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Patogenesis

PSORIASIS: INTEGRATING GENETICS AND IMMUNOLOGY HLA-Cw6. (Fig. 18-4).


As has been made clear by detailed fine mapping, genetic linkage, and association studies,
HLA-C is by far the major genetic risk factor for psoriasis. 30,34,35,38,57 Because it presents
antigens to CD8+ T cells, HLA-Cw6 is an excellent candidate for functional involvement in
psoriasis. Psoriasis has long been known to be triggered by streptococcal pharyngitis, and is
the only infection that has been shown to trigger psoriasis in a prospective cohort study. 227
Because tonsillar T cells are cutaneous lymphoid antigen (CLA)-positive and recognize
activated skin endothelium228 they can traffic into the skin, explaining why the same CLApositive T-cell clones are found in the tonsils and in the lesional skin of psoriatic patients. 229
CD8+ T cells comprise at least 80% of the T cells in the epidermis of psoriatic lesions,230 and
epidermal invasion correlates with lesional development.94,231,232 CD8+ T cells selectively
traffic to the epidermis because they express integrin 11 (also known as VLA-1), which
binds to type IV basement membrane collagen, 191 as well as integrin E7, which binds to
keratinocyte E-cadherin.222 Once in the epidermis, CD8+ T cells interrogate peptides bound
to HLA-Cw6 on the surface of dendritic APCs and/or keratinocytes. In normal immune
responses, CD4+ T cells provide critical help in processing and presentation of intracellular
viral components and tumor antigens, in a process called cross-priming. While CD4+ and
CD8+ memory T cells can traffic between the skin and lymph nodes and blood, increasing
evidence suggest that they spend most of their time in the skin itself.233 This may help to
account for the characteristic distribution of psoriatic plaques, which tend to recur in the same
places after therapeutic or spontaneous improvement. As mentioned earlier, there is a very
strong association between HLA-Cw6 and guttate psoriasis. This form of psoriasis is often
self-limiting5,234 but can progress to chronic plaque psoriasis, which has a fluctuating
inflammatory course in the absence of ongoing streptococcal infection. The transition from
guttate to chronic plaque psoriasis likely reflects a transition from a self-limited cutaneous
immune reaction triggered by streptococci encountered in the tonsils during a guttate flare, to
a persistent and inappropriate immune reaction directed against host proteins in chronic
plaque disease.235
Figure 18-4 Proposed role of HLA-Cw6 in the pathogenesis of psoriasis. Antigen (Ag) in the
binding pocket of HLA-Cw6 interacts with a T-cell receptor. The role of HLA-Cw6 in
psoriasis is likely to be twofold. HLA-Cw6 is active in cross-presenting peptides on the

surface of dendritic cells, allowing activation and clonal expansion of antigen-specific CD8+
T cells. This process is dependent on CD4+ T-cell help for cross-presentation of intracellular
antigens and is likely to happen both in the dermis (activation of memory resident T cells)
and local lymph nodes (activation of naive T cells). Subsequently, the CD8+ T cells are able
to migrate into the epidermis where they encounter HLA-Cw6 on the surface of the
keratinocytes presenting those same pathogenic peptides. Activated CD8+ T-cells may
recognize peptides presented by HLA-Cw6 on keratinocyte cell surface. Because these Tcells express perforin, they could directly damage keratinocytes in the traditional cytotoxic
manner.435 Activated CD8+ T cells could also trigger the local release soluble factors,
including cytokines, chemokines, eicosanoids, and/or innate immune mediators, which could
further increase local inflammation and stimulate keratinocyte proliferation.173 In response
to either insult, keratinocytes could respond by elaborating autocrine growth factors such as
TGF- and AREG, thereby encouraging their own proliferation and survival.436
Figure 18-5 Proposed model integrating the genetics and immunology of psoriasis. The
majority of the CD8+ T-cells (lilac) are located in the epidermis, whereas CD4+ T-cells (blue)
predominate in the dermis along with antigen presenting cells/dendritic cells (DCs) (blue) and
macrophages (Ms)(light blue). Confirmed association signals are indicated by the likely
candidate genes they contain. Please see text for additional details. (Adapted from Nair RP et
al: Psoriasis bench to bedside: Genetics meets immunology. Arch Dermatol 145(4):462-464,
2009, with permission.)

