JEADV
DOI: 10.1111/jdv.13023
ORIGINAL ARTICLE
Homocysteine plasma levels in psoriasis patients: our experience and review of the literature M. Giannoni,† V. Consales,† A. Campanati,* G. Ganzetti, K. Giuliodori, V. Postacchini, G. Liberati, L. Azzaretto, S.Vichi, F. Guanciarossa, A. Offidani Dermatological Unit, Department of Clinical and Molecular Sciences, Polytechnic University of the Marche Region, Ancona, Italy * Correspondence: A. Campanati. E-mail: [email protected] and [email protected]
Abstract Background People with psoriasis are at higher cardiovascular risk. Plasma levels of homocysteine over the normal range have been recognized as marker of cardiovascular risk. Psoriasis patients express higher levels of plasma homocysteine than healthy people. Objective Our study aims to investigate the correlation between homocysteinaemia, severity and duration of psoriasis and psoriasis arthritis, and to evaluate the effect of a 12-week administration of a target therapy for psoriasis on homocysteinaemia. Methods Fifty-two psoriasis patients (study group) submitted to different kind of therapy for psoriasis (biological, systemic not biological and topical) and 24 healthy Italian subject (control group) were evaluated for their plasmatic homocysteine levels, both at baseline (T0) and 12 weeks after they a specific therapy for psoriasis. Results A significant difference between the homocysteinaemia of psoriasis patients (mean 19.71 11.16) and control group (13.90 11.18), P < 0.05 (Fig. 1), was found at baseline (T0). The mean plasma levels of homocysteine were directly correlated with disease severity (P = 0.0401), but not with disease duration (P = 0.6018) or presence of arthritis (P = 0.6221) at baseline. None among the treatments administered to psoriasis patients caused a significant reduction in homocysteinaemia after 12 weeks of treatment. Conclusion Our results confirm that psoriasis patients with more severe disease, can have hyperhomocysteinaemia, without regard to disease duration or joint involvement. Hyperhomocysteinaemia is not influenced by a target therapy for psoriasis and it is as greater as psoriasis severity. However, limitation of our study is the relatively small number of cases. Homocysteine plasmatic levels should be advisable as a further independent risk factor for cardiovascular disease in psoriasis patients. Received: 10 September 2014; Accepted: 12 January 2015
Conflicts of Interest None declared.
Funding Sources None declared.
Introduction Psoriasis is a Th1–Th17 immune mediated and inflammatory disease with a worldwide prevalence of 1–2%.1 Psoriasis derives from a complex interaction between genetic background, environmental factors and immune response, which leads to a chronic, low-grade inflammatory status. ‘The psoriatic march’, is a new intriguing model describing the psoriasis progression over time, focusing on the way how chronic and persistent inflammatory status could drive to skin lesions firstly, and then to cardiovascular comorbidities. In this model, the role †
The two authors equally contributed to the manuscript.
JEADV 2015
of several pro-inflammatory cytokines (TNF-alpha, IL6, IL17, IL20, IL23) in driving psoriasis towards cardiovascular comorbidities has been well described.2 However, the risk of cardiovascular comorbidities in psoriasis has been attributed also to many other independent risk factors including obesity, hypertension, smoking, dyslipidaemia, diabetes mellitus and increased levels of homocysteinaemia3 and mean platelet volume.4 Elevated plasma levels of homocysteinaemia is also considered a risk factor for venous thrombosis.5 Despite all data from literature agree that psoriatic patients have lower plasmatic levels of folate and conversely higher plasmatic levels of homocysteine, the correlation between homo-
© 2015 European Academy of Dermatology and Venereology
Giannoni et al.
2
Homocysteine
80
Disease activity evaluation
Psoriasis diagnosis was clinically made by a trained dermatologist, disease severity/extension was evaluated by Psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA) score derived from the mean of two indexes calculated by two independent trained dermatologists.
