Department of Dermatology, University of Texas Medical Branch, Galveston, TX, USA

ABSTRACT
The pregnancy-specific skin disorders are pruritic, inflammatory eruptions. The current classification by Ambros-Rudolph et al. includes four entities: pemphigoid gestationis (PG), polymorphic eruption of pregnancy (PEP), atopic eruption of pregnancy (AEP), and intrahepatic cholestasis of pregnancy (ICP). Although these disorders are all characterized by intense pruritus during pregnancy, they can be distinguished by timing, morphology, histopathology, treatment and potential for fetal complications. Diagnosis is made by clinical presentation, histology, and immunofluorescence. PEP and AEP typically resolve without sequelae; however, PG may lead to prematurity and low birth weight, and ICP is associated with an increased risk of prematurity, fetal distress, and intrauterine fetal demise. The potential for serious fetal complications necessitates a thorough evaluation of pregnancy-related pruritus. This article will discuss the skin disorders specific to pregnancy, with a focus on clinical presentation, potential for fetal complications, pathogenesis, diagnosis, and treatment.

Key Words:
atopic eruption, intrahepatic cholestasis, pemphigoid gestationis, polymorphic eruption, pregnancy complications, pruritus, skin disease

Introduction

While pregnancy may result in a number of skin changes, there are pruritic eruptions that occur specific to pregnancy and the postpartum period.^1-3 In 1983, Holmes and Black proposed a classification of pregnancy-specific skin disorders, which included pemphigoid gestationis, polymorphic eruption of pregnancy, prurigo of pregnancy, and pruritic folliculitis of pregnancy.⁴ In 1998, Shornick proposed the addition of intrahepatic cholestasis of pregnancy.⁵ The current classification was proposed by Ambros-Rudolph et al. in 2006 on the basis of a large retrospective study of 505 patients, and includes four entities: pemphigoid gestastionis, polymorphic eruption of pregnancy, atopic eruption of pregnancy (encompassing prurigo of pregnancy and pruritic folliculitis of pregnancy), and intrahepatic cholestasis of pregnancy.²

A major etiology of skin changes in pregnancy involves alterations in the maternal immune system. To prevent fetal rejection, an imbalance is created between cellular and humoral immunity.^1-3 T helper type 2 (Th2) cytokine production is favored over Th1, enhancing humoral immunity and stunting cell-mediated immunity. The changes in maternal hormones are also believed to have an effect, as many skin disorders develop during the third trimester.³

This article will discuss the skin disorders specific to pregnancy, with a focus on clinical presentation, potential for fetal complications, pathogenesis, diagnosis, and treatment.

Discussion

Pemphigoid Gestationis

Pemphigoid gestationis (PG), previously known as herpes gestationis, is the most rare of the pregnancy-specific disorders, with incidence of 1:2,000 to 1:60,000, varying with the prevalence of human leukocyte antigens (HLA)-DR3 and HLA-DR4.^1,3 PG initially presents with pruritic, erythematous urticarial papules and plaques that progress to a vesiculobullous eruption. PG characteristically involves the umbilicus, and often spreads to the chest, back, and extremities.^3,4,6 Palms and soles can be affected, but not typically the face and mucosa.^3,4 The eruption develops most often in the third trimester.³ The course fluctuates throughout pregnancy and, in 75% of patients, a flare occurs at delivery.¹ PG usually clears spontaneously within a few months after delivery. Recurrence during subsequent pregnancies is common, and is often characterized by earlier presentation and increased severity.^1,3 There have also been reports of flares during menstruation or with the use of oral contraceptives.^1,6,7 There is an increased incidence of prematurity and small-for-gestational age infants, especially with more severe maternal disease, marked by blister formation and onset before the third trimester.^1,3 Approximately 10% of infants develop a transient, bullous eruption due to the transfer of antibodies via the placenta.^1,3,4

Autoimmune diseases commonly present during pregnancy due to the immunosuppression required to maintain fetal life. PG is an autoimmune condition in which antibodies develop against the NC16A domain of collagen XVII (BPAG2, BP180), which is present in the amniotic, placental, and umbilical cord tissues, in addition to the basement membrane of the skin.³ The antibodies activate the complement cascade leading to inflammation and bullae formation.^1,3,8 Immunoglobulin G (IgG) is the main crossreacting antibody seen in PG, specifically IgG4.^3,8 Women who present with this disorder are at a higher risk of autoimmune disease, particularly Grave’s disease.¹ An association with HLADR3 and HLA-DR4 has been observed.³

Histologically, pre-bullous PG is characterized by dermal edema and perivascular inflammation with lymphocytes, histiocytes, and eosinophils. A sub-epidermal split is observed in the vesiculobullous lesions, with an eosinophil-predominant infiltrate.^1,4,6 Direct immunofluorescence of peri-lesional skin shows linear deposition of complement 3 (C3) along the basement membrane zone in all patients.^1,3 Some patients also have IgG deposition along the basement membrane.¹ Enzyme-linked immunosorbent assay (ELISA) detects the specific antibodies against collagen XVII, which correlates with disease activity and can be monitored to assess treatment effectiveness.^1,3

Treatment of PG is focused on managing pruritus and bullae formation.^1,3 In mild cases, topical corticosteroids and antihistamines are effective. In severe bullous PG, it is appropriate to use systemic corticosteroids. The dose can be decreased after adequate control is attained, however, it is often increased prior to delivery due to the high risk of flare.³ Use of systemic corticosteroids does not increase fetal risk, and may actually decrease risk due to control of placental inflammation.⁹

Polymorphic Eruption of Pregnancy

Polymorphic eruption of pregnancy (PEP), previously called pruritic urticarial papules and plaques of pregnancy, is a benign, pruritic inflammatory disorder that affects approximately 1 in 160 pregnancies.^1,4,10 It is typically observed during the late third trimester or immediate postpartum period of first pregnancies, and the risk is increased with multiple gestations and rapid weight gain. Urticarial papules and plaques first appear within striae distensae on the abdomen, and unlike PG, spare the umbilicus. The eruption commonly spreads to the thighs and buttocks, and rarely may generalize.^1-3,10 One-to-two millimeter vesicles may develop, but in contrast to PG, bullae are not observed.¹ Target lesions and widespread erythema may also be present.⁴ The eruption is self-limited and clears spontaneously in 4-6 weeks without relation to delivery. It does not typically recur; however, there have been recurrences with earlier presentation of the lesions in subsequent pregnancies that are multiple gestations. No adverse fetal outcomes have been described.^1,3

It is theorized that connective tissue damage from excessive stretching plays a major role in the pathogenesis of the disorder. The stretching may elicit an immune response to the damaged connective tissue antigen.^1,3

Histological findings are similar to PG. In early PEP, a superficial to mid-dermal perivascular infiltrate of lymphocytes, histiocytes, and sporadic eosinophils is observed with edema of the dermis. Later stages of PEP demonstrate epidermal spongiosis.^1,3,4,6 Immunofluorescence is negative, distinguishing PEP from PG.^1-3,10

Treatment of PEP is based on symptomatic relief with the use of topical corticosteroids and antihistamines. If the rash becomes generalized, a short systemic corticosteroid taper can be used.^1,3

Atopic Eruption of Pregnancy

Atopic eruption of pregnancy (AEP) is the most common pregnancy-specific skin disorder, accounting for almost 50% of cases. It has also been referred to by several other names including prurigo of pregnancy, prurigo gestationis, early-onset prurigo of pregnancy, Spangler’s papular dermatitis of pregnancy, pruritic folliculitis of pregnancy, and eczema of pregnancy.^1-3 AEP is a benign disorder characterized by a pruritic eczematous or papular eruption.¹ It usually presents before the third trimester, in contrast to the other dermatoses of pregnancy.^1,4 Two-thirds of AEP cases are characterized by eczematous skin changes in the common atopic sites such as neck and flexor surfaces. The remaining cases are characterized by a papular eruption of the abdomen and extremities.¹ Lesions typically respond well to treatment and spontaneously clear postpartum; however, AEP is likely to recur in future pregnancies.^1,3 The fetus is unaffected, but is at increased risk for atopic dermatitis as an infant.¹

It is thought that the pathogenesis of atopic eruption of pregnancy is initiated by pregnancy-related immune system changes.^1,3 There is a shift towards humoral immunity, with increased Th2 activation.¹ Patients who develop AEP may have an existing predisposition to atopic dermatitis, but 80% of the patients develop these skin changes for the first time during their pregnancy.¹ A family history of atopic dermatitis is frequently observed.³

AEP is commonly a diagnosis of exclusion, as diagnostic testing is nonspecific. Serum IgE levels are elevated in 20-70% of patients.¹ Other pregnancy-specific skin disorders, particularly ICP, must be excluded. Additionally, pruritic eruptions not specific to pregnancy, such as scabies and drug eruptions, must be considered in the differential diagnosis of AEP.

Topical corticosteroids are the mainstay of treatment. In severe cases, systemic corticosteroids and antihistamines may be indicated for short-term use. Phototherapy can also be considered.¹

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP), known previously as obstetric cholestasis, cholestasis of pregnancy and jaundice of pregnancy, is a reversible cholestasis that appears to be hormonally triggered towards the end of pregnancy in predisposed women. It is characterized by pruritus of acute onset that often starts on the palms and soles and then generalizes. On exam, there are only secondary lesions, such as excoriations and prurigo nodules. Ten percent develop jaundice due to concomitant extrahepatic cholestasis. After delivery, pruritus resolves within a few weeks. There is a risk of recurrence in future pregnancies and with the use of oral contraceptives.^1,11

Recognition of ICP is critical due to its association with serious sequelae. Potential fetal complications include prematurity, intrauterine fetal distress, and intrauterine fetal demise.^1,11 Fetal complication rates correlate with total bile acids in maternal serum, but do not increase significantly until bile acid levels exceed 40 µmol/L.¹² In cases of severe ICP complicated by jaundice, there is risk of maternal or fetal hemorrhage due to malabsorption of vitamin K.^1,11

The severe pruritus present in ICP is due to elevated conjugated bile salts in the blood caused by impaired secretion, a multifactorial process influenced by genetics, environment and hormones.¹ There is a higher incidence of ICP in twin pregnancy.¹¹

ICP is diagnosed by elevated bile acid level. Hyperbilirubinemia is noted in only the most severe cases, about 10-20%, and liver function tests can be normal in 30%. Histology is nonspecific and immunofluorescence is negative.^1,11

Treatment targets serum bile acid levels to reduce fetal risk and control maternal symptoms.^1,11 Recommended treatment is ursodeoxycholic acid (UDCA).^1,3,11 Other drugs have been found to decrease pruritus but not fetal risk, including antihistamines, S-adenosyl-L-methionine, dexamethasone, and cholestyramine.¹ Anion exchange resins, such as cholestyramine, can cause a vitamin K deficiency independent of ICP and, therefore, should be avoided.¹¹

Conclusion

The four skin disorders specific to pregnancy, pemphigoid gestationis, polymorphic eruption of pregnancy, atopic eruption of pregnancy, and intrahepatic cholestasis of pregnancy, can be distinguished by clinical presentation, histopatholgy, pathogenesis, and potential for fetal complication. Only pemphigoid gestationis and intrahepatic cholestasis of pregnancy are associated with significant risk to the fetus. As these dermatoses are all characterized by pruritus, careful evaluation of any pregnancy related pruritus is essential to appropriately treat the mother and manage any potential risk to the fetus.