Patogenesis Andrew
Pathogenesis
Psoriasis is a hyperproliferative disorder, but the proliferation is driven by a complex cascade
of inflammatory mediators. Psoriasis appears to represent a mixed T-helper (Th)1 and Th17
inflammatory disease. Th17 cells appear to be more proximal in the inflammatory cascade. T
cells and cytokines play pivotal roles in the pathophysiology of psoriasis. Overexpression of
type 1 cytokines, such as IL-2, IL-6, IL-8, IL-12, IFN- and TNF-, has been demonstrated,
and overexpression of IL-8 leads to the accumulation of neutrophils. The main signal for Th1
development is IL-12, which promotes intracellular IFN- production. In animal models,
shifting from Th1 to Th2 responses improves psoriasis. IL-4 is capable of inducing Th2
responses and improving psoriasis. Reduced expression of the anti-inflammatory cytokines

IL-1RA and IL-10 has been found, and polymorphisms for IL-10 genes correlate with
psoriasis. IL-10 is a type 2 cytokine with major influences on immunoregulation, inhibiting
type 1 proinflammatory cytokine production. Patients on established traditional therapies
show rising levels of IL-10 mRNA expression, suggesting that IL-10 may have antipsoriatic
capacity. The response to biologic agents has demonstrated that CD2+ lymphocytes, CD-11a
and TNF- are important in the pathogenesis of psoriasis. IL-15 triggers inflammatory cell
recruitment, angiogenesis, and production of inflammatory cytokines, including IFN-, TNF, and IL-17, all of which are upregulated in psoriatic lesions. The interplay is complex, but
IL-17

appears to be proinflammatory, while IL-22 may serve to retard keratinocyte

differentiation. IL-23 stimulates survival, as well as proliferation of Th17 cells. Circulating


NK cells are reduced in psoriasis. Specific targets for therapy include TNF-, leukocyte
function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) binding,
and LFA-3/CD2 binding. An IL-15 monoclonal antibody has been shown to be effective in a
mouse model of psoriasis. Streptococci Streptococci play a role in some patients. Patients
with psoriasis report sore throat more often than controls. Beta-hemolytic streptococci of
Lancefield groups A, C, and G can cause exacerbation of chronic plaque psoriasis. Th1 cells
recognize cellwall extract isolated from group A streptococci. HLA variation has a significant
effect on the immune response to group A streptococci. Stress Various studies have shown a
positive correlation between stress and severity of disease. In almost half of patients studied,
stress appears to play a significant role. Drug-induced psoriasis Psoriasis may be induced by
-blockers, lithium, antimalarials, terbinafine, calcium channel blockers, captopril, glyburide,
granulocyte colony-stimulating factor, interleukins, interferons, and lipid-lowering drugs.
Systemic steroids may cause rebound or pustular flares. Antimalarials are associated with
erythrodermic flares, but patients traveling to malaria-endemic regions should take
appropriate prophylaxis. Often, drugs such as doxycycline or mefloquine are appropriate for
the geographic area, but when a quinine derivative offers the best protection, it is generally
better to take the prophylactic doses of a quinine derivative than to risk disease and full-dose
treatment.

Gambaran klinis
CLINICAL PATTERNS OF SKIN PRESENTATION297
PSORIASIS VULGARIS, CHRONIC STATIONARY PSORIASIS, PLAQUE-TYPE
PSORIASIS.
Psoriasis vulgaris is the most common form of psoriasis, seen in approximately 90% of
patients. 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. 18-7). Other sites of predilection
include the umbilicus and the intergluteal cleft. The extent of involvement varies widely from
patient to patient. There is constant production of large amounts of scale with little alteration
in shape or distribution of individual plaques. Single small lesions may become confluent,
forming plaques in which the borders resemble a land map (psoriasis geographica). Lesions
may extend laterally and become circinate because of the confluence of several plaques
(psoriasis gyrata). Occasionally, there is partial central clearing, resulting in ring-like lesions
(annular psoriasis) (Fig. 18-10). This is usually associated with lesional clearing and portends
a good prognosis. Other clinical variants of plaque psoriasis have been described depending
on the morphology of the lesions; particularly those associated with gross hyperkeratosis (see
Fig. 18-10).
Diagnosis
CUTANEOUS LESIONS297
The classic lesion of psoriasis is a well-demarcated, raised, red plaque with a white scaly
surface (Fig. 18-7). Lesions can vary in size from pinpoint papules to plaques that cover large
areas of the body. 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. 18-8).297 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. 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 (i.e., if psoriasis occurs at one site of injury it will occur at
all sites of injury) (Fig. 18-9). The Koebner reaction usually occurs 714 days after injury,

