Mild-to-Moderate Psoriasis - part 6 pptx

To better define the frequency of PUVA therapy, a prospective,randomized, half-side study was performed in Austria, using 18 patientswith chronic plaque psoriasis who received paired PUVA

70 mg Following oral administration, there are significant inter- andintraindividual variations in the absorption of 8-MOP Therefore, it is veryimportant that the psoralen dose, type and amount of food intake, and tim-ing of phototherapy after ingestion of psoralen are kept constant Psoralen

is preferable to be taken on an empty stomach, as food intake slows tion and reduces the peak blood levels However, due to gastrointestinal sideeffects, especially with 8-MOP, non-fat small meals may be taken to allevi-ate some of these symptoms In some patients, the capsules may have to

absorp-be ingested 10 minutes apart to minimize the gastrointestinal side effects.Antiemetics may have to be given to some patients

In patients who are unable to tolerate systemic PUVA, psoralen can beadministered in a bath or cream/lotion, avoiding the gastrointestinal tract

In our institution, topical PUVA is administered using 0.1% 8-MOP solution

in Lubriderm1 lotion, applied 20 minutes prior to exposure to UVA TheUVA dose protocol is shown in Table 3 Bath PUVA is only performed invery few centers in the United States because of the need for a bathtub

A bath containing 0.5–5.0 mg/L of 8-MOP, or 0.33 mg/L of TMP, needs

to be freshly prepared; the patient will then soak in it for 15 to 30 minutes

At some phototherapy facilities [e.g., University of California, San Francisco(UCSF)], effective bath PUVA is being conducted simply by dissolving 50 mg

of Oxsoralen Ultra in a hot cup of water first and then adding it to 100 L ofbath water Exposure to the UVA needs to be performed within 30 minutesafter the patient steps out of the bathtub

In Europe, oral 5-MOP is commonly used It is less phototoxic than8-MOP, therefore requiring a higher cumulative UVA dose The dose rangeused is 1.2–1.8 mg/kg It has less of a gastrointestinal side effect, hence isbetter tolerated It is not available in the United States

Avoidance of prolonged sun exposure and wearing UVA-absorbingsunscreens on the days of PUVA therapy are necessary to prevent significantphototoxicity Unlike UVB-induced erythema, PUVA-induced phototoxic-ity begins approximately 24 hours after exposure and peaks at 48–72 hoursafter exposure This is the reason that PUVA should not be administeredtwo days in a row If PUVA is administered on consecutive days, a treatment

Table 3 Topical Psoralen and Ultraviolet A Protocol

lotion is applied to the affected areas20–30 min prior to treatment This is only applied in the medical office

Photochemotherapy is given three times per week

Once the condition has improved, treatment frequency can be decreased to twice perweek for 4–8 weeks and then once per week for 4–8 weeks, then discontinued

protocol more often used in Europe, the dose is kept constant on the first twodays of the week, followed by a nontreatment third day; an increased butidentical dose may be given on the fourth and fifth day of the week (34).The initial dose of UVA can either be determined by minimal photo-toxicity dose (MPD) or more commonly by Fitzpatrick skin type The MPD

is the minimal dose of PUVA that produces well-defined erythema Thesereadings are performed at 48–72 hours The skin-type–based protocol used

at our institution is shown in Table 4 The dose of UVA should be adjusted,usually decreased by 25%, if patients are taking photosensitizing medica-tions UVA doses should also be decreased if topical or systemic retinoidsare used during a course of PUVA because they thin the stratum corneum,reducing the amount of light required for phototoxicity

During the UVA exposure, protective eyewear should be used Malegenitalia are particularly sensitive to the development of squamous cell car-cinomas (SCCs) (41); male genitals should be shielded during all of the UVAexposure If PUVA is required for limited disease, careful shielding of unaf-fected skin is recommended

Therapy is usually administered twice to three times per week until thepsoriasis is well controlled; it then can be decreased to twice and eventuallyonce a week Maintenance therapy has been shown to decrease the probabil-ity of remission; however, it will increase the patient’s cumulative dose ofUVA The British Phototherapy Group recommends that long-term PUVAtherapy should only be considered in patients with a history of rapidrelapses (42) However, whether this applies to non-Caucasians is not clear