60 40
P = 0.0003
20
Laboratory evaluations
s ol tr on C
Ps
or
ia tic s
0
Figure 1 Homocysteine plasmatic levels in psoriasis patients vs. healthy subjects.
cysteine plasmatic levels and psoriasis remains controversial: some authors demonstrated a direct proportionality between them,6,7 others failed to find it,8,9 moreover other authors reported a relationship between homocysteine plasmatic levels and psoriasis duration.10 Primary aims of this study are to investigate the correlation between homocysteine plasmatic levels and severity and duration of psoriasis and psoriatic arthritis. Secondary aim of the study is to evaluate if the administration of a specific psoriasis therapy, for 12 weeks, can modulate the plasmatic levels of homocysteine in psoriatic patients.
Materials and methods
Venous blood samples were taken from all included subjects in a fasting state at T0, and after twelve weeks (T12) of treatment whit biologics or not biological systemic agents or skin direct therapy alone. All samples were submitted to the laboratory analysis of United Hospitals of Ancona and the plasmatic homocysteine concentration was determined by chemiluminescent microparticle immunoassay (CMIA). According to the normal range of homocysteine (5–15 lmol/L) hyperhomocysteinaemia was set at plasma levels >15 lmol/L. Statistical analysis
Data were analysed using Graph-Pad Prism (version 5.0, El Camino REAL, SAN Diego, CA, USA). The distribution of variables, taken into consideration, was evaluated for both study and control groups (Gaussian vs. nonGaussian). The individual parameters were expressed as mean SD. The percentage change of parameters was calculated through a percentage change calculator. The analysed variables were compared between groups of patients selected by the use of multivariate statistical analysis one-way ANOVA non-parametric tests (Mann–Whitney test), and correlation test was used to evaluate the relationship between analysed variables. An interval of confidence of 95% (P < 0.05) was considered for statistical significance.
Study design
The study is a prospective, non-randomized case–control analysis approved by Polytechnic Marche University Ethical Committee, and conducted in accordance with the Declaration of Helsinski.
Results According to the inclusion and exclusion criteria, the study comprised 52 patients suffering from psoriasis: 25 female and 27
Study population
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80 P = 0.0401
Homocysteine
One hundred and fifty-four out-patients with stable, chronic plaque type psoriasis consecutively attended the Dermatological Department of the Polytechnic Marche University from Jan 2012 to Jan 2013. Fifty-two patients met all the above mentioned tabulated criteria and were thus included into the study. No stratification according to psoriasis subtype has been made, however cases of drug-induced psoriasis have been excluded. Twenty-four healthy Italian patients, referring to Dermatological outpatient for melanoma screening and matched for demographic characteristics were recruited to set the control group.
r = 0.2856
60 40 20 0 0
10
20
PASI
30
40
Figure 2 Plasmatic levels of homocysteine and disease severity.
© 2015 European Academy of Dermatology and Venereology
Homocysteine plasma levels in psoriatic patients
25
BT
P > 0.05
20
P > 0.05
SNBT
3
SDT
P > 0.05
15 10
Post
Pre
Post
Pre
Post
0
Pre
5
Figure 3 Reduction of homocysteinaemia serum levels after twelve weeks of therapy.
Males, mean age 49 years (range 18–78) and 38 healthy subjects, mean age 51.7 years (range 19–75) as controls. Among psoriatic patients, 38 receive biological therapy (26 Etanercept, 10 Adalimumab, two Ustekinumab), 10 systemic therapy (five Cyclosporin, three Acitretin, two Methotrexate supplemented with folates) and four local therapy (one UVAtherapy and three UVB-nb). The mean plasma levels of homocysteine in psoriasis patients (mean 19.71 11.16) were significantly higher than in and control group (13.90 11.18) (P = 0.0003; Fig. 1). We found a statistically significant correlation between the plasmatic levels of homocysteine and disease severity (P = 0.0401; r = 0.2856; Fig. 2), but no correlations were found between homocysteinaemia and disease duration (P = 0.6018) or presence of arthritis (P = 0.6221) at baseline. Psoriasis patients were then addressed into three different therapy groups: biological treatments (BT), systemic not biological treatments (NBT), and skin-directed treatments (SDT); none among the administered treatments (including also patients receiving folate supplementation and methotrexate) caused a significant percentage reduction of homocysteinaemia after 12 weeks (T12) (Fig. 3). Moreover no statistically significant differences were found between of homocysteine plasmatic level among the three groups at T12.
