198 Correspondence Table 1 Gauss (G) levels at various points in and around the ultraviolet therapy cubicle Direct current Inside component enclosure Fan motor 2
30 Ballast 0
50 Adjacent to cubicle 0
02 Inside cubicle 0
02 Background 0
02

Alternating current 91
70 4
00 0
04 0
04 0
04

2 International Commission on Non-Ionizing Radiation Protection (ICNIRP). ICNIRP guidelines for limiting exposure to electric fields induced by movement of the human body in a static magnetic field and by time-varying magnetic fields below 1 Hz. Available at: http://www.icnirp.de/ (last accessed 27 March 2014). 3 Official Journal of the European Union. Directive 2103/35/EU of the European Parliament and of the Council of 26 June 2013 on the minimum health and safety requirements regarding the exposure of workers to the risks arising from physical agents (electromagnetic fields) (20th individual Directive within the meaning of Article 16(1) of Directive 89/391/EEC and repealing Directive 2004/40/EC. Available at: http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=OJ:L:2013:179:0001:0021:EN:PDF (last accessed 27 March 2014). 4 Medtronic. Electromagnetic Compatibility Table for Pacemakers and Defibrillators (ICD). Watford: Medtronic, 2010. Funding sources: None. Conflicts of interest: None declared.

Effect of narrowband ultraviolet B treatment on endocannabinoid plasma levels in patients with psoriasis DOI: 10.1111/bjd.12916

Fig 2. Ballast enclosure with cover removed.

magnetic fields > 10 G when they disable the defibrillator circuits and the pacemaker defaults to 85 beats per minute. The devices return to normal operation once the magnetic field is removed.4 As can be seen in Table 1, no DC or AC magnetic fields of any significant level > 6 G or orientation were detected at the position of the patient or adjacent to the cubicle. The only reading > 6 G was measured next to, indeed virtually touching, the fan motor with the covers removed. It is unlikely that any patient would enter the cubicle with the covers removed. Our measurements indicate that treatment in these types of UV therapy cabinets is safe for patients fitted with electrical implanted devices, such as pacemakers. Additionally, it is safe for the operators of the cubicles and any person who may accompany the patient. Leeds Teaching Hospitals Trust, Leeds LS7 4SA, U.K. E-mail: [email protected]

D. TURNER J. BRITTON N. TASSELL D. BIRD V. GOULDEN

References 1 BSI. Procedure for the Assessment of the Exposure to Electromagnetic Fields of Workers Bearing Active Implantable Medical Devices. General. BS EN 505271:2010. London: BSI, 2010. British Journal of Dermatology (2014) 171, pp190–203

DEAR EDITOR, The endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), are lipid mediators that are produced ‘on demand’ from membrane phospholipids.1 The skin has a functional endocannabinoid system (ECS).1 We have shown that this cutaneous ECS responds to ultraviolet B (UVB) irradiation.2 However, the effect of narrowband UVB (nbUVB) phototherapy on endocannabinoid plasma levels in humans is still unknown. Psoriasis has been linked to obesity and metabolic syndrome,3,4 which are conditions in which ECS dysregulation has been demonstrated.5 The relationship between systemic inflammation and obesity has been described in psoriasis and related to cardiovascular risk.4,6 Mediators, such as leptin and/or endocannabinoids, released from adipose tissue may be involved in cardiovascular disease.7 The impact of endocannabinoids on psoriasis is unknown. We evaluated endocannabinoid plasma levels in patients with psoriasis, the influence of nbUVB phototherapy on these levels, and their correlation with inflammatory and metabolic parameters and leptin levels. The regional ethical committee approved this open observational study and all participants gave informed consent. We enrolled 21 patients with plaque psoriasis and indication for phototherapy, and 15 controls matched for age, sex and body mass index (BMI). Psoriasis severity was measured by Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI). Patients were evaluated before phototherapy (baseline), after 3 weeks (W3) and 6 weeks (W6) of treatment, and 4 weeks after stopping (W10). In each evaluation © 2014 British Association of Dermatologists

© 2014 British Association of Dermatologists

Values are means  SD. BMI, body mass index; PASI, Psoriasis Area and Severity Index; DLQI, Dermatology Life Quality Index; AEA, anandamide; 2-AG, 2-arachidonoylglycerol; OEA, N-oleylethanolamine; PEA, N-palmitoylethanolamine. aP < 0
05 (W3 vs. baseline), bP < 0
05 (W6 vs. W3), cP < 0
05 (W6 vs. baseline), dP < 0
05 (W10 vs. baseline). Bold indicates significance.