References

1. Ambros-Rudolph CM. Dermatoses of pregnancy – clues to diagnosis, fetal risk and therapy. Ann Dermatol. 2011 Aug;23(3):265-75.
2. Ambros-Rudolph CM, Mullegger RR, Vaughan-Jones SA, et al. The specific dermatoses of pregnancy revisited and reclassified: results of a retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol. 2006 Mar;54(3):395-404.
3. Warshauer E, Mercurio M. Update on dermatoses of pregnancy. Int J Dermatol. 2013 Jan;52(1):6-13.
4. Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol. 1983 Mar;8(3):405-12.
5. Shornick JK. Dermatoses of pregnancy. Semin Cutan Med Surg. 1998 Sep;17(3):172-81.
6. Shornick JK, Bangert JL, Freeman RG, et al. Herpes gestationis: clinical and histologic features of twenty-eight cases. J Am Acad Dermatol. 1983 Feb;8(2):214-24.
7. Lawley TJ, Stingl G, Katz SI. Fetal and maternal risk factors in herpes gestationis. Arch Dermatol. 1978 Apr;114(4):552-5.
8. Patton T, Plunkett RW, Beutner EH, et al. IgG4 as the predominant IgG subclass in pemphigoides gestationis. J Cutan Pathol. 2006 Apr;33(4):299-302.
9. Chi CC, Wang SH, Charles-Holmes R, et al. Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol. 2009 Jun;160(6):1222-8.
10. Ghazeeri G, Kibbi AG, Abbas O. Pruritic urticarial papules and plaques of pregnancy: epidemiological, clinical, and histopathological study of 18 cases from Lebanon. Int J Dermatol. 2012 Sep;51(9):1047-53.
11. Lammert F, Marschall HU, Glantz A, et al. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol. 2000 Dec;33(6):1012-21.
12. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology. 2004 Aug;40(2):467-74.

¹Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX USA
²Department of Dermatology, The University of Texas Medical Branch at Galveston, Galveston, TX USA

ABSTRACT

Methotrexate has been used for over half a century to treat a wide spectrum of skin conditions. It is a valuable steroid sparing agent, preventing protracted steroid courses and their undesirable side effects. While many alternative therapies exist and continue to emerge to treat these dermatologic conditions, the long history, affordability, and relative safety associated with methotrexate ensure its enduring utility. Further, ongoing research focusing on the pharmacogenetic properties of the drug may allow for more effective and targeted therapeutic strategies.

Key Words:
amethopterin, methotrexate, MTX, skin disease

Introduction

Dermatologists have employed the antineoplastic agent methotrexate (MTX, amethopterin) for over 6 decades to treat a variety of skin conditions (Table 1), most prominently psoriasis. MTX is often used as a steroid sparing agent in dermatologic patients requiring prolonged steroid courses. The long history of use chronicled in the literature elucidates MTX’s efficacy, toxicity and relative safety, and portends to its ongoing utility. Recently, there has been a trend towards biologic therapy for several dermatologic conditions, placing the future of MTX treatment in jeopardy. However, MTX is significantly less expensive and novel studies in pharmacogenomics may allow a more personalized approach to its use. The following is a general review of MTX, focusing on its application in dermatologic diseases.

Pharmacology

MTX is a folic acid analogue that irreversibly binds to dihydrofolate reductase (DHFR), inhibiting the formation of reduced folates, which are essential cofactors for many enzymes. Consequently, the amounts of available purines, thymidylic acid, methionine, and serine decrease, ultimately impairing DNA, RNA, and protein synthesis.^1-4 The maximum cytoxic effects are S-phase specific.^1-3

The anti-inflammatory properties of MTX are likely explained by intracellular accumulation of AICAR, 5-amino-1-β-Dribofuranosyl- imidazole-4-carboxamide (from MTX inhibition of aminoimidazole-carboxamide ribonucleoside transformylase), which leads to increased extracellular and intracellular adenosine. This inhibits neutrophil chemotaxis and adherence, superoxide anion formation, and secretion of proinflammatory cytokines. Furthermore, MTX becomes polyglutamated intracellularly, favoring retention secondary to the increased negative charge. These active metabolites are much longer acting than the parent drug.^1-4

MTX has multiple drug interactions; therefore, prior to initiating therapy, a thorough review of the patient’s medications is essential. For instance, MTX binds albumin and is excreted primarily by the kidney. Thus, medications that displace MTX from albumin (i.e., acetylsalicylic acid, barbiturates, sulfonamides, tetracylines, and sulfonylureas) or interfere with its renal secretion and clearance (i.e., probenacid, penicillin, and nonsteroidal anti-inflammatory drugs) may result in toxicity. Other drugs that enhance the antifolate effect like trimethoprimsulfamethoxazole and sulfonamides increase bone marrow toxicity and are contraindicated during MTX therapy.^1,2,4,5

Adverse Effects

The most commonly reported side effects are mild and include gastrointestinal complaints, such as nausea, vomiting, and diarrhea. Hematologic complications are the major cause of death with therapy, and manifest as anemia, leukopenia, thrombocytopenia, or pancytopenia. Renal insufficiency, increased mean corpuscular volume, age, and drug interactions are risks. Hepatotoxicity is also a concern so the drug should be avoided in current or previous liver disease. Patients should be counseled to avoid alcohol and have routine monitoring of liver function.^1,2,4 Monitoring for liver toxicity is discussed below. The drug predisposes patients to opportunistic infections as it is immunosuppressive. Idiosyncratic pneumonitis is a rare but dangerous complication. Dermatologic effects have been reported, including alopecia and toxic epidermal necrolysis (TEN). In psoriatics, a combination of long-term ultraviolet light therapy and MTX increases their squamous carcinoma risk.^1,2,4 At high doses the drug can precipitate in the renal tubules causing damage. Adequate hydration and alkalinization of the urine help prevent this adverse effect.

Folic acid supplementation can reduce complications and folinic acid (leucovorin) can be used for rescue if significant pancytopenia occurs, since it bypasses the inhibited DHFR.^1,2,4 Dose dividing (i.e., one-third of the dose given 12 hours apart) or parenteral or intramuscular administration are other options for managing side effects.^2,4

MTX is a potent teratogen and abortifacient; thus, it is contraindicated in pregnancy. In general, women and men (MTX can lead to genetic aberrations in sperm) should avoid conception for at least 3 months after discontinuation of therapy and women should not breastfeed.^1,2,4

Pre-methotrexate Screening and Monitoring

In general, the literature regarding pre-treatment screening and monitoring reflect the treatment protocol for psoriasis. Patients should be questioned about current medications and all contraindications to therapy (i.e., desire for pregnancy and current or past alcohol abuse). Initial laboratory testing should include a CBC with differential, renal function tests (BUN, creatinine), unrinalysis, liver function tests (LFT) (e.g., AST, ALT, alkaline phosphatase, bilirubin, and albumin), hepatitis serology (HBV and HCV), and HIV, TB, and pregnancy tests in at risk individuals.^2,4 The patient’s blood counts and liver and renal function tests should be monitored throughout treatment. Initially done weekly and then with dose changes, the interval between blood tests can increase once the therapy has stabilized.^1,2,4

Regarding liver fibrosis screening, various guidelines are available.^6-10 Recently, Paul et al. compiled the available evidence and garnered expert opinion, publishing optimal dosing recommendations, conditions predisposing to hepatic fibrosis, and guidelines for screening for development of hepatic fibrosis in Europe.⁹ Additionally, Menter et al. have standardized guidelines for physicians in the United States. These include a liver biopsy typically performed after a cumulative dose of 3.5-4 g, with subsequent biopsies after each additional administration of 1-1.5 g. If risk factors including personal or family history of liver disease, excessive alcohol consumption, obesity, diabetes, or abnormal LFTs are present, then a baseline biopsy may be indicated.¹⁰ A serum assay for PIIINP (type III procollagen N-terminal peptide, a marker of fibrosis) reduces the need for liver biopsies.^1,2,4,8,9,11 Though currently not widely offered, it should be used where available. Overall, the monitoring route a physician chooses to follow should be based on the condition treated, anticipated therapy duration, and availability of the tests.

Dosing

The dose of MTX must be individualized. It is available in 2.5 mg tablets and 12.5 or 25 mg/mL solutions. Although it is typically given orally, it can be administered subcutaneously (SC), intramuscularly (IM), or intravenously (IV) to avoid gastrointestinal upset. A small test dose (2.5-5 mg) is advisable to screen for patients who may be hypersensitive. If blood work is stable after 1 week, subsequent doses may be incrementally increased (usually by 2.5-7.5 mg) with the ultimate goal of controlling disease at the lowest dose feasible. Typically, dermatologic conditions require 7.5-20 mg weekly. In certain populations, such as the elderly, 2.5 mg may be adequate. Others may require up to 30 mg or more. Daily folic acid supplementation of 1-5 mg is standard but still debatable.^1,2,11

Clinical Uses

Psoriasis and Palmoplantar Pustulosis

The most frequent use for MTX worldwide is psoriasis, a common, chronic, recurring inflammatory disease with a strong genetic component.¹ MTX is widely used for psoriatic erythroderma, psoriatic arthritis, acute pustular psoriasis, and extensive plaque psoriasis.^4,12 Because the condition is lifelong, physicians must consider treatment cost. Although monitoring associated with MTX is expensive, the drug itself is affordable. In addition, cost analysis studies suggest MTX is overall more cost-effective than biologics.¹³ One retrospective study revealed 81% of 113 patients treated with MTX (maximum 15 mg/week) achieved prolonged improvement (mean duration of therapy was 8 years and 11 months), though 73% experienced side effects, which necessitated discontinuation in 29%.¹⁴ A similar review demonstrated only 6% of 157 patients exhibited a poor response to oral or IV MTX (7.5- 40 mg/week), while 94% showed moderate to good benefit with a mean treatment duration of 237 weeks. A total of 61% of patients experienced side effects, with 20% discontinuing therapy.¹⁵

Palmoplantar pustulosis is characterized by recurrent pruritic and painful sterile pustules, crusts, erythema, and scaling of volar surfaces. Only 8 of 25 patients improved with oral MTX (25 mg/ week) for 2 months, but in responders the onset of effect was evident within 2 weeks.¹⁶

Pityriasis Rubra Pilaris (PRP)