Discussion Homocysteine is a sulphur-containing amino acid metabolized by remethylation to methionine or by trans-sulphuration to cysteine via cystathionine,11 it derives from the normal metabolism of proteins, its increase can lead to damage of endothelial cells.12 Plasmatic homocysteine can promote atherosclerotic disease, including coronary disease, stroke and peripheral vascular disease16 through several mechanisms: damage of endothelial cells, decreased flexibility of blood vessels leading to aortic stiffness and to reduction of the speed of blood flow,13 reduced production of the vasodilator nitric oxide (NO), a well-known protec-
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tive agent for blood vessels against atherosclerosis and thrombosis.13,14 A meta-analysis of cross-sectional epidemiological studies has pointed out that a 5 lmol homocysteine plasma rate increase gives up to 60% higher prevalence of ischaemic heart disease.15 Some studies demonstrated that the treatment of hyperhomocysteinaemia reduces atherosclerotic plaque area, with a decrease in the risk of deepvein thrombosis (DVT), stroke and ischaemic heart disease.16 Moreover experimental induction of hyperhomocysteinaemia brings down endothelial cells function, especially after the administration of 10– 20 lmol/L.17,18 In this study we found a higher prevalence of hyperhomocysteinaemia (>15 lmol/L) in psoriasis patients (19.71 11.16) than healthy controls (13.90 11.18): this could suggest that the management of cardiovascular risk in psoriatic patients should consider homocysteine plasmatic levels in addition to the traditional parameters (obesity, smoking, hyperglycaemia, hyperlipidaemia and hyperhomocysteinaemia).19 Our results at baseline are in agreement with the majority of the studies in the current literature. Refsum et al.20 studied plasma homocysteine and folic acid levels in 13 severe psoriasis cases, reporting higher levels of homocysteine and lower levels of folic acid compared with healthy controls. They concluded that increased homocysteine level might be due to the rapid proliferative germinative cell layer. Vanizor Kural et al.21 studied plasma homocysteine and its relationship with atherothrombotic markers in 30 psoriasis patients. They found higher plasmatic homocysteine and lower vitamin B12 and folic acid levels, concluding that the increased homocysteine plasmatic concentration may play an important role for the development of atherothrombotic complications with psoriasis. Malerba et al.6 have suggested that patients with psoriasis might have a tendency to develop hyperhomocysteinaemia, which could predispose them to higher cardiovascular risk. They studied plasma homocysteine, folic acid and vitamin B6 and B12 levels in 40 psoriasis patients and they reported higher homocysteine and lower folic acid levels in psoriasis patients when compared with control group. The lower levels of vitamin B12 and folate often observed in psoriasis patients could depend from an increased vitamins need by psoriasis keratinocytes with high turnover rate, and from microscopic inflammatory changes in colon mucosa that may be responsible for folic acid malabsorption. In their study, Tobin AM et al.22 reported that plasmatic homocysteine level was not directly correlated with psoriasis severity index, conversely in our study we have seen a correlation between Psoriasis Area and Severity Index and homocysteine levels (P = 0.0401), as previously reported by Cakmak et al.7 This discrepancy could be related to the different spectrum of disease severity included into the reported studies.
© 2015 European Academy of Dermatology and Venereology
Giannoni et al.
4
We failed to find any correlation between disease duration, in contrast with other authors reporting a relationship between homocysteine plasmatic levels and psoriasis duration.10 Since psoriatic arthritis has an important inflammatory background23 and homocysteine is directly involved in the inflammatory ‘psoriasis march’, a correlation between psoriasis arthritis and prevalence of hyperhomocysteinaemia could be expected, however the serum levels of homocysteine in patients with psoriasis arthritis did not differ from those found in psoriasis patients without arthritis. This could be due to the good compensation of the arthritis status in the included patients. Several studies evaluated the impact of therapy on global metabolic condition in psoriasis patients as well.24–32 Sattar et al.33 were the first to demonstrate that anti-TNF-alpha drugs can significantly decrease some cardiovascular risks markers as Lp(a), ApoA-I, SHBG and homocysteine concentration. Also Wakke et al.34 reported on the positive effects of systemic treatments in reducing dyslipidaemia, hypertension and hyperhomocysteinaemia, oxidative stress, and endothelial cell dysfunction in psoriasis patients. In our experience, the administration of a12-week-long systemic treatment for psoriasis do not influence the plasmatic levels of homocysteine. Our results seem to confirm that psoriasis patients could have hyperhomocysteinaemia as risk factor for cardiovascular diseases, especially those with higher severity psoriasis. Thus, in addition to the traditional parameters, the evaluation of homocysteine plasmatic levels should be advisable in psoriasis patient with severe disease. Owing to the fact that this is a single centre study, its major limitation is the relatively small number of reported cases. Our preliminary results seem to indicate that systemic therapies appear do not influence the homocysteinaemia status, however further studies are needed to clarify the role of TNF-alpha inhibitors on homocysteine plasma levels, and the use of an implementation therapy with folates and vitamine B12, and the role of hyperhomocysteinaemia in the global cardiovascular risk factor of psoriasis patients. Finally dermatologists should be aware about the opportunity to evaluate the homocysteine plasma levels in psoriatic patients.
