4 - 28 - PSORIASIS

Question 1

HISTOPATHOLOGY of fully developed lesions

Answer 1

• uniform elongation of the rete ridges,
• with dilated blood vessels,
• thinning of the suprapapillary plate, and
• intermittent parakeratosis.
• Epidermal and perivascular dermal infiltrates of lymphocytes, with neutrophils occasionally in aggregates in the epidermis.

Question 2

Define psoriasis

Answer 2

Psoriasis is a common, immunologically mediated, inflammatory disease characterized by skin inflammation, epidermal hyperplasia, and increased risk of a painful and destructive arthritis as well as cardiovascular morbidity and psychosocial challenges.

Question 3

Age predilection of psoriasis

Answer 3

Psoriasis may begin at any age, but it is uncommon before the age of 10 years. It is most likely to appear between the ages of 15 and 30 years.

Question 4

2 forms of psoriasis

Answer 4

Possession of certain human leukocyte antigen (HLA) class I antigens, particularly HLA-Cw6, is associated with an earlier age of onset and with a positive family history.

This finding led Henseler and Christophers 3 to propose that two different forms of psoriasis exist:

• type I, with age of onset before 40 years and HLA associated, and
• type II, with age of onset after 40 years, although many patients do not fit into this classification.

Question 5

Classic lesion of psoriasis

Answer 5

well-demarcated, raised, red plaque with a white scaly surface

Lesions can vary in size from pinpoint papules to plaques that cover large areas of the body.

Psoriasis tends to be a symmetric eruption, and symmetry is a helpful feature in establishing a diagnosis. Unilateral involvement can occur, however. The psoriatic phenotype may present a changing spectrum of disease expression even within the same patient.

Question 6

What is Auspitz sign

Answer 6

Under the scale, the skin has a glossy homogeneous erythema, and bleeding points appear when the scale is removed, traumatizing the dilated capillaries below (the Auspitz sign) (Fig. 28-2).

Question 7

Define koebner phenomenon

Answer 7

The Koebner phenomenon (also known as the isomorphic response) is the traumatic induction of psoriasis on nonlesional skin; it occurs more frequently during flares of disease and is an all-or-none phenomenon (ie, if psoriasis occurs at one site of injury, it will occur at all sites of injury) (Fig. 28-3). The Koebner reaction usually occurs 7 to 14 days after injury, and from 25% to 75% of patients may develop trauma-related Koebner phenomenon at some point during their disease.

Question 8

most common form of psoriasis, seen in approximately 90% of patients.

Answer 8

Psoriasis vulgaris

Question 9

Describe the lesions of Psoriasis vulgaris

Answer 9

Red, scaly, symmetrically distributed plaques are characteristically localized to the extensor aspects of the extremities; particularly the elbows and knees, along with scalp, lower lumbosacral, buttocks, and genital involvement (see Fig. 28-1).

Question 10

refers to lesions in the shape of a cone or limpet

Answer 10

Rupioid psoriasis

B, Rupioid psoriasis in an infant. Note the cone-shaped lesions.

Question 11

refers to a ringlike, hyperkeratotic concave lesion, resembling an oyster shell

Answer 11

Ostraceous psoriasis

Question 12

uncommon form characterized by thickly scaling, large plaques, usually on the lower extremities

Answer 12

elephantine psoriasis

D, Elephantine psoriasis of the lower extremities. Note psoriatic involvement of toenails.

Question 13

A hypopigmented ring surrounding individual psoriatic lesions may occasionally be seen and is usually associated with treatment, most commonly UV radiation or topical corticosteroids (see Fig. 28-4).

What do you call this ring?

Answer 13

Woronoff ring

The pathogenesis of the Woronoff ring is not well understood but may result from inhibition of prostaglandin synthesis.

C, Psoriatic patient undergoing modified Goeckerman therapy (ultraviolet B light, coal tar, and topical steroid), demonstrating Woronoff rings.

Question 14

Describe the lesions of GUTTATE (ERUPTIVE) PSORIASIS

Answer 14

Guttate psoriasis (from the Latin gutta, meaning “a drop”) is characterized by eruption of small (0.5–1.5 cm in diameter) papules over the upper trunk and proximal extremities (Fig. 28-5).

It typically manifests at an early age and as such is found frequently in young adults. This form of psoriasis has the strongest association to HLA-Cw6, and streptococcal throat infection frequently precedes or is concomitant with the onset or flare of guttate psoriasis. 6 However, antibiotic treatment has not been shown to be beneficial or to shorten the disease course. 7 Patients with a history of chronic plaque psoriasis may develop guttate lesions, with or without worsening of their chronic plaques.

Question 15

Describe the lesions of SMALL PLAQUE PSORIASIS

Answer 15

Small plaque psoriasis resembles guttate psoriasis clinically but can be distinguished by its onset in older patients, by its chronicity, and by having somewhat larger lesions (typically 1–2 cm) that are thicker and scalier than in guttate disease. It is said to be a common adult-onset presentation of psoriasis in Korea and other Asian countries.8

Question 16

Describe the lesions of INVERSE PSORIASIS

Answer 16

Psoriasis lesions may be localized in the major skin folds, such as the axillae, the genitocrural region, and the neck. Scaling is usually minimal or absent, and the lesions show a glossy sharply demarcated erythema, which is often localized to areas of skin-to-skin contact (Fig. 28-6). Sweating is impaired in affected areas.

Question 17

Describe the lesions of ERYTHRODERMIC PSORIASIS

Answer 17

Psoriatic erythroderma affects all body sites, including the face, hands, feet, nails, trunk, and extremities (Fig. 28-7). Although all the symptoms of psoriasis are present, erythema is the most prominent feature, and scaling is different compared with chronic stationary psoriasis. Instead of thick, adherent, white scale, there is superficial scaling. Patients with erythrodermic psoriasis lose excessive heat because of generalized vasodilatation, and this may cause hypothermia.

Patients may shiver in an attempt to raise their body temperature. Psoriatic skin is often hypohidrotic because of occlusion of the sweat ducts, and there is an attendant risk of hyperthermia in warm climates. Lower extremity edema is common secondary to vasodilation and loss of protein from the blood vessels into the tissues. High-output cardiac failure and impaired hepatic and renal function may also occur. Psoriatic erythroderma has a variable presentation, but two forms are thought to exist. In the first form, chronic plaque psoriasis may worsen to involve most or all of the skin surface, and patients remain relative responsive to therapy. In the second form, generalized erythroderma may present suddenly and unexpectedly or result from nontolerated external treatment (eg, UVB, anthralin), thus representing a generalized Koebner reaction. Generalized pustular psoriasis (see later) may revert to erythroderma with diminished or absent pustule formation. Occasional diagnostic problems may arise in differentiating psoriatic erythroderma from other causes.

Question 18

What are the clinical variants of pustular psoriasis?

Answer 18

• generalized pustular psoriasis (von Zumbusch type),
• annular pustular psoriasis,
• impetigo herpetiformis, and
• two variants of localized pustular psoriasis— pustulosis palmaris et plantaris and acrodermatitis continua of Hallopeau.

In children, pustular psoriasis can be complicated by sterile, lytic lesions of bones and can be a manifestation of the SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis).

Question 19

Describe Generalized Pustular Psoriasis (von Zumbusch)

Answer 19

This is a distinctive acute variant of psoriasis that is usually preceded by other forms of the disease. Attacks are characterized by fever that lasts several days and a sudden generalized eruption of sterile pustules 2 to 3 mm in diameter (Fig. 28-8). The pustules are disseminated over the trunk and extremities, including the nail beds, palms, and soles.

The pustules usually arise on highly erythematous skin, first as patches (see Fig. 28-8) and then become confluent as the disease becomes more severe. With prolonged disease, the fingertips may become atrophic. The erythema that surrounds the pustules often spreads and becomes confluent, leading to erythroderma. Characteristically, the disease occurs in waves of fevers and pustules. The cause of generalized psoriasis von Zumbusch type is unknown. Various provoking agents include infections, irritating topical treatment (Koebner phenomenon), and withdrawal of oral corticosteroids. 9 This form of psoriasis is usually associated with prominent systemic signs and can potentially have life-threatening complications such as hypocalcemia, bacterial superinfection, sepsis, and dehydration. Severe pustular psoriasis can be difficult to control and requires a potent treatment regimen with rapid onset of action to avoid lifethreatening complications.

Question 20

Describe Exanthematic Pustular Psoriasis

Answer 20

Exanthematic pustular psoriasis tends to occur after a viral infection and consists of widespread pustules with generalized plaque psoriasis. However, unlike the von Zumbusch pattern, there are no constitutional symptoms, and the disorder tends not to recur. There is an overlap between this form of pustular psoriasis and acute generalized exanthematous pustulosis, a type of drug eruption.

Question 21

Describe Annular Pustular Psoriasis

Answer 21

Annular pustular psoriasis is a rare variant of pustular psoriasis. It usually presents in an annular or circinate form. Lesions may appear at the onset of pustular psoriasis, with a tendency to spread and form enlarged rings, or they may develop during the course of generalized pustular psoriasis. The characteristic features are pustules on a ringlike erythema that sometimes resembles erythema annulare centrifugum. Identical lesions are found in patients with impetigo herpetiformis, an entity defined by some as a variant of pustular psoriasis occurring in pregnancy. Onset in pregnancy is usually early in the third trimester and persists until delivery. It tends to develop earlier in subsequent pregnancies. Impetigo herpetiformis is often associated with hypocalcemia. 9 There is usually no personal or family history of psoriasis.