PRP is a rare papulosquamous eruption, classically presenting suddenly in adults with craniocaudally progressing small circumscribed follicular keratoses with accompanying palmoplantar keratoderma. The keratoses may evolve into salmon-colored, scaling plaques with characteristic islands of sparing. Erythroderma may develop. PRP is associated with infection (especially HIV), malignancy, and rheumatologic conditions.^17-20 An early study demonstrated only 17 of 42 patients responded to MTX.¹⁸ Another report recognized that adding MTX (5-30 mg/week) to oral retinoids over 16 weeks increased the response by over 50% in 8 of 11 patients, but the combination may lead to increased hepatotoxicity.¹⁹ Furthermore, a review by Dicken of 8 patients described benefits from low dose MTX (10-25 mg/week) for 6 months.²⁰

Sarcoidosis

This systemic granulomatous disease affects a multitude of organ systems including the skin. Highest prevalence is found amongst African American women in their third to fourth decade. In an open study, skin lesions cleared in 12 of 16 patients treated with oral MTX (25 mg/week).²¹ In a retrospective analysis of 50 patients who completed at least 2 years of oral MTX (average 10 mg/week), 16 of 17 patients with cutaneous involvement responded favorably.²² While it may take up to 6 months to be effective, MTX has successfully demonstrated steroid sparing properties and may be particularly useful in treating the cutaneous manifestations of sarcoidosis.^21-23

Dermatomyositis (DM)

DM is an autoimmune disease manifesting as proximal muscle weakness from an inflammatory myositis with elevated creatine kinase and skin disease characterized by a heliotrope rash, shawl sign, Gottron’s papules, and mechanic’s hands. Patients also exhibit systemic signs such as fever, malaise, and weight loss. DM is more common in women and is associated with underlying malignancy in adults.^24-26 A retrospective study of cutaneous responses in steroid resistant DM concluded 8 of 11 (73%) patients exhibited significant improvement in skin lesions with SC MTX (5-25 mg/week). Interestingly, the nonresponders had less inflammation on histology, indicating inhibition of lymphocyte migration might be a primary mechanism of utility in DM.²⁵ Another study of 13 patients demonstrated complete to moderate clearing of cutaneous manifestations with oral MTX (2.5-30 mg/week). All patients were able to either discontinue or reduce their steroid dose.²⁶

Cutaneous Lupus Erythematosus (CLE)

Lupus erythematosus is an autoimmune inflammatory condition characterized by a host of autoantibodies that may target any organ system. The skin is frequently involved and manifestations range from the classic malar rash to papular or urticarial type lesions. Scarring results in the chronic discoid form. A retrospective study cited improvement in 42 of 43 CLE patients (98%) treated with IV or oral MTX (7.5-25 mg/week) for 2-67 months.²⁷

Vesiculobullous Diseases

Bullous pemphigoid (BP) typically afflicts the elderly and is characterized by large, tense, subepidermal bullae with a predilection for the axillae, trunk, flexor forearms, thighs, and groin, leaving large denuded areas after rupture. The pathophysiology is related to anti-hemidesmosomal immunoglobulin G (IgG) antibodies, which result in dermoepidermal junction separation, complement factor C3 deposition, and an associated inflammatory infiltrate rich in eosinophils.^28-31 A retrospective study showed 8 of 34 patients resistant to traditional therapy improved with the addition of oral MTX (average 5-10 mg/week) for 1 month, allowing a reduction in steroid dose.²⁹ In addition, a prospective study of oral MTX (5-12.5 mg/week) in 11 geriatric patients who failed to respond to potent topical steroids demonstrated decreased disease activity after less than a month.³⁰ Additionally, a prospective study of 18 patients utilized whole-body clobetasol for 2-3 weeks combined with oral or IM MTX (7.5-10 mg/week) reported all subjects responded to the induction regimen. Remission with MTX monotherapy (7.5-12.5 mg/week) occurred in 17 of 18 (94%) patients, which eventually allowed a treatment hiatus (mean of almost 7 months) in 13 of the subjects.³¹ A likely underlying mechanism of MTX’s efficacy in BP is that it induces apoptosis of eosinophils.³²

Mucous membrane pemphigoid is an autoimmune subepidermal bullous disease characterized by chronic inflammation that progresses to scarring. A retrospective review examined 17 patients with ocular cicatricial pemphigoid (OCP) and druginduced OCP, 14 of which were treated with oral MTX (5-25 mg/ week) as first-line therapy. After an average treatment duration of 15 months, MTX controlled or suppressed conjunctival inflammation in 15 of 17 patients, facilitating improved or preserved visual acuity.³³

Linear IgA bullous dermatosis is an acquired autoimmune vesiculobullous disease targeting skin and mucous membranes. Groups of curved blisters and urticarial plaques are typical. The diagnosis hinges on IgA immunofluorescence in the basement membrane zone. One case highlights a female geriatric patient who failed treatments with dapsone, sulphapyridine, sulphamethoxypyridazine, azathioprine, colchicine, and prednisolone alone or in combination. She finally responded to MTX (7.5-10 mg/week) plus prednisolone, and the steroid dose was eventually quartered. The disease remained quiescent under this regimen for 18 months until drug-induced hepatitis required MTX discontinuation.³⁴

Pemphigus is an autoimmune blistering disease that affects the skin (antidesmoglein 1 antibodies) as well as mucous membranes (antidesmoglein 3 antibodies). Conventionally, it is divided into three subtypes: vulgaris, foliaceus, and paraneoplastic.^35-37 MTX’s efficacy was recognized early, but physicians avoided use for years because of associated toxicity. However, this observation is likely attributable to the high doses that were first used.³⁵ One study reported MTX (25-50 mg/week) in combination with prednisone was effective in 42 of 53 patients.³⁶ More recently, MTX (maximized at 10-17.5 mg/week) in 9 patients in combination with prednisone permitted discontinuation of steroids in 6 of 9 patients after 6 months. Disease flared within 7-55 days after stopping MTX.³⁷

Benign familial chronic pemphigus, or Hailey-Hailey disease, is an autosomal dominant condition with recurring vesicles and erosions in flexural surfaces precipitated by inherent friction in these areas. One patient treated with IM MTX (15 mg/week) cleared after 1 month of therapy; however, the disease recurred within 2 months of MTX cessation.³⁸

Lymphoproliferative Disorders

Cutaneous T-cell lymphoma, or mycosis fungoides (MF), is a rare malignant T lymphocyte proliferative disease that typically presents in older males and follows an indolent course. Treatment aims at controlling the symptoms and slowing progression. One retrospective study extols the use of oral, IM, or most commonly SC MTX (5-125 mg/week) in 29 patients with erythrodermic MF. Over 50% of patients achieved complete (41%) or partial (17%) response. Median response duration was 31 months and median survival was 8.4 years.³⁹

Pityriasis lichenoides et varioliformis acuta (PLEVA), or Mucha- Habermann disease, presents as a sudden onset of erythematous macules, papules, and papulovesicles in children or young adults that appear in patches from a few to over 100 lesions. The course is variable, but spontaneous resolution can occur in as little as a few weeks. Six patients given oral MTX (7.5-20 mg/week) all experienced rapid clearance, but prompt recurrence was often seen upon discontinuation of therapy.⁴⁰

Pityriasis lichenoides chronica (PLC) affects children and presents as multiple erythematous, scaly macules and flat papules with slow evolution that last months. The overall disease course is years as relapses are common. Three severe cases of PLC treated with oral or IM MTX (25 mg/week) quickly responded, but 2 patients relapsed upon discontinuation.⁴¹

Lymphomatoid papulosis (LyP) is a rare skin disorder that usually occurs in adults and presents with papulonecrotic or papulonodular lesions in various developmental stages on their trunk and extremities. Individual LyP lesions often self-heal within 3 months, but the total disease duration may last years. The disorder is associated with malignant cutaneous lymphomas, particularly MF, but has an excellent prognosis. Patients with multiple lesions or residual scarring may elect treatment with MTX. One review illustrated satisfactory long-term control in 39 of 45 patients with oral, IM, or SC MTX (10-60 mg/week with subsequent increases in administration intervals up to every 4 weeks). The authors proposed a protocol of establishing an effective 10-25 mg weekly dose with successive increases in the dosing interval to maintain control while minimizing untoward effects.42

Eczema

Atopic dermatitis (AD), or eczema, is a common, chronic, and relapsing disease with worldwide prevalence. It is hallmarked by dry skin, excessive pruritus, and acute flares. The cause of AD is genetic and has been linked to epidermal barrier dysfunction from filaggrin mutations resulting in increased transepidermal water loss, secondary inflammation, and frequent skin infections.^43,44 Physical exam reveals eczematous patches and plaques, and lichenification is common.⁴⁴ In a 24 week trial, oral MTX (average of 15 mg/week) improved symptoms in 52% of 11 patients, with 8 of 9 subjects exhibiting lasting improvement 12 weeks after drug cessation.⁴⁵ A retrospective study examining 20 patients revealed 75% experienced improvement at 3 months with oral MTX (7.5-25 mg/week).⁴⁶ Another retrospective study concluded 16 of 20 subjects responded to oral or IM MTX (7.5-25 mg/ week) within 2 weeks to 3 months. The authors noted a 43.5% improvement in patients’ quality of life.⁴⁷ An additional study reported 9 patients (100%) responded to oral MTX (10-20 mg/ week) within 3-7 weeks, with 6 subjects achieving full remission by 3 months.⁴⁸ Additionally, in a case series involving 5 geriatric patients, oral MTX (5-10 mg/week) effectively controlled the disease in 80% of patients even after eventual dose reduction to 2.5 mg/week.⁴⁹ While an abundance of therapeutic approaches are available, MTX is emerging as a viable systemic treatment option to induce and maintain remission.^43-49

Pompholyx or dyshidrotic eczema is a pruritic, vesicular rash found on glabrous surfaces. In 5 patients with recalcitrant disease, oral MTX (12.5-22.5 mg/week) allowed dose reduction or elimination of oral steroids.⁵⁰

Other

In reviewing the literature, evidence of the benefits of MTX in other dermatologic disorders is often restricted to case reports or case series. The rarity of these diseases likely precludes more robust studies. However, a cursory review does reveal that MTX is often used alone or in conjunction with other standard therapies.