References 1 Siow KY, Safdar NA, Chong KH et al. A clinical appraisal of patients with psoriasis treated in Seremban General Hospital, Malaysia. Med J Malaysia 2004; 59: 330–334. 2 Orciani M, Campanati A, Salvolini E et al. The mesenchymal stem cell profile in psoriasis. Br J Dermatol 2011; 165: 585–592. 3 Bardazzi F, Balestri R, Baldi E et al. Correlation between BMI and PASI in patients affected by moderate to severe psoriasis undergoing biological therapy. Dermatol Ther 2010; 23(Suppl. 1): S14–S19. 4 Capo A, Di NM, Auriemma M et al. Mean platelet volume variation after biologic therapy in psoriasis and psoriatic arthritis. Eur J Dermatol 2014; 24: 133–135.
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5 Quere I, Gris JC, Dauzat M. Homocysteine and venous thrombosis. Semin Vasc Med 2005; 5: 183–189. Review. 6 Malerba M, Gisondi P, Radaeli A et al. Plasma homocysteine and folate levels in patients with chronic plaque psoriasis. Br J Dermatol 2006; 155: 1165–1169. 7 Cakmak SK, Gul U, Kilic C et al. Homocysteine, vitamin B12 and folic acid levels in psoriasis patients. J Eur Acad Dermatol Venereol 2009; 23: 300–303. 8 Tobin AM, Hughes R, Hand EB et al. Homocysteine status and cardiovascular risk factors in patients with psoriasis: a case-control study. Clin Exp Dermatol 2011; 36: 19–23. 9 Brazzelli V, Grasso V, Fornara L et al. Homocysteine, vitamin B12 and folic acid levels in psoriatic patients and correlation with disease severity. Int J Immunopathol Pharmacol 2010; 23: 911–916. 10 Gisondi P, Tessari G, Conti A et al. Prevalence of metabolic syndrome in patients with psoriasis: a hospital-based case-control study. Br J Dermatol 2007; 157: 68–73. 11 Herrmann W, Quast S, Ullrich M et al. Hyperhomocysteinemia in highaged subjects: relation of B-vitamins, folic acid, renal function and the methylenetetrahydrofolate reductase mutation. Atherosclerosis 1999; 144: 91–101. 12 Baszczuk A, Kopczynski Z, Thielemann A. Endothelial dysfunction in patients with primary hypertension and hyperhomocysteinemia. Postepy Hig Med Dosw 2014; 68: 91–100. 13 Stuhlinger MC, Oka RK, Graf EE et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation 2003; 108: 933–938. 14 Stuhlinger MC, Stanger O. Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction. Curr Drug Metab 2005; 6: 3–14. 15 Boushey CJ, Beresford SA, Omenn GS et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049–1057. 16 Peterson JC, Spence JD. Vitamins and progression of atherosclerosis in hyper-homocyst(e)inaemia. Lancet 1998; 351: 263. 17 Kanani PM, Sinkey CA, Browning RL et al. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 1999; 100: 1161–1168. 18 Schnyder G, Roffi M, Pin R et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345: 1593–1600. 19 Capo A, Di Nicola M, Auriemma M et al. Mean platelet volume variation after biologic therapy in psoriasis and psoriatic arthritis. Eur J Dermatol 2014; 24: 133–135. 