¹DermSurgery Associates, Houston, TX, USA
²Department of Dermatology, Weill Cornell Medical College, The Methodist Hospital, Houston, TX, USA
³Department of Dermatology, The University of Texas Medical School at Houston, Houston, TX, USA

ABSTRACT

Pregnancy is characterized by multiple physiologic changes. During the entire gestational period, both mother and infant are vulnerable to a variety of external and internal factors. Maternal disease, use of certain medications, drugs, alcohol, smoking, and radiation exposure can have devastating effects on the fetus. Pregnancy-related complications in women with psoriasis can be caused by both the disease and the treatment. The response of the maternal placenta to psoriasis-induced inflammation and comorbid conditions, such as obesity, hypertension, and depression, may also influence the pregnancy. Herein, we review the relationship between psoriasis and undesirable pregnancy outcomes.

Key Words:
comorbidities, complications, drug therapy, pregnancy, psoriasis, risk factors

Introduction

Pregnancy is a unique physiologic state characterized by an array of significant changes in the endocrine, vascular, and respiratory systems. These changes facilitate fetal growth and development and prepare the woman’s body for labor and delivery. During the first trimester of pregnancy (weeks 0-13), the developing embryo undergoes organogenesis and is especially susceptible to injury from systemic maternal diseases, medications, drugs, alcohol, and smoking. During this period many pregnant women are often unaware that they are even pregnant, and therefore do not actively minimize risks to the fetus.¹ This may include women with chronic diseases, such as those with moderate to severe psoriasis, who require multiple drugs for treatment.

Psoriasis is an autoimmune inflammatory skin disease with manifestations resulting from a complex interplay between genetics and the environment. The incidence of psoriasis is bimodal, with one peak between the ages of 15-30 years and a second between 50-60 years.^2,3 The average age of diagnosis in women is 28, a prime age for pregnancy.^3,4 Annually, there are approximately 65,000-107,000 births to women with psoriasis, of whom 9,000-15,000 have moderate to severe disease.²

Psoriasis lesions are well-circumscribed, erythematous plaques with a fine silvery scale; they predominate on the scalp and extensor surfaces, yet can occur anywhere on the body; there may also be nail changes. The severity of the condition is determined by two major criteria: 1) the extent of body surface area (BSA) involved and 2) the location of the lesions (for example, if psoriatic plaques are present on the palms and soles, it is considered severe, regardless of percentage of BSA involvement). In general, mild psoriasis occurs when lesions are limited to < 3% BSA, moderate psoriasis with 3-10% BSA, and severe psoriasis with >10% BSA. Quality of life issues for the patient also determine severity. While mild psoriasis can typically be controlled with topical treatments, moderate to severe psoriasis may require systemic therapy.

The management of psoriasis in pregnant women is challenging, since the physician and patient must balance teratogenic risks associated with certain drug therapies to potential adverse pregnancy outcomes from uncontrolled skin inflammation and excess cytokines inherent with the disease process. There is very little data detailing the effects of psoriasis on pregnancy outcomes.^2,4-6 Herein, we explore potential direct and indirect effects of psoriasis on pregnancy and the effects of pregnancy on psoriasis.

Direct Effects of Psoriasis on Pregnancy

In general, inflammatory/autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and psoriasis have been shown to be associated with low birth weight (LBW), preterm birth, and abortions.^5,7 Autoimmune inflammation in psoriasis results from dysfunctional T helper cells with a concomitant amplification of pro-inflammatory cytokines (most notably TNF-alpha, IL1 and IL6). Excess cytokines yield endothelial dysfunction with resulting systemic and placental vasculopathy through induction of platelet aggregation, intermittent vasospasm, and activation of the clotting system.^5,8 Placental vasculopathy has been postulated to contribute to LBW infants.⁵ LBW is also a complication of preeclampsia, which is similarly associated with an activated inflammatory state and increased levels of the same cytokines seen in psoriasis (CRP, TNF-alpha and IL6).^8-10 There is conflicting data regarding the correlation between psoriasis during pregnancy and infant birth weight.^5-7 Yang et al studied 1,436 mothers with psoriasis compared to 11,704 mothers without psoriasis, and found that LBW was associated only with severe psoriasis (defined as any mother who had received photochemotherapy or systemic therapy within the 2 years prior to delivery).⁵ In contrast, Cohen-Barak et al analyzed 68 pregnant women, but found that mothers with moderate to severe psoriasis were more likely to give birth to large infants when compared with controls.⁷ This group found psoriasis to be associated with a higher risk for spontaneous and induced abortions, which is also seen in inflammatory conditions including rheumatoid arthritis and systemic lupus erythematosus.⁷