Question 22

Describe Pustulosis Palmaris et Plantaris

Answer 22

Palmo-plantar pustular psoriasis (PPPP) is a rare variant of pustular psoriasis that is localized to the palms and soles. It may coexist with chronic plaque psoriasis with approximately 27% of patients having concomitant chronic plaque psoriasis. 10 It differs from chronic plaque psoriasis both in terms of genetic predisposition 11 and transcriptional changes. 12 Therefore, many authors make a distinction between palmoplantar pustulosis (PPP) and PPPP, in which chronic plaque psoriasis is present, although the lesions of PPPP and PPP are indistinguishable by themselves both clinically and transcriptionally. 12 Pustulosis palmaris et plantaris is more common in females (about 78%) with a median age of onset of 47 years. 10 Psoriatic arthritis (PsA) can be seen with pustulosis palmaris et plantaris, with a prevalence of 13% to 25%. 10 Smoking is strongly associated with pustulosis palmaris et plantaris, and about 80% of patients are tobacco smokers at the time of presentation.

Question 23

Describe Acrodermatitis Continua of Hallopeau

Answer 23

Acrodermatitis continua of Hallopeau, also known as dermatitis repens, is an extremely rare localized sterile pustular eruption of the fingers and toes. 13 It typically involves the distal portions of the fingers and toes and may occur after minor trauma or infection. Pustules often coalesce to form lakes of pus and nail loss is common. Over time, sclerosis of the underlying soft tissues and osteolysis of the distal phalanges may occur. Similar to pustulosis palmaris et plantaris, it is more common in middle-aged women. Evolution of acrodermatitis continua into generalized pustular psoriasis has been described.

Question 24

Describe SEBOPSORIASIS

Answer 24

A common clinical entity, sebopsoriasis presents with erythematous plaques with greasy scales localized to seborrheic areas (scalp, glabella, nasolabial folds, perioral and presternal areas, and intertriginous areas). In the absence of typical findings of psoriasis elsewhere, distinction from seborrheic dermatitis is difficult. Sebopsoriasis may represent a modification of seborrheic dermatitis by the genetic background of psoriasis and is relatively resistant to treatment. Although an etiologic role of Pityrosporum remains unproven, antifungal agents may be useful.

Question 25

Describe NAPKIN PSORIASIS

Answer 25

Napkin psoriasis usually begins between the ages of 3 and 6 months and first appears in the diaper (napkin) areas as a confluent red area with appearance a few days later of small red papules on the trunk that may also involve the limbs. These papules have the typical white scales of psoriasis. The face may also be involved with red scaly eruption. Unlike other forms of psoriasis, the rash responds readily to treatment and tends to disappear after the age of 1 year.

Question 26

Describe LINEAR PSORIASIS

Answer 26

Linear psoriasis is quite rare. The psoriatic lesion presents as linear lesion most commonly on the limbs but may also be limited to a dermatome on the trunk. This may be an underlying nevus, possibly an inflammatory linear verrucous epidermal nevus (ILVEN) because these lesions resemble linear psoriasis both clinically and histologically. The existence of a linear form of psoriasis distinct from ILVEN is controversial.

Question 27

Nail Changes in Psoriasis

Answer 27

Nail changes are frequent in psoriasis, being found in up to 40% of patients, 14 and are rare in the absence of skin disease elsewhere. Nail involvement increases with age, with duration and extent of disease, and with the presence of PsA. Several distinct changes have been described and can be grouped according to the portion of the nail that is affected (Table 28-1). Nail pitting is one of the commonest features of psoriasis, involving the fingers more often than the toes (Fig. 28-9). Pits range from 0.5 to 2.0 mm in size and can be single or multiple. The proximal nail matrix forms the dorsal (superficial) portion of the nail plate, and psoriatic involvement of this region results in pitting caused by defective keratinization. Other alterations in the nail matrix resulting in deformity of the nail plate (onychodystrophy) include leukonychia, crumbling nail, and red spots in the lunula. Onychodystrophy has a stronger association with PsA than other nail changes. 14 Oil spots and salmon patches are translucent, yellow-red discolorations observed beneath the nail plate often extending distally toward the hyponychium caused by psoriasiform hyperplasia, parakeratosis, microvascular changes, and trapping of neutrophils in the nail bed. 15 Unlike pitting, which is also seen in alopecia areata and other disorders, oil spotting is considered to be nearly specific for psoriasis. Splinter hemorrhages result from capillary bleeding underneath the thin suprapapillary plate of the psoriatic nail bed. Subungual hyperkeratosis is caused by hyperkeratosis of the nail bed and is often accompanied by onycholysis (separation of the nail plate from the nail bed), which usually involves the distal aspect of the nail. Anonychia is total loss of the nail plate. Although nail changes are rarely seen in the localized pustular variant of pustulosis palmaris et plantaris, anonychia can be seen in other forms of pustular psoriasis.

Question 28

Nail finding that has a stronger association with PsA than other nail changes

Answer 28

Onychodystrophy

Question 29

What causes oil spots and salmon patches?

Answer 29

Oil spots and salmon patches are translucent, yellow-red discolorations observed beneath the nail plate often extending distally toward the hyponychium caused by psoriasiform hyperplasia, parakeratosis, microvascular changes, and trapping of neutrophils in the nail bed. Unlike pitting, which is also seen in alopecia areata and other disorders, oil spotting is considered to be nearly specific for psoriasis.

Question 30

What causes splinter hemorrhages?

Answer 30

Splinter hemorrhages result from capillary bleeding underneath the thin suprapapillary plate of the psoriatic nail bed.

Question 31

What causes subungual hyperkeratosis

Answer 31

Subungual hyperkeratosis is caused by hyperkeratosis of the nail bed and is often accompanied by onycholysis (separation of the nail plate from the nail bed), which usually involves the distal aspect of the nail

Question 32

idiopathic inflammatory disorder resulting in the local loss of filiform papillae

Answer 32

Geographic tongue, also known as benign migratory glossitis or glossitis areata migrans

The condition usually presents as asymptomatic erythematous patches with serpiginous borders, resembling a map. These lesions characteristically have a migratory nature. Geographic tongue has been postulated to be an oral variant of psoriasis because these lesions show several histologic features of psoriasis, including acanthosis, clubbing of the rete ridges, focal parakeratosis, and neutrophilic infiltrate. Although the prevalence of geographic tongue is increased in psoriatic patients, this is a relatively common condition that is seen in many nonpsoriatic individuals, so its relationship to psoriasis needs further clarification.

Question 33

common extracutaneous manifestation of psoriasis seen in up to 40% of patients.

Answer 33

Arthritis

It has a strong genetic component, and several overlapping subtypes exist.

Question 34

CARDIOVASCULAR MORBIDITY

Answer 34

Patients with psoriasis have an increased morbidity and mortality from cardiovascular events, particularly those with severe and long duration of psoriasis skin disease. 17 Risk of myocardial infarction is particularly elevated in younger patients with severe psoriasis, 18 and vascular inflammation as detected by 18 F-fluorodeoxyglucose–positron emission tomography computed tomography (PET/CT) correlates directly with the extent of cutaneous involvement.19 In a recent study of 1.3 million German health care recipients, metabolic syndrome was 2.9-fold more frequent among patients with psoriasis, and the most common diagnoses were hypertension (35.6% in psoriasis vs 20.6% in control participants) and hyperlipidemia (29.9% vs 17.1%). 20 Patients with psoriasis have also been shown to be at increased risk for rheumatoid arthritis (RA), Crohn’s disease, and ulcerative colitis20 as well as Hodgkin’s lymphoma and cutaneous T-cell lymphoma.

Question 35

PSYCHOSOCIAL RAMIFICATIONS

Answer 35

Psoriasis is emotionally disabling, carrying with it significant psychosocial difficulties. Emotional difficulties arise from concerns about appearance, resulting in lowered self-esteem, social rejection, guilt, embarrassment, emptiness, sexual problems, and impairment of professional ability. 22 The presence of pruritus and pain can aggravate these symptoms. Psychological aspects can modify the course of illness; in particular, feeling stigmatized can lead to treatment noncompliance and worsening of psoriasis. Likewise, psychological stress can also lead to depression and anxiety. The prevalence of suicidal ideation and depression in patients with psoriasis is higher than that reported in people with other medical conditions and the general population. A comparative study reported reduction in physical and mental functioning comparable with that seen in cancer, arthritis, hypertension, heart disease, diabetes, and depression. 23 According to one survey, 79% of patients with severe psoriasis reported a negative impact on their lives.24

Question 36

Development of psoriatic lesions.