Behcet’s disease is a systemic vasculitis comprised of oral and genital aphthae, uveitis, arthritis, and various skin lesions. Two cases cleared with oral MTX (15-20 mg/week).⁵¹ Further, cutaneous polyarteritis nodosa typically presents as livedo reticularis with nodules and ulcerations of the lower extremities. All 3 patients in a case series benefited with oral MTX (5-20 mg/ week).⁵¹

Morphea, or localized scleroderma, is a connective tissue disease resulting in fibrotic reactions and cicatrization that can be disfiguring and disabling.^52-53 Nine of 10 pediatric patients treated with oral or SC MTX (7.5-20 mg/week), in addition to corticosteroids in 8 of these individuals, responded within 2 to 13 months, with a median response time of 3 months.² Additionally, 6 of 9 adults with widespread morphea in a 24-week prospective trial benefited from oral MTX (initial 15 mg/week, adjusted to 7.5-25 mg/week).⁵³

Eosinophilic fasciitis, or Shulman’s syndrome, is characterized by a symmetric woody induration of the extremities, usually sparing the hands and feet, has been linked to vigorous exercise. One individual resistant to corticosteroids improved with the addition of IM MTX (15 mg/week), allowing a reduction in steroid therapy.⁵⁴

Lichen myxedematous presents clinically as fleshy or erythematous papules and plaques that may appear shiny and usually affect the arms, face, and neck. In severe cases, the infiltration of the skin by mucin-producing fibroblasts may restrict movement such as opening of the mouth. Sclerodactyly, Raynaud’s phenomenom, and esophageal dysmotility may accompany the systemic form, scleromyxedema, mimicking systemic sclerosis. An associated serum IgG gammopathy with scleromyxedema often distinguishes these entities. When proximal muscle weakness is present, muscle biopsy specimens often display vacuolar change and lack the chronic inflammatory cell infiltrates observed in other myopathies like dermatomyositis and polymyositis. Two of 3 reported cases of scleromyxedema myopathy responded to IV MTX. The more recent case utilized MTX at an initial dose of 5 mg/week with incremental increases to 30 mg/week in combination with oral steroids.⁵⁵

Lichen planus is an extraordinarily pruritic papulosquamous condition associated with hepatitis C and many drugs (e.g., thiazide diuretics, antimalarials, and phenothiazines). It can be erosive and painful when lesions affect the oral cavity. Ten of 18 patients with oral lichen planus achieved greater than 75% clearance after treatment with MTX (2.5-12.5 mg/week).⁵⁶

Keratoacanthomas (KAs) are distinct neoplasms. Classified in the spectrum of squamous cell carcinomas, these tumors swiftly evolve into firm, dome-shaped, crateriform masses with the potential for spontaneous involution. In cases when excision is deemed imprudent, intralesional MTX can be effective.^57,58 Following 1-2 injections of 5-37.5 mg MTX (total 5-50 mg), 9 patients with solitary KAs exhibited complete tumor clearance in 2-4 weeks without recurrence up to 6 years later.⁵⁷ Another case series of 6 patients with solitary KAs demonstrated partial tumor regression within 10 days and complete resolution within 1.5-5.7 weeks of intralesional MTX (1-4 doses of 12.5-25 mg totaling 12.5-62.5 mg).⁵⁸

Pyoderma gangrenosum (PG) presents as enlarging pustules that form ulcers with dusky, undermined borders. At least half of cases are associated with a systemic disorder and therapy aimed at the underlying disease tends to improve the PG. Overall, PG is a stubborn disease to treat, often demanding high dose systemic steroids. One patient’s disease was undetectable after 2 months of oral MTX (7.5-15 mg/week), allowing tapering of high dose prednisone. Of note, one relapse occurred in this patient that resolved with prednisone, but at a dose reduction of one-third than previously required to control the disease.⁵⁹

Multicentric reticulohistiocystosis is rare and characterized by destructive, symmetric polyarthritis and slow-growing skincolored, tan, or erythematous papules and nodules with a predilection for the hands. The skin and synovia are infiltrated by histiocytes and multinucleated giant cells with an eosinophilic, ground glass cytoplasm. Oral MTX (15-20 mg/week) has benefited at least 3 individuals with this devastating condition.⁶⁰

The clinical triad of conjunctivitis, nongonococcal urethritis, and oligoarthritis associated with human leukocyte antigen B27 (HLA-B27) is referred to as reactive arthritis, formerly Reiter syndrome. Circinate balanitis and keratoderma blennorrhagica are the classic dermatologic lesions. Eighteen of 20 patients experienced dramatic improvement in their skin lesions within 2 weeks of receiving oral or parenteral MTX (10-50 mg/week).⁶¹

Relapsing polychondritis is a rare, idiopathic, painful, and potentially fatal condition linked to HLA-DR4. Manifestations include recurrent inflammation of cartilage and other connective tissues affecting the eyes, inner ears, kidneys, nerves, heart, skin, and blood vessels. While corticosteroids are the mainstay of treatment, MTX (average 17.5 mg/week) reduced the steroid burden in 23 of 31 patients.⁶²

Mycobacterium leprae affects the skin and peripheral nerves in Hansen’s disease (leprosy). Anesthetic hypopigmented macules and erythematous papules, nodules, or plaques are typical features of skin lesions. A spectrum of presentations exists (from tuberculoid to lepromatous) dictated by cell-mediated immunity. Additionally, immune-mediated leprosy reactions may occur at any time regardless of treatment stage.^63-64 MTX (5-7.5 mg/week) allowed discontinuation of steroids after 2 months and resulted in marked improvement in the skin lesions within 6 months in a patient with a type I reaction (reversal reaction).⁶³ Further, oral MTX (7.5-15 mg/week) permitted corticosteroid reduction in 1 patient with a type II reaction (erythema nodosum leprosum).⁶⁴

Future

The precise pharmacokinetic, pharmocodynamic, and pharmacogenetic properties of MTX are still being pursued with a particular emphasis on predicting efficacy and the potential for adverse responses. For instance, one study revealed rheumatoid arthritis patients with higher levels of glutamylation of MTX have better results,⁶⁵ though a smaller study in psoriatics did not reproduce this finding.⁶⁶

Multiple reports have investigated how genetic variations correlate with MTX’s therapeutic response and adverse outcomes.^67-74 Some of these pharmacokinetic and hereditary differences may be quantifiable with simple urine or blood testing.^65,75,76 While this evidence is preliminary, the associations established or refuted between therapeutic response and toxicity indicate a future where treatment may be individually directed.⁷⁷ Perhaps one day a comprehensive genetic index will be developed to predict and maximize outcomes.

Conclusion

Methotrexate is an effective and relatively safe treatment for multiple dermatologic conditions. Though many alternative options exist and continue to emerge, the long history, affordability, and ongoing research are harbingers of its enduring therapeutic value. Also, with new biologic therapies, long-term safety data is currently lacking. Investigations focusing on the pharmacogenetic properties of methotrexate may allow for more effective and targeted therapeutic strategies.

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ABSTRACT

Several variants of psoriasis are seen in children, the most prevalent types include plaque, guttate, and psoriatic diaper rash; pustular and erythrodermic psoriasis are less frequently observed. Genetic susceptibility and environmental triggers are both involved in the development of this autoimmune disease. As well as improving symptoms, a treatment plan should strive to identify and eliminate precipitating factors. Topical medications are the first choice therapy for children with psoriasis. Systemic agents are used to treat more severe cases. Patient education and supportive care should be incorporated into the treatment plan.

Key Words:
adolescent, children, psoriasis

Introduction

Psoriasis is a common condition that affects about 3.5% of the population.¹ In greater than 33% of patients, the initial presentation of psoriasis occurs within the first two decades of life.^2-5 It is estimated that 10% of patients develop psoriasis before the age of 10.⁶ In a review of 1262 cases of psoriasis, initial disease onset occurring before the age of 2 years was found in 14-27%.⁷ Children present with the same clinical variants of psoriasis seen in adults, though they may differ in distribution, morphology, and natural history.⁵

Etiology

Psoriasis is a T-cell mediated chronic inflammatory condition characterized by keratinocyte hyperproliferation, vascular endothelial proliferation, and inflammatory cell infiltration.^8,9 The exact cause and pathogenesis of psoriasis are not well understood, but are known to be multifactorial, having both genetic and environmental influences.⁹ Seventy-one percent of children with psoriasis have a positive history for psoriasis in a first degree relative.⁷ The PSORS1 gene has been shown to be a major genetic determinant of Type 1 early onset non-pustular psoriasis.^5,10 HLA-Cw6 is the major disease allele at the PSORS1 locus that confers susceptibility to early onset disease.^2,5,11,12

Exogenous and endogenous factors, such as upper respiratory infection, emotional stress, skin injury, and drugs, can precipitate and exacerbate psoriasis in children.^2,6,8,13 Streptococcal pharyngitis and perianal streptococcal dermatitis are common causes of guttate psoriasis in children.^2,7,8 Frequency of sore throat and skin trauma leading to an exacerbation of psoriasis is greater in pediatric onset psoriasis than adult onset.^5,13 The appearance of new lesions in times of emotional stress is also more common in pediatric patients.¹³ Injury or irritation of normal skin can induce new psoriatic lesions at the site, known as the Koebner phenomenon. Antimalarials and the withdrawal of corticosteroids play a significant role in rebound psoriasis and the induction of childhood psoriasis, whereas β-blocking agents and lithium are recognized triggers for psoriasis in adult patients.^11,14

Presentation

Classic psoriasis presents as sharply demarcated, deep red plaques with silvery scales.⁹ The presentation in children may be atypical, thus making a diagnosis difficult in such cases; however, there are a few clinical features that can aid in identification. The Auspitz sign, which is pinpoint bleeding upon removal of scales, is characteristic of psoriasis.^2,15 Nail changes, such as oil spots, onycholysis, subungual hyperkeratosis and pitting (the most common finding), are frequently observed in adolescents with psoriasis and are valuable clues in establishing diagnosis.^2,8,9,16,17

Psoriasis often presents differently in children than in adults. Involvement of the face and flexural regions are more common in children than adults, and psoriatic lesions in the diaper area are prevalent during infancy.⁸ Plaque-type psoriasis is the most common variant in both adults and children, however, lesions in children are smaller, thinner, and less scaly than those seen in adults.^2,5,7 Pustular and erythrodermic psoriasis are less frequently seen in pediatric than adult patients. Though rare in occurrence, there are also reports of congenital^6,18 and naevoid¹⁹ forms of psoriasis.

