatomical sites and histological types did not differ substantially between OTR- and population-BCCs. CONCLUSIONS: Risk of BCC was strikingly elevated in OTRs compared with the general population. Risk was higher in kidney recipients and increased with follow-up time. These findings support a tumour-promoting effect of immunosuppressive drugs in BCC development. The low SCC to BCC ratio was possibly attributed to short follow-up time.

Time trends in risk and risk determinants of non-Hodgkin lymphoma in solid organ transplant recipients.

Organ transplantation increases risk of non-Hodgkin lymphoma (NHL), but long-term risk and time trends have seldom been evaluated. Immunosuppressive drug load is an important risk determinant, but the details are unclear. We studied NHL risk in a nationwide Swedish cohort of 11 081 graft recipients transplanted 1970-2008. Relative risks (RRs) were estimated within the cohort and versus the general population by age, sex, follow-up time and calendar period. NHL risk was also assessed by cumulative and average doses of immunosuppressive treatments in a nested case-control design throughout 1997 using conditional logistic regression. We observed 153 NHL cases during 97 853 years of follow-up. Compared with the general population, NHL risk was eightfold increased (RR 7.9; 95% confidence interval [CI] 6.6-9.4), and increased risks persisted after ≥15 years of follow-up among kidney (6.1; 95% CI 3.5-10) and nonkidney recipients (44; 14-103). Among nonkidney recipients, NHL risk was lower in the 2000s compared with the 1990s (0.5; 95% CI 0.3-1.0; p = 0.04). A high average dose of antithymocyte immunoglobulin (ATG) conferred an eightfold increased risk of NHL (OR 8.5; 95% CI 1.9-38). To conclude, posttransplant NHL risk decreased during the last decade among nonkidney recipients, possibly because of a more careful use of ATG, the introduction of new drugs, or both.

Allergy and autoimmune disease: a registry-based study.

BACKGROUND: Allergy and autoimmunity are two potential outcomes of a dysregulated immune system, but the relationship between them is unclear. It has been hypothesized that they could be inversely associated because of different T helper cell reactivity patterns. However, both positive and negative associations have been reported. Therefore, our aim was to perform a large epidemiological study with a defined allergic disease cohort. METHODS: During the years 1990-2002, 68 770 subjects were tested for total serum IgE (Total-IgE) and 72 228 were tested with Phadiatop for diagnosing allergic disease at Karolinska University Hospital, Stockholm, Sweden. This cohort was then linked with the Swedish Inpatient Registry 1968-2004 for a follow-up with regard to recorded discharges for 28 autoimmune diseases. We then used Cox regression and logistic regression to estimate the risk of autoimmune diseases in general in the allergy-tested subjects. RESULTS: Subjects with positive Phadiatop test were at a statistically decreased risk of subsequent autoimmune disease in comparison with subjects with negative test; hazard ratio (HR): 0.80 [95% (Confidence interval) CI: 0.68-0.94). Prior autoimmune disease was associated with a decreased risk of positive Phadiatop test [odds ratio: 0.83 (95% CI: 0.72-0.96)] in comparison with negative test. Subjects with highly elevated Total-IgE were at a statistically increased risk of a subsequent autoimmune disease in comparison with subjects with normal levels [HR: 1.36 (95% CI: 1.09-1.70)], but no association was found between prior autoimmune disease and different Total-IgE levels. CONCLUSION: The study supports the hypothesis that allergy, defined as positive Phadiatop test, could be inversely related to autoimmune disease but this association is weak.

Allergy and cancer.

BACKGROUND: Conflicting results have provided support for two distinct and contradictory hypotheses: (i) allergy has a protective effect against cancer by enhanced immune surveillance, and (ii) allergy is associated with an increased risk of cancer by chronic immune stimulation. We therefore aimed us to perform a large epidemiological study with a defined allergic disease cohort. METHODS: During the years 1988-2000, 70 136 patients tested for total serum immunoglobulin E (IgE) and 57 815 tested with Phadiatop for diagnosing allergic disease at Karolinska University Hospital, Stockholm, Sweden, were linked with the Swedish Cancer Registry for a virtually complete follow up with regard to cancer. FINDINGS: The total number of observed cancers was normal in the total serum IgE-cohort; standardized incidence ratio (SIR) = 0.98 (95% CI: 0.92-1.04) and in the Phadiatop-cohort: SIR = 0.99 (0.92-1.06) independent of the level of IgE and positive or negative Phadiatop. Specific analysis was done for cancer of the lung, cervix, pancreas, lymphoma, and nonmelanoma skin cancer. None of these forms of cancer had increased risks. INTERPRETATION: The study does not support the hypothesis that allergy has a protective effect against cancer, nor does it support an increased risk.