Answer 36

Detailed light, electron microscopic, immunohistochemical, and molecular studies of involved and uninvolved skin of newly appearing and established psoriatic lesions provide a useful framework for relating the many cellular events that take place in a psoriatic lesion. They are illustrated schematically in Fig. 28-10 and with actual photomicrographs in Fig. 28-11. The normal-appearing skin of psoriatic patients has long been known to manifest subclinical morphologic and biochemical changes, particularly involving lipid biosynthesis. 25 In the initial pinheadsized macular lesions, there is marked edema, and mononuclear cell infiltrates are found in the upper dermis, 26 usually confined to the area of one or two papillae. The overlying epidermis soon becomes spongiotic, with focal loss of the granular layer. The venules in the upper dermis dilate and become surrounded by a mononuclear cell infiltrate. Similar findings have been described in early macules and papules of psoriasis and in the uninvolved skin of guttate psoriasis.27 The clinical margins of somewhat larger lesions (0.5–1.0 cm) manifest doubling of epidermal thickness, increased metabolic activity of epidermal cells, and increased mast cells and dermal macrophages with increased mast cell degranulation, as well as increased dermal T cells and dendritic cells (DCs). Toward the center of these evolving lesions, there are increasing bandlike epidermal thickness, parakeratosis, and capillary elongation, as well as perivascular infiltration of lymphocytes and macrophages without exudation into the epidermis. Squamous cells manifest enlarged extracellular spaces with only a few desmosomal connections, and parakeratosis is typically mounded or spotty. More mature lesions of psoriasis manifest uniform elongation of rete ridges, with thinning of the epidermis overlying the dermal papillae. 25 Epidermal mass is increased three to five times, and many more mitoses are observed, frequently above the basal layer. About 10% of basal keratinocytes are cycling in normal skin, but this value rises to 100% in lesional psoriatic skin. 28 Widening of the extracellular spaces between keratinocytes persists but is less prominent than in developing lesions and is more uniform than the typical spongiosis of eczematous skin lesions. The tips of the rete ridges are often clubbed or fused with adjacent ones, with thin, elongated, edematous papillae containing dilated, tortuous capillaries. Parakeratosis, with accompanying loss of the granular layer, is often horizontally confluent but may alternate with orthokeratosis. The inflammatory infiltrate around the blood vessels in the papillary dermis becomes more intense but still consists of lymphocytes, macrophages, DCs, and mast cells. Unlike the initial lesion and the transitional zone, lymphocytes are observed in the epidermis of the mature lesion. Neutrophils exit from the tips of a subset of dermal capillaries (the “squirting papillae”), leading to their accumulation in the overlying parakeratotic stratum corneum (Munro’s microabscesses) and, less frequently, in the spinous layer (spongiform pustules of Kogoj). Collections of serum can also be seen in the epidermis and stratum corneum.

Question 37

Histopathology of psoriasis

Answer 37

Question 38

The cytokine network in psoriasis

Answer 38

T cells play an essential role in psoriasis as demonstrated in 1996, when it was shown that psoriasis could be induced by injecting activated autologous T cells into uninvolved psoriatic skin transplanted onto severe combined immunodeficient mice. 29 Early studies suggested that at least some T-cell responses are antigen specific because oligoclonal expansions of both CD4 + and CD8 + T cells have repeatedly been identified in psoriatic lesions. 30 However, more recent studies using deep T-cell receptor (TCR) sequencing indicate most of the T cells in normal, uninvolved and lesional psoriatic skin are polyclonal with approximately equal diversity 31 and thus may accumulate in response to the cytokine environment of the lesion. There is virtually no evidence for B-cell involvement or antibody-mediated processes in psoriasis. The bestcharacterized T cells are the CD4 + and CD8 + subsets. Predominantly of the memory phenotype (CD45RO+ ), these cells express the cutaneous lymphocyte antigen, a ligand for E-selectin, which is selectively expressed on skin capillaries and therefore provides them with access to the skin. 32 Whereas CD8 + T cells are predominantly located in the epidermis, CD4 + T cells are predominantly located in the upper dermis. Epidermal T cells, particularly CD8 + cells, appear to have a critical role in development of psoriatic plaques as either blocking the entry of these cells into the epidermis, 33 or neutralization of CD8 + T cells 34 prevents development of psoriasis in a xenograft model.

The cytokine profile of psoriatic lesions is rich in interferon (IFN)-γ, indicative of T helper 1 (Th1) polarization of CD4 + cells, and T cytotoxic 1 (Tc1) polarization of CD8 + cells (Fig. 28-12). Two other subsets of CD4 + T cells, stimulated by interleukin (IL)-23 and

characterized by production of IL-17 (Th17, ∼20% of T cells) or IL-22 (Th22, ∼15% of T cells), have been shown to play a major role in maintaining chronic inflammation in psoriasis 35 (Fig. 28-13) as well as other autoinflammatory conditions. In addition to IFN-γ–producing Tc1 cells, CD8 + T-cells producing IL-17 (Tc17) and IL-22 (Tc22) are found in psoriasis, most of which localize to the epidermis. These T-cell subsets have considerable functional plasticity and conversions of Tc17 to Tc1 and Th17 to Th1 have been described. Regulatory T cells (Tregs) suppress immune responses in an antigen-specific fashion and are responsible not only for downregulating successful responses to pathogens but also for the maintenance of immunologic tolerance. Several different populations

of Tregs exist, but the best characterized one is the CD4 + CD25 + subset. 36 Tregs manifest impaired inhibitory function and failure to suppress effector T-cell proliferation in psoriasis. 37 Other “unconventional” lymphocytes implicated in the pathogenesis of psoriasis include natural killer (NK) cells, NK-T cells, γδ T-cells, mucosal-associated invariant T (MAIT) cells, and innate lymphoid cells (ILCs). These populations also represent important sources of IL-17, IFN-γ, tumor necrosis factor (TNF), and other cytokines.

Question 39

The inflammatory and genetic network in psoriasis.

Answer 39

T cells in psoriatic lesions are in constant communication with DCs, which have a role in both the priming of adaptive immune responses and the induction of selftolerance (see Chap. 11; Fig. 28-13). Several subsets of DCs have been defined, and many of these are found in markedly increased numbers within psoriatic lesions.40 However, the specific role of each subset is still somewhat unclear. As noted earlier, macrophages are prominent in developing psoriasis lesions, with neutrophils appearing somewhat later. Studies in a mouse model that was used to implicate macrophages suggested that neutrophils may be unnecessary for lesional development. 41 However, neutrophils are likely to play a major role in pustular psoriasis by amplifying the local inflammatory reaction through secretion of proteases such as cathepsin G, elastase, and proteinase-3. These proteases are capable of processing inactive IL-36 family cytokines (IL-36α, IL-36β, and IL-36γ) secreted by keratinocytes into their active forms. When activated, IL-36 cytokines are strong activators of keratinocytes, leading to secretion of chemotactic proteins, particularly neutrophil chemokines, thereby amplifying and sustaining the inflammatory process.

Question 40

Comprising the bulk of the epidermis and its appendages, ________ are a major producer of proinflammatory cytokines, chemokines, and growth factors, as well as other inflammatory mediators such as eicosanoids and mediators of innate immunity such as cathelicidins, defensins, and S100 proteins.

Answer 40

keratinocytes

Psoriatic keratinocytes are engaged in an alternative pathway of keratinocyte differentiation called regenerative maturation. 42 Regenerative maturation is activated in response to immunologic stimulation. Besides keratinocytes, other skin-resident cell types, such as endothelial cells and fibroblasts, are also likely participants in the pathogenic process.

Question 41

Proposed model integrating the genetics and immunology of psoriasis.

Answer 41

In recent years, many genetic variants contributing to psoriasis susceptibility have been identified, initially through linkage studies and more recently through genome-wide association studies (GWAS). An overview of the major genetically-implicated pathways in psoriasis is provided in Fig. 28-14, and a list of genetic loci identified to date is provided in Table 28-2.

Question 42

Proposed role of HLA-Cw6 in the pathogenesis of psoriasis

Answer 42

Overall, the major histocompatibility complex (MHC) accounts for the bulk of the overall genetic risk for psoriasis. Thus, although 63 currently known Europeanorigin signals explain 28% of the genetic heritability of psoriasis, MHC signals alone contribute 11.2% of the 28%, or about 40% of the detectable heritability.43 The major genetic signal for psoriasis in the MHC is HLAC ∗ 0602, which encodes HLA-Cw6 protein.44,45 HLA-Cw6 presents antigens to CD8 + T cells, which are MHC class I restricted and comprise about 80% of the T cells in the epidermis of psoriatic lesions (Fig. 28-15). CD8 + T cells selectively traffic to the epidermis because they express integrin α1β1, which binds to Type IV basement membrane collagen 33 as well as integrin αEβ7, which binds to keratinocyte E-cadherin.

Functionally, epidermal invasion by CD8 + T cells correlates with lesional development in a xenograft model of psoraisis. 47 Further emphasizing the importance of MHC class I antigen presentation, several other MHC class I risk variants are associated with psoriasis independently of HLA-Cw6 in both European-origin45 and Chinese populations. 48 The fact that oligoclonal T-cell expansions are found in CD8 + T-cells in psoriatic skin 30 suggests that in the epidermis, CD8 + T cells “interrogate” peptides bound to HLA-Cw6 on the surface of dendritic antigen-presenting cells (APCs) and expand in response to one or more specific antigens (see Figs. 28-14 and 28-15).

