Advances in Psoriasis Treatment
Associate Professor of Dermatology and Pathology, Director, Psoriasis Treatment Center Director, Westwood-Squibb Center for
Dermatology Research Wake Forest University School of Medicine Winston-Salem, NC
Dermatology Online Journal 6(1): 4
Psoriasis is a complex disorder that negatively impacts quality of life. Treatment strategies must address both psychosocial and physical aspects of the disease. Psoriasis can be categorized into localized and generalized forms for treatment purposes. In either case, the treatment plan should include obtaining rapid control of the disease and maintaining that control. For localized disease, recent data support the combined use of topical corticosteroids with a noncorticosteroid agent (topical calcipotriene or tazarotene). For generalized disease, UVB phototherapy is an effective treatment that permits both rapid control and long-term maintenance. Use of low doses of acitretin (25mg qd or qod) potentiates both UVB and PUVA therapy. For patients unresponsive to phototherapy or who are not able to come on a regular basis, methotrexate is an effective alternative. Cyclosporine is useful, especially for short-term use in settings of acute exacerbation, but should be replaced by other modalities for long-term maintenance. Other agents that have a place in treatment of generalized psoriasis include hydroxyurea and mycophenolate mofetil.
Psoriasis is a complex disorder,a multigenic phenomenon in which certain infectious, pharmaceutical, and recreational (alcohol,cigarettes) agents may play an important role as triggers. In addition, patients commonly point out the role of stress in psoriatic flares. Dry skin appears to act similarly to other skin injuries in initiating Koebnerization. When initiating psoriasis therapy, psychosocial factors such as stress and alcohol use should be addressed as well as the other precipitating factors.Quality of life in psoriasis
There is growing emphasis on quality of life research in all of medicine, and psoriasis impacts on every dimension of health-related quality of life.[2,3] In my patient population, many of my patients are spending an hour a day taking care of their psoriasis and are using numerous treatments (including alternative medicines).[4,5] Psoriasis treatment is costly, financially and psycologically. Twenty-five percent of our patient population with psoriasis reported that in some time during their life they wished they were dead because of their psoriasis. Eighty percent of patients with psoriasis report that stress makes their psoriasis worse and most feel that their psoriasis itself is a very significant stressor. Specific aspects of the disease that are particularly bothersome to patients include itching, appearance, scaling, and their inability to control the psoriasis.[3,7] An effective dermatologist must address the specific aspects of the disease that concern each individual patient.
When one compares the quality of life in psoriasis to that in other medical conditions it becomes clear that the reduction in quality of life that these patients experience is comparable to the reduction in quality of life with other medical illnesses. On the physical dimensions of health-related quality of life, psoriasis has less impact than congestive heart failure, but greater impact than hypertension, diabetes, post-myocardial infarction and depression. However, on the mental dimensions of health-related quality of life, psoriasis was considered worse than all these conditions except depression. These findings have importance not just for psoriasis but for skin disease in general. These are not cosmetic problems; these diseases cause quantifiable reductions in health-related quality of life. The National Psoriasis Foundation (NPF) was founded with the goals of providing psychosocial support and education to psoriasis patients. It is important for dermatologists to encourage their patients to join this supportive and politically effective organization.Treatment goals
It is helpful to set with patients a realistic goal of therapy. Generally, a goal of complete clearance of psoriasis is not realistic; few patients actually achieve prolonged clearance. To minimize adverse medication effects, it is safest to try to reduce the psoriasis to a manageable level, rather than to maximize doses in an attempt to obtain complete clearing. The histopathology of psoriatic lesions reveals inflammation, keratinocyte hyperproliferation, and vascular dilation, offering multiple targets for intervention. Often, a combination of modalities can be utilized to enhance the therapeutic effect and minimize the adverse effects that could result from excessive use of one agent.