To better define the frequency of PUVA therapy, a prospective,randomized, half-side study was performed in Austria, using 18 patientswith chronic plaque psoriasis who received paired PUVA regimens (43) Itwas shown that reducing the number of treatments while maintaining thesame UVA dose per week did not reduce efficacy Reducing the number

of treatments from four times per week to twice a week and reducing theUVA dose from 1 to 0.75 or 0.5 MPD per treatment only slightly affectedTable 4 Guideline for Psoralen and Ultraviolet A Photo-

chemotherapy for the Treatment of Psoriasis Based on Skin Type

Skin type

Initial dose

Dose increaseper treatment

intermediate therapeutic efficacy, and had no effect on final clearance rates

or time to complete clearance The mean cumulative UVA dose was cantly lower for the least intensive dose regimen (0.5 MPD twice/wk) thanfor the more intensive regimens

signifi-Due to the increased development of cutaneous malignancies withPUVA therapy, one should strongly consider the combination with otherdrugs such as retinoids or in rotation with other treatments to minimizetotal cumulative dose of PUVA

Adverse Effects

The acute side effects can be due to either the psoralen or the UVA tion Systemic psoralen causes nausea and occasionally vomiting in up to30% of patients taking 8-MOP 5-MOP has fewer gastrointestinal symptomsand is better tolerated Most drug-induced photosensitivities are due toUVA; therefore, a careful medication history will help prevent this adverseevent PUVA-induced phototoxic reactions, such as erythema and vesicula-tion, appear at 24–36 hours and peak at 48–72 hours; they can persist for aweek or longer Other known side effects include photo-onycholysis, mela-nonychia, and friction blisters Subacute side effects can be an intractablepruritus known as ‘‘PUVA itch.’’ In some patients, therapy may have to

radia-be stopped until the pruritus resolves, and one can then consider restartingthe treatment with a lower UVA dose Tanning is a constant feature, espe-cially in patients with darker skin

Long-term side effects include photoaging, the development of smallbrown to black macules in PUVA-exposed sites, known as PUVA lentigines,and photocarcinogenesis Many of these long-term side effects have beenreported by the PUVA follow-up study, a 16-center prospective cohort study

of 1380 patients first treated with PUVA in 1975–1976 in the United States(44) In a study on photoaging, actinic damage was observed in the hands

of 61% of patients, and in the buttocks of 21% Pigmentary changes were seen

in the hands of 59% of patients, and in the buttocks of 25% (45)

Increased risk of SCCs is a well-documented dose-dependent adverseeffect in Caucasians In the U.S 16-center study, there was no increase innon-melanoma skin cancer in the first 15 years of the study However, after

25 years, 50% of patients who had received greater than 400 treatments hadSCC, and 33% of patients who had received greater than 200 treatmentshad BCC (44) A Swedish study followed 4799 patients who had receivedPUVA between 1974 and 1985 with an average follow-up period of 15.9 yearsfor men and 16.2 for women; increase in the risk for SCC was also observed:the relative risk for SCC was 5.6 for men and 3.6 for women (46) In contrast,

a meta-analysis of all available long-term data on non-Caucasians withrespect to non-melanoma skin cancer so far revealed no increase in risk innon-melanoma skin cancer in non-Caucasians (47)

There is a significant dose-dependent increase in SCC in the genitals ofPUVA-treated male patients The incidence of invasive penile and scrotalSCCs was increased by 52.6-fold This dose-dependent increase in the risk

of genital tumors is persistent long after PUVA therapy has been stopped,especially among those with high-dose exposures to both PUVA and tar

or UVB (41)

There are conflicting results on long-term studies on the incidence ofmelanoma after PUVA therapy The PUVA follow-up study reported anincreased risk of melanoma, greatest in patients exposed to high doses ofPUVA (
250 treatments), beginning 15 years after first exposure to PUVA.The incidence rate ratio was 8.4 (48) In contrast, the Swedish follow-upstudy of 4799 patients who had received PUVA between 1974 and 1985 with

an average follow-up period of 15.9 years for men and 16.2 for women didnot find an increased risk for melanoma, nor in a subcohort comprising 1867patients followed for 15–21 years (46)