The nature of these antigens remains a topic of active investigation. Besides candidate antigens described in previous editions of this chapter, three recent publications have implicated additional candidate autoantigens in psoriasis, including the antimicrobial protein LL37, 49 neolipid antigens generated by mast cell phospholipase and presented by the MHC -like class I antigen-presenting protein CD1a, 50 and the melanocyte

antigen ADAMTSL5. Of these, the ADAMTSL5 antigen is of genetic interest because it is presented specifically by HLA-Cw6. 51 Of note, recent immunohistochemical data suggest that expression of ADAMTSL5 may not be limited to melanocytes. 52 Although much remains to be learned about specific autoantigens, the observations that multiple HLA alleles are implicated genetically and that expanded TCR rearrangements are usually oligoclonal in nature suggest that multiple autoantigens may be involved in the pathogenesis of psoriasis.

CD4 + T cells predominate in the dermis of psoriasis lesions and are also clonally expanded in psoriasis. CD4 + T cells are also required for the development of psoriasis lesions from uninvolved skin in a xenograft model. 53 This is consistent with the identification of genetic signals in the MHC class II region in both European-origin 45 and Chinese 48 populations. Although CD4 + and CD8 + memory T cells can traffic among the skin, lymph nodes, and blood, increasing evidence indicates that when initially activated in the cutaneous environment, they spend most of their time in the skin site at which they were activated, as resident memory T cells. 32 This would be consistent with the behavior of psoriatic plaques, which tend to recur in the same body sites after therapeutic or spontaneous improvement.

Question 43

NONMAJOR HISTOCOMPATIBILITY COMPLEX GENES

Answer 43

Over the past decade, GWAS have identified 86 genomic regions that are associated with psoriasis at genome-wide significance (see Table 28-2). Eleven of the 86 known psoriasis risk loci are shared by European and Chinese populations, 55 loci have been established for Europeans only, and 20 loci have been established for Chinese only. Sixteen loci have also been established as susceptibility loci for PsA and 12 for purely cutaneous psoriasis. 45,54,55 Perhaps surprisingly, most of the genetic signals identified in psoriasis thus far do not affect the structure of a protein and instead are regulatory in nature. 43 Moreover, because of topologic looping of DNA in chromatin, the regulatory signals affected by genetic variation may lie at a substantial distance from the causal gene being regulated. Thus, the “candidate genes” listed in Table 28-2 cannot simply be assumed to be the causal genes underlying the observed associations. However, there is strong bioinformatic evidence indicating that the genes underlying these psoriasis genetic signals are disproportionately involved in immunity and host defense, including functions such as lymphocyte differentiation and regulation, type I IFN and pattern recognition, nuclear factor kappa B (NF-κB) signaling, and response to viruses and bacteria. 43 Correspondingly, psoriasis signals are enriched in regulatory elements active in several T-cell subsets, including CD8 + T cells, and CD4 + T-cell subsets, including Th 0, Th 1, and Th 17. 43 Thus, there can be little doubt that “psoriasis genes” are involved in various aspects of immunity and host defense even if many of them remain to be formally identified. Most of the non-MHC associations identified thus far fall into several interconnected functional axes: IL-23–IL-17 signaling, interferon signaling, NF-κB signaling, DC–macrophage function, and keratinocyte responses (see Fig. 28-14 and Table 28-2).

Question 44

IL-23–IL-17 Signaling

Three strong regions of association map near genes involved in IL-23 signaling:

Answer 44

1. IL12B (encoding the p40 subunit of IL-23 and IL-12),
2. IL23A (encoding the p19 subunit of IL-23), and
3. IL23R (encoding a subunit of the IL-23 receptor)

These associations are further supported by the impressive efficacy of biologics targeting the p40 subunit common to IL-12 and IL-23 56 as well as the p19 subunit, 57 which is unique to IL-23. IL-23 signaling promotes the survival and expansion of IL-17–expressing T-cells, which protect epithelia against microbial pathogens. 58 Ankylosing spondylitis (AS) is another HLA class I–associated autoimmune disorder that is clinically associated with inflammatory bowel disease 59 and genetically associated with IL23R. 60 PsA shares a number of clinical similarities with AS, and is genetically associated with IL12B, IL23A, and IL23R (see Chap. 65). Other candidate genes relevant to this signaling axis include TRAF3IP2 encoding Act1; a ubiquitin ligase coupling IL-17 receptors to downstream signaling pathways; RUNX3, which encodes a transcription factor (TF) required for development of Th17 cells; NFKBIZ, a TF whose expression is stimulated by IL-17 via Act161 ; and IRF4, encoding a TF that regulates IL-17A promoter activity.

Question 45

Interferon Signaling

Answer 45

Although the IFNG gene

does not itself map to a psoriasis susceptibility region, its product IFN-γ is secreted by activated Th1 cells and stimulates DC to produce IL-23. 62 This may explain why Th1 and Th17 cells are co-localized in psoriasis lesions and many other sites of inflammation.62 Another psoriasis susceptibility region contains the IL4 and IL13 genes. In addition to biasing T-cell differentiation away from Th1 and toward Th2, IL-4 inhibits Th17 cell development. 63 Moreover, treatment of psoriasis with IL-4 resulted in significant clinical improvement by selective silencing of IL-23 in APCs. 64 Other psoriasis genetic signals suggest involvement of Type I IFN signaling in disease pathogenesis, including associations with DDX58 encoding RIG-I and IFIH1 encoding MDA5. Each of these proteins bind viral nucleic acids and activate the mitochondrial antiviral signaling protein (MAVS), leading ultimately to activation of type I IFNs and IFN-stimulated genes as well as NF-κB. 65 TYK2 encodes Tyk2, which also prominently involved in downstream type I IFN signaling and mediates responses to several other cytokines.66

Question 46

NF-jB Signaling

Answer 46

Several

478

psoriasis-associated genomic regions contain genes involved with controlling signaling through the TF NF-κB. TNF-α is a major activator of NF-κB signaling, and these associations are clinically reinforced by the dramatic therapeutic response of psoriasis to anti-TNF biologicals (see Treatment). TNFAIP3 and TNIP1, respectively, encode A20 and ABIN-1, which interact with each other to regulate the ubiquitin-mediated destruction of IKKγ/ NEMO, a central nexus of NF-κB signaling. 67 TNFAIP3 is genetically associated with RA, and both TNFAIP3 and TNIP1 are associated with systemic lupus erythematosus (SLE). The polymorphisms implicated in RA and SLE show no association with psoriasis, suggesting that each of these diseases is driven by different variants of the TNFAIP3 gene. CHUK encodes IKK-α, which activates NF-κB via degradation of IκBα, and NFKBIA encodes IκBα, which inhibits NF-κB signaling by sequestering it in the cytoplasm. Other notable candidate genes in this category include FASLG encoding Fas ligand (CD95), a transmembrane protein of the TNF family; REL and NFKB1, both of which encode members of the NF-κB family; TNFSF15 encoding TL1, a TNF-inducible cytokine that activates NF-κB; IKBKE encoding IKK-ε, which functions downstream of viral sensors to activate NF-κB; and CARD14 encoding CARMA2, which activates NF-κB via interactions with BCL10. Notably, CARD14 has been identified as the causative gene in the PSORS2 locus, initially identified in a large pedigree by linkage analysis

Question 47

Dendritic Cell and Macrophage Function in psoriasis

Answer 47

Besides the MHC, two other regions of association contain genes whose products function in antigen presentation: PSMA6, which encodes a proteasomal subunit involved in MHC class I antigen processing, and ERAP1, an IFN-γ–inducible aminopeptidase that trims peptides for optimal binding to the MHC class I peptide groove. Macrophages and inflammatory DCs are major sources of IL-23, TNF-α and inducible nitric oxide synthetase (iNOS). Psoriasis risk variants are present in NOS2 (encoding iNOS) and ZC3H12C encoding the zinc-finger protein MCPIP3, both of which are important for macrophage function.

Question 48

Keratinocyte Responses

Answer 48

Although the TNF-α and IL-23–Th17 axes described above converge strongly at a physiological level to stimulate production of innate inflammatory mediators such as hBD2 by keratinocytes, 69 relatively few psoriasis-associated regions contain genes that are thought to function primarily in keratinocytes. The most well-established association is an insertion-deletion (indel) polymorphism of the late cornified envelope genes LCE3B and LCE3C, which was independently discovered in European-origin 70 and Chinese 71 populations. Located in the epidermal differentiation complex (EDC), these genes are expressed very late in keratinocyte terminal differentiation and are markedly overexpressed in psoriasis, wound healing, and epidermal stress. 72 Notably,

the LCE3B/3C indel is associated with cutaneous psoriasis but not with PsA. 54 Another psoriasis risk variant resides near the KLF4 gene, which is a TF required for establishment of skin barrier function. TRAF3IP2- and NFKBIZ –encoded proteins are known to function in IL-17 responses of epidermal cells, and several genes implicated in the pathogenesis of generalized or PPPP are primarily expressed in the epidermis, including IL36RN, AP1S3, and CARD14.