Plaque-type psoriasis is the most prevalent variant that affects children. Plaque psoriasis routinely affects the scalp. Scalp involvement characterized by pityriasis amiantacea (thick, adherent white scales that encase the hair shaft) may lead to temporary hair loss and visible psoriatic alopecia.^2,8 Plaque psoriasis can also affect the face, as well as extensor and flexor surfaces of the knees and elbows.^2,9

Psoriatic diaper rash is the next most common variant, with highest prevalence in children under the age of 2 years.^5,7 Psoriatic diaper rash features a bright red, well-demarcated, glazed, diaper rash that may be followed by widespread dissemination of small psoriasis-like lesions.² This clinical variant can be differentiated from irritant diaper dermatitis by its unique presentation and poor response to conventional treatment for diaper dermatitis.²

Guttate type psoriasis presents as annular, localized, red to salmon colored plaques with hyperkeratosis, commonly located on the trunk, abdomen, and back.⁸ Streptococcal pharyngitis and perianal dermatitis frequently precede abrupt appearances of guttate psoriasis.²⁰ Acute guttate psoriasis that is preceded by an upper respiratory infection may resolve spontaneously after 3-4 months; however, a significant portion of patients eventually develop chronic plaque disease.^2,9

Pustular and erythrodermic psoriasis are less frequently seen in children than adults.^2,9 Pustular psoriasis is distinguished by the presence of sterile pustules on erythematous skin; the pustules may be either localized or generalized.² Generalized pustular psoriasis in children has a more benign course than in adults.²¹ Annular pustular psoriasis, a manifestation of generalized pustular psoriasis, occurs more frequently in children than in adults.^2,22 It is characterized by annular lesions with erythematous, scaly, and pustular margins. Erythrodermic psoriasis presents as erythema on >90% of the body surface area with less scales than plaque psoriasis.²¹

Treatment

When treating children with psoriasis, it is important to educate both patients and parents about the nature of the disease. It must be made clear that psoriasis is a chronic skin disorder without a permanent cure and, therefore, the goal of treatment is to establish disease control and prolong periods between flares.²³ Treatment results may vary from flattened plaques and reduced visibility of lesions (e.g., less redness and scale) to complete remission.² Proper education about the disease and treatment options often enhances the compliance of patients and their parents.^2,9

The patient’s age, quality of life factors, Psoriasis Area and Severity Index (PASI) score, and therapeutic preferences should all be considered when determining treatment selection.^5,8 The majority of children have mild disease that can be successfully treated with topical agents. Systemic drug therapy in children is generally reserved for severe disease that is resistant to other treatments.⁵ A prevention strategy should aim to control and reduce known exogenous and endogenous factors that trigger or contribute to disease exacerbation, like skin trauma, emotional stress, aggravating drugs, and upper respiratory infections.¹³

A chronic, visible condition like psoriasis can have a significant impact on children’s psychosocial development.²⁴ Through school years and adolescence, children may require substantial family and professional support to cope with the psychological and social sequelae of psoriasis, particularly the negative reactions of other children.²⁵

Topical Medications

Corticosteroids

Corticosteroids have anti-inflammatory and antiproliferative properties that reduce erythema, scaling, and pruritus.^5,9 Corticosteroids have high acceptability among patients because they do not stain and are almost odorless. This acceptance combined with wide availability, ease of use, and faster onset of action make corticosteroids the first choice treatment of childhood psoriasis, especially in flexural disease.² Very high potency corticosteroids should be used only sparingly in combination or rotation with steroid sparing alternatives, such as coal tar, liquor carbonis detergens, anthralin, calcipotriene (calcipotriol), and topical calcineurin inhibitors.⁵ Combination therapy can help reduce side-effects caused by topical steroids without reducing the efficacy of the treatment.⁹ Side-effects of topical steroids include skin atrophy, striae, telangiectasia, acneiform eruptions, and in rare cases, suppression of the hypothalamic-pituitaryadrenal axis may occur after prolonged widespread application or overuse, especially of potent preparations.^2,5 There are reports of tachyphylaxis associated with prolonged corticosteroid use in the treatment of psoriasis. However, some attribute this phenomenon to decreased adherence to long-term therapeutic regimens.^5,26,27 Treatment with corticosteroids should be gradually withdrawn to prevent rebound flares.⁹

Coal Tar

The use of coal tar, which is both antiproliferative and antipruritic, is limited by its strong odor and ability to stain. A modified coal tar preparation, liquor carbonis detergens (LCD), has largely replaced crude coal tar in outpatient settings because of its superior cosmetic acceptability.⁵ Coal tar is less irritating than calcipotriene and anthralin on the face and flexures, sites commonly affected in children.²⁵

Anthralin

Anthralin (dithranol) is a potent anti-inflammatory and antiproliferative agent. Its negligible systemic absorption makes it a safe and easy treatment option for children.⁵ Anthralin’s use is limited due to its tendency to stain skin and clothing and irritate healthy skin. It is not recommended for application on the face, flexures and genitalia, and should not be used in erythrodermic or pustular psoriasis.⁹ In an open study of 58 children ages 5-10 years, remission was achieved in 47 patients (81%) using dithranol at concentrations up to 1%.²⁸

Calcipotriene

Calcipotriene (calcipotriol) is a vitamin D analogue that stimulates keratinocyte differentiation and inhibits DNA synthesis and proliferation.²³ It is considered to be a successful and safe treatment for children with mild to moderate plaque psoriasis involving <30% of the body surface.² Calcipotriene is non-staining and odorless.⁹ Potential side-effects include local intolerance or irritation.⁸

Topical Calcineurin Inhibitors

Tacrolimus and pimecrolimus are non-steroidal immunomodulating macrolactams that inhibit the production and release of interleukin-2 (IL-2) and subsequent T-cell activation and proliferation, through blockade of the enzyme calcineurin.⁵ They are particularly useful for treating pediatric psoriasis in areas where atrophy is a risk, such as the face, intertriginous regions, and the groin.⁹

Salicylic Acid

Salicylic acid is recommended for use on thick localized plaques.^2,5 However, salicylic acid should be avoided in infants and children less than 6 years of age, or otherwise used with caution, as there is a risk of percutaneous absorption and salicylate intoxication.^2,5

Phototherapy

Phototherapy is extensively used in adults and is a treatment option for children with widespread plaques.² Narrowband UVB (NB-UVB) phototherapy may be combined with topical therapies to enhance efficacy of both modalities and to reduce the NB-UVB dose and carcinogenic risk.^2,5 Psoralen + UVA (PUVA) therapy is not generally recommended in young children, but may be used in adolescents with caution.^5,9,25 When PUVA is administered, topical psoralens are chosen preferentially over oral psoralens to avoid gastrointestinal side-effects and the necessity to wear protective eye gear for 24 hours.^2,8 NB-UVB is considered the first-line phototherapy because it is as effective as PUVA, more convenient, and less carcinogenic.^5,29

Systemic Medications

Acitretin

Acitretin, a retinoid, is an effective treatment for severe plaque, pustular, and erythrodermic psoriasis in adolescents.⁵ It can be used as monotherapy or in combination with topical agents and NB-UVB phototherapy. Side-effects include cheilitis, pruritus, and hair loss.² Because of its high teratogenic risk, acitretin should be used with caution in girls of childbearing age and must be accompanied by oral contraceptive therapy, as well as counseling, to avoid pregnancy during and 3 years after the completion of treatment.³⁰ Long-term use can lead to premature epiphyseal closure and radiologic bone evaluations may be required.³⁰

Methotrexate

Methotrexate, a folic acid antagonist, is rarely used in children and reserved for severe psoriasis unresponsive to other treatments.^30,31 Side-effects include nausea, headache and gastrointestinal upset, which can be minimized with folic acid supplements.⁹ Regular screening of the patient’s blood count, liver enzymes, and renal function is necessary to monitor for potential development of acute hematotoxicity and hepatotoxicity.^2,9

Cyclosporine

Cyclosporine is an immunosuppressant that can be used to treat extremely severe cases of pediatric psoriasis. The initial dose of cyclosporine is 3 mg to 5 mg/kg per day and should be gradually tapered to the lowest dose that can maintain disease control.^2,5 Major risks of hypertension and renal dysfunction necessitate close monitoring.

Biologics

Biologics are a class of drugs that include antibodies and fusion proteins targeting cytokines. Etanercept and infliximab are tumor necrosis factor-alpha inhibitors that are used for the treatment of pediatric autoimmune diseases. Etanercept is an effective method of treatment for moderate to severe plaque-type childhood psoriasis.^31,32 In a double-blind trial designed to assess the efficacy and safety of etanercept in children with plaque-type psoriasis, both non-infectious and infectious adverse effects from treatment were observed, the most serious of which were gastroenteritis and pneumonia.³² All adverse affects were resolved without sequelae.³²

Antibiotics and Tonsillectomy

Pharyngeal and perianal streptococcal infections may precipitate or exacerbate acute guttate and pustular psoriasis.²⁰ Antibiotics may be prescribed to treat patients with recurrence or flare of guttate psoriasis, and tonsillectomy may be considered for refractory psoriasis and recurrent tonsillitis.³⁰ However, these treatments are controversial, as there is a lack of controlled studies to support their efficacy.

Conclusion

Psoriasis is a life-long disease that often begins during childhood. In order to correctly diagnose and treat children and adolescents, it is important to recognize the different presentations of the disease in this cohort. Children with psoriasis, including their parents and caregivers, should be educated about the natural history and exogenous and endogenous factors responsible for increased disease morbidity, as well as receive support and counseling to help cope with their condition.

References

1. Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol 2009 Feb;60(2):218-24.
2. Benoit S, Hamm H. Childhood psoriasis. Clin Dermatol 2007 Nov-Dec; 25(6):555-62.
3. Romiti R, Maragno L, Arnone M, et al. [Psoriasis in childhood and adolescence]. An Bras Dermatol 2009 Jan-Feb;84(1):9-20.
4. Rogers M. Childhood psoriasis. Curr Opin Pediatr 2002 Aug;14(4):404-9.
5. Cordoro KM. Management of childhood psoriasis. Adv Dermatol 2008; 24:125-69.
6. Farber EM, Jacobs AH. Infantile psoriasis. Am J Dis Child 1977 Nov; 131(11):1266-9.
7. Morris A, Rogers M, Fischer G, et al. Childhood psoriasis: a clinical review of 1262 cases. Pediatr Dermatol 2001 May-Jun;18(3):188-98.
8. Silverberg NB. Pediatric psoriasis: an update. Ther Clin Risk Manag 2009; 5:849-56.
9. Leman J, Burden D. Psoriasis in children: a guide to its diagnosis and management. Paediatr Drugs 2001;3(9):673-80.
10. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 1985 Sep;13(3):450-6.
11. Nair RP, Stuart PE, Nistor I, et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 2006 May;78(5):827-51.
12. Valdimarsson H. The genetic basis of psoriasis. Clin Dermatol 2007 Nov-Dec;25(6):563-7.
13. Raychaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with adult onset psoriasis. Pediatr Dermatol 2000 May-Jun;17(3):174-8.
14. O’Brien M, Koo J. The mechanism of lithium and beta-blocking agents in inducing and exacerbating psoriasis. J Drugs Dermatol 2006 May;5(5):426-32.
15. Bernhard JD. Clinical pearl: Auspitz sign in psoriasis scale. J Am Acad Dermatol 1997 Apr;36(4):621.
16. Al-Mutairi N, Manchanda Y, Nour-Eldin O. Nail changes in childhood psoriasis: a study from Kuwait. Pediatr Dermatol 2007 Jan-Feb;24(1):7-10.
17. Kumar B, Jain R, Sandhu K, et al. Epidemiology of childhood psoriasis: a study of 419 patients from northern India. Int J Dermatol 2004 Sep;43(9):654-8.
18. Lerner MR, Lerner AB. Congenital psoriasis: report of three cases. Arch Dermatol 1972 Apr;105(4):598-601.
19. Atherton DJ, Kahana M, Russell-Jones R. Naevoid psoriasis. Br J Dermatol 1989 Jun;120(6):837-41.
20. Honig PJ. Guttate psoriasis associated with perianal streptococcal disease. J Pediatr 1988 Dec;113(6):1037-9.
21. Howard R, Tsuchiya A. Adult skin disease in the pediatric patient. Dermatol Clin 1998 Jul;16(3):593-608.
22. Liao PB, Rubinson R, Howard R, et al. Annular pustular psoriasis–most common form of pustular psoriasis in children: report of three cases and review of the literature. Pediatr Dermatol 2002 Jan-Feb;19(1):19-25.
23. Kragballe K, Wildfang IL. Calcipotriol (MC 903), a novel vitamin D3 analogue stimulates terminal differentiation and inhibits proliferation of cultured human keratinocytes. Arch Dermatol Res 1990;282(3):164-7.
24. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol 2006 Jul;155(1):145-51.
25. Burden AD. Management of psoriasis in childhood. Clin Exp Dermatol 1999 Sep;24(5):341-5.
26. Zivkovich AH, Feldman SR. Are ointments better than other vehicles for corticosteroid treatment of psoriasis? J Drugs Dermatol 2009 Jun;8(6):570-2.
27. Feldman SR. Tachyphylaxis to topical corticosteroids: the more you use them, the less they work? Clin Dermatol 2006 May-Jun;24(3):229-30.
28. Zvulunov A, Anisfeld A, Metzker A. Efficacy of short-contact therapy with dithranol in childhood psoriasis. Int J Dermatol 1994 Nov;33(11):808-10.
29. Van Weelden H, Baart de la Faille H, Young E, et al. Comparison of narrowband UV-B phototherapy and PUVA photochemotherapy in the treatment of psoriasis. Acta Derm Venereol 1990;70(3):212-5.
30. Cordoro KM. Systemic and light therapies for the management of childhood psoriasis: part II. Skin Therapy Lett 2008 May;13(4):1-3.
31. de Jager ME, de Jong EM, van de Kerkhof PC, et al. Efficacy and safety of treatments for childhood psoriasis: a systematic literature review. J Am Acad Dermatol 2010 Jun;62(6):1013-30.
32. Paller AS, Siefried EC, Langley RG, et al. Etanercept treatment for children and adolescent with plaque psoriasis. N Engl J Med 2008 Jan 17;358(3):241-51.