Treatment of localized psoriasis
|Table 1: Treatments for Localized Psoriasis|
For treatment purposes, we can define localized psoriasis as present when the patient is willing to apply topical therapy to all the spots (usually less that 20% body surface area). Thus, the primary treatment options for localized psoriasis include tar preparations, topical corticosteroids, topical calcipotriene (Dovonex), topical tazarotene (Tazorac) and anthralin (Table 1). Other useful treatments include occlusive corticosteroid tape for chronically excoriated lesions of psoriasis, and intralesional triamcinolone injections for very localized, refractory lesions.Tar
Tar has limited effectiveness and may be used at night with more appealing topical corticosteroid preparations during the day. There are continued "advances" in tar treatments reported but little if any scientific evidence to show that these new tar treatments are more effective than any other. For example, patients may have heard about Exorex, a tar with banana peel extract. One marketing study suggested that it could be as effective as topical calcipotriene, however, the patient number was so small that no valid conclusions can be drawn. Topical corticosteroids
Topical corticosteroids are a mainstay in the treatment of localized psoriasis and are used in their appropriate potency in their appropriate settings. "Skin Cap," a seemingly miraculous OTC product thought to contain only a formulation of zinc pyrithrone, was removed from the market when it was revealed that it contained clobetasol propionate. [10,11,12] In an effort to duplicate the popular product, the company which markets "DermaZinc" readily supplies information on compounding its product with clobetasol. Direct comparisons of efficacy of this compounded product with commercially available clobetasol products are not available. However, studies of topical clobetasol solution (Temovate scalp) showed that 80% of patients in the clinical trials had 80-100% improvement in only two weeks.  Increased efficacy by compounding with DermaZinc will be difficult to show.
|Table 2: Topical Corticosteroids|
Another advance in the area of topical corticosteroids for psoriasis is the development of betamethasone valerate in a new foam vehicle delivery system (Luxiq). It is designed and approved for scalp treatment, though patient preference for this vehicle is very high and there is no reason not to use it on non-scalp sites. The foam melts only when it reaches body temperature, therefore, steroid delivery will be to the scalp and not the hair. Gram per gram it is priced the same as brand name mid potency topical steroids but it comes in a 100 g can. Also, it appears that it covers about the same area of skin as do other topical corticosteroids when considered on a gram per gram basis. It is very easy to apply.Topical calcipotriene (Dovonex)
Topical calcipotriene became available in the U.S in 1994. In the original studies designed to demonstrate efficacy, the drug was used as monotherapy with twice daily dosing, and demonstrated similar efficacy to fluocinonide ointment. However, the effects of the drug occur more slowly than seen with Class I or II topical corticosteroids and require 8 to 12 weeks for maximal effect. In addition, the side effect of irritation occurs in 10-15% of patients. In clinical practice, many patients will not continue to apply a medication for the 8-12 weeks necessary to see the full benefit of treatment and will also immediately discontinue use of a drug if they experience irritation from the product. Using topical calcipotriene in combination with topical corticosteroids facilitates more rapid improvement in the psoriasis and prevents the side effect of irritation.[16,17,18] The combination that has been best characterized is with halobetasol (Ultravate). Concomittant use of halobetasol cream or ointment or halcinonide (Halog) with calcipotriene scalp solution does not appear to inactivate calcipotriene, though some other corticosteroid preparations may. In additon, calcipotriene should not be combined with salicylic acid or other acid products, as calcipotriene is rapidly inactivated in an acidic environment.  A safe, effective approach to treatment of localized psoriasis is to apply both topical calcipotriene and topical halobetasol twice daily. Rapid improvement may be expected in 2 weeks, faster than when either agent is used alone. Once significant improvement is attained, it may be best to taper off the potent topical corticosteroid quickly. A sensible approach may be first to switch to weekend use of the topical corticosteroid while continuing the twice daily topical calcipotriene and then stopping the topical corticosteroid altogether.
|Table 3: Topical Calcipotriene|
Hypercalcemia has been reported with topical calcipotriene, but it is rare as long as the dose is maintained under 120 g/wk in adults. At such doses, no monitoring is required unless there are preexisting conditions predisposing to hypercalcemia. Topical calcipotriene should not be combined with salicylic acid or other acid products, as topical calcipotriene is rapidly inactivated in an acid environment. Topical calcipotriene scalp solution may be used in combination with halcinonide (Halog) solution and perhaps other topical steroids solutions, but it should not be mixed with 6% salicylic acid (as has been done with the combination of 6% salicylic acid [Keralyte gel], fluocinonide [Lidex] gel, and tar [Estar] gel for the treatment of hyperkeratotic lesions of psoriasis.
Another issue with topical calcipotriene is its use in combination with ultraviolet light (UVL) treatment. The combination of topical calcipotriene with either UVB or PUVA is synergistic. There are data that topical calcipotriene is inactivated by UVA, so it is best not to apply it immediately before PUVA treatment. Moreover, topical calcipotriene can absorb UVB, so it is best not to apply a thick layer immediately before going out in the sun or before getting into a UVB lightbox.