3
16d 4
19d 0
13d 1
12 1
29 2
85 7
41 (4
44–31
84) 5
95 (4
44–21
67) 9
17 (6
89–31
84) 2
84 3
84 1
99 6
98 19
24 32
51 12
13 11
60 12
72

        

26
3  3
9 –

26
2 6
5 5
21 5
12 2
56 6
88 21
42 36
31 11
24 10
96 11
40

          

3
8 0
5 3
42a 5
08a 0
28 0
76 1
85 4
87 6
27 (3
67–26
26) 5
47 (4
32–18
10) 7
81 (3
67–26
26)

26
3 21
9 2
42 3
84 1
90 6
29 18
81 32
35 10
19 9
53 11
01

          

3
8 6
1 2
57b 4
29b 0
12c 0
58 1
17 2
77 5
78b (3
73–25
52) 4
72b (3
73–15
20) 7
36 (3
78–25
52)

– – – – – –

8 (38
1)/13 (61
9) 51
2  13
4 26
3  3
9 0 10
20  5
02 9
60  6
23 3
19  0
49 7
37  0
79 20
80  1
46 32
04  2
14 10
46  7
19 (2
38–27
71) 10
19  7
02 (2
38–21
78) 11
37  8
05 (3
00–27
71) 5 (33
3)/10 (66
7) 46
33  2
36 25
6  4
2 – – – 2
55  0
35 7
14  1
17 19
13  1
41 33
64  2
24 – – – Sex, women ⁄men (%) Age (years) BMI (kg m 2) UVB total dose (J cm 2) PASI DLQI AEA (pmol mL 1) 2-AG (pmol mL 1) OEA (pmol mL 1) PEA (pmol mL 1) Total leptin (ng mL 1) Leptin (ng mL 1), men Leptin (ng mL 1), women

Psoriasis W10 Psoriasis W6 Psoriasis W3 Psoriasis baseline Controls

BMI, PASI and DLQI were calculated, and fasting venous blood samples were taken in the morning for measurement of anandamide, 2-AG, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) by isotope-dilution liquid chromatography–atmospheric pressure chemical ionization mass spectrometry as described.5 Fasting plasma leptin was determined with an enzyme-linked immunosorbent assay kit (Millipore, Billerica, MA, U.S.A.). The nbUVB irradiation (311  2 nm) was administered (Waldmann-7001-cabin, UVB-TL01; Waldmannn Medizintechnik, Villigen-Schwenningen, Germany); the initial dose was 0
3–0
5 J cm 2, increasing 0
1 J cm 2 in every session (three times weekly for 6 weeks) until reaching a dose of 2
0 J cm 2. Data are presented as means  SD, and ANOVA with repeated measures was used to determine statistical significance. P-values < 0
05 were considered significant. Correlation analysis was performed by calculating the Spearman coefficient of correlation. Endocannabinoid plasma levels did not differ significantly between controls and patients, and both groups had a mean BMI > 25 kg m 2 (Table 1). Before phototherapy, high-sensitivity C-reactive protein (hsCRP) levels were positively correlated with BMI (R2 = 0
29; P = 0
02) and low-density lipoprotein cholesterol (R2 = 0
43; P = 0
004), and negatively with high-density lipoprotein cholesterol (R2 = 0
23; P = 0
04). No correlation was observed between PASI score and hsCRP or CRP values. Anandamide plasma levels significantly decreased after phototherapy (P < 0
001) (Fig. 1). The percentage of decrease in anandamide from baseline to W6 was positively correlated with BMI (R2 = 0
35; P = 0
006) and with anandamide levels before phototherapy (R2 = 0
57; P = 0
0002), but no correlation was found with PASI. No significant nbUVB effect on the levels of the other endocannabinoids and related mediators was found (Table 1). Regarding metabolic and inflammatory parameters, there was no significant effect of phototherapy. A slight reduction of leptin levels was observed in men (Table 1). A positive correlation was seen between baseline hsCRP and anandamide levels (R2 = 0
63; P = 0
002). No correlation was found between baseline endocannabinoid, OEA and PEA levels and other clinical and metabolic parameters. This study provides evidence that nbUVB phototherapy in patients with psoriasis decreases plasma levels of anandamide without changing the levels of 2-AG, OEA or PEA. Around 65% of the studied patients were overweight. The decrease in anandamide levels was positively correlated with baseline BMI. Elevated circulating anandamide levels are associated with coronary dysfunction in obese people and proposed as a novel cardiovascular risk factor.7 The observed UVB-induced anandamide decrease might, therefore, suggest a beneficial effect of phototherapy in patients with psoriasis at cardiovascular risk. However, this hypothesis, which needs further investigation, is supported by the observation that baseline anandamide levels were positively correlated with hsCRP, a biomarker for both cardiovascular events and inflam-