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).

¹The University of Texas Medical School at Houston, Houston, TX, USA

²Center for Clinical Studies, Houston, TX, USA

³Department of Dermatology, University of Texas Health Sciences Center, Houston, TX, USA

ABSTRACT

In atopic dermatitis (AD), the stratum corneum of patients appears to have alterations that predispose them to colonization and invasion by various bacteria, most notably Staphylococcus aureus (S. aureus). This bacterial co-existence is accepted to be an important factor in AD disease activity. Exactly when to initiate antimicrobial treatment is controversial, but such intervention, when warranted, has repeatedly been demonstrated to improve the course of AD. However, the increase in antibiotic resistance presents a therapeutic challenge in the management of AD patients, which highlights the need for novel mechanism topical antibacterial agents. Retapamulin is a relatively new pleuromutilin antibiotic designed for topical use. In vitro studies have demonstrated its low potential for the development of antibacterial resistance and high degree of potency against Gram-positive bacteria found in skin infections, including many S. aureus strains that are resistant to methicillin, fusidic acid, and mupirocin. Clinical studies exploring the treatment of secondarily infected dermatitis reveal that the efficacy of topical retapamulin is comparable to a 10-day course of oral cephalexin or to topical fusidic acid. Retapamulin appears to be a much needed antimicrobial option for treating the AD population due to their common carriage of bacterial pathogens and frequency of infectious complications.

Key Words:
antibacterial, atopic dermatitis, retapamulin, skin infections

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease that affects approximately 20% of children and 1-3% of adults; incidence is on the rise due to modern environmental factors in addition to genetic predisposition.^1-5 AD is a condition that encompasses eczematous changes within the epidermis, consisting of a multifaceted underlying etiology including, but not limited to, epidermal barrier dysfunction, atopic diathesis, and an increased incidence of secondary infections.^3,4,6 Acute lesions are characterized by erythema, oozing, and crusting, whereas chronic lesions can feature papules and lichenification. Affected individuals experience a decreased quality of life that is secondary to intermittent skin eruptions and difficult-to-control pruritus.^7,8

One of the main factors in the pathogenesis of AD involves a compromised function of the natural skin barrier. AD patients are deficient in ceramides, the sphingolipid constituents of protective and potently antimicrobial lamellar sheets in the stratum corneum.^9,10 A second factor is a reduced amount of antimicrobial peptides in the skin of AD patients.^4,5,10 Keratinocytes produce 2 major classes of innate antimicrobials: Β-defensins and cathelicidins; both are essential to defend the skin against bacterial invasion. In AD, the high concentrations of interleukin-10 and T2 helper cytokines cause a down regulation in the production of these antimicrobial peptides. Furthermore, the skin of AD patients has decreased moisture content. Together, these alterations in the microenvironment of the skin predispose AD patients to widespread microbial colonization and infection. For instance, it has been reported that AD patients have a 200- fold increase in S. aureus colonization when compared with individuals with healthy skin.^4,11 On both lesional and nonlesional skin, >90% of AD patients are colonized by S. aureus, whereas the prevalence is only 5-20% in non-AD individuals.^7,8,12 Among AD patients, the mean colonization density of S. aureus is markedly higher within the atopic lesions.^4,8,11 The presence of such a high microbial load is associated with increased disease severity.^1,2,8

Overview of Standard Treatment

Standard AD care includes topical glucocorticoids as firstline agents, followed by newer options, such as calcineurin inhibitors and anti-IgE antibodies.⁵ With regard to secondary infections, antimicrobial therapy can either be administered orally or topically. Topical antimicrobials are preferentially given due to the fact that administration can be directly targeted to the infected area, therefore reducing the potential for systemic side-effects, such as gastrointestinal distress and undesired drug interactions.¹³ Until recently, topical antimicrobials have been limited in availability; the main options include fusidic acid (introduced in 1962) and mupirocin (introduced in 1985). Recent reports indicate that multiple bacterial organisms have successfully developed resistance to these 2 drugs.^14,15 This rising prevalence increasingly limits their use to specific conditions, e.g., systemic fusidic acid for severe bone infections and topical mupiricin to eradicate nasal methicillin-resistant Staphylococcus aureus (MRSA).¹⁴ However, due to the aforementioned phenomena of increased susceptibility to colonization with microorganisms, combined with a compromised ability to defend against them, the addition of antimicrobial therapy to the standard care regimen of AD is recommended in certain clinical circumstances, which include:⁴

a) early signs of secondary bacterial infection;

b) AD exacerbation that cannot be otherwise explained; and

c) AD that is poorly controlled by monotherapy with topical anti-inflammatories.

Topical Retapamulin

Retapamulin ointment 1% (Altabax^®/Altargo^®, GlaxoSmithKline) is the first approved pleuromutilin antimicrobial for the treatment of uncomplicated superficial skin infections caused by staphylococcal, streptococcal, and anaerobic Grampositive organisms; it is not substantially effective against Gram-negative organisms.^16,17 Currently, it is approved for use in the EU for patients with impetigo or small infected wounds, and in the US for impetigo. Retapamulin has not received US FDA approval for MRSA skin infections. However, based on in vitro studies and incidental clinical trials data, it holds promise in the treatment of bacterial skin infections owing to its high in vitro potency against many common skin pathogens, low potential for development of bacterial resistance, and targeted application to the sites of involvement without significant systemic exposure.^13,16,18

Retapamulin is a semisynthetic pleuromutilin derivative isolated from Clitopilus scyphoides (an edible mushroom) and functions by selectively targeting the 50S subunit of bacterial ribosomes to inhibit protein synthesis.¹⁴ It acts at a site distinct from other available drugs; therefore, crossresistance is not yet a concern. The in vitro minimum inhibitory concentration required to suppress the growth of 90% of organisms (MIC90) by retapamulin was 0.12g/ml against S. aureus, including methicillin- and mupirocinresistant, and Staphylococcus Epidermidis isolates. Retapamulin was also shown to be very active against Streptococcus Pyogenes (S. Pyogenes), approximately 1000 times as potent as mupiricin or fusidic acid.¹⁵

A large study of over 6500 bacterial isolates, including staphylococcus and streptococcus from 13 countries, obtained from both hospital and community settings, further demonstrated the in vitro efficacy of retapamulin against these bacteria. Between 2005-2006, this Global Surveillance Program found retapamulin to also be effective against strains of S. aureus with resistance to methicillin, mupirocin, and fusidic acid^19-21. Other in vitro studies have reported similar findings.¹⁸ In addition to Gram-positive coverage,²¹ retapamulin has shown mixed antimicrobial activity against anaerobes^14,22 and exhibited very minimal efficacy against enterococci and Gram-negative bacteria. Despite this in vitro data, clinical studies thus far have focused on Gram-positive skin infections. A low potential for the development of bacterial resistance has also been reported with retapamulin, and if resistance does develop, it does so very gradually and by mechanisms distinct from those known to occur against other available antimicrobial options.^23,24 The main mechanisms of resistance are twofold and include mutations in the retapamulin ribosomal binding site and a non-target-specific efflux mechanism.^25-27 These results have been reproduced in both single-step and multistep passage studies.^14,23,24

Efficacy of Retapamulin

The overall findings from multiple trials indicate that retapamulin is a safe therapeutic alternative and it is at least as effective as conventional treatment options.

Impetigo

One of the initial retapamulin trials consisted of 7 days of treatment with topical retapamulin 1% vs. placebo for impetigo in 210 patients. Clinical success rates were significantly higher for the retapamulin-treated group as compared with placebo (85.6% vs. 52.1%). Microbiological success rates were even higher for retapamulin vs. placebo (91.2% vs. 50.9%).²⁸

A multicenter trial of noninferiority comparison of retapamulin ointment 1% twice daily for 5 days with sodium fusidate ointment 2% 3 times daily for 7 days was completed. Over 500 adults and children ≥9 months of age with impetigo were treated in this randomized, observer-blinded phase 3 study. The group treated with retapamulin exhibited a 99% clinical success rate vs. 94% in the sodium fusidate treated arm. Cases of MRSA isolated at baseline were treated in the retapamulin group (n=8) and in the sodium fusidate group (n=2); both agents were 100% effective in treating these cases of MRSA impetigo.¹³

Secondarily Infected Traumatic Lesions

For the treatment of secondarily infected traumatic lesions, over 1900 patients participated in 2 identical, randomized, double-blind, controlled, multicenter trials of retapamulin 1% ointment twice daily for 5 days vs. oral cephalexin 500mg twice daily for 10 days.²⁹ Retapamulin was approximately 90% effective in successfully treating these skin infections compared with 92% for cephalexin. Compliance rates were significantly higher in the retapamulin group. Another randomized, double-blind, double-dummy noninferiority trial with 547 adults and children ≥9 months of age with secondarily infected dermatitis (SID) was performed with retapamulin.¹⁶ Patients with SID were randomized to treatment with retapamulin ointment 1% twice daily for 5 days or oral cephalexin 500mg twice daily for 10 days. Clinical success rates were 86% and 90%, respectively.