Question 49

Risk factors associated with psoriasis

Answer 49

OBESITY - It has been demonstrated that obese individuals are more likely to present with severe psoriasis. However, obesity does not appear to have a role in defining the onset of psoriasis.73

SMOKING - Heavy smoking (>20 cigarettes daily) has been associated with more than a twofold increased risk of severe psoriasis. 74 Unlike obesity, smoking appears to have a role in the onset of psoriasis.

INFECTIONS - An association between streptococcal throat infection and guttate psoriasis has been repeatedly confirmed.

Streptococcal throat infections have also been demonstrated to exacerbate preexisting chronic plaque psoriasis, 75 and tonsillectomy has been shown to lead to long-term improvement in psoriasis, 76 particularly in HLA-Cw6 carriers. 77 Severe exacerbation of psoriasis can be a manifestation of HIV infection. The prevalence of psoriasis in HIV infection is no higher than in the general population, indicating that this infection is not a trigger for psoriasis but rather a modifying agent. Psoriasis is increasingly more severe with progression of immunodeficiency but can remit in the terminal phase. This paradoxical exacerbation of psoriasis may be caused by loss of Tregs and increased activity of the CD8 T-cell subset.78 Psoriasis exacerbation in HIV disease may be effectively treated with antiretroviral therapy. Psoriasis has also been associated with hepatitis C infection.

DRUGS - Medications that exacerbate psoriasis include antimalarials, β blockers, lithium, nonsteroidal antiinflammatory drugs (NSAIDs), IFNs-α and -γ, imiquimod, angiotensin-converting enzyme inhibitors, and gemfibrozil. Imiquimod acts on plasmacytoid dendritic cells (pDCs) and stimulates IFN-α production, which then strengthens both innate and Th1 immune responses.79 Exacerbations and onset of psoriasis have been described in patients receiving TNF inhibitor therapy. The majority of these patients have PPP, but about one third develop chronic plaque psoriasis. 80 New-onset psoriasis has also been described after the anti-IL-6 treatment tocilizumab. Lithium has been proposed to cause exacerbation by interfering with calcium release within keratinocytes, whereas β blockers are thought to interfere with intracellular cyclic adenosine monophosphate levels. 81 The mechanisms by which the remaining medications exacerbate psoriasis are largely unknown.

Question 50

Diagnosis and treatment algorithm for patients with psoriasis.

Answer 50

The diagnosis of psoriasis is usually based on clinical features. In the few cases in which clinical history and examination is not diagnostic, biopsy is indicated to establish the correct diagnosis. The majority of psoriasis cases fall into three major categories; guttate, erythrodermic/pustular, and chronic plaque, of which the latter is by far the most common. Guttate psoriasis is often a self-limited disease with spontaneous resolution within 6 to 12 weeks. In mild cases of guttate psoriasis, treatment may not be needed, but with widespread disease, ultraviolet B (UVB) phototherapy in association with topical therapy is very effective. Erythrodermic/ pustular psoriasis is often associated with systemic symptoms and necessitates treatment with fast-acting systemic medications. The most commonly used drug for erythrodermic and pustular psoriasis is acitretin. In occasional cases of pustular psoriasis, systemic steroids may be indicated (asterisk). Dotted arrows indicate that guttate, erythrodermic, and pustular forms often evolve into chronic plaque psoriasis. Therapeutic choices for chronic plaque psoriasis are typically based on the extent of the disease. Among the main treatment regimens (topical treatment, phototherapy, day treatment centers, and systemic treatments), first- and second-line modalities are indicated by the solid and dashed lines, respectively. Individuals with conditions that limit their activities, including painful palmoplantar involvement and psoriatic arthritis, may require more potent treatments irrespective of the extent of affected body surface area. Likewise, psychological issues and the impact on quality of life should be taken into consideration. Within each treatment regimen, first-line and second-line choices are grouped. Cyclosporin A is not considered a first-line long-term systemic treatment because of its side effects, but short-term treatment can be helpful for induction of remission. If patients have incomplete response to or are unable to tolerate individual first-line systemic medications, combination regimens, rotational treatments, or use of biologic therapies should be considered. BB-UVB, broadband UVB; BSA, body surface area; DDx, differential diagnosis; FAE, fumaric acid ester; NB-UVB, narrowband UVB; PUVA, psoralen and ultraviolet A light; tx, therapy.

Question 51

LABORATORY TESTING

Answer 51

Laboratory abnormalities in psoriasis are usually not specific and may not be performed in all patients.

In severe psoriasis vulgaris, generalized pustular psoriasis, and erythroderma, a negative nitrogen balance can be detected, manifested by a decrease of serum albumin. Patients with psoriasis manifest altered lipid profiles, even at the onset of their skin disease. 82 Whether these differences in lipid profile can explain or are contributing to an increased incidence of cardiovascular events in psoriasis remains to be seen. The serum uric acid is elevated in up to 50% of patients and is mainly correlated with the extent of lesions and the activity of disease. There is an increased risk of developing gouty arthritis. Serum uric acid levels usually normalize after therapy. Markers of systemic inflammation, including C-reactive protein, α2 -macroglobulin, and erythrocyte sedimentation rate, can be increased. However, such elevations are rare in chronic plaque psoriasis uncomplicated by arthritis. Increased serum immunoglobulin (Ig) A levels and IgA immune complexes, as well as secondary amyloidosis, have also been observed in psoriasis, and the latter carries a poor prognosis.

Question 52

DIFFERENTIAL DIAGNOSIS

Answer 52

Question 53

CLINICAL COURSE AND PROGNOSIS

Answer 53

It is useful to determine the age at onset and the presence or absence of a family history of psoriasis because a younger age of onset and positive family history have been associated with more widespread and recurrent disease. 3,14 In addition, the physician should inquire about the prior course of the disease because major differences exist between “acute” and “chronic” disease. In the latter form, lesions may persist unchanged for months or even years, but acute disease shows sudden outbreak of lesions within a short time (days). Likewise, patients have great variability in regard to relapses. Some patients have frequent relapses occurring weekly or monthly, but others have more stable disease with only occasional recurrence. The frequently relapsing patients tend to develop more severe disease with rapidly enlarging lesions covering significant portions of the body surface 83 and may require more rigorous treatment than those with more stable disease. The physician should also inquire about joint complaints. Although osteoarthritis is extremely common and can coexist with psoriasis, a history of onset of joint symptoms before the fourth decade or a history of warm, swollen joints should raise the suspicion of PsA (see Chap. 65). Guttate psoriasis is often a self-limited disease, lasting from 12 to 16 weeks without treatment. It has been estimated that one third to two thirds of these patients later develop the chronic plaque type of psoriasis. 84 In contrast, chronic plaque psoriasis is in most cases a lifelong disease, manifesting at unpredictable intervals. Spontaneous remissions, lasting for variable periods of time, may occur in the course of psoriasis in up to 50% of patients. The duration of remission ranges from 1 year to several decades. Erythrodermic and generalized pustular psoriasis have a poorer prognosis, with the disease tending to be severe and persistent.

Question 54

Topical Treatments for Psoriasis

Answer 54

Most cases of psoriasis are treated topically. 86 Because topical treatments are often cosmetically unacceptable and time consuming to use, noncompliance is on the order of 40%. 87 In most cases, ointment formulations are more effective than creams but are less cosmetically acceptable. For many patients, it is worth prescribing both cream and ointment formulations—cream for use in the morning and ointment for nighttime. Topical agents are also used adjunctively for resistant lesions in patients with more extensive psoriasis and who are concurrently being treated with either UV light or systemic agents. 88 It is worth noting that around 400 g of a topical agent is required to cover the entire body surface of an average-sized adult when used twice daily for 1 week.

Question 55

Genaral considerations for management

Answer 55

Figure 28-16 is an algorithm showing recommended treatments for various forms of psoriasis.

A broad spectrum of antipsoriatic treatments, both topical and systemic, is available for the management of psoriasis. As detailed in Tables 28-4 to 28-7, it is notable that most, if not all, of these treatments are immunomodulatory. When choosing a treatment regimen (see Fig. 28-16), it is important to reconcile the extent and the measurable severity of the disease with the patient’s own perception of his or her disease. One study found that 40% of patients felt frustrated with the ineffectiveness of their current therapies, and 32% reported that treatment was not aggressive enough. 24 As psoriasis is a chronic condition, it is important to know the safety of a treatment during long-term use. In most treatments, the duration of a treatment is restricted because of the cumulative toxicity potential of an individual treatment, and in some instances, treatment efficacy may diminish with time (tachyphylaxis). Some treatments, such as calcipotriol, methotrexate (MTX), and acitretin, can be regarded as appropriate for continuous use. 85 These treatments maintain efficacy and have low cumulative toxicity potential. In contrast, topical corticosteroids, dithranol, tar, photo(chemo) therapy, and cyclosporin are not indicated for continuous chronic use, and combinatorial or rotational treatments 85 are suggested. However, patients with stable chronic plaque psoriasis who respond well to local treatments may not require a change of treatment. 85 In cases of itchy or pruritic psoriasis, treatments with an irritative potential, such as dithranol, vitamin D 3 analogues, and photo(chemo) therapy, should be used cautiously; treatments with potent antiinflammatory effects, such as topical corticosteroids, are more appropriate. 85 In patients with erythrodermic and pustular psoriasis, treatments with an irritant potential should be avoided, and acitretin, MTX, or short-course cyclosporin are the treatments of first choice. 85 See Table 28-8 for special considerations in the treatment of women of childbearing potential.