In another study by the U.S PUVA follow-up group of over 1000patients treated with PUVA, UVB exposure (
300 treatments vs <300 treat-ments) was associated with a modest but significant increase in SCC and BCCrisk (49) These occurred on body sites typically exposed to UVB therapy, butnot on chronically sun-exposed sites typically covered during therapy.Using the U.S PUVA follow-up database, 135 patients who had usedoral retinoids for greater than 26 weeks in one year were studied The devel-opment of SCC and BCC for each patient during the retinoid use year wascompared to the non-retinoid use years It was found that oral retinoidsreduced the risk of SCC but did not significantly alter BCC incidence (50)

TARGETED (LOCALIZED) PHOTOTHERAPY

The appeal of targeted, or localized, phototherapy is its ability to sparehealthy skin from the side effects of UV radiation In addition, the affectedareas can usually tolerate a higher dose than unaffected skin, as the rate-determining factor for generalized phototherapy is usually erythema ofuninvolved skin It is known that normal skin can be exposed to up to threeMEDs without blistering, while psoriatic skin may be exposed to up tothree times this dose (nine MEDs) without blistering (51,52) The recentcommercial introduction of fiber-coupled UVB phototherapy systems facil-itates the use of this treatment modality for localized psoriasis plaques.The mechanism of action of targeted phototherapy is similar to that ofthe other UV-based therapy, namely by inducing T-cell apoptosis, suppression

of DNA synthesis, and generation of prostaglandins and cytokines It hasbeen reported that the 308 nm excimer laser is more effective in the induction

of T-cell apoptosis compared to NB-UVB (6)

At the time of this writing, there are several targeted phototherapysystems available (Table 5): XTrac excimer laser system (PhotoMedex,

Montgomeryville, Pennsylvania, U.S.A.), BClear targeted photoclearingsystem (Lumenis, Santa Clara, California, U.S.A.), DuaLight UVA/UVBphototherapy system (TheraLight Inc., Carlsbad, California, U.S.A.), Lovely

II (MSq Ltd., Caesarea, Israel), MultiClear (Curelight Ltd., Margate, Florida,U.S.A.), T-500x (Daavlin, Bryan, Ohio, U.S.A.), Excilite-m (NationalBiological Corporation, Twinsburg, Ohio, U.S.A.) XTrac is the only laser-targeted phototherapy system; the rest are non-laser light sources

Efficacy

Most of the published studies on targeted phototherapy have been performedwith the 308 nm excimer laser system, which will be the focus of the discus-sion in this section There are not a lot of published studies on the other

UV phototherapy machines; however, because their wavelengths are similar

to that of BB-UVB, NB-UVB, or UVA, theoretically they should be asefficacious as booth phototherapy

Initial case reports and subsequent larger studies (53) have shownsignificant improvement and even remission of psoriatic lesions followingexposure to the 308 nm excimer laser In a multicenter study of 80 patients,stable mild to moderate plaque-type psoriasis was treated twice per weekfor a total of 10 treatments or clear disease (54) The initial dose was based

on MED testing and the following treatments were based on plaqueresponse Seventy-two percent achieved at least 75% clearing in an average

of 6.2 treatments Eighty-four percent of patients reached improvement of

at least 75% after 10 or fewer treatments Fifty percent reached improvement

of at least 90% after 10 or fewer treatments In a follow-up study, 55% ofpatients reported an overall satisfaction with their treatments and 25%reported that their treatment was better than other therapies they had triedfor localized disease (55)

Higher doses can be used on psoriatic plaques with faster clearing anddecreased cumulative dose as compared to conventional booth phototherapy(56) A dose-response study showed clearance of psoriasis with high fluences(8–16 times MED) in as little as one treatment (52) Koebner reactions werenot observed despite the side effects of transient painful blistering Treatmentwith higher fluences was more effective than with low and medium fluences