Potential Side-Effects of Retapamulin

The most common adverse event with the use of retapamulin ointment was localized application site irritation (e.g., pruritis), which was reported by less than 2% of all patients. Additionally, there exist 2 newly published case reports detailing allergic contact dermatitis as a result of retapamulin usage.^30,31 These patients ranged in age from 6 to 79 years and were all diagnostically worked up via patch testing, which identified retapamulin as the cause and excluded other ingredients in the formulation. While this has been reported as an extremely rare occurrence, no detailed studies have yet been conducted to estimate its true incidence. Nonetheless, a limited duration regimen of topical retapamulin can still ease AD progression and increase compliance vs. other longer term topical treatments or oral regimens. Improved treatment compliance may also contribute to decreased resistance.

The Use of Antibiotics in AD Treatment

Conflicting data exists with regard to the role of antibiotic therapy in the treatment of AD. One controlled study showed that systemic cloxacillin or erythromycin cleared S. aureus with at least 6 months of sustained clinical improvement.³² However, a second study among patients with no overt signs of infection indicated that there was no improvement after flucloxacillin treatment.³³ Numerous open and doubleblinded placebo-controlled experiments have since evaluated the combination of corticosteroids with topical antimicrobials in AD treatment. The majority of findings from these studies have shown significant benefit (1 of these studies specified benefit only in the case of severe disease), which included decreased colonization density and at least partial improvement of skin lesions. However, 1 study showed only marginal improvement and 2 showed no benefit.^7,8,10,34-37

Bacterial Decolonization

A meta-analysis by Birnie et al. investigated whether or not interventions to decrease S. aureus colonization in AD patients should be prescribed.¹ They looked at 21 studies and analyzed different eradication mechanisms, and concluded that treatment simply to decrease the colony load of S. aureus in AD patients without an overt infection was not recommended. However, the study team stated that this conclusion is limited by multiple factors, such as poor study design, improper reporting of results, and failure to include outcome findings related to quality of life and longterm improvement. The investigators do recommend further research in this area.

Conclusion

Finite topical antimicrobial therapy (for approximately 2 weeks) can be an important addition to the standard treatment of AD in many instances, especially when there are overt signs of a secondary infection or if manifestations cannot be well controlled with anti-inflammatories alone. Data is conflicting as to exactly when antimicrobials should be introduced for the treatment of AD, but following their use, overall improvement in disease course has been shown in multiple studies. Considering that resistance to current topical antimicrobials is increasing, leading to further challenges in treating skin infections, the need for new treatment options is very real. The advent of retapamulin offers a safe, effective, and distinct alternative to its predecessors, and can serve as an adjunctive therapeutic option in specified AD patients. While no clinical trials with retapamulin have been performed specifically for AD, its safety and efficacy are proven in uncomplicated superficial skin infections involving the same bacterial isolates, notably S. aureus, MRSA, and S. pyogenes.

References

1. Birnie AJ, Bath-Hextall FJ, Ravenscroft JC, et al. Interventions to reduce Staphylococcus aureus in the management of atopic eczema. Cochrane Database Syst Rev (3):CD003871 (2008).
2. Gilani SJ, Gonzalez M, Hussain I, et al. Staphylococcus aureus re-colonization in atopic dermatitis: beyond the skin. Clin Exp Dermatol 30(1):10-3 (2005 Jan).
3. Katoh N. Future perspectives in the treatment of atopic dermatitis. J Dermatol 36(7):367-76 (2009 Jul).
4. Lin YT, Wang CT, Chiang BL. Role of bacterial pathogens in atopic dermatitis. Clin Rev Allergy Immunol 33(3):167-77 (2007 Dec).
5. Novak N. New insights into the mechanism and management of allergic diseases: atopic dermatitis. Allergy 64(2):265-75 (2009 Feb).
6. Komine M. Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment: keratinocytes in atopic dermatitis – their pathogenic involvement. J Pharmacol Sci 110(3):260-4 (2009 Jul).
7. Breuer K, HÄussler S, Kapp A, et al. Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis. Br J Dermatol 147(1):55-61 (2002 Jul).
8. Gong JQ, Lin L, Lin T, et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol 155(4):680-7 (2006 Oct).
9. Arikawa J, Ishibashi M, Kawashima M, et al. Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol 119(2):433-9 (2002 Aug).
10. Biedermann T. Dissecting the role of infections in atopic dermatitis. Acta Derm Venereol 86(2):99-109 (2006).
11. Kedzierska A, Kapinska-Mrowiecka M, Czubak-Macugowska M, et al. Susceptibility testing and resistance phenotype detection in Staphylococcus aureus strains isolated from patients with atopic dermatitis, with apparent and recurrent skin colonization. Br J Dermatol 159(6):1290-9 (2008 Dec).
12. Hauser C, Wuethrich B, Matter L, et al. Staphylococcus aureus skin colonization in atopic dermatitis patients. Dermatologica 170(1):35-9 (1985).
13. Oranje AP, Chosidow O, Sacchidanand S, et al. Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observer-blinded, noninferiority study. Dermatology 215(4):331-40 (2007).
14. Yang LP, Keam SJ. Retapamulin: a review of its use in the management of impetigo and other uncomplicated superficial skin infections. Drugs 68(6):855-73 (2008).
15. Rittenhouse S, Biswas S, Broskey J, et al. Selection of retapamulin, a novel pleuromutilin for topical use. Antimicrob Agents Chemother 50(11):3882-5 (2006 Nov).
16. Parish LC, Jorizzo JL, Breton JJ, et al. Topical retapamulin ointment (1%, wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial. J Am Acad Dermatol 55(6):1003-13 (2006 Dec).
17. Yang LP, Keam SJ. Spotlight on retapamulin in impetigo and other uncomplicated superficial skin infections. Am J Clin Dermatol 9(6):411-3 (2008).
18. Woodford N, Afzal-Shah M, Warner M, et al. In vitro activity of retapamulin against Staphylococcus aureus isolates resistant to fusidic acid and mupirocin. J Antimicrob Chemother 62(4):766-8 (2008 Oct).
19. Scangarella-Oman NE, Shawar RM, Bouchillon S, et al. Microbiological profile of a new topical antibacterial: retapamulin ointment 1%. Expert Rev Anti Infect Ther 7(3):269-79 (2009 Apr).
20. Jones RN, Fritsche TR, Sader HS, et al. Activity of retapamulin (SB-275833), a novel pleuromutilin, against selected resistant gram-positive cocci. Antimicrob Agents Chemother 50(7):2583-6 (2006 Jul).
21. Pankuch GA, Lin G, Hoellman DB, et al. Activity of retapamulin against Streptococcus pyogenes and Staphylococcus aureus evaluated by agar dilution, microdilution, E-test, and disk diffusion methodologies. Antimicrob Agents Chemother 50(5):1727-30 (2006 May).
22. Odou MF, Muller C, Calvet L, et al. In vitro activity against anaerobes of retapamulin, a new topical antibiotic for treatment of skin infections. J Antimicrob Chemother 59(4):646-51 (2007 Apr).
23. Kosowska-Shick K, Clark C, Credito K, et al. Single- and multistep resistance selection studies on the activity of retapamulin compared to other agents against Staphylococcus aureus and Streptococcus pyogenes. Antimicrob Agents Chemother 50(2):765-9 (2006 Feb).
24. Gentry DR, Rittenhouse SF, McCloskey L, et al. Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin. Antimicrob Agents Chemother 51(6):2048-52 (2007 Jun).
25. Davidovich C, Bashan A, Auerbach-Nevo T, et al. Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity. Proc Natl Acad Sci U S A 104(11):4291-6 (2007 Mar 13).
26. Champney WS, Rodgers WK. Retapamulin inhibition of translation and 50S ribosomal subunit formation in Staphylococcus aureus cells. Antimicrob Agents Chemother 51(9):3385-7 (2007 Sep).
27. Yan K, Madden L, Choudhry AE, et al. Biochemical characterization of the interactions of the novel pleuromutilin derivative retapamulin with bacterial ribosomes. Antimicrob Agents Chemother 50(11):3875-81 (2006 Nov).
28. Koning S, van der Wouden JC, Chosidow O, et al. Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized double-blind multicentre placebo-controlled trial. Br J Dermatol 158(5):1077-82 (2008 May).
29. Free A, Roth E, Dalessandro M, et al. Retapamulin ointment twice daily for 5 days vs oral cephalexin twice daily for 10 days for empiric treatment of secondarily infected traumatic lesions of the skin. Skinmed 5(5):224-32 (2006 Sep-Oct).
30. Schalock PC. Allergic contact dermatitis to retapamulin ointment. Contact Dermatitis 61(2):126 (2009 Aug).
31. Warshaw EM, Toby Mathias CG, Baker DR. Allergic contact dermatitis from retapamulin ointment. Dermatitis 20(4):220-1 (2009 Aug).
32. Dhar S, Kanwar AJ, Kaur S, et al. Role of bacterial flora in the pathogenesis & management of atopic dermatitis. Indian J Med Res 95:234-8 (1992 Sep).
33. Ewing CI, Ashcroft C, Gibbs AC, et al. Flucloxacillin in the treatment of atopic dermatitis. Br J Dermatol 138(6):1022-9 (1998 Jun).
34. Hjorth N, Schmidt H, Thomsen K. Fusidic acid plus betamethasone in infected or potentially infected eczema. Pharmatherapeutica 4(2):126-31 (1985).
35. Huang JT, Abrams M, Tlougan B, et al. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 123(5):e808-14 (2009 May).
36. Leyden JJ, Kligman AM. The case for steroid–antibiotic combinations. Br J Dermatol 96(2):179-87 (1977 Feb).
37. Wachs GN, Maibach HI. Co-operative double-blind trial of an antibiotic/corticoid combination in impetiginized atopic dermatitis. Br J Dermatol 95(3):323-8 (1976 Sep).

1. Center for Clinical Studies, Houston, TX, USA
2. The University of Texas Medical School at Houston, Houston, TX, USA
3. Department of Dermatology, University of Texas Health Sciences Center, Houston, TX, USA

ABSTRACT

Psoriasis is a common chronic inflammatory skin disease that is mediated, in part by the body’s T-cell inflammatory response mechanisms. Further insight into the pathogenesis of the disease and the role of various cytokines, particularly interleukin(IL)-12 and IL-23, has led to advances in the treatment of this disease. A relatively new class of drugs that inhibit these interleukins is being developed and studied. Current data regarding the efficacy of these agents show they may have the potential to become the new clinical gold standard for biologic therapy to treat psoriasis.