and approximately 25% of patients may have a history of trauma-related Koebner


phenomenon at some point in their lives. 298 Estimates of lifetime prevalence rise as high as
76% when factors such as infection, emotional stress, and drug reactions are included. 4 The
Koebner phenomenon is not specific for psoriasis but can be helpful in making the diagnosis
when present.

Test laboratorium
LABORATORY TESTS
Although histopathologic examination is rarely necessary to make the diagnosis, it can be
helpful in difficult cases. The histopathologic findings of guttate and chronic plaque psoriasis
have already been described (see Section Development of Lesions). In early lesions of
pustular psoriasis, the epidermis is usually only slightly acanthotic, whereas psoriasiform
hyperplasia is seen in older and persistent lesions. Neutrophils migrate from dilated vessels in
the upper dermis into the epidermis where they aggregate beneath the stratum corneum and in
the upper Malpighian layer to form the spongiform pustules of Kogoj. Other laboratory
abnormalities in psoriasis are usually not specific and may not be found 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. 327 Psoriasis
patients manifest altered lipid profiles, even at the onset of their skin disease. 328 Patients had
15% higher levels of high-density lipoproteins, and their cholesteroltriglyceride ratio for
very low-density lipoprotein particles was 19% higher. Furthermore, plasma apolipoproteinA1 concentrations were 11% higher in psoriasis patients. 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 can be increased, including Creactive protein, 2-macroglobulin, and erythrocyte sedimentation rate. 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.329

Treatment
Treatment Topical therapy is generally suitable for limited plaques. Localized treatments,
such as the excimer laser or other forms of intense pulsed light, may be suitable for limited
plaques. Phototherapy remains highly cost-effective for widespread psoriasis. Cyclosporine
has a rapid onset of action, but is generally not suitable for sustained therapy. Attention
should be paid to comorbidities including metabolic syndrome, cardiac risk, and joint
manifestations.
Topical treatment
Corticosteroids
Topical application of corticosteroids in creams, ointments, lotions, foams, and sprays is the
most frequently prescribed therapy for psoriasis. Class I steroids are suitable for 2-week
courses of therapy on most body areas. Therapy can be continued with pulse applications on
weekends to reduce the incidence of local adverse effects. To augment effectiveness of
topical corticosteroids in areas with thick keratotic scale, the area should be hydrated prior to
application, and covered with an occlusive dressing of a polyethylene film (Saran wrap) or a
sauna suit. Unfortunately, there is typically a rapid recurrence of disease when topical
corticosteroid therapy is discontinued. Side effects include epidermal atrophy, steroid acne,
miliaria, and pyoderma.
Anthralin
Anthralin is effective, but is irritating and stains skin, clothing, and bedding. To avoid these
drawbacks, short-contact anthralin treatment (SCAT) can be helpful, with anthralin washed
off after 1530 min. In warmer climates, SCAT is often done outdoors to keep the mess out of
the house. Anthralin exerts a direct effect on keratinocytes and leukocytes by suppressing
neutrophil superoxide generation and inhibiting monocytederived IL-6, IL-8, and TNF-.
Tazarotene
Tazarotene is a nonisomerizable retinoic acid receptor-specific retinoid. It appears to treat
psoriasis by modulating keratinocyte differentiation and hyperproliferation, as well as by
suppressing inflammation. Combining its use with a topical corticosteroid and weekend pulse
therapy can decrease irritation.