In addition, the lesions treated with high fluences remained in remissionlonger The four-month relapse-free outcome is comparable or better thanthe standard topical or systemic therapy for psoriasis (52) In a study withfour children with psoriasis, mean age 11, the excimer laser was found to

be a safe and effective treatment for localized psoriasis in these children (57).Two studies have compared the excimer laser to incoherent UVBphototherapy with similar outcomes Tanghetti and Gillis (58) comparedthe clinical outcome of treatment with the excimer laser to a continuous-wave, incoherent UVB light source Both systems cleared the treatedpsoriasis plaques equivalently, requiring no more than two to five weeks

of treatment When used at equally erythemogenic high doses, both systemsproduced rapid plaque clearance with minimal side effects Ko¨llner et al.(59) treated 15 patients with plaque psoriasis Three different psoriaticlesions were treated with either the xenon chloride 308 nm excimer laser,the 308 nm excimer lamp, or 311 nm NB-UVB three times per week UVBdoses were increased slowly and stepwise There was no statistically significantdifference among the three groups after 10 weeks The mean number of treat-ments needed to achieve clearance was 24 Both 308 nm light sources treatedpsoriasis with a similar efficacy to standard NB-UVB phototherapy.

Advantages and Disadvantages

The advantages of targeted phototherapy include sparing healthy tissue from

UV radiation and ability to deliver high fluences to affected areas This couldresult in faster rate of response, and probably less cumulative dose However,the time to administer therapy is greatly increased as compared to boothphototherapy One can spend up to 20 minutes per session twice to threetimes per week Under appropriate supervision, the therapy can be delivered

by an experienced nurse, phototherapy technician, or physician

Dosage and Administration

This topic has been studied most extensively with the 308 nm excimer laser.There are various treatment regimes reported and this is still an area of activeinvestigation Treatments are usually delivered twice or three times per week.The initial dosing is usually based on a predetermined MED as well as plaquethickness and location Fluences should be adjusted according to symptomsand response to treatment The initial dose is usually maintained until theplaques flatten, at which point the dose is decreased Likewise, if there is

no improvement with the initial dose, the fluence should be increased

Housman et al (60), have found that twice-weekly excimer laser ments promote clearance of psoriatic plaques and tapering the treatmentsmay be beneficial in maintaining the level of plaque clearance obtained frombiweekly laser treatments.

treat-Ko¨llner et al (59) treated 16 patients with the 308 nm excimer laser orwith the 308 nm lamp with an accelerated scheme three times per week Theycompared this with UVB therapy in which the dose was increased every sec-ond treatment With the accelerated scheme, clearance was achieved withfewer treatments and with half the cumulative dose of a slow and stepwiseregime The side effects such as blistering and crusting were also increased.Adverse Effects

The adverse effects of targeted phototherapy are related to the wavelengthadministered The lesional and perilesional skin can develop erythema, tan-ning, vesiculation, erosion, or crusting This may result in an uneven skin toneand may be a cosmetic concern for some patients This dyspigmentation fadesgradually with time once phototherapy is stopped Interestingly, koebneriza-tion has not been reported with vesiculation In fact, just the opposite, fasterclearance in the vesiculated areas or a ‘‘reverse’’ Koebner phenomenon hasbeen reported There are no long-term studies on carcinogenesis

ULTRAVIOLET A1

UVA1 is a relatively new type of phototherapy in the United States; ever, it has been used since the early 1990s in Europe Its main indicationsare for the treatment of atopic dermatitis and sclerosing disorders

how-Efficacy

There are two small studies published on the use of UVA1 for the treatment

of psoriasis Kowalzick et al (61) performed a paired controlled trial in threepatients using medium dose UVA1 and BB-UVB for three weeks Both theUVA1- and BB-UVB–treated lesions improved A review cited three HIV-positive psoriatic patients who benefited from UVA1 phototherapy (62).However, in a review of Mang and Krutmann’s (63) personal experience,there is little to no efficacy of UVA1 for the treatment of psoriasis

It has been suggested that UVA1 is the phototherapy of choice forHIV-positive patients with psoriasis (63) Three HIV patients with psoriasiswere treated with high dose (130 J/cm2) UVA1 with benefit A quantitativepolymerase chain reaction (PCR)-based assay was performed in bothlesional and nonlesional skin after one UVB or UVA1 exposure TheUVB-treated skin showed a 6–15-fold increase in the HIV copy number,whereas the UVA1-treated skin did not show any increase (62) Furtherstudies are clearly needed

to be used with caution.