Key Words:
IL-12; IL-23; ustekinumab; psoriasis

The Role of IL-12 & IL-23 in the Pathogenesis of Psoriasis

Psoriasis is a chronic skin disease affecting approximately 2%-3% of the general population and is mediated, at least partially, by the body’s T-cell inflammatory response mechanisms. Two interleukins (IL) in particular, IL-12 and IL-23, have been specifically implicated as key players in the pathogenesis of psoriasis secondary to their role in linking the innate and adaptive immune responses.¹ IL-12 and IL-23 are composed of the p40 subunit, which is common to both, as well as the unique subunits, p35 and p19, respectively. The individual subunits facilitate the distinctive biological actions of each molecule. IL-12 functions to induce and sustain TH1 immune responses leading to the secretion of interferon (IFN)-ã and the homing of T cells to the skin via the induction of cutaneous lymphocyte antigen (CLA), whereas, IL-23 functions to maintain chronic autoimmune inflammation via the induction of IL-17, regulation of T memory cells, and direct activation of macrophages.^1-4

Support for IL-12 and IL-23 Involvement in Psoriasis

Through various approaches, a plethora of studies involving transgenic mice, the human genome, and samples from human psoriatic lesions support the hypothesis that IL-12 and IL-23 have a significant role in the disease process. According to the genome-wide association study (GWAS) conducted by Cargill et al., an association exists between psoriasis and the genes for IL-12 and IL-23. This finding was reproduced by Smith et al. in a study of approximately 600 patients with psoriasis. Additionally, scrapings from psoriatic lesions have exhibited not only increased levels of IL-12 and IL-23, but also higher levels of their downstream effectors, including CLA+ T-cells, IFN-ã, and IL-17.^1,4 Recent findings indicate that people with genetic over-expression of this common p40 subunit have a greater risk for the development of psoriasis, and that psoriatic lesions contain high levels of IL-12, IL-23 and their downstream effectors. In light of these findings, further investigation has been directed towards illustrating not only their specific role in its pathogenesis, but also whether direct inhibition may play an integral role in its treatment.^1-3

Mechanism of Action

Both IL-12 and IL-23 bind to the b1 receptor of T cells and natural killer cells via their shared p40 subunit.^1,7 This new class of drugs has been designed to function by binding with high affinity to the p40 subunit, thus preventing its binding at the receptor and the subsequent downstream signaling. Currently, at least 2 drugs exist in this class: the first is CNTO-1275 (ustekinumab), which is being developed by Centocor and ABT-874, which is being developed by Abbott.^1,2 Both drugs, given as subcutaneous injections, are fully human monoclonal antibodies targeting the shared p40 subunit of IL-12 and IL-23. An oral version of these drugs was introduced by Synta Pharmaceuticals as STA-5326, but this version failed in Phase II clinical trials for the treatment of psoriasis; it is still being tested for the treatment of rheumatoid arthritis and common variable immunodeficiency.⁸

Advantages of IL-12/IL-23 Inhibitors

Four double-blinded, placebo controlled trials, 3 evaluating CNTO-1275 and 1 evaluating ABT-874, have shown that both drugs are very effective in the treatment of psoriasis. These studies all used 3 universal criteria to delineate an adequate response:

1. Psoriasis Area and Severity Index (PASI), which combines assessments of the extent of body surface involvement and the severity of desquamation, erythema, and plaque induration
2. Physician’s Global Assessment (PGA), which rates the patient’s psoriasis relative to baseline
3. Dermatology Quality of Life Index (DQLI), which is a 10 item questionnaire to assess the patient’s perspective on how psoriasis is affecting his or her own quality of life.

The Four Studies

Krueger et al.³ evaluated the efficacy of 4 dosing regimens of CNTO-1275:

• one 45mg dose
• one 90mg dose
• 4 weekly 45mg doses
• 4 weekly 90mg doses.

At least 75% improvement from the baseline PASI was seen in more than 50% (54%-81%) of subjects at 12 weeks in all 4 treatment arms. A higher dose of drug correlated with a higher percentage of subjects with a PASI-75 or better. This degree of improvement was seen in only 2% of those who received placebo. With regards to the PGA and DQLI, all active-treatment groups significantly improved when compared with the placebo group.

The PHOENIX 1 and 2 trials^9,10 also evaluated the efficacy of CNTO-1275 by considering 2 treatment arms:

• one 45mg dose at week 0 and week 4, followed by one 45mg dose every 12 weeks
• one 90mg dose in the same dosing schedule.

Both trials illustrated improvement of at least 75% from baseline in more than 50% of both CNTO-1275 arms (66.4% and 63.1% in the 45mg arms, and 66.4% and 72% in the 90mg arms). In the PHOENIX 1 trial, patients who had achieved a satisfactory PASI-75 by weeks 28 or 40 were then rerandomized to a withdrawal vs. maintenance phase. Those who received the maintenance dose did much better than those who were withdrawn.⁹ Furthermore, in both PHOENIX trials, after the primary efficacy data was collected at week 12, patients originally allocated to the placebo arm were again randomized into either 45mg or 90mg dosing every 12 weeks. The results of these crossover randomizations paralleled those of the original treatment groups.

Kimball et al.² conducted a similar study evaluating the efficacy of 5 dosing regimens of ABT-874:

• one 200mg dose at week 0
• 100mg every other week for 12 weeks
• 200mg weekly for 4 weeks
• 200mg every other week for 12 weeks
• 200mg every week for 12 weeks.

Ninety percent of the patients in the ABT-874 multiple-dose arms exhibited improvement of at least 75% from baseline vs. only 3% in the placebo group.

These studies exhibited a dose-response phenomenon, and response rates declined across all dosages after treatment was discontinued for more than 12 weeks.³ Additional support for this drug class as a treatment option for psoriasis includes a short response latency and sustainable efficacy. Response time for both drugs was very rapid, measured by PASI-50 at week 2 and PASI-75 by week 4.^2,9,10 The PHOENIX 1 trial continued for a total follow-up time of 76 weeks, and the PHOENIX 2 trial for 52 weeks, illustrating that maintenance dosing every 8-12 weeks ensures a sustained response.
This further indicates that IL-12 and IL-23 inhibitors have the potential to provide a treatment regimen that is not only successful but also convenient.¹²
Data further showed that maximum effects were reached by week 20, and that response rates had stabilized by week 28. They were successfully maintained throughout the remainder of the study at the dosage frequency of 1 dose (either the 45mg or 90mg originally assigned) every 8-12 weeks.^9,10

Disadvantages of IL-12/IL-23 Inhibitors

For studies using CNTO-1275, there were no significant differences in adverse events (AEs) between the treatment groups and placebo groups.^3,9,10 However, for ABT-874, Kimball et al.² reported a higher percentage of AEs in the treatment group vs. the placebo group.²
Patients receiving any dose of ABT-874 were significantly more likely to experience an AE than those in the placebo group, 36.1% vs. 10%, respectively. The AEs in the ABT-874 treated group were most commonly related to reactions at the injection site (erythema, pruritus, and irritation), but also included nasopharyngitis (12.0%) and upper respiratory tract infections (10.7%), followed by bronchitis and viral infection (both 2.7%). The incidences of other AEs were not statistically significantly different in the ABT-874 treatment group compared with placebo-treated patients.

The most commonly encountered AE was infection, which, surprisingly, did not show a significant dose-related trend. One major difference noted between CNTO-1275 and ABT-874 was the rate of AEs at the injection site. Such events occurred at a much higher frequency with ABT-874. Injection site reactions occurred in 16.7% of patients in the study arms treated with ABT-8742 vs. only 1.2%-2% in the CNTO-1275 studies.^3,9,10 In all 4 studies the occurrence of adverse injection reactions among the placebo groups was 0%-2%. The development of antibodies to the drugs also remains a concern with these treatments.


Krueger et al.3 reported AEs in 51 of 64 patients (79%) in the treatment group vs. 46 of 64 patients (72%) in the placebo group (p=0.19). Three of these patients (4%) developed antibodies to CNTO-1275. AEs leading to hospitalizations and discontinuation of treatment occurred in 3 patients in the treatment group vs. 1 in the placebo group (p=0.69). Among the patients in the groups receiving treatment who experienced a serious AE, 2 of them were hospitalized for infections (1 for cellulitis and 1 for pneumonia).

The PHOENIX 1 trial9 reported AEs in 54% of patients in either treatment arm and in 48% of patients in the placebo arm. Of the patients who were getting CNTO-1275, 5.1% developed antibodies to this formulation. Serious AEs occurred in 1.2% of treatment groups vs. 0.8% in the placebo group.

The PHOENIX 2 trial10 reported AEs at an equal frequency among the treatment and placebo arms, both measuring in at approximately 50%. Twelve percent of patients developed antibodies to CNTO-1275. For the most part, these antibodies were found to be neutralizing. Serious AEs occurred in 2% of treatment groups vs. 0% in the placebo group.

Prior to the use of IL-12 and IL-23 inhibitors for the treatment of psoriasis, concern arose because of unrelated studies involving people and transgenic mice with IL-12 deficiencies. Populations of people with a congenital deficiency of the IL-12 p40 subunit or the IL-12 receptor were found to have an increased susceptibility to intracellular pathogens, including tuberculosis, Toxoplasma gondii and Leishmania major, as well as defective delayed type hypersensitivity reactions. Furthermore, IL-12 plays an integral role in immunity against multiple viruses, including herpes simplex virus, vesicular stomatitis virus, and murine aquired immunodeficiency syndrome (MAIDS).⁷ These specific concerns have not yet been proven to be an issue in the trials, but due to the tuberculosis concern, an exclusion criterion common to all 4 studies outlined that no person with active disease would be allowed to participate. Ultimately, long-term consequences of IL-12 and IL-23 inhibitor usage beyond 76 weeks have yet to be determined as the clinical trials are very recent.

Various studies involving autoimmune diseases in non-human models have shown that targeting IL-23 alone instead of targeting both may be a better strategy.1 Specifically, a study by Chan et al. showed that direct intradermal administration into mice of IL-23 alone, but not IL-12 alone, initiates a psoriatic type reaction. This TNF-mediated spectrum of events culminates in erythema, and acanthosis with parakeratosis that is accompanied by a mixed dermal infiltrate.

Another important consideration is the cost of these drugs. Although the exact market cost has not yet been established, biologic agents tend to be very expensive, and IL-12 and IL-23 inhibitors will likely not be an exception to this trend.

Conclusions

IL-12 and IL-23 inhibitors remain on the forefront of treatment options for inflammatory diseases such as psoriasis, Crohn’s disease, multiple sclerosis, and rheumatoid arthritis. Although the current data does not provide insight into the long-term effects of these drugs, results have been extremely encouraging. In light of the current research and results, IL-12 and IL-23 inhibitors are a very promising option in the treatment of psoriasis.

While the therapeutic effects were shown to have a dose-response relationship, the AEs illustrated no such trend. Furthermore, although the rate of AEs was higher in the ABT-874 treatment groups, these events were reported to be generally tolerable, easily managed, and did not cause a significant percentage of subjects to be discontinued from the study.² The current standard of care for psoriasis includes the use of broad spectrum anti-T-cell agents with accompanying immunosuppression,¹² and often necessitates early discontinuation and subsequent psoriatic flares. With the introduction of the IL-12 and IL-23 inhibitors, there is new hope for patients battling psoriasis, as these formulations offer a favorable balance between disease treatment, resolution, tolerable side-effects, and an overall improved quality of life.

References

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