Question 56

CORTICOSTEROIDS

Answer 56

Glucocorticoids exert many, if not all, of their myriad effects by stabilizing and causing nuclear translocation of glucocorticoid receptors, which are members of the nuclear hormone receptor superfamily. Topical glucocorticoids are commonly first-line therapy in mild to moderate psoriasis and in sites such as the flexures and genitalia, where other topical treatments can induce irritation. Improvement is usually achieved within 2 to 4 weeks, with maintenance treatment consisting of intermittent applications (often restricted to the weekends). Tachyphylaxis to treatment with topical corticosteroids is a well-established phenomenon in psoriasis. Long-term topical corticosteroids may cause skin atrophy, telangiectasia, striae (Fig. 28-17), and adrenal suppression. Another concern is that when topical steroids are discontinued, patients may reflare, sometimes worse than it was before treatment. 88 This class of agents is discussed in detail in Chap. 184

Question 57

VITAMIN D 3 AND ANALOGUES

Answer 57

Vitamin D exerts its actions by binding to the vitamin D receptor, another member of the nuclear hormone receptor superfamily. Vitamin D 3 acts to regulate cell growth, differentiation, and immune function, as well as calcium and phosphorous metabolism. Vitamin D has been shown to inhibit the proliferation of keratinocytes in culture and to modulate epidermal differentiation. Furthermore, vitamin D inhibits production of several proinflammatory cytokines by psoriatic T-cell clones, including IL-2 and IFN-γ. Analogues of vitamin D that have been used for the treatment of skin diseases are calcipotriene, (calcipotriol), tacalcitol, and maxacalcitol. In short-term studies, potent topical corticosteroids were found to be superior to calcipotriene. When compared with shortcontact anthralin or 15% coal tar, calcipotriene was the more effective agent. The efficacy of calcipotriene is not reduced with long-term treatment. Calcipotriene applied twice daily is more effective than oncedaily use. Hypercalcemia is the only major concern with the use of topical vitamin D preparations. When the amount used does not exceed the recommended 100 g/week, calcipotriene can be used with a great margin of safety. Vitamin D analogues are often used in combination with or in rotation with topical corticosteroids in an effort to maximize therapeutic effectiveness while minimizing steroid-related skin atrophy.

Question 58

ANTHRALIN (DITHRANOL)

Answer 58

Dithranol (1,8-dihydroxy-9-anthrone) is a naturally occurring substance found in the bark of the araroba tree in South America. It can also be synthesized from anthrone. Dithranol is made up in a cream, ointment, or paste. Dithranol is approved for the treatment of chronic plaque psoriasis. Its most common use has been in the treatment of psoriasis, particularly on plaques resistant to other therapies. It can be combined with UVB phototherapy with good results (the Ingram regimen). Most common side effects are irritant contact dermatitis and staining of clothing, skin, hair, and nails. Anthralin possesses antiproliferative activity on human keratinocytes along with potent antiinflammatory effects. Classic anthralin therapy starts with low concentrations (0.05%–0.1%) incorporated in petrolatum or zinc paste and given once daily. To prevent auto-oxidation, salicylic acid (1% to 2%) should be added. The concentration is increased weekly in individually adjusted increments up to 4% until the lesions resolve. Scalp psoriasis should be treated with great caution as anthralin can stain hair purple to green.

Question 59

COAL TAR

Answer 59

The use of tar to treat skin diseases dates back nearly 2000 years. In 1925, Goeckerman introduced the use of crude coal tar and UV light for the treatment of psoriasis. Its mode of action is not understood, and because of its inherent chemical complexity, tar is not pharmacologically standardized. It was recently suggested that carbazole, a coal-derived chemical, is the main active ingredient in tar. 89 Coal tar can be compounded in creams, ointments, and pastes at concentrations of 5% to 20%. It is often combined with salicylic acid (2%–5%), which by its keratolytic action leads to better absorption of the coal tar. Occasionally, patients become sensitized, and a folliculitis may occur. Furthermore, it has an unwelcome smell and appearance and can stain clothing. Coal tar is carcinogenic.

Question 60

TAZAROTENE

Answer 60

Tazarotene is a third-generation retinoid for topical use that reduces mainly scaling and plaque thickness, with limited effectiveness on erythema. It is thought to act by binding to retinoic acid receptors. It is available in 0.05% and 0.1% gels, and a cream formulation has been developed. When this drug is used as a monotherapy, a significant proportion of patients develop local irritation. Efficacy of this drug can be enhanced by combination with mid- to high-potency glucocorticoids or UVB phototherapy. When used in combination with phototherapy, it lowers the minimal erythema dose (MED) for both UVB and UVA. It has been recommended that UV doses be reduced by at least one third if tazarotene is added to phototherapy.

Question 61

TOPICAL CALCINEURIN INHIBITORS

Answer 61

Tacrolimus (FK-506) is a macrolide antibiotic, derived from the bacteria Streptomyces tsukubaensis, which, by binding to immunophilin (FK506 binding protein), creates a complex that inhibits calcineurin, thus blocking both T-lymphocyte signal transduction and IL-2 transcription. Pimecrolimus is also a calcineurin inhibitor and works in a manner similar to tacrolimus. In a study of 70 patients with chronic plaque psoriasis treated with topical tacrolimus, there was no improvement beyond that seen for placebo. However, for treatment of inverse and facial psoriasis, these agents appear to provide effective treatment. 90 The main side effect of these medications is a burning sensation at application site. Anecdotal reports of lymph node or skin malignancy require further evaluation in controlled studies, and these drugs currently carry a U.S. Food and Drug Administration (FDA) “black box warning.”

Question 62

SALICYLIC ACID

Answer 62

Salicylic acid is a topical keratolytic agent. Its mechanism of action includes reduction of keratinocyte adhesion and lowering the pH of the stratum corneum, which results in reduced scaling and softening of the plaques, thereby enhancing absorption of other agents. Therefore, salicylic acid is often combined with other topical therapies such as corticosteroids and coal tar. Topical salicylic acid decreases the efficacy of UVB phototherapy, 88 and systemic absorption can occur, particularly in patients with abnormal hepatic or renal function and when applied to more than 20% of the body surface area. No placebo-controlled studies have been performed to verify the efficacy and safety of salicylic acid as a monotherapy.

Question 63

BLAND EMOLLIENTS

Answer 63

Between treatment periods, skin care with emollients should be performed to avoid dryness. Emollients reduce scaling, may limit painful fissuring, and can help control pruritus. They are best applied immediately after bathing or showering. The addition of urea (up to 10%) is helpful to improve hydration of the skin and remove scaling of early lesions. The use of liberal bland emollients over a thin layer of topical prescription treatments improves hydration while minimizing treatment costs.

Question 64

Phototherapy of Psoriasis

Answer 64

Phototherapy of psoriasis with artificial light sources dates back to 1925 when Goeckerman introduced a combination of topical crude coal tar and subsequent UV irradiation. In the 1970s, it was shown that broadband UVB radiation alone, if given in doses that produce a faint erythematous reaction, could clear the milder clinical forms of psoriasis. Major steps forward were the introduction of photochemotherapy with psoralen and UVA light (PUVA) in the 1970s and narrowband UVB (311–313 nm) in the 1980s.91

The mechanism of action of phototherapy appears to involve selective depletion of T cells, predominantly those that reside in the epidermis. 78 The mechanism of depletion may involve apoptosis, accompanied by a shift from a Th1 to a Th2 response in lesional skin.

Question 65

ULTRAVIOLET B LIGHT

Answer 65

Ultraviolet B (UVB) light is in the range of 290-320 nm. The initial therapeutic UVB dose lies at 50% to 75% of the MED. Treatments are given two to five times per week. Because peak UVB erythema appears within 24 hours of exposure, increments can be performed at each successive treatment. The objective is to maintain a minimally perceptible erythema as a clinical indicator of optimal dosing. Treatments are given until total remission is reached or until no further improvement can be obtained with continued treatment. 92 The main side effects of UVB phototherapy are summarized in Chap. 198.

Narrowband (312 nm) UVB (NB-UVB) phototherapy is superior to conventional broadband UVB with respect to both clearing and remission times. Although early studies found NB-UVB to be as effective as PUVA, a controlled trial found that PUVA was more effective, albeit less convenient. 93 On clearing, treatment is either discontinued, or patients are subjected to maintenance therapy for 1 or 2 months. During this period, the frequency of UVB treatments is reduced while maintaining the last dose given at the time of clearing. 91,92 Systemic drugs, such as retinoids, increase the efficacy of UVB light, particularly in patients with chronic and hyperkeratotic plaque–type psoriasis.

Question 66

PSORALEN AND ULTRAVIOLET A LIGHT

Answer 66

PUVA is the combined use of psoralens (P) and longwave UVA radiation. The combination of drug and radiation results in a therapeutic effect, which is not achieved by the single component alone. Remission is induced by repeated controlled phototoxic reactions. A detailed account of PUVA therapy and its short- and long-term side effects is to be found in Chap. 199.