Topical calcipotriene is very safe. Though hypercalcemia has been reported, it is extremely rare if the dose is kept under 120 g/wk. The package insert for topical calcipotriene recommends it not be used on the face or intertriginous areas due to irritation. However, if used in combination with a topical corticosteroid initially, irritation is unlikely. Topical calcipotriene may be the safest treatment for long-term control of face or genital disease because there is no risk of atrophy.Topical tazarotene
|Table 4: Topical Tazarotene (0.1% and 0.05%)|
Another drug used similarly to topical calcipotriene is topical tazarotene gel (Tazorac 0.05 and 0.1%).[22,23,24] An advantage of this product is that it is applied once per day and is a gel that is more cosmetically pleasing than the ointment vehicles typically used to treat psoriasis. It can be used on the face or scalp (the 0.1% gel is FDA-approved as a treatment for treatment for acne). Tazorac works less quickly than high potency topical corticosteroids, with approximately 70% response at 3 months. Typical retinoid side effects of burning and itching occur in 20-40% of patients in clinical trials and approximately 10% drop out. Patients must be told of the potential for irritation, and tazarotene should probably only be used in combination with Class I or II topical corticosteroids both to improve efficacy and to help minimize the potential for irritation.Tacrolimus (Prograf)
Tacrolimus is a specific modulator of T-cell function approved for the treatment of renal allograft rejection. Topical tacrolimus (formulated to 0.03-0.3%) has been the subject of considerable recent enthusiasm. While effective for atopic dermatitis, it is less effective for psoriasis. This may be due to poor penetration through psoriatic plaque. It is not yet known whether its penetration and efficacy in psoriasis would be aided by concomitant use of salicylic acid or other keratolytics.
Treatment of Generalized Psoriasis
Patients with generalized psoriasis have severe illness. The goal of therapy is to obtain control as quickly as possible and then maintain the improvement long term. Treatments with the least side effects should generally be tried first and more aggressive treatments instituted when recalcitrance is demonstrated. (Table 5).
|Table 5: Treatments for Generalized Psoriasis|
|UVB Phototherapy||Safe and effective for both initial clearing and long term control. Efficacy may be increased by day treatment regimens or combination with low-dose acitretin. Narrow-band UVB may be more effective than broadband.|
|Psoralen + UVA (PUVA) and PUVA + acitretin (Re-PUVA)||More effective than broadband UVB but causes high risk of cutaneous malignancy. PUVA should probably be used in combination with oral retinoids when possible to help minimize PUVA exposure.|
|Acitretin (Soriatane)||Very effective therapy for pustular psoriasis. Less effective as a monotherapy for plaque psoriasis. Very helpful as an adjunct to phototherapy. Relatively safe as a long-term treatment.|
|Methotrexate||Highly effective therapy. Patients appreciate the simplicity of the treatment regimen. There is the risk of life-threatening hematologic toxicity at any time during therapy and both acute and chronic hepatotoxicity. Careful monitoring is essential|
|Cyclosporine (Neoral)||Very effective treatment. Especially helpful for immediate control of severe disease. Less helpful as a long-term therapy (>1 year) due to renal toxicity.|
|Other immune inhibitors||
UVB treatments are generally performed 3 to 5 or more times weekly. They are extremely safe. There are some risks of causing phototoxicity, but the sunburn reactions of UVB typically are not severe. Chronic adverse effects include photoaging, so the face should not be treated if there is no psoriasis there. Skin cancer is another potential risk, but this risk must be small because the long-term studies of patients who received Goeckerman (UVB + tar) for years were unable to detect an increased risk.[27,28] If a patient has already had skin cancer, alternative therapies should be considered, but even so, the risks of UVB are probably still small. If patients have had melanoma, acitretin should be considered as an alternative.
Combining UVB with topical or oral treatments makes UVB more effective. Generally, patients have some heterogeneity to their lesions. Typically, the legs have thicker plaques and these lesions are slower to clear. Extra light can be given to these areas, but adjunctive topical therapy with calcipotriene or tazarotene may be helpful. The use of corticosteroids during phototherapy should generally be avoided to prevent shortening of remission periods though this belief has been refuted in one study. [ ] Outpatient day treatment regimens that utilize the Goeckerman (UVB plus tar under occlusive wraps) or Ingram (UVB plus anthralin paste) methods may be used for severe disease unlikely to clear with UVB alone. These day treatment regimens are very effective and very safe. Unfortunately, they are very time consuming and fit the lives of only some retired people, people who can bring their work with them, 3rd shift workers, or the unemployed. Oral therapies such as acitretin or methotrexate may also enhance the effect of UVB.
