Systemic evaluation of cutaneous sarcoidosis: 15-year dermatology experience at University Hospital Limerick.

Sarcoidosis is a multisystem granulomatous disease that can affect almost any organ including the skin, liver, ocular, cardiac, renal, nervous, musculoskeletal and endocrine systems. Systemic evaluation is indicated in all patients diagnosed with cutaneous sarcoidosis, as it is associated with asymptomatic systemic disease in 30%-40% of patients. Guidelines recommend that patients diagnosed with sarcoidosis undergo baseline and surveillance investigations including full blood count (FBC), renal and liver profile, Vitamin D, serum calcium, electrocardiography (ECG), chest radiography, pulmonary function tests (PFTs) and ophthalmology examination to assess for systemic involvement. Recommendations for surveillance monitoring vary on interval duration but include regular FBC, biochemistry, chest radiography and PFTs, with additional investigations and prompt referral to respective specialties as indicated.. We conducted a retrospective analysis to evaluate extracutaneous involvement and systemic evaluation of patients diagnosed with cutaneous sarcoidosis during the period 2004-2020, and compared our findings with international guidelines. Cutaneous manifestation was the primary presentation for 67% of the patients (12 of 18), an extracutaneous disease subsequently developed in 67% (8 of 12) of these patients. Baseline investigations included chest radiography (94%; 17 of 18), PFTs (39%; 7 of 18), FBC (94% (17 of 18), renal profile (89%; 16 of 18), liver function tests (83%; 15 of 18) and serum calcium (89%; 16 of 18); ECG was performed for 4 (25%) of 16 patients. No Vitamin D levels were recorded. Specialist referral was required for 89% (16 of 18); of these 16 patients, 94% (15 of 16) required referral to the Respiratory Medicine department, 69% (11 of 16) to Ophthalmology and 19% (3 of 16) to Nephrology. The results highlight the importance of a structured protocol for the systemic evaluation of patients diagnosed with cutaneous sarcoidosis. We subsequently developed a baseline and surveillance protocol for the assessment of extracutaneous disease in patients at University Hospital Limerick.

An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study.

An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization.

Do vitamin A serum levels moderate outcome or the protective effect of vitamin D on outcome from malignant melanoma?

BACKGROUND & AIMS: Low serum vitamin D levels (25-OH-vit D2/3) are reported to be associated with thicker melanomas and poorer outcome. Vitamin A metabolites and vitamin D bind to the same heterodimeric receptor. We report a study testing the hypothesis that high vitamin A levels may reduce the protective effect of vitamin D on outcome. METHODS: Serum vitamin A levels were measured in 795 melanoma cases and assessed for association with Breslow thickness, overall (OS) and melanoma-specific survival (MSS), and modification of the effect of vitamin D levels on survival. RESULTS: Higher vitamin A levels (≥ 2.2 µmol/l) conferred a non-significant increased risk of melanoma-specific death (adjusted HR = 1.11, 95%CI(0.74-1.67), p = 0.60) but not for death overall (adjusted HR = 0.95, 95%CI(0.65-1.39), p = 0.79). There was reduction in the protective effect of vitamin D on OS in patients with high vitamin A levels (≥ 2.2 µmol/l)(HR = 0.99, 95%CI(0.72-1.36),p = 0.93) compared to patients with low levels (<2.2 µmol)(HR = 0.77, 95%CI(0.64-0.93),p = 0.007), although the difference was not statistically significant (p = 0.26). CONCLUSIONS: High vitamin A levels may reduce the protective effect of vitamin D. As sub-optimal levels of vitamin D are common in temperate climates, and are usually managed by dietary supplementation, we suggest vitamin D3 supplementation alone might be preferable for melanoma patients than preparations containing vitamin D and A.

Vitamin D and melanoma.

Recreational sun exposure and sunburn are causal for melanoma but the risk is strongly genetically determined. Health promotion advice about sun protection should be aimed at susceptible individuals (pale skin, freckles, large numbers of melanocytic nevi and a family history). We discuss here the evidence that sun-sensitive people have lower vitamin D levels and that, in practice, it is very difficult for such individuals to achieve sufficient levels without supplementation in the UK at least. We conclude that melanoma susceptible sun-avoidant individuals should be advised to avoid insufficiency by supplementation. Vitamin D is anti-proliferative in vitro for some melanoma cell lines. In a large melanoma cohort we have observed that lower serum 25-hydroxyvitamin D2/D3 levels at diagnosis were associated with thicker tumors and poorer prognosis (study as yet not validated). In the UK, melanoma patients commonly have sub-optimal 25-hydroxyvitamin D2/D3 levels at and post diagnosis; we discuss approaches to management of such patients based on some new data from our group.

Melanoma and vitamin D.

Vitamin D is a fat-soluble steroid hormone, which is essential to health and for which epidemiological studies suggest a role in autoimmune disease, infections, cardiovascular disease and cancer. It is ingested in foods such as oily fish and supplements, so that average levels vary between countries, but most individuals worldwide make most of their vitamin D as a result of the effects of sun exposure on the skin. Many studies in different populations around the world have in recent years shown that sub-optimal levels of vitamin D (<70 nmol/L) are common. A series of epidemiological studies have suggested that low vitamin D levels increase the risk of cancers, particularly of the breast and gastrointestinal tracts, so that there has been much interest in understanding the effects of vitamin D on cancer cells. Vitamin D binds to the vitamin D receptor (VDR) resulting in transcription of a number of genes playing a role in inhibition of MAPK signalling, induction of apoptosis and cell-cycle inhibition, and therefore vitamin D has anti-proliferative and pro-apoptotic effects in cells of many lineages. It also has suppressive effects on adaptive immunity and is reported to promote innate immunity. Here we review data on vitamin D and melanoma. There are in vitro data, which suggest that vitamin D has the same anti-proliferative effects on melanoma cells as have been demonstrated in other cells. We have reported data to suggest that vitamin D levels at diagnosis have a role in determining outcome for melanoma patients. There is a curious relationship between melanoma risk and sun exposure where sunburn is causal but occupational sun exposure is not (at least in temperate climes). Seeking to understand this, we discuss data, which suggest (but by no means prove) that vitamin D might also have a role in susceptibility to melanoma. In conclusion, much remains unknown about vitamin D in general and certainly about vitamin D and melanoma. However, the effects of avoidance of suboptimal vitamin D levels on cancer cell proliferation are likely to be beneficial to the melanoma patient. The possible results of high vitamin D levels on the immune system remain unclear however and a source of some concern, but the data support the view that serum levels in the range 70-100 nmol/L might be a reasonable target for melanoma patients as much as for other members of the population.