Table 1 Characteristics and endocannabinoid, OEA and PEA levels of controls and patients with psoriasis before phototherapy (psoriasis baseline), 3 weeks (W3) and 6 weeks (W6) after narrowband ultraviolet B (nbUVB) phototherapy three times weekly and 1 month after the last nbUVB exposure (W10)

Correspondence 199

British Journal of Dermatology (2014) 171, pp190–203

200 Correspondence

inflammation.9 However, the mechanism by which UVB might specifically alter anandamide remains to be explored. It will be important to evaluate the influence of other psoriasis treatments on endocannabinoid plasma levels in order to clarify whether the UVB-induced decrease of anandamide plasma levels is a radiation effect per se or is related to disease remission.

Acknowledgments We thank the participants for their contribution to the study. We also thank all the nursing staff from our Dermatology Department for their help in the project. A special thanks to Carla Vieira for helping with the study. 1

Fig 1. Plasma anandamide levels in patients with psoriasis (n = 21) before (baseline) and 3 and 6 weeks after narrowband ultraviolet B phototherapy three times weekly. **P < 0
01.

mation. In another study,7 only anandamide plasma levels were correlated with CRP and an endocannabinoid-mediated association between metabolic and inflammatory cardiovascular disease mechanisms was proposed. The link between psoriasis and cardiovascular risk depends on disease severity.8 A limitation of our study was that patient profiles corresponded with those of candidates for phototherapy and, therefore, subjects with severe disease were not represented. This might explain why anandamide levels were not different between patients with psoriasis and controls, possibly also because the two populations were both overweight. Despite the good clinical response to UVB, no correlation was observed between endocannabinoid levels and disease activity. Despite the role of endocannabinoids in metabolic syndrome, in our populations no correlation was observed between endocannabinoid levels and leptin or metabolic parameters. Indeed, some of these correlations have been found so far only for obese patients (BMI ≥ 30) and/or only for 2-AG.5 Unlike 2-AG, anandamide, OEA and PEA are all N-acylethanolamines and share similar metabolic pathways.9 Therefore, it was somewhat surprising not to find similar changes for OEA and PEA as with anandamide, considering that for both compounds anti-inflammatory actions mediated by noncannabinoid receptors have been reported.10 This finding might suggest that the observed changes specifically reflect, or impact on, the activity of the ECS, thus supporting their possible relevance to psoriasis- and cardiovascular-related British Journal of Dermatology (2014) 171, pp190–203

S. MAGINA1,2,3 Department of Pharmacology and Therapeutics, Faculty of Medicine and M.A. VIEIRA-COELHO1,2 2 MedInUP, Center for Drug Discovery and E. MOURA1 Innovative Medicines, University of Porto, M . P . S E R R A~O 1 , 2 4200-319 Porto, Portugal F. PISCITELLI4,5 3 Dermatology and Venereology Department, D. MOURA1,2 4 H. S. Jo~ao, Endocannabinoid Research V. DI MARZO4,5 5 Group; and Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, NA, Italy E-mail: [email protected]

References 1 Biro T, Toth BI, Hasko G et al. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci 2009; 30:411–20. 2 Magina S, Esteves-Pinto C, Moura E et al. Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB(1) receptors: a keratinocyte-dependent effect. Arch Dermatol Res 2011; 303:201–10. 3 Kaur S, Zilmer K, Leping V et al. The levels of adiponectin and leptin and their relation to other markers of cardiovascular risk in patients with psoriasis. J Eur Acad Dermatol Venereol 2011; 25:1328–33. 4 Reich K. The concept of psoriasis as a systemic inflammation: implications for disease management. J Eur Acad Dermatol Venereol 2012; 26 (Suppl. 2):3–11. 5 Cote M, Matias I, Lemieux I et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond) 2007; 31:692–9. 6 Boehncke WH, Boehncke S, Tobin AM et al. The ‘psoriatic march’: a concept of how severe psoriasis may drive cardiovascular comorbidity. Exp Dermatol 2011; 20:303–7. 7 Quercioli A, Pataky Z, Vincenti G et al. Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J 2011; 32:1369–78. 8 Yiu KH, Yeung CK, Chan HT et al. Increased arterial stiffness in patients with psoriasis is associated with active systemic inflammation. Br J Dermatol 2011; 164:514–20. 9 Petrosino S, Ligresti A, Di Marzo V. Endocannabinoid chemical biology: a tool for the development of novel therapies. Curr Opin Chem Biol 2009; 13:309–20.