Question 67

EXCIMER LASER

Answer 67

Supraerythemogenic fluences of UVB and PUVA are known to result in faster clearing of psoriasis; however, the limiting factor for the use of such high fluences lies with the intolerance of the uninvolved surrounding skin as psoriatic lesions can often withstand much higher UV exposures. The monochromatic 308-nm excimer laser can deliver such supraerythemogenic doses of light (up to 6 MED, usually in the range of 2–6 MEDs) focally to lesional skin. The dosing is guided by the patients’ skin type and thickness of the plaque with subsequent doses based on the response to therapy or development of side effects. 92 In a study on 124 patients, 72% of study participants achieved at least 75% clearing in an average of 6.2 treatments delivered twice weekly. 94 This treatment is commonly used for patients with stable recalcitrant plaques, particularly of the elbows and knees.

Question 68

CLIMATIC THERAPY

Answer 68

It is well known that going to a sunny climate can improve psoriasis, although a small proportion of patients actually deteriorate. Patients should be warned not to overexpose themselves in the first few days because sunburn may progress to psoriasis (Koebner phenomenon). The best-studied effects are from the Dead Sea area, 95 and the therapeutic effects may be attributed, at least partially, to its unique climate. Because it is situated 400 m below sea level, the evaporation of the sea forms an aerosol that stays in the atmosphere above the sea and surrounding beaches. This aerosol screens out the majority of the UVB rays but not the UVA. This mixture of UV light appears to be sufficient to clear psoriasis but without sunburn. Thus, patients can stay on the shores of the Dead Sea for long periods of time with a greatly reduced risk of sunburn. This treatment is carried out over a period of 3 to 4 weeks, and improvements comparable to NB-UVB or PUVA treatments are observed. The main disadvantages are time and expense.

Question 69

Systemic Treatments for Psoriasis

Answer 69

Question 70

Question 71

Question 72

METHOTREXATE

Answer 72

Methotrexate is highly effective for chronic plaque psoriasis and is also indicated for the long-term management of severe forms of psoriasis, including psoriatic erythroderma and pustular psoriasis. 96 For mechanisms of action, see Chap. 190. When first used for the treatment of psoriasis, MTX was thought to act directly to inhibit epidermal hyperproliferation via inhibition of dihydrofolate reductase (DHFR). However, it was found to be effective at much lower doses (0.1–0.3 mg/kg/wk) in the management of psoriasis, PsA, and other inflammatory conditions such as RA. At these concentrations, MTX inhibits the in vitro proliferation of lymphocytes but not proliferation of keratinocytes. It is now thought that the main mechanism of antiinflammatory action of MTX is inhibition of (AICAR [5-aminoimidazole-4-carboxamide ribonucleotide] transformylase), an enzyme involved in purine metabolism. This leads to accumulation of extracellular adenosine, which has potent anti-inflammatory activities. 99 Consistent with a DHFR-independent mechanism of action, concomitant administration of folic acid (1–5 mg/day) reduces certain side effects, such as nausea and megaloblastic anemia, without diminishing the efficacy of anti-psoriatic treatment. The very long half-life of MTX may account for its efficacy after weekly administration and may help to explain why its onset of action is rather slow (therapeutic effects usually require 4–8 weeks to become evident). MTX is renally excreted and should therefore not be administered to patients with impairment in renal function because MTX side effects are generally dose related. Short-term toxicity and long-term concerns are discussed in Chap. 190. Recent guidelines98 suggest that patients be divided into two separate groups based on their risk factors for liver injury: The low risk patients follow the American College of Rheumatology guidelines and are not asked to undergo liver biopsy until they have reached a cumulative MTX dose of 3.5 to 4.0 g. In contrast, patients with one or more risk factors continue to follow the previous, more stringent guidelines requiring baseline liver biopsy either before treatment or after 2 to 6 months of treatment and then at each cumulative MTX dose of 1.0 to 1.5 g. 98 The risk factors include current or past alcohol consumption, persistent abnormalities of liver function enzymes, personal, or family history of liver disease, exposure to hepatotoxic drugs or chemicals, diabetes mellitus, hyperlipidemia, and obesity. Some groups have recommended the use of amino terminal type III procollagen peptide assay for screening of liver fibrosis. Another well-known side effect of MTX is myelosuppression, especially pancytopenia, which usually occurs in the setting of folate deficiency. Leucovorin calcium (folinic acid) is the only antidote for the hematologic toxicity of MTX. When an overdose is suspected, an immediate leucovorin dose of 20 mg should be given parenterally or orally, and subsequent doses should be given every 6 hours. Pneumonitis can develop, and mucosal and skin ulcerations have also been reported in patients treated with MTX.

Discontinuation of MTX treatment is required in the event of hepatotoxicity, hematopoietic suppression, active infections, nausea, and pneumonitis. MTX is also teratogenic and should therefore not be prescribed for women who are pregnant or breastfeeding. Several classes of drugs, including NSAIDs and sulfonamides, may interact with MTX to increase toxicity.

Question 73

ACITRETIN

Answer 73

Acitretin is a second-generation, systemic retinoid that has been approved for the treatment of psoriasis since 1997 and is discussed in Chap. 185. The clinical forms most responsive to etretinate or acitretin as monotherapy include generalized pustular and erythrodermic psoriasis. 100 Acitretin induces clearance of psoriasis in a dose-dependent fashion. Overall, higher starting doses appeared to clear psoriasis faster. The mechanism of action of retinoids for psoriasis is not fully understood. The optimal initial dose of acitretin for psoriasis is reported at 25 mg/day, with a maintenance dose of 20 to 50 mg/day. Adverse effects, such as hair loss and paronychia, occur more frequently with higher initial dose (ie, ≥50 mg/day). Most patients relapse within 2 months after discontinuing etretinate or acitretin. Acitretin should be discontinued if liver dysfunction, hyperlipidemia, or diffuse idiopathic hyperostosis develops.

Question 74

APREMILAST

Answer 74

Apremilast is a small-molecule inhibitor of phosphodiesterase (PDE)-4, which degrades cyclic adenosine monophosphate (cAMP) intracellularly. The inhibition of PDE4 increases intracellular levels of cAMP resulting in increased activity of the TF CREB (cAMP response element-binding protein), while inhibiting NF-κB signaling. To reduce risk of gastrointestinal (GI) symptoms the drug is titrated over a period of 1 week, starting at 10-mg dosing at day 1 and ending in 30-mg twice-a-day dosing on day 6, which is maintained for the duration of treatment. Adverse effects include GI symptoms such as diarrhea, nausea, and headaches. Worsening of depression has been described, and the drug should be used with caution in individuals with history of depression or suicidal thoughts or behaviors.

Question 75

TOFACITINIB

Answer 75

Tofacitinib is an oral Janus kinase (JAK) inhibitor. Janus kinases are a family of four tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) and have a role in downstream signaling of multiple proinflammatory cytokines, including IL-2, IL-4, IL-9, IL-13, IL-21, type I and II IFN signaling, IL-6, and to a lesser extent IL-12 and IL-23. 101 At the time of this writing, tofacitinib is only approved for RA, but several clinical trials in psoriasis have been completed using either 5 mg twice a day or 10 mg twice a day. 102,103 Patients should be screened for tuberculosis before initiation, and patients need to be monitored for changes in hemoglobin, leukopenias, or lipid abnormalities. Increased incidences of viral infections, particularly herpes zoster, have been reported in patients with RA taking tofacitinib.

Question 76

CYCLOSPORIN A

Answer 76

Cyclosporin A (CsA) is a neutral cyclic undecapeptide derived from the fungus Tolypocladium inflatum gams. Its mechanism of action and side effects are discussed in Chap. 192. The only formulation approved for treatment of psoriasis is available as an oral solution or in capsules. It is highly effective for cutaneous psoriasis and can also be effective for nail psoriasis (see Fig. 28-9). CsA is particularly useful in patients who present with widespread, intensely inflammatory, or frankly erythrodermic psoriasis. The dosage ranges from 2 to 5 mg/kg/day. Because the nephrotoxic effects of CsA are largely irreversible, CsA treatment should be discontinued if kidney dysfunction or hypertension occurs. CsA-induced hypertension may be treated with calcium antagonists such as nifedipine. The most common adverse effects noted in patients using CsA for short periods of time are neurologic, including tremors, headache, paresthesia, or hyperesthesia. Long-term treatment of psoriasis with low-dose CsA was found to increase risk of nonmelanoma skin cancers. However, unlike organ transplant patients treated with higher doses of CsA, there is little or no increased risk of lymphoma.