UVB phototherapy is a very gratifying means of obtaining long-term control of psoriasis. If initial control of psoriasis is obtained with one of the variations of UVB phototherapy, then long-term control of the disease will usually be achieved either because the patient will have a long-term remission of their disease or by giving the patient maintenance UVB phototherapy, either in the form of sun exposure or with a home UVB phototherapy device. Patients generally love home UVB phototherapy, perhaps in part because of the sense of control that it gives them over their disease. Several arguments against home UVB phototherapy have been made:
- 1.It is too much like giving a patient an unlimited prescription for a treatment that has potential side effects and that should be monitored. Only prescribe home UVB phototherapy devices (such as the one made by the National Biologic Corporation) that have incorporated prescription timers. These devices provide a predetermined number of treatments and then stop working until the patient receives a code from their dermatologist, in essence, a refill on their light prescription.
- 2.Patients may not be compliant with appropriate use of UVB. Prescribe patients home UVB units only after they have had a course of office UVB treatments. First make sure that UVB works for them and that they are aware of and compliant with genital protection and UVB dosing. The NPF brochure on home UVB phototherapy is an excellent way to educate patients about this treatment.
- 3.The dose of home UVB phototherapy cannot be adequately controlled. Many dermatologists recommend sun exposure for patients with psoriasis. There is much better control of UVB dose with home UVB phototherapy compared with sun exposure.
Another way to obtain phototherapy is the use of a commercial tanning bed. Tanning beds are available in even the smallest towns in the U.S. and are probably a very useful treatment for patients who live in areas inaccessible to office UVB phototherapy treatments. One study found that use of one particular tanning bed resulted in improvement in >90% of patients. Tanning bed treatments are not a replacement for office phototherapy. It is not known if it is the UVA tanning light that is effective or a contaminant of UVB; moreover there is probably tremendous heterogeneity between tanning bed units in the community. Moreover, tanning bed treatments would not be medically supervised as was the case in the published trial. Nevertheless, for somebody who cannot get office UVB phototherapy, tanning beds may be a helpful option. Psoralens should not be used in combination with tanning bed light as there may be severe, life threatening burns!Psoralen plus UVA photochemotherapy (PUVA)
|Table 6: Psoralen plus UVA photochemotherapy (PUVA)|
PUVA is a very effective treatment for psoriasis, but the side effects are greater than for UVB. There is more risk for sunburn-like photoreactions, and they are more severe than the burns that occur with UVB. There is a well-documented increase in the risk for future development of squamous cell carcinomas. Moreover, patients who have been on PUVA for years get unusual appearing pigmented lesions, PUVA lentigines. One long-term follow-up study suggests there is an increased risk of melanoma. An advantage of PUVA is it can be used for maintenance (treatments given 1x/wk to 1x/month as needed) after the initial clearing phase (2-3x/wk). Acitretin improves the efficacy of PUVA, helping to reduce the number of treatments needed (and hopefully, therefore, the long-term risk of carcinogenesis). If any psoriasis treatment reduces the risk of skin cancer, it is probably oral retinoid.
|Table 7: Acitretin (Soriatane)|
Acitretin is modestly effective for plaque psoriasis. It is more effective as a monotherapy for pustular and erythrodermic psoriasis. Acitretin may be the safest systemic treatment for psoriasis except for the associated teratogenic risk that lasts two to three years after discontinuing treatment. Acitretin can be converted in vivo in the presence of ethanol to etretinate (Tegison), which has an even longer half-life. Therefore, if a woman of childbearing potential requires oral retinoid therapy, consider a course of isotretinoin (Accutane) instead of acitretin. While both drugs are potent teratogens, pregnancy can be safely initiated one month after discontinuing isotretinoin.