Tobacco smoking, snuff dipping and the risk of cutaneous squamous cell carcinoma: a nationwide cohort study in Sweden.

We investigated whether tobacco use causes cutaneous squamous cell carcinoma (CSCC) in a large cohort study with complete and long-term follow-up. A total of 756 incident cases occurred in a cohort of 337,311 men during a 30-year follow-up period, but no association was found between any kind of smoking tobacco use and CSCC risk, nor any risk change with increasing dose, duration or time since smoking cessation. Snuff use was associated with a decreased risk of CSCC. Overall, our study provides no evidence that tobacco use increases the risk of CSCC.

Cancer risk following organ transplantation: a nationwide cohort study in Sweden.

A substantial excess risk of lymphomas and nonmelanoma skin cancer has been demonstrated following organ transplantation. Large sample size and long follow-up time may, however, allow more accurate risk estimates and detailed understanding of long-term cancer risk. The objective of the study was to assess the risk of cancer following organ transplantation. A nationwide cohort study comprising 5931 patients who underwent transplantation of kidney, liver or other organs during 1970-1997 in Sweden was conducted. Complete follow-up was accomplished through linkage to nationwide databases. We used comparisons with the entire Swedish population to calculate standardised incidence ratios (SIRs), and Poisson regression for multivariate internal analyses of relative risks (RRs) with 95% confidence intervals (CI). Overall, we observed 692 incident first cancers vs 171 expected (SIR 4.0; 95% CI 3.7-4.4). We confirmed marked excesses of nonmelanoma skin cancer (SIR 56.2; 95% CI 49.8-63.2), lip cancer (SIR 53.3; 95% CI 38.0-72.5) and of non-Hodgkin's lymphoma (NHL) (SIR 6.0; 95% CI 4.4-8.0). Compared with patients who underwent kidney transplantation, those who received other organs were at substantially higher risk of NHL (RR 8.4; 95% CI 4.3-16). Besides, we found, significantly, about 20-fold excess risk of cancer of the vulva and vagina, 10-fold of anal cancer, and five-fold of oral cavity and kidney cancer, as well as two- to four-fold excesses of cancer in the oesophagus, stomach, large bowel, urinary bladder, lung and thyroid gland. In conclusion, organ transplantation entails a persistent, about four-fold increased overall cancer risk. The complex pattern of excess risk at many sites challenges current understanding of oncogenic infections that might become activated by immunologic alterations.

Analysis of hereditary component of cancer by use of a familial index by site.

To quantify hereditary factors in the risk of cancer, we matched 1283047 cancer patients listed in the Swedish Cancer Registry with healthy controls from a national database, and identified the number of individuals who were first-degree relatives of other individuals in the same cohort. Division of the number of relatives in the patient cohort by the number in the control cohort yielded a "familial index". The following cancers had high familial indices: eye 16.5 (95% CI 2.5-666), testis 9.0 (3.2-35), Hodgkin's disease 6.5 (2.3-26.0), and thyroid 6.2 (3.7-12). Overall, however, familial factors made only a minor contribution to susceptibility to cancer.

Cancer risk in a population-based cohort of patients hospitalized for psoriasis in Sweden.

Studies of clinical series of psoriasis patients have suggested an increased risk of nonmelanoma skin cancer and melanoma; the risk of other neoplasms has rarely been studied. In order to assess the incidence of cancer in a nationwide series of psoriasis patients from Sweden, we followed up, for the years 1965-89, 9773 patients with a hospital discharge diagnosis of psoriasis made during 1965-83, who were alive and free from malignancy 1 y after first discharge. We compared their incidence of neoplasms with that of the national population by computing standardized incidence ratios (SIR). We observed a total of 789 neoplasms [SIR 1.37, 95% confidence interval (CI) 1.28, 1.47]. There was an increase in the risk of cancers of the oral cavity and pharynx (SIR 2.80, 95% CI 1.96, 3.87), liver (SIR 1.91, 95% CI 1.28, 2.74), pancreas (SIR 1.56, 95% CI 1.02, 2.23), lung (SIR 2.13, 95% CI 1.71, 2.61), skin (squamous cell carcinoma, SIR 2.46, 95% CI 1.82, 3.27), female breast (SIR 1.27, 95% CI 1.00, 1.58), vulva (SIR 3.24, 95% CI 1.18, 7.06), penis (SIR 4.66, 95% CI 1.50, 10.9), bladder (SIR 1.43, 95% CI 1.03, 1.92), and kidney (SIR 1.56, 95% CI 1.04, 2.25). The risk of malignant melanoma was decreased (SIR 0.32, 95% CI 0.10, 0.74). Despite some limitations (possible diagnostic misclassification, lack of data on treatment, relatively short follow-up), our study provides evidence against an increased risk of melanoma among patients hospitalized for psoriasis. In addition to nonmelanoma skin and genital cancers, patients hospitalized for psoriasis were at increased risk of several malignancies, in particular those associated with alcohol drinking and tobacco smoking.

Incidence of skin cancer in 5356 patients following organ transplantation.

BACKGROUND: Skin cancer following solid organ transplantation is an important cause of morbidity in long-term survivors. This risk is well known but imprecisely quantified. OBJECTIVES: We aimed to determine: (i) the skin cancer risks in transplant patients more precisely; (ii) whether the risk of malignant melanoma is altered; and (iii) whether the risk of epithelial cancers occurring at non-exposed sites is comparable with that seen in sun-exposed sites. METHODS: We linked a population-based cohort of 5356 patients who had received organ transplants in Sweden between 1970 and 1994 with the compulsory Swedish Cancer Registry, to identify all cancer cases except basal cell carcinomas, which are not registered. RESULTS: After a mean follow-up of 5.6 years post-transplantation, 172 of 5356 patients developed 325 non-melanoma skin cancers (excluding basal cell carcinomas) and six malignant melanomas. The relative risk of non-melanoma skin cancer was 108.6 [95% confidence interval (CI) 94.6-123.1] for men and 92.8 (95% CI 73.2-116.0) for women. The highest risks were noted for upper limbs, and the risk increased with time. No significant increase in malignant melanomas was noted: the relative risk was 1.6 (95% CI 0.5-3.7) for men and 0.5 (95% CI 0. 0-2.6) for women. Except for the lip, which is also sun-exposed, other epithelial sites did not show comparable increases in cancer risk. CONCLUSIONS: We conclude that organ transplant recipients are at a highly increased risk for non-melanoma skin cancer and must be closely followed throughout their lives. Cancer risk associated with transplantation is higher for sun-exposed than for non-sun-exposed epithelial tissues, even among populations living in regions with low solar insolation.

Trioxsalen bath PUVA did not increase the risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944 Swedish and Finnish patients with psoriasis.

It has been suggested that trioxsalen bath and ultraviolet (UV) A (PUVA) is associated with a very low or no risk of non-melanoma skin cancer, but the numbers of patients in individual studies have been limited. In order to attain statistically relevant information about the cancer risk associated with trioxsalen bath PUVA, two follow-up studies were combined and the joined cancer incidence was analysed among 944 Swedish and Finnish patients with psoriasis. The mean follow-up time for skin cancer was 14.7 years. Standardized incidence ratios (SIR) were calculated as a ratio of observed and expected numbers of cases. The expected numbers of cases were based on the national cancer incidence rates in the respective countries. There was no excess of squamous cell skin carcinoma [SIR 1.1, 95% confidence interval (CI) 0.2-3.2] or malignant melanoma (SIR 0.9, 95% CI 0.1-3.2) in the combined cohort. Basal cell skin carcinoma was not studied. The incidence of all non-cutaneous cancers was not increased (SIR 1.1, 95% CI 0.8-1.4). A threefold excess risk of squamous cell skin carcinoma after trioxsalen bath PUVA could therefore be excluded, which is a markedly lower risk than that associated with oral 8-methoxypsoralen PUVA. The result needs to be confirmed in a future follow-up, however, as the number of patients with high PUVA exposures was low.

PUVA and cancer risk: the Swedish follow-up study.

There is concern about the long-term carcinogenic effects of psoralen and ultraviolet A radiation (PUVA) for treatment of skin disorders. Many authors have found an increased risk for cutaneous squamous cell carcinoma (SCC). Except in anecdotal reports, malignant melanoma had not been observed in patients treated with PUVA until recently. In the U.S.A., a 16-centre prospective study of 1380 patients showed for the first time that there might also be an increased risk for malignant melanoma in patients treated with high cumulative dosages of PUVA. We have therefore followed up the Swedish PUVA cohort until 1994. This cohort had previously been followed up until 1985. Information from 4799 Swedish patients (2343 men, 2456 women) who had received PUVA between 1974 and 1985 was linked to the compulsory Swedish Cancer Registry in order to identify individuals with cancer. The average follow-up period was 15.9 years for men and 16.2 for women. We did not find any increased risk for malignant melanoma in our total cohort of 4799 patients treated with PUVA or in a subcohort comprising 1867 patients followed for 15-21 years. For cutaneous SCC there was an increase in the risk: the relative risk was 5.6 (95% confidence interval, CI 4. 4-7.1) for men and 3.6 (95% CI 2.1-5.8) for women. Significant (P < 0.05) increases were also found in the incidence of respiratory cancer in men and women and of kidney cancer in women. In conclusion, we did not find any increased risk for malignant melanoma in our patients treated with high doses of PUVA and followed up for a long time. We confirm previous reports of an increase in the incidence of cutaneous SCC in patients treated with PUVA, and recommend that patients should be carefully selected for PUVA and rigorously followed up.

Squamous cell carcinoma complicating chronic venous leg ulceration: a study of the histopathology, course and survival in 25 patients.

We have studied 25 cases of squamous cell carcinoma in chronic venous leg ulcers. Twenty-three of the patients were dead and two were alive. The mean age at cancer diagnosis was 78.5 years. The median survival was 1 year. Eleven tumours were well-differentiated, 10 moderately and four poorly. All patients with a poorly differentiated tumour died within a year. Metastases were certain in eight cases. The disease was lethal in 10 cases which included all poorly differentiated tumours. The survival of the study group was significantly shortened compared with a control group of patients with lower limb non-melanoma skin cancer (n = 433) from the Swedish Cancer Registry (P = 0.0084). When diagnosed, squamous cell carcinoma in chronic leg ulcers merits a thorough investigation of the degree of differentiation and spread. Assertive treatment is indicated as poorly differentiated tumours and some moderately differentiated tumours may be fatal.

Risk of melanoma with psoralen/ultraviolet A therapy for psoriasis. Do the known risks now outweigh the benefits?

Since the introduction in the 1970s of treatment with oral psoralens with longwave ultraviolet radiation in the A range (PUVA), there has been an increasing concern about the long term carcinogenic effect of the therapy. The main indication for PUVA is psoriasis, a common, chronic and intractable skin disease that affects 1 to 3% of the world's population. The effectiveness of PUVA in inducing and maintaining the remission of severe psoriasis has been amply documented. Although psoriasis is not a life-threatening disorder, it may be associated with restriction of activities and days lost to hospitalisation. Therefore, a number of systemic treatments such as methotrexate and cyclosporin have been used. None of these treatments has been as carefully studied for long term adverse effects as PUVA. The short-term adverse effects of PUVA are generally well known and tolerated. The major mid-term adverse effect, squamous cell carcinoma of the skin, has been well documented in a number of large-scale epidemiological studies that have led to recommendations such as to restrict the lifetime number of treatments. Although squamous cell carcinoma is potentially life-threatening, it is usually slow growing and can be adequately managed by proper surveillance, treatment and follow-up. The situation is quite different for malignant melanoma, which is often fast growing and fatal. Except for anecdotal reports, malignant melanoma has not been observed in PUVA patients until recently. However, a report of a cohort of 1380 patients with psoriasis has concluded that about 15 years after the first treatment the risk of melanoma is increased approximately 5-fold in patients treated with high doses. Although this report needs to be confirmed by other multicentre trials, it is alarming since the association between exposure to ultraviolet light and development of melanoma is well established both in humans and in experimental animals. Until this study is validated, it is recommended that the guidelines for PUVA therapy should be rigorously followed and that the contra-indications should be extended to include history or family history of melanoma and patients who have already received > 200 treatments.

Melanocytic naevus or malignant melanoma? A large-scale epidemiological study of diagnostic accuracy.

While the early detection of malignant melanoma is important and has been emphasized widely in the past few years, it is difficult to accomplish. The purpose of this study is to assess how well dermatologists recognize malignant melanomas in patients with naevi. Information from 9,121 patients visiting two dermatological clinics in Stockholm and diagnosed melanocytic naevi was linked with the Swedish Cancer Registry to identify individuals with records of malignant melanoma. One-hundred-and-thirteen cases of malignant melanoma were detected in the study population. Sixty patients were diagnosed malignant melanoma prior to the naevus diagnosis and most of them were under continuous follow-up. A further 35 patients were diagnosed malignant melanoma and naevus at the same time. The remaining 18 were given the diagnoses malignant melanoma after the naevus diagnosis and, of these, 6 cases were detected more than 6 years after examination and malignant melanoma was considered not present at the time of consultation. Three cases can be considered as missed (6%) and four others as partially missed or delayed. Thus, of 47 cases of probable recognizable malignant melanoma, there was insufficient management of 7 (15%). Six cases were detected during dermatological examination for other conditions and five through general examination of naevi. Although a few possibly detectable malignant melanomas were not discovered, the results of this study reflect a high clinical detection rate. In addition, a number of cases were discovered by chance during examinations for other dermatological conditions.