20 Refsum H, Helland S, Ueland PM. Fasting plasma homocysteine as a sensitive parameter of antifolate effect: a study of psoriasis patients receiving low-dose methotrexate treatment. Clin Pharmacol Ther 1989; 46: 510–520. 21 Vanizor KB, Orem A, Cimsit G et al. Plasma homocysteine and its relationships with atherothrombotic markers in psoriatic patients. Clin Chim Acta 2003; 332: 23–30. 22 Tobin AM, Veale DJ, Fitzgerald O et al. Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis. J Rheumatol 2010; 37: 1386–1394. 23 Gonzalez-Gay MA, Gonzalez-Juanatey C, Llorca J et al. The influence of inflammation in the development of subclinical atherosclerosis in psoriatic arthritis: comment on ‘Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review’ by Jamnistki et al. Ann Rheum Dis 2014; 73: e27. 24 De Simone C, Amerio P, Amoruso G et al. Immunogenicity of anti-TNFalpha therapy in psoriasis: a clinical issue? Expert Opin Biol Ther 2013; 13: 1673–1682. 25 Campanati A, Ganzetti G, Di Sario A et al. Insulin resistance, serum insulin and HOMA-R. J Gastroenterol 2013; 48: 673. 26 Campanati A, Orciani M, Gorbi S et al. Effect of biologic therapies targeting tumour necrosis factor-alpha on cutaneous mesenchymal stem cells in psoriasis. Br J Dermatol 2012; 167: 68–76.
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Homocysteine plasma levels in psoriatic patients
27 Campanati A, Moronicini G, Ganzetti G et al. Adalimumab modulates angiogenesis in psoriatic skin. Eur J Inflamm 2013; 2: 489–498. 28 Campanati A, Ganzetti G, Di Sario A et al. The effect of etanercept on hepatic fibrosis risk in patients with non-alcoholic fatty liver disease, metabolic syndrome, and psoriasis. J Gastroenterol 2013; 48: 839–846. 29 Ganzetti G, Campanati A, Offidani A. Alopecia Areata: a possible extraintestinal manifestation of Crohn’s disease. J Crohns Colitis. 2012; 6(9): 962–3. 30 Ferretti G, Bacchetti T, Campanati A, Simonetti O, Liberati G, Offidani A. Correlation between lipoprotein(a) and lipid peroxidation in psoriasis: role of the enzyme paraoxonase-1. Br J Dermatol. 2012; 166(1): 204–7. 31 Campanati A, Goteri G, Simonetti O, Ganzetti G, Giuliodori K, Giuliano A, Sabato S, Stramazzotti D, Gulini E, Dusi D, De Blasio S, Fabris G,
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Offidani A. Angiogenesis in psoriatic skin and its modifications after administration of etanercept: videocapillaroscopic, histological and immunohistochemical evaluation. Int J Immunopathol Pharmacol. 2009; 22(2): 371–7. 32 Campanati A, Giuliodori K, Ganzetti G et al. A patient with psoriasis and vitiligo treated with etanercept. Am J Clin Dermatol 2010; 11(Suppl. 1): 46–48. 33 Sattar N, Crompton P, Cherry L et al. Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: a double-blind, placebo-controlled study. Arthritis Rheum 2007; 56: 831– 839. 34 Wakkee M, Thio HB, Prens EP, et al. Unfavorable cardiovascular risk profiles in untreated and treated psoriasis patients. Atherosclerosis 2007; 190: 1–9.