Calcipotriene
Vitamin D3 affects keratinocyte differentiation partly through its regulation of epidermal
responsiveness to calcium. Treatment with the vitamin D analog calcipotriene (Dovonex) in
ointment, cream, or solution form has been shown to be very effective in the treatment of
plaque-type and scalp psoriasis. Combination therapy with calcipotriene and highpotency
steroids may provide greater response rates, fewer side effects, and steroid-sparing.
Calcipotriene is unstable in the presence of many other topical agents and degrades in the
presence of UV light. Monitoring of serum calcium levels in adults is not required.
Calcipotriene plus betamethasone dipropionate (Taclonex) is more effective than either agent
alone. Macrolactams (calcineurin inhibitors) Topical macrolactams such as tacrolimus and
pimecrolimus are especially helpful for thin lesions in areas prone to atrophy or steroid acne.
The burning commonly associated with these agents can be problematic, but may be avoided
by prior treatment with a corticosteroid, and by application to dry skin, rather than after
bathing.
Salicylic acid
Salicylic acid is used as a keratolytic agent in shampoos, creams, and gels. It can promote the
absorption of other topical agents. Widespread application may lead to salicylate toxicity
manifesting with tinnitus, acute confusion, and refractory hypoglycemia, especially in
patients with diabetes and those with compromised renal function.
Ultraviolet light
Phototherapy is a cost-effective and underutilized modality for psoriasis. In most instances
sunlight improves psoriasis. However, severe burning of the skin may cause the Koebner
phenomenon and an exacerbation. Artificial UVB light is produced by fluorescent bulbs in
broad-band or narrow-band spectrums. Maximal effect is usually achieved at MEDs.
Although suberythemogenic doses can be effective, the response is slower than with
erythemogenic regimens. With treatment, a tanning response occurs, and the dose must be
increased to maintain efficacy. Maintenance UVB phototherapy after clearing contributes to
the duration of remission and is justified for many patients. Using a monochromator, it has
been shown that wavelengths of 254, 280, and 290 nm are ineffective; at 296, 300, 304, and
313 nm there is clearing. Narrow-band UVB (peak emission around 311 nm) has been shown
to be more effective in treating psoriasis than broad-band UVB. Erythemogenic doses are not

required in order to achieve a response. The response rates are better than 70% and close to
those achievable with PUVA therapy.

Systemic treatment
Corticosteroids
The hazards of the injudicious use of systemic corticosteroids must be emphasized. There is
great risk of rebound or induction of pustular psoriasis when therapy is stopped.
Corticosteroid use is generally restricted to unique circumstances, such as impetigo
herpetiformis when expeditious delivery is not possible.
Methotrexate This folic acid antagonist remains the standard against which other systemic
treatments are measured. Methotrexate has a greater affinity for dihydrofolic acid reductase
than has folic acid. The indications for the use of methotrexate include psoriatic
erythroderma, psoriatic arthritis, acute pustular psoriasis (von Zumbusch type), or widespread
body surface involvement. Localized pustular psoriasis or palmoplantar psoriasis that impairs
normal function and employment may also require systemic treatment. It is important to
make sure that the patient has no history of liver or kidney disease. Methotrexate can be toxic
to the liver and decreased renal clearance can enhance toxicity. Other important factors to
consider are alcohol abuse, cryptogenic cirrhosis, severe illness, debility, pregnancy,
leukopenia, thrombocytopenia, active infectious disease, immunodeficiency, anemia, colitis,
and ability to comply with directions. Hepatic enzymes, bilirubin, serum albumin, creatinine,
alkaline phosphatase, complete blood count (CBC), platelet count, hepatitis serology (B and
C), HIV antibody, and urinalysis should all be evaluated before starting treatment. Patients
with hypoalbuminemia have a higher risk of developing pulmonary complications. The need
for liver biopsy remains controversial. Biopsy is not without risks and is not commonly
performed in the setting of methotrexate therapy for rheumatic disease. However, patients
with psoriasis have a greater risk of liver disease than other patient populations. In most
patients with no risk factors for liver disease, the first liver biopsy is commonly obtained at
approximately 1.01.5 g of cumulative methotrexate and repeated every subsequent 1.52.0 g
until a total of 4.0 g is reached. The frequency then changes to every 1.01.5 g cumulative
intervals. These recommendations are likely to change as more data are evaluated. Weekly
blood counts and monthly liver enzyme assessment are recommended at the onset of therapy