Question 77

FUMARIC ACID ESTERS

Answer 77

Fumaric acid was first reported in 1959 to be beneficial in the systemic treatment of psoriasis 104 and is licensed in Germany for the treatment of psoriasis. Because fumaric acid itself is poorly absorbed after oral intake, esters are used for treatment. The esters are almost completely absorbed in the small intestine, and dimethylfumarate is rapidly hydrolyzed by esterases to monomethylfumarate, which is regarded as the active metabolite. The mode of action in psoriasis is not fully understood. 104 Patients with severe concomitant disease, chronic disease of the GI tract, chronic kidney disease, or with bone marrow disease leading to leukocytopenias or leukocyte dysfunction should not be treated. Likewise, pregnant or lactating women and patients with malignant disease (including positive history of malignancy) should be excluded from treatment. Prolonged therapy (up to 2 years) to prevent relapse in psoriasis patients with high disease activity is possible. Another therapeutic option is short-course intermittent therapy. Fumaric acid esters (FAEs) are given until a major improvement is achieved and are then withdrawn. If a patient remains lesion-free during prolonged treatment, the FAE dose should be gradually decreased to reach the individual’s threshold. 104 Therapy with FAEs can be stopped abruptly because rebound phenomena have not been observed.

Question 78

SULFASALAZINE

Answer 78

Sulfasalazine is an uncommonly used systemic agent in the management of psoriasis. In the only prospective double-blind study on the efficacy of sulfasalazine in psoriasis, moderate effects were seen, with 41% of the patients showing marked improvement, 41% with moderate improvement, and 18% with minimal improvement after 8 weeks of treatment.105

Question 79

SYSTEMIC STEROIDS

Answer 79

In general, systemic steroids should not be used in the routine care of psoriasis. When systemic steroids are used, clearance of psoriasis is rapid, but the disease usually breaks through, requiring progressively higher doses to control symptoms. If withdrawal is attempted, the disease tends to relapse promptly and may rebound in the form of erythrodermic and pustular psoriasis. However, systemic steroids may have a role in the management of persistent, otherwise uncontrollable, erythroderma and in fulminant generalized pustular psoriasis (von Zumbusch type) if other drugs are ineffective.

Question 80

MYCOPHENOLATE MOFETIL

Answer 80

Mycophenolate mofetil is a prodrug of mycophenolic acid, an inhibitor of inosine-5′-monophosphate dehydrogenase. Mycophenolic acid depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation. The drug is usually well tolerated with few side effects. Few studies have been done on this medication for psoriasis, but in a prospective open-label trial on 23 patients with dosage between 2 to 3 g/day, a 24% reduction of the Psoriasis Area and Severity Index (PASI) was seen after 6 weeks, with 47% improvement at 12 weeks.

Question 81

6THIOGUANINE

Answer 81

6-Thioguanine is a purine analog that has been highly effective for psoriasis. Apart from bone marrow suppression, GI complaints, including nausea and diarrhea, can occur, and elevation of liver function test results is common. 96 Isolated instances of hepatic venoocclusive disease have been reported.

Question 82

HYDROXYUREA

Answer 82

Hydroxyurea is an antimetabolite that has been shown to be effective as monotherapy, but nearly 50% of patients who achieve marked improvement develop bone marrow toxicity with leukopenia or thrombocytopenia. Megaloblastic anemia is also common but rarely requires treatment. 96 Cutaneous reactions affect most patients treated with hydroxyurea, including leg ulcers, which are the most troublesome.

Question 83

Biologic Treatments for Psoriasis

Answer 83

Based on the continuous progress in psoriasis research and advances in molecular biology, a new class of agents—targeted biologic therapies—has emerged. These agents are designed to block specific molecular steps important in the pathogenesis of psoriasis or have been transferred to the psoriasis arena after being developed for other inflammatory diseases. Currently, three types of biologics are approved or are in development for psoriasis: (1) recombinant human cytokines, (2) fusion proteins, and (3) monoclonal antibodies, which may be fully human, humanized or chimeric. Because of the risk of the development of antibodies to mouse sequences, humanized or fully human antibodies are preferred for clinical use.

Using internationally acknowledged safety and efficacy endpoints, the overall utility and benefit of biologics have been demonstrated based on the percentage of patients achieving at least a 50% improvement in PASI (PASI-50), a 75% improvement in PASI (PASI-75), the impact of treatment on quality of life, and safety and tolerability. Many of these agents have antipsoriatic activity roughly comparable to that of MTX and lack its risk of hepatotoxicity. However, they are far more expensive and carry risks of immunosuppression, infusion reactions, and antibody formation, and their long-term safety remains to be evaluated. In the opinion of the authors, use of biologic agents should be reserved for treatment of moderate to severe psoriasis that is either unresponsive to MTX or in patients for whom the use of MTX is contraindicated.

Question 84

TUMOR NECROSIS FACTORα ANTAGONISTS

Answer 84

The clinical application of TNF antagonists in inflammatory diseases has exploded on the clinical realm in a manner reminiscent of the discovery of the activity of corticosteroids. TNF-α is a homotrimeric protein that exists in both transmembrane and soluble forms, the latter resulting from proteolytic cleavage and release. It is still unclear which form is more important in mediating its proinflammatory activities or the relative importance of the two p55- and p75-kd TNF-α–binding receptors. Currently, five anti-TNF biologics are available in the United States. Infliximab is a chimeric monoclonal antibody that has high specificity, affinity, and avidity for TNF-α. An example of an excellent treatment outcome with infliximab is shown in Fig. 28-17. Etanercept is a human recombinant, soluble, TNF-α receptor-Fc IgG fusion protein that binds TNF-α and neutralizes its activity. Adalimumab and golimumab are fully human recombinant IgG1 monoclonal antibodies and

specifically targets TNF-α. Certolizumab pegol is a polyethylene glycol (PEG) Fab′ fragment of a humanized TNF inhibitor monoclonal antibody. The pegylation is thought to reduce immunogenicity of the drug and prolongs serum half-life without compromising activity. Currently, golimumab and certolizumab pegol are only FDA approved for PsA. Clinical trials have shown that each of these agents is well tolerated and appears suitable for long-term use in chronic plaque psoriasis. However, like all the targeted biologic therapies, they carry risks of immunosuppression.

Clinical studies have found infliximab and adalimumab to be slightly more effective than etanercept in the treatment of psoriasis. It is likely that the differential effects of these agents are associated with selectivity in their ability to perturb these receptor–ligand interactions. It is known that infliximab, adalimumab, golimumab, and etanercept bind TNF differently; whereas infliximab and adalimumab bind to both soluble and membrane-bound TNF, etanercept binds primarily to soluble TNF. Binding to membrane-bound TNF can induce a dose-dependent increase in apoptosis of T cells, but the relevance of this mechanism in psoriasis has not been evaluated. New onset of psoriasis has been described several times in patients on these agents for other conditions such as Crohn disease or RA. These paradoxical reactions are characterized by increased production of IFN-α.

Question 85

INTERLEUKIN12 AND INTERLEUKIN23 ANTAGONISTS

Answer 85

Ustekinumab is a human monoclonal antibody that binds the shared p40 subunit of IL-12 and IL-23 and prevents interaction with their receptors. This treatment blocks IL-12, which is critical for Th1 differentiation, but its inhibitory effect on IL-23 may be more important. As described earlier, IL-23 supports chronic inflammation mediated by Th17 and Th22 cells. Clinical studies have found ustekinumab to be slightly more effective than etanercept in the treatment of psoriasis, 108 but direct comparison with infliximab or adalimumab has not been reported.

Several agents specifically targeting the p19 subunit of IL-23 are currently in development and appear to be highly effective, consistent with a key role for IL-23 in psoriasis pathogenesis.57,109,110

Question 86

INTERLEUKIN17A ANTAGONISTS

Answer 86

Two IL-17A antagonists are currently approved for the treatment of psoriasis. Secukinumab is a fully human antibody, and ixekizumab is a humanized antibody that binds and neutralizes IL-17A. IL-17A is a critical cytokine in the pathogenesis of psoriasis, and biologics targeting IL-17A are among the most effective drugs available for the treatment of psoriasis.111-113 Brodalumab, a fully human antibody targeting the IL-17 receptor α chain, is also highly effective 114 and has recently been FDA approved for use in psoriasis after screening for depression and suicidal ideation.

Question 87

COMBINATION TREATMENTS

Answer 87

Combination treatment may increase efficacy and reduce side effects, so it may result in a more substantial improvement, or alternatively, may permit reduced doses to reach the same improvement as compared with monotherapy. 85 Data on combination of biologics with other systemic or topical agents are not yet widely available, but some combinations commonly used in the treatment of inflammatory arthritides, such as a combination of MTX and anti-TNF agents, may be appropriate for treatment of recalcitrant psoriatic disease.

Question 88

TREATMENT OF PALMOPLANTAR PUSTULAR PSORIASIS

Answer 88

Palmoplantar pustular psoriasis (including PPP and PPPP) tends to be difficult to treat and is often unresponsive to treatments used for chronic plaque psoriasis. Given its rarity, randomized controlled trials are lacking. Phototherapy, cyclosporine, and topical steroids are the treatments with the most welldocumented efficacy. 115 Tonsillectomy has been used to treat pustulosis palmaris et plantaris, and in a cohort of 116 Japanese patients, clinical improvement was seen in 109 (94%). 116 Notably, given its strong association with smoking, smoking cessation provides substantial clinical improvement.117

Question 89

PREVENTION

Answer 89

There is no known prevention for psoriasis.

Question 90

Treatment of Women of Childbearing Potential and During Pregnancy

Answer 90