Indirect Effects of Psoriasis on Pregnancy

Comorbidity Induced Adverse Effects

The stress associated with chronic, relapsing diseases may affect mental health, increasing the tendency for alcohol misuse, depression, weight gain, and smoking. Psoriasis is also associated with higher rates of comorbid systemic conditions including diabetes mellitus (DM), cardiovascular disease (atherosclerosis, congestive heart failure, and myocardial infarction), obesity, and metabolic syndrome (consisting of obesity, high blood sugars, high triglyceride levels, low high-density lipoprotein, and hypertension). Obesity and hypertension have been shown to be at least twice as common in patients with psoriasis.^4,11 Pregnant women with psoriasis are more likely to be overweight/obese, depressed, smoke in their first trimester, and are also less likely to take prenatal vitamins or supplements.⁴

Both the comorbid conditions associated with psoriasis and the drugs used to treat them may be harmful to the developing fetus. Hypertension (HTN) is known to be associated with LBW secondary to placental insufficiency, perinatal mortality, and preterm delivery, in addition to increased risk for acute maternal morbidities.¹² The drugs commonly used to treat HTN, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, can be teratogenic.^13,14 DM is associated with increased neonatal mortality and multiple morbidities including, fetal macrosomia, post-natal hypoglycemia, and congenital malformations including transposition of the great vessels.¹⁵ Furthermore, pregnancy has been shown to hasten the progression of DM; healthy women may even develop diabetes only during pregnancy, which is known as gestational DM.¹⁵ Alcohol misuse may result in fetal alcohol syndrome and LBW. Maternal consequences of depression include inadequate weight gain, insufficient utilization of prenatal care, and increased substance abuse, whereas fetal consequences can include premature birth, LBW, decreased Apgar scores, and smaller head circumference.¹⁶ Obesity has been associated with macrosomia, low Apgar scores, and premature birth.⁴ Smoking may increase the risk for oral clefts and reduced birth weight.⁴

Treatment Induced Adverse Effects

Little evidence exists to delineate the effects of psoriatic medications on human pregnancy due to ethical implications associated with investigating potentially teratogenic medications.¹ General guidelines are based on retrospective data and on cases in which a woman may have used a questionable medicine without yet realizing she was pregnant. Mild psoriasis can usually be adequately treated with topical medications, while severe psoriasis may require systemic treatment. Limited amounts of topical preparations including corticosteroids, calcipotriene, coal tar, and anthralin appear to be safe. There is a low likelihood for significant systemic absorption with these topical preparations if used in conservative application patterns.^1,5 The risk for potential teratogenicity increases in a dose-dependant manner as systemic absorption increases. The factors that increase systemic absorption include prolonged duration of treatment, large amounts of medication applied, a compromised epidermal barrier, and occlusion.¹

Systemic medications used for psoriasis unresponsive to topical therapies include acitretin, methotrexate, mycophenolate mofetil, and biologics such as adalimumab, alefacept, etanercept, infliximab, and ustekinumab. Most of the systemic antipsoriatic therapies are associated with significant toxic effects to the fetus and should be avoided during pregnancy. Acitretin (an oral retinoid) is strictly prohibited before or during pregnancy since it can cause a classic retinoid syndrome, consisting of well-characterized craniofacial, cardiac, thymic, and CNS malformations.¹ Furthermore, acitretin can linger for over 2 months after the last dose, so patients should stop this drug months before attempting to conceive.¹ Methotrexate is an antimetabolite that is associated with a specific constellation of prenatal growth deformities, including growth retardation, large fontanelles, craniosynostosis, ocular hypertelorism, micrognathia, limb abnormalities, and developmental delay; these effects are dose-related. Mycophenolate mofetil interferes with DNA and RNA synthesis, and case reports indicate that it can cause microtia or anotia, cleft lip/palate and heart defects. Systemic corticosteroids are not commonly used for psoriasis; however, they remain the best available treatment for a rare condition, known as impetigo herpetiformis, a form of pustular psoriasis seen in pregnancy.¹⁷ The side-effects of systemic steroids have mostly been studied in pregnant patients with asthma and they include orofacial clefts, intrauterine growth restriction, and suppression of the hypothalamic-pituitary axis.¹ There is very limited data with regard to the biologics, but infliximab has been associated with congenital malformations in two infants and death in a third due to uncontrollable intracranial and pulmonary bleeding.^1,18