© 2014 British Association of Dermatologists

Correspondence 201 10 Petrosino S, Iuvone T, Di Marzo V. N-palmitoyl-ethanolamine: biochemistry and new therapeutic opportunities. Biochimie 2010; 92:724–7. Funding sources: None. Conflicts of interest: None declared.

Concurrent cutaneous polyarteritis nodosa and arteritis temporalis in a 68-year-old woman DOI: 10.1111/bjd.12907 DEAR EDITOR, Cutaneous polyarteritis nodosa (CPN) is a rare vasculitis affecting the small and medium arteries in the reticular dermis and subcutaneous tissue. CPN should be distinguished from systemic polyarteritis nodosa (PAN), which is an aggressive systemic vasculitis with internal organ involvement. Extracutaneous findings of CPN include fever, myalgia, arthralgia and neuropathy.1 In contrast, temporal arteritis (TA) or giant-cell arteritis (GCA) is a vasculitis that involves the medium and large arteries, and may develop together with polymyalgia rheumatica.2 An overlapping vasculitic syndrome of PAN and TA has been reported in the literature.3–8 To our knowledge, CPN with TA has only been described in one previous case report.9 We report a 68-year-old woman who presented with livedo reticularis with necrotic centres in a starburst pattern on the back, chest and upper arms of 3-week duration (Fig. 1). Extracutaneous findings included fever, myalgia and weakness in the thighs. She had no other neurological symptoms or symptoms from the gastrointestinal or genitourinary tract. She also denied having any cardiopulmonary symptoms. Her medical history included long-term treatment for depression. A punch biopsy was performed on the upper arm and she was started

on prednisolone 50 mg daily. Laboratory tests revealed normal haemoglobin, slightly elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and leucocytosis. Urine analysis, s-creatinine, glomerular filtration rate and creatine kinase were normal. Hepatitis A, B and C serology were negative. Immunoglobulin levels, cryoglobulins, antinuclear antibody, antineutrophil cytoplasmic antibody and rheumatoid factor were normal. Echocardiography and bone marrow aspirate were normal. A computed tomography (CT) scan of the chest, abdomen and pelvis showed no sign of malignancy. A 18F-fluorodeoxyglucose–positron emission tomography scan revealed a rectal adenoma, which was surgically removed. Histology of the punch biopsy showed vasculitis in the small and medium arteries in subcutaneous tissue (Fig. 2a, b), which are typical findings of PAN. An abdominal angiography showed no involvement of the abdominal vessels. A revised final diagnosis of CPN was made. The patient improved on prednisolone treatment, which was tapered off over the next few months. The cutaneous ulcers healed and the other symptoms disappeared. She had no further relapse. Eight months later, she presented with low-back pain along with nausea and weight loss. She had fever, moderate leucocytosis, elevated CRP and high ESR. Physical examination of the abdomen revealed right upper quadrant tenderness with hepatomegaly. She was admitted and started on intravenous antibiotics but did not improve. A CT scan of the chest, abdomen and pelvis showed slight dilatation of the ductus choledochus. Magnetic resonance cholangiopancreatography only revealed a number of liver cysts. After 2 days she complained of tenderness of the scalp. Physical examination revealed infiltration of the temples on both sides. She had no other symptoms of TA. A right temporal artery biopsy was performed showing inflammatory cell infiltration in relation to the internal elastic lamina with a few multinucleate giant cells and some lymphocytes – typical histological findings of TA (Fig. 2c, d). She responded to oral prednisone 50 mg daily with complete resolution of her symptoms. At 10-month

(a)

(b)

Fig 1. Clinical presentation of livedo reticularis with necrotic centres in a starburst pattern on (a) the chest and upper arms and (b) the back. © 2014 British Association of Dermatologists

British Journal of Dermatology (2014) 171, pp190–203