or when the dosage is changed. Monitoring of aminoterminal procollagen III peptide and
metabolic panels that predict the risk of fibrosis (NASH Fibrosure) may r
educe the need for liver biopsy. Numerous treatment schedules have evolved. The authors
recommend either three divided oral doses (12 h apart) weekly, weekly single doses orally, or
single weekly subcutaneous injections. The weekly dose varies from 5 mg to more than 50
mg, with most patients requiring 1530 mg a week. Once a single dose exceeds 25 mg, oral
absorption is unpredictable and subcutaneous injections are recommended. Mid-week doses
can result in severe toxicity and must be avoided. Oral or cutaneous ulceration may be a sign
that the patient has taken a mid-week dose. Oral folic acid has been reported to decrease side
effects, especially nausea, and doses of 14 mg/day are used. Oral folic acid is not adequate
for the treatment of overdosage and leukovorin must be used in such cases. Cyclosporine
The therapeutic benefit of cyclosporine in psoriatic disease may be related to
downmodulation of proinflammatory epidermal cytokines. The microemulsion formulation
Neoral has greater bioavailability and is now standard. Doses of 25 mg/kg/day generally
produce rapid clearing of psoriasis. Unfortunately, the lesions recur rapidly as well, and
transition to another form of therapy is required. Treatment durations of up to 6 months are
associated with a low incidence of renal complications, but blood pressure and serum
creatinine must be monitored and doses adjusted accordingly. Usually, the dose is reduced if
the baseline creatinine increases by one-third.

Histologi
Psoriasis Vulgaris
Clinical Summary
Psoriasis vulgaris is characterized by pink to red papules and plaques which are of variable
size, sharply demarcated, dry, and usually covered with layers of fine, silvery scales. As the
scales are removed by gentle scraping, fine bleeding points usually are seen, the so-called
Auspitz sign. The scalp, sacral region, and extensor surfaces of the extremities are commonly
involved, although in some patients the flexural and intertriginous areas (inverse psoriasis)
are mainly affected. An acute variant, guttate, or eruptive psoriasis, is often seen in younger
patients and is

characterized by an abrupt eruption of small lesions associated with acute group A hemolytic streptococcal infections. Involvement of the nails is common; the most frequent
alteration of the nail plate surface is the presence of pits. In severe cases the disease may
affect the entire skin and present as generalized erythrodermic psoriasis. Pustules generally
are absent in psoriasis vulgaris, although pustules on palms and soles occasionally occur, and
rarely, severe psoriasis vulgaris develops into generalized pustular psoriasis. Oral lesions
such as stomatitis areata migrans (geographic stomatitis) and benign migratory glossitis may
be seen in psoriasis. Psoriatic arthritis characteristically involves the terminal interphalangeal
joints, but frequently the large joints are also affected so that a clinical differentiation from
rheumatoid arthritis often is impossible, although rheumatoid factor generally is absent.
Clin. Fig. IIID2.a Pustular psoriasis. Rapid development of sterile pustules complicated a
case of erythroderma.
Clin. Fig. IIID2.b Psoriasis, plaque lesion. Well-demarcated erythematous plaque with a
thick, white silvery scale on extensor surfaces.
Fig. IIID2.a Psoriasis vulgaris, low power. The hyperkeratotic scale is composed of ortho and
parakeratin. The epidermis is evenly acanthotic. There is papillomatosis and an infiltrate
about dermal vessels and in the dermal papillae.
Fig. IIID2.b Psoriasis vulgaris, medium power. The parakeratotic scale contains fragments of
neutrophils. The epidermis shows even acanthosis with some rete ridge fusion. The papillary
dermis is edematous and well vascularized.
Fig. IIID2.c Psoriasis vulgaris, high power. The scale contains a collection of
polymorphonuclear leukocytes and parakeratin. The epidermis is acanthotic. The papillary
dermis is well vascularized with discrete areas of hemorrhage.