Phototherapy with broad-band (290-320 nm) ultraviolet B (UVB) and narrow-band UVB (311-312 nm) appear to be safe during pregnancy.¹ The safety of systemic PUVA with psoralens is unknown, although mutagenic potential has been shown in rat studies; however, topical PUVA limited to small areas might be safe. Cyclosporin A in pregnant organ transplant recipients have failed to show an increased risk to the fetus1 and may therefore be an option in pregnant psoriatic patients.

Effects of Pregnancy on Psoriasis

Pregnancy may influence the severity of psoriasis.^6,19 In fact, psoriasis often improves during pregnancy. Boyd et al reported on a study of 90 women with psoriasis, who responded to a questionnaire regarding the condition of their psoriasis during pregnancy.⁶ Seventy-seven percent of these women noticed a change in their psoriasis, the majority of whom (63%) experienced improvement; within 4 months of giving birth, however, 88% of the women subsequently developed a “post-partum flare” of their psoriasis. Similarly, Murase et al found that 55% of women noted improvement in their psoriasis during pregnancy and 65% experienced worsening of their psoriasis post-partum.¹⁹ The patients with greater than 10% BSA who reported improvement during pregnancy noted that lesions decreased on average by 84%.19 Furthermore, the authors found that estrogen, but not progesterone, was associated with changes in psoriasis; they attributed the improvement in psoriasis to the high ratio of estrogen to progesterone.¹⁹ The authors hypothesized that the alterations in immunity (the immune response shifts from TH1 to TH2 dominance) due to hormonal changes in pregnancy, leads to the improvement in psoriasis, as previously shown in other TH1 mediated autoimmune diseases (i.e., rheumatoid arthritis and multiple sclerosis).¹⁹ While the exact mechanism is still not understood, it appears that psoriasis is more likely to improve than worsen during pregnancy with a post-partum flare.

Conclusion

The extent of the potential effects that psoriasis can have on pregnancy is variable. When possible, pregnant women should modify their behaviors and treatments to decrease any risk to themselves and their unborn children. Registries such as the International Psoriasis Council – project on pregnancy and psoriasis2 and the OTIS Autoimmune Diseases in Pregnancy Project4 are in the process of compiling more extensive data for this population. As data from these registries becomes more readily available, we will better understand the true implications of pregnancy on psoriasis and of psoriasis on pregnancy. Treatment plans can subsequently be developed that balance the risks from therapy versus the harmful effects of psoriasis and its associated comorbidities.

References

1. Lam J, Polifka JE, Dohil MA. Safety of dermatologic drugs used in pregnant patients with psoriasis and other inflammatory skin diseases. J Am Acad Dermatol 59(2):295-315 (2008 Aug).
2. Horn EJ, Chambers CD, Menter A, et al. Pregnancy outcomes in psoriasis: why do we know so little? J Am Acad Dermatol 61(2):e5-8 (2009 Aug).
3. Levine D, Gottlieb A. Evaluation and management of psoriasis: an internist’s guide. Med Clin North Am 93(6):1291-303 (2009 Nov).
4. Bandoli G, Johnson DL, Jones KL, et al. Potentially modifiable risk factors for adverse pregnancy outcomes in women with psoriasis. Br J Dermatol 163(2):334-9 (2010 Aug).
5. Yang YW, Chen CS, Chen YH, et al. Psoriasis and pregnancy outcomes: a nationwide population-based study. J Am Acad Dermatol 64(1):71-7 (2011 Jan).
6. Boyd AS, Morris LF, Phillips CM, et al. Psoriasis and pregnancy: hormone and immune system interaction. Int J Dermatol 35(3):169-72 (1996 Mar).
7. Cohen-Barak E, Nachum Z, Rozenman D, et al. Pregnancy outcomes in women with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol 25(9):1041-7 (2011 Sep).
8. Guven MA, Coskun A, Ertas IE, et al. Association of maternal serum CRP, IL-6, TNF-alpha, homocysteine, folic acid and vitamin B12 levels with the severity of preeclampsia and fetal birth weight. Hypertens Pregnancy 28(2):190-200 (2009 May).
9. Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 180(2 Pt 1):499-506 (1999 Feb).
10. Sacks GP, Studena K, Sargent K, et al. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol 179(1):80-6 (1998 Jul).
11. Henseler T, Christophers E. Disease concomitance in psoriasis. J Am Acad Dermatol 32(6):982-6 (1995 Jun).
12. Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 25(4):391-403 (2011 Aug).
13. Podymow T, August P. Antihypertensive drugs in pregnancy. Semin Nephrol 31(1):70-85 (2011 Jan).
14. Rakusan K. Drugs in pregnancy: Implications for a cardiologist. Exp Clin Cardiol 15(4):e100-3 (2010 Winter).
15. Tieu J, Middleton P, Crowther CA. Preconception care for diabetic women for improving maternal and infant health. Cochrane Database Syst Rev (12):CD007776 (2010).
16. Marcus SM. Depression during pregnancy: rates, risks and consequences– Motherisk Update 2008. Can J Clin Pharmacol 16(1):e15-22 (2009 Winter).
17. Oumeish OY, Parish JL. Impetigo herpetiformis. Clin Dermatol 24(2):101-4 (2006 Mar-Apr).
18. Srinivasan R. Infliximab treatment and pregnancy outcome in active Crohn’s disease. Am J Gastroenterol 96(7):2274-5 (2001 Jul).
19. Murase JE, Chan KK, Garite TJ, et al. Hormonal effect on psoriasis in pregnancy and post partum. Arch Dermatol 141(5):601-6 (2005 May).

^1. Weill Cornell Medical College, Methodist Hospital, Houston, TX, USA
^2. DermSurgery Associates, Houston, TX, USA
^3. Department of Dermatology, The University of Texas Medical School at Houston, Houston, TX USA

ABSTRACT

Alcohol is a serious cause of morbidity and mortality in our society and is implicated in multiple health conditions, including hepatic failure, neurological damage, hematological disorders, and nutritional deficiencies, to name a few. Although alcohol induced cutaneous abnormalities can also cause significant morbidity, they tend to be overshadowed by the other disease states associated with alcohol use. In addition to the cutaneous stigmata linked to chronic alcoholic liver disease, alcohol can directly cause or exacerbate several skin conditions. In particular, alcohol misuse is implicated in the development of psoriasis and discoid eczema, as well as confers increased susceptibility to skin and systemic infections. Alcohol misuse might also exacerbate rosacea, porphyria cutanea tarda, and post adolescent acne. Herein, we review the evidence concerning the influences of alcohol in skin conditions with a focus on psoriasis.

Key Words:
alcohol drinking, psoriasis, risk factors, skin disorders

Physiology of Alcohol Induced Toxicity

Alcohol induces a wide range of physiological derangements in the human body. Alcohol is cytotoxic to the liver, leading to alcoholic steatosis, hepatitis and, at later stages, cirrhosis1 with systemic sequelae. Alcohol is also toxic to the bone marrow, particularly the T cells, which in turn leads to attenuated immune function.^2-4 The cardiovascular system may also be adversely affected by excess alcohol use. Specifically, high output cardiac failure, hypertension, and peripheral vasodilatation may be consequences of chronic and acute alcohol intake.^2,5 Finally, alcohol misuse results in a myriad of nutritional deficiencies, including vitamin and trace element deficiencies^2,5 secondary to interference with proper intestinal absorption and poor nutrition. All of these physiological conditions can contribute to the development of cutaneous manifestations associated with alcohol consumption.

Skin Changes Indirectly Caused by Alcohol

The majority of cutaneous manifestations associated with excess alcohol use are indirectly mediated through the impairment of various organ systems.

Hepatic dysfunction impairs estrogen and bile salt metabolism, resulting in characteristic findings of spider angiomata, palmar erythema, and pruritis.^2,3,5 Male alcoholics are consequently hyperestrogenic.² In addition to high estrogen levels, testosterone production is also inhibited, further exacerbating the problem. Direct inhibition of testosterone production leads to gynecomastia, which presents as a disappearance and redistribution of body and pubic hair and female pattern fat redistribution.² Caput medusae and hemorrhoids are the result of hepatofugal blood flow caused by portal hypertension from liver cirrhosis.

Systemic and superficial skin infections, including bacterial and fungal infections, represent another health problem found to be more prevalent in alcoholics.^2-4 The higher incidence of infections is likely attributable to multiple factors, including alcohol associated nutritional deficiencies in combination with immunodeficiency. Most notably, zinc and vitamin C deficiencies lead to poor wound healing, weakened mucosal barriers, and altered immune defenses with increased risk for infections.

Group A streptococci, Corynebacterium, and Staphylococcus aureus are common bacterial culprits,² as are fungal infections with various tinea and Candida species.^2,3

Malabsorption associated with alcoholism is another mode by which alcohol can produce cutaneous abnormalities. Angular stomatitis, glossitis, perifollicular hemorrhages, pellagra, petechia, and ecchymosis are just a few such cutaneous manifestations.

Skin Changes Directly Caused by Alcohol

Porphyria Cutanea Tarda (PCT) is a metabolic disorder with cutaneous manifestations resulting from an aberration in hepatic heme biosynthesis. Whether acquired or inherited, PCT results from a deficiency in one of the hepatic enzymes involved in porphyrin metabolism, specifically uroporphyrinogen decarboxylase.^2,3,6 The resultant upstream accumulation of photoreactive porphyrin precursors renders the skin extremely photosensitive.² Alcohol is a potent inducer of the hepatic enzymes and the heme metabolic pathway, leading to an accumulation of photoreactive porphyrin compounds proximal to the enzymatic defect and, thus, precipitating PCT flare-ups.^3,6 The cutaneous characteristics of an acute PCT attack include skin blistering and erosions on sun exposed areas^2,3 that resolve leaving residual scarring and milia.

Alcohol impairs the vasomotor center of the brain, inducing peripheral vasodilatation.^2,3 Hence, it has been suggested that this resultant cutaneous vasodilatation may exacerbate rosacea,2,3 contributing to the hallmark redness and flushing. Alcohol can also promote facial erythema in people without rosacea through a genetic deficiency involving an alcohol metabolism enzyme. This phenomenon is most commonly recognized in Asians, as studies have shown that 50% lack the ability to make aldehyde dehydrogenase, leading to an accumulation of acetaldehyde after alcohol consumption.²

The Role of Alcohol in the Pathogenesis of Psoriasis

Psoriasis is a common chronic inflammatory autoimmune condition, affecting approximately 2% of the population in North America.³ It is characterized by epidermal hyperproliferation3,7 and a multifactorial etiology. A complex interplay between genetics and extrinsic factors, including the environment, trauma, infection, and social behaviors appear to be influential on the origin and clinical course of the disease.^3,8-11

Extensive evidence demonstrates a link between excessive alcohol consumption and psoriasis.^3,4,11,12 The amount of alcohol consumed and the type of alcoholic beverage have both been shown to confer the most risk for development and/or exacerbation of plaque psoriasis.¹² A recent prospective study following 82,869 women for 14 years showed that consumption of more then ^2.3 alcoholic beverages per week was a significant risk factor for new onset psoriasis.12 Furthermore, the same study found that consuming non-light beer appears to be an independent risk factor for developing psoriasis in females.¹² Similarly, in males, excess alcohol consumption (at levels higher then 100g/day) appears to be a risk factor for the development and increased activity of psoriasis.^11,13 Moreover, the misuse of alcohol in patients with psoriasis has been shown to be associated with decreased response to treatment.^2,13,14 Interestingly, the cutaneous distribution of psoriasis in heavy drinkers tends to be predominantly acral, involving the dorsum of the hands and digits, resembling that seen in immunocompromised patients, such as those with human immunodeficiency virus (HIV) infection.^2,4 This distribution highlights the potential role of alcohol induced immunosuppression in the development of psoriasis.