© 2015 European Academy of Dermatology and Venereology
DOI: 10.1111/jdv.13023
ORIGINAL ARTICLE
Homocysteine plasma levels in psoriasis patients: our experience and review of the literature M. Giannoni,† V. Consales,† A. Campanati,* G. Ganzetti, K. Giuliodori, V. Postacchini, G. Liberati, L. Azzaretto, S.Vichi, F. Guanciarossa, A. Offidani Dermatological Unit, Department of Clinical and Molecular Sciences, Polytechnic University of the Marche Region, Ancona, Italy * Correspondence: A. Campanati. E-mail: [email protected] and [email protected]
Abstract Background People with psoriasis are at higher cardiovascular risk. Plasma levels of homocysteine over the normal range have been recognized as marker of cardiovascular risk. Psoriasis patients express higher levels of plasma homocysteine than healthy people. Objective Our study aims to investigate the correlation between homocysteinaemia, severity and duration of psoriasis and psoriasis arthritis, and to evaluate the effect of a 12-week administration of a target therapy for psoriasis on homocysteinaemia. Methods Fifty-two psoriasis patients (study group) submitted to different kind of therapy for psoriasis (biological, systemic not biological and topical) and 24 healthy Italian subject (control group) were evaluated for their plasmatic homocysteine levels, both at baseline (T0) and 12 weeks after they a specific therapy for psoriasis. Results A significant difference between the homocysteinaemia of psoriasis patients (mean 19.71 11.16) and control group (13.90 11.18), P < 0.05 (Fig. 1), was found at baseline (T0). The mean plasma levels of homocysteine were directly correlated with disease severity (P = 0.0401), but not with disease duration (P = 0.6018) or presence of arthritis (P = 0.6221) at baseline. None among the treatments administered to psoriasis patients caused a significant reduction in homocysteinaemia after 12 weeks of treatment. Conclusion Our results confirm that psoriasis patients with more severe disease, can have hyperhomocysteinaemia, without regard to disease duration or joint involvement. Hyperhomocysteinaemia is not influenced by a target therapy for psoriasis and it is as greater as psoriasis severity. However, limitation of our study is the relatively small number of cases. Homocysteine plasmatic levels should be advisable as a further independent risk factor for cardiovascular disease in psoriasis patients. Received: 10 September 2014; Accepted: 12 January 2015
Conflicts of Interest None declared.
Funding Sources None declared.
Introduction Psoriasis is a Th1–Th17 immune mediated and inflammatory disease with a worldwide prevalence of 1–2%.1 Psoriasis derives from a complex interaction between genetic background, environmental factors and immune response, which leads to a chronic, low-grade inflammatory status. ‘The psoriatic march’, is a new intriguing model describing the psoriasis progression over time, focusing on the way how chronic and persistent inflammatory status could drive to skin lesions firstly, and then to cardiovascular comorbidities. In this model, the role †
The two authors equally contributed to the manuscript.
JEADV 2015
of several pro-inflammatory cytokines (TNF-alpha, IL6, IL17, IL20, IL23) in driving psoriasis towards cardiovascular comorbidities has been well described.2 However, the risk of cardiovascular comorbidities in psoriasis has been attributed also to many other independent risk factors including obesity, hypertension, smoking, dyslipidaemia, diabetes mellitus and increased levels of homocysteinaemia3 and mean platelet volume.4 Elevated plasma levels of homocysteinaemia is also considered a risk factor for venous thrombosis.5 Despite all data from literature agree that psoriatic patients have lower plasmatic levels of folate and conversely higher plasmatic levels of homocysteine, the correlation between homo-
© 2015 European Academy of Dermatology and Venereology
Giannoni et al.
2
Homocysteine
80
Disease activity evaluation
Psoriasis diagnosis was clinically made by a trained dermatologist, disease severity/extension was evaluated by Psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA) score derived from the mean of two indexes calculated by two independent trained dermatologists.
60 40
P = 0.0003
20
Laboratory evaluations
s ol tr on C
Ps
or
ia tic s
0
Figure 1 Homocysteine plasmatic levels in psoriasis patients vs. healthy subjects.
cysteine plasmatic levels and psoriasis remains controversial: some authors demonstrated a direct proportionality between them,6,7 others failed to find it,8,9 moreover other authors reported a relationship between homocysteine plasmatic levels and psoriasis duration.10 Primary aims of this study are to investigate the correlation between homocysteine plasmatic levels and severity and duration of psoriasis and psoriatic arthritis. Secondary aim of the study is to evaluate if the administration of a specific psoriasis therapy, for 12 weeks, can modulate the plasmatic levels of homocysteine in psoriatic patients.
Materials and methods
Venous blood samples were taken from all included subjects in a fasting state at T0, and after twelve weeks (T12) of treatment whit biologics or not biological systemic agents or skin direct therapy alone. All samples were submitted to the laboratory analysis of United Hospitals of Ancona and the plasmatic homocysteine concentration was determined by chemiluminescent microparticle immunoassay (CMIA). According to the normal range of homocysteine (5–15 lmol/L) hyperhomocysteinaemia was set at plasma levels >15 lmol/L. Statistical analysis
Data were analysed using Graph-Pad Prism (version 5.0, El Camino REAL, SAN Diego, CA, USA). The distribution of variables, taken into consideration, was evaluated for both study and control groups (Gaussian vs. nonGaussian). The individual parameters were expressed as mean SD. The percentage change of parameters was calculated through a percentage change calculator. The analysed variables were compared between groups of patients selected by the use of multivariate statistical analysis one-way ANOVA non-parametric tests (Mann–Whitney test), and correlation test was used to evaluate the relationship between analysed variables. An interval of confidence of 95% (P < 0.05) was considered for statistical significance.
Study design
The study is a prospective, non-randomized case–control analysis approved by Polytechnic Marche University Ethical Committee, and conducted in accordance with the Declaration of Helsinski.
Results According to the inclusion and exclusion criteria, the study comprised 52 patients suffering from psoriasis: 25 female and 27
Study population
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80 P = 0.0401
Homocysteine
One hundred and fifty-four out-patients with stable, chronic plaque type psoriasis consecutively attended the Dermatological Department of the Polytechnic Marche University from Jan 2012 to Jan 2013. Fifty-two patients met all the above mentioned tabulated criteria and were thus included into the study. No stratification according to psoriasis subtype has been made, however cases of drug-induced psoriasis have been excluded. Twenty-four healthy Italian patients, referring to Dermatological outpatient for melanoma screening and matched for demographic characteristics were recruited to set the control group.
r = 0.2856
60 40 20 0 0
10
20
PASI
30
40
Figure 2 Plasmatic levels of homocysteine and disease severity.
© 2015 European Academy of Dermatology and Venereology
Homocysteine plasma levels in psoriatic patients
25
BT
P > 0.05
20
P > 0.05
SNBT
3
SDT
P > 0.05
15 10
Post
Pre
Post
Pre
Post
0
Pre
5
Figure 3 Reduction of homocysteinaemia serum levels after twelve weeks of therapy.
Males, mean age 49 years (range 18–78) and 38 healthy subjects, mean age 51.7 years (range 19–75) as controls. Among psoriatic patients, 38 receive biological therapy (26 Etanercept, 10 Adalimumab, two Ustekinumab), 10 systemic therapy (five Cyclosporin, three Acitretin, two Methotrexate supplemented with folates) and four local therapy (one UVAtherapy and three UVB-nb). The mean plasma levels of homocysteine in psoriasis patients (mean 19.71 11.16) were significantly higher than in and control group (13.90 11.18) (P = 0.0003; Fig. 1). We found a statistically significant correlation between the plasmatic levels of homocysteine and disease severity (P = 0.0401; r = 0.2856; Fig. 2), but no correlations were found between homocysteinaemia and disease duration (P = 0.6018) or presence of arthritis (P = 0.6221) at baseline. Psoriasis patients were then addressed into three different therapy groups: biological treatments (BT), systemic not biological treatments (NBT), and skin-directed treatments (SDT); none among the administered treatments (including also patients receiving folate supplementation and methotrexate) caused a significant percentage reduction of homocysteinaemia after 12 weeks (T12) (Fig. 3). Moreover no statistically significant differences were found between of homocysteine plasmatic level among the three groups at T12.