Advantages and Disadvantages

Further studies are necessary

Dosage and Administration

Until further study with psoriasis shows good efficacy, there is no establisheddose for this treatment For atopic dermatitis and localized scleroderma, stud-ies have been done using low dose (20 J/cm2), medium dose (50–60 J/cm2),and high dose (120 J/cm2) The low and medium doses are the more com-monly used regimen at the present time

Adverse Effects

UVA1 is generally well tolerated Exposed skin will become tanned There is

a significant amount of heat generated by the equipment throughout thetreatment Other possible side effects include xerosis, pruritus, and rarelyskin burning The long-term side effects are not known In animal models,UVA1 has induced squamous cell cancers (64)

CONCLUSION

Phototherapy and photochemotherapy have a role in the treatment oflocalized and generalized psoriasis Patient compliance and the ability forthe patient to come to the office regularly for the treatment are factors thatneed to be considered Targeted phototherapy sparing uninvolved skin is anew development that is beneficial for selected patients The side effects ofPUVA are well established UVB, when judiciously administered, has mini-mal side effects

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Boston, Massachusetts, U.S.A.

THE RATIONALE FOR COMBINATION THERAPY

Even in mild cases of psoriasis, therapy with a single topical agent often fails

to provide patients with adequate disease control Fortunately, valid natives are available, as topical agents can be used in conjunction with othertopical medications, systemic therapies, and phototherapy through a com-binational, sequential, or rotational approach to treatment This translatesinto management plans that extend from the simultaneous use of twotreatment entities to well-choreographed time courses featuring multipletherapeutic agents Situations in the treatment of mild to moderate psoriasisthat may warrant this approach include refractory disease, acute flares, poorquality of life, or an upcoming major life event for which total clearance isdesired Diversifying treatment tends to reduce the required dosages andadverse effects associated with aggressive treatment modalities, as well asbenefit the patient through potential cost reduction, ease of administration,and improved quality of life

alter-The concept of maximizing efficacy and minimizing adverse effectsthrough the combined use of multiple treatment modalities for psoriasishas been used extensively (1) Combination therapy is most useful to treat

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patients who have failed monotherapy, are taking or may take a medicationwhose toxicity will decrease when used in combination, or require taperingfrom a single therapeutic agent (1) This approach frequently involves usingsmaller doses of each agent for a limited period of time, with the more potentagent discontinued as clinical improvement is attained Just as there is no sin-gle topical agent that can be used to treat all patients with psoriasis, flexibilitywith combinational therapeutics is also necessary to achieve disease control.Guidelines to diagnosing combination therapy can be found in Table 1.There is evidence that combination therapy is often superior to mono-therapy In a 2000 review investigating disease clearance rates associatedwith various treatments for psoriasis, phototherapy was associated with63% to 86% clearing and systemic therapy (with a non-retinoid) with 65%

to 81% clearing (2) This was in comparison to the 2% to 36% clearing ratefor topical therapies When a second topical agent was added to topicalmonotherapy, there was a higher likelihood of clearing Combination thera-pies involving systemic agents or phototherapy, however, yielded evenhigher clearing rates with the pair of acitretin plus psoralen and ultraviolet

A (PUVA) and the Goeckerman regimen reaching 100% clearance Includedamong the most successful combinations were ultraviolet B (UVB) plusanthralin, PUVA plus anthralin, and PUVA plus topical calcipotriol, withreported clearance rates of greater than 90% (2) Combination therapieshave been superior to monotherapy in many double-blind studies, particu-larly the pairs of calcipotriol with betamethasone valerate ointments,acitretin with PUVA, and calcipotriol ointment with PUVA

PHOTOTHERAPY COMBINATIONS

The use of phototherapy combinations is very common and widely used.Many combinations exist including therapy with UVB and PUVA, as well

Table 1 Combination Therapy Guidelines

Factors in considering the switch to combination therapy

 Monotherapy is not or no longer effective

 Cumulative and/or acute toxicity is projected to be less

 Side effects are projected to be fewer

 Improved therapeutic outcome (e.g., time, likelihood of clearing)

 Increased possibility of tailoring therapy to individual needs

Factors in choosing a particular combination of agents

 Severity of disease

 Patient’s expectations and ease of use

 History, relative to use of agents in the combination

 Response

 Side Effects

 Reported efficacy and cost

Source: From Ref 1.