The exact molecular mechanisms by which alcohol triggers or exacerbates psoriasis are yet to be fully elucidated. One theory is that alcohol misuse may induce immune dysfunction with resultant relative immunosuppression.^2,3 Alcohol may also enhance the production of inflammatory cytokines and cell cycle activators, such as cyclin D1 and Keratinocyte Growth Factor, which could lead to epidermal hyperproliferation.^2,7,15 Additionally, increased susceptibility to superficial infections commonly observed in alcoholics, such as those caused by Streptococcus and trauma, has also been postulated to have implications in the development of psoriasis.⁷

Although the environment and genetics may not be amenable to prevention or alteration, social behaviors such as alcohol consumption can be modified with appropriate counseling and pharmacological interventions, and therefore, appears to be a promising adjunct to the medical therapy of psoriasis.

Conclusion

An overwhelming amount of evidence suggests a significant link between alcohol and psoriasis – a multifactorial autoimmune disorder. Not only may alcohol contribute, in the presence of appropriate genetic makeup, to the development of psoriasis, it also results in more extensive and treatment resistant disease. Ascertaining carefully the presence of this risk factor in all patients suffering from psoriasis and providing appropriate counseling and education may help the clinician to minimize the risks of disease exacerbation and achieve better therapeutic outcomes.

References

1. Menon KV, Gores GJ, Shah VH. Pathogenesis, diagnosis, and treatment of alcoholic liver disease. Mayo Clin Proc 76(10):1021-9 (2001 Oct).
2. Smith KE, Fenske NA. Cutaneous manifestations of alcohol abuse. J Am Acad Dermatol 43(1 Pt 1):1-16 (2000 Jul).
3. Higgins EM, du Vivier AW. Cutaneous disease and alcohol misuse. Br Med Bull 50(1):85-98 (1994 Jan).
4. Higgins EM, du Vivier AW. Alcohol and the skin. Alcohol Alcohol 27(6):595-602 (1992 Nov).
5. Chou SP, Grant BF, Dawson DA. Medical consequences of alcohol consumption–United States, 1992. Alcohol Clin Exp Res 20(8):1423-9 (1996 Nov).
6. McColl KE, Moore MR, Thompson GG, et al. Abnormal haem biosynthesis in chronic alcoholics. Eur J Clin Invest 11(6):461-8 (1981 Dec).
7. Farkas A, Kemeny L, Szell M, et al. Ethanol and acetone stimulate the proliferation of HaCaT keratinocytes: the possible role of alcohol in exacerbating psoriasis. Arch Dermatol Res 295(2):56-62 (2003 Jun).
8. Liu SW, Lien MH, Fenske NA. The effects of alcohol and drug abuse on the skin. Clin Dermatol 28(4):391-9 (2010 Jul-Aug).
9. Shelling ML, Kirsner RS. Failure to counsel patients with psoriasis to decrease alcohol consumption (and smoking). Arch Dermatol 146(12):1370 (2010 Dec).
10. Higgins E. Alcohol, smoking and psoriasis. Clin Exp Dermatol 25(2):107-10 (2000 Mar).
11. Poikolainen K, Reunala T, Karvonen J, et al. Alcohol intake: a risk factor for psoriasis in young and middle aged men? BMJ 300(6727):780-3 (1990 Mar 24).
12. Qureshi AA, Dominguez PL, Choi HK, et al. Alcohol intake and risk of incident psoriasis in US women: a prospective study. Arch Dermatol 146(12):1364-9 (2010 Dec).
13. Gupta MA, Schork NJ, Gupta AK, et al. Alcohol intake and treatment responsiveness of psoriasis: a prospective study. J Am Acad Dermatol 28(5 Pt 1):730-2 (1993 May).
14. Higgins EA, du Vivier AWP. Alcohol abuse and treatment resistance in skin disease. J Am Acad Dermatol 30(6):1048 (1994 Jun).
15. Ockenfels HM, Keim-Maas C, Funk R, et al. Ethanol enhances the IFN-gamma, TGF-alpha and IL-6 secretion in psoriatic co-cultures. Br J Dermatol 135(5):746-51 (1996 Nov).