Discussion Homocysteine is a sulphur-containing amino acid metabolized by remethylation to methionine or by trans-sulphuration to cysteine via cystathionine,11 it derives from the normal metabolism of proteins, its increase can lead to damage of endothelial cells.12 Plasmatic homocysteine can promote atherosclerotic disease, including coronary disease, stroke and peripheral vascular disease16 through several mechanisms: damage of endothelial cells, decreased flexibility of blood vessels leading to aortic stiffness and to reduction of the speed of blood flow,13 reduced production of the vasodilator nitric oxide (NO), a well-known protec-
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tive agent for blood vessels against atherosclerosis and thrombosis.13,14 A meta-analysis of cross-sectional epidemiological studies has pointed out that a 5 lmol homocysteine plasma rate increase gives up to 60% higher prevalence of ischaemic heart disease.15 Some studies demonstrated that the treatment of hyperhomocysteinaemia reduces atherosclerotic plaque area, with a decrease in the risk of deepvein thrombosis (DVT), stroke and ischaemic heart disease.16 Moreover experimental induction of hyperhomocysteinaemia brings down endothelial cells function, especially after the administration of 10– 20 lmol/L.17,18 In this study we found a higher prevalence of hyperhomocysteinaemia (>15 lmol/L) in psoriasis patients (19.71 11.16) than healthy controls (13.90 11.18): this could suggest that the management of cardiovascular risk in psoriatic patients should consider homocysteine plasmatic levels in addition to the traditional parameters (obesity, smoking, hyperglycaemia, hyperlipidaemia and hyperhomocysteinaemia).19 Our results at baseline are in agreement with the majority of the studies in the current literature. Refsum et al.20 studied plasma homocysteine and folic acid levels in 13 severe psoriasis cases, reporting higher levels of homocysteine and lower levels of folic acid compared with healthy controls. They concluded that increased homocysteine level might be due to the rapid proliferative germinative cell layer. Vanizor Kural et al.21 studied plasma homocysteine and its relationship with atherothrombotic markers in 30 psoriasis patients. They found higher plasmatic homocysteine and lower vitamin B12 and folic acid levels, concluding that the increased homocysteine plasmatic concentration may play an important role for the development of atherothrombotic complications with psoriasis. Malerba et al.6 have suggested that patients with psoriasis might have a tendency to develop hyperhomocysteinaemia, which could predispose them to higher cardiovascular risk. They studied plasma homocysteine, folic acid and vitamin B6 and B12 levels in 40 psoriasis patients and they reported higher homocysteine and lower folic acid levels in psoriasis patients when compared with control group. The lower levels of vitamin B12 and folate often observed in psoriasis patients could depend from an increased vitamins need by psoriasis keratinocytes with high turnover rate, and from microscopic inflammatory changes in colon mucosa that may be responsible for folic acid malabsorption. In their study, Tobin AM et al.22 reported that plasmatic homocysteine level was not directly correlated with psoriasis severity index, conversely in our study we have seen a correlation between Psoriasis Area and Severity Index and homocysteine levels (P = 0.0401), as previously reported by Cakmak et al.7 This discrepancy could be related to the different spectrum of disease severity included into the reported studies.
© 2015 European Academy of Dermatology and Venereology
Giannoni et al.
4
We failed to find any correlation between disease duration, in contrast with other authors reporting a relationship between homocysteine plasmatic levels and psoriasis duration.10 Since psoriatic arthritis has an important inflammatory background23 and homocysteine is directly involved in the inflammatory ‘psoriasis march’, a correlation between psoriasis arthritis and prevalence of hyperhomocysteinaemia could be expected, however the serum levels of homocysteine in patients with psoriasis arthritis did not differ from those found in psoriasis patients without arthritis. This could be due to the good compensation of the arthritis status in the included patients. Several studies evaluated the impact of therapy on global metabolic condition in psoriasis patients as well.24–32 Sattar et al.33 were the first to demonstrate that anti-TNF-alpha drugs can significantly decrease some cardiovascular risks markers as Lp(a), ApoA-I, SHBG and homocysteine concentration. Also Wakke et al.34 reported on the positive effects of systemic treatments in reducing dyslipidaemia, hypertension and hyperhomocysteinaemia, oxidative stress, and endothelial cell dysfunction in psoriasis patients. In our experience, the administration of a12-week-long systemic treatment for psoriasis do not influence the plasmatic levels of homocysteine. Our results seem to confirm that psoriasis patients could have hyperhomocysteinaemia as risk factor for cardiovascular diseases, especially those with higher severity psoriasis. Thus, in addition to the traditional parameters, the evaluation of homocysteine plasmatic levels should be advisable in psoriasis patient with severe disease. Owing to the fact that this is a single centre study, its major limitation is the relatively small number of reported cases. Our preliminary results seem to indicate that systemic therapies appear do not influence the homocysteinaemia status, however further studies are needed to clarify the role of TNF-alpha inhibitors on homocysteine plasma levels, and the use of an implementation therapy with folates and vitamine B12, and the role of hyperhomocysteinaemia in the global cardiovascular risk factor of psoriasis patients. Finally dermatologists should be aware about the opportunity to evaluate the homocysteine plasma levels in psoriatic patients.
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