Other adverse effects of acitretin include hypertriglyceridemia and hepatotoxicity. Monitoring should include liver function tests and triglyceride levels at baseline and at 2-4 week intervals until stable levels are achieved. If hypertriglyceridemia does occur, use of a lipid-lowering agent may be helpful. Pancreatitis can occur with extremely high triglyceride levels. Acitretin may cause alopecia and other bothersome retinoid side effects. Low dose therapy (25mg/day or 25mg every other day) is well tolerated and is usually sufficient to improve the efficacy of phototherapy.[40,41] Such doses of acitretin are also helpful in the treatment of palmoplantar psoriasis.Methotrexate
Methotrexate is very effective for psoriasis. Unfortunately, it may be associated with severe acute and chronic adverse reactions including acute hematologic toxicity and acute and chronic hepatotoxicity. This therapy should be limited to patients with refractory, disabling psoriasis. The goal of methotrexate therapy in psoriasis is to control the eruption not to completely eliminate it. Careful dosing and monitoring is essential. Baseline laboratory tests should include complete blood count and differential and liver function tests. Most often, a test dose of 2.5 to 5.0 mg is given followed by laboratory testing in 5-7 days. Monitoring is repeated weekly during the period of dosage increases to a maximum of 15-25 mg/week. Because methotrexate is cleared by renal excretion, caution must be exercised in patients with suspected renal impairment, especially the elderly. Before utilizing methotrexate, the dermatologist should be completely familiar with recommendations from the 1998 consensus conferance which details recommendations for pretreatment evaluation and laboratory and liver biopsy monitoring. In addition, a description of leukovorin (folinic acid) rescue for methotrexate overdosage is given as well as a detailed listing of drugs that interact with methotrexate to increase toxicity and the mechanism of the interactions. Though this is frequently neglected, the physician should document the reasons (history, physical exam) for choosing methotrexate and the risk/benefit counselling the patient received.
|Table 8: Methotrexate|
Laboratory studies should be repeated one week after every increase in dose of the medication. After a stable dose is reached, the frequency of the laboratory testing may be reduced. There are published recommendations for continued repeat blood tests every 4 to 6 weeks, although such frequent testing is probably not necessary in patients on stable doses of methotrexate. A number of factors may increase methotrexate blood levels including concomitant administration of another inhibitor of folate metabolism (the commonly used antibiotic trimethoprim-sulfamethoxazole [Septra, Bactrim] and reduction of renal clearance (which may occur with nonsteroidal anti-inflammatories). It is essential that patients be aware of these potential interactions, however it is not clear that the frequency of laboratory testing alone will prevent these events. Folinic acid (Leucovorin) may be given if acute hematologic toxicity occurs; it should be instituted as early as possible. Folic acid is not a replacement for folinic acid in this situation.
In a review of the literature most physicians did not document the history/physical exam findings on which they based giving methotrexate, nor did they carefully document informing their patients of the risks of this treatment. Very helpful in this regard is the NPF brochure on methotrexate. Written in language for the lay person and reviewed by dermatologists, the brochure provides patients the necessary information on the risks of treatment. It is good medicine both to provide this information and to document that it was provided.
Liver biopsies are done to monitor for chronic hepatotoxicity that may not be revealed by blood tests. Pretreatment liver biopsy is probably unnecessary in patients without a history suggestive of preexisting hepatotoxicity. If a baseline liver biopsy is to be done, it may be best to wait until it is clear that the patient will tolerate the drug (some do not due to severe nausea), that the drug is effective in controlling the patient's psoriasis (sometimes it is not), and that the drug will be needed long-term. Repeat liver biopsies may be done after approximately every 1.5 g cumulative dose. There is some question whether liver biopsy needs to be done at all. If in doubt, it may be wise to defer the decision to a gastroenterologist who specializes in liver disease and liver biopsy. There are certainly some scenarios in which the risk of liver biopsy is greater than the risk of chronic methotrexate hepatotoxicity. Intolerance to methotrexate due to nausea can be extremely severe and sometimes may be managed by switching to intramuscular methotrexate or by administration of folic acid 1-5 mg/day.
The cost of methotrexate therapy may be reduced by switching from pills to oral administration of the intravenous solution in appropriate patients. The cost is approximately $100/100 mg of methotrexate pills versus $15/100 mg for the solution (50mg of methotrexate in 2cc vial). Accurate dosing is essential. Patients should consider purchasing insulin syringes when purchasing the methotrexate and returning to the office for instructions on how much should be drawn up. The methotrexate solution can be put into a glass of water or flavored beverage and consumed.Cyclosporine
Short-term use of methotrexate may be effective for some patients who have acute exacerbation of otherwise stable psoriasis.[47,48,49] Short-term use of cyclosporine allows very rapid control of psoriasis and is safer (though more expensive) than two week tapers of oral corticosteroids. Administration of cyclosporine for as little as 5 days has been reported effective for the treatment of guttate psoriasis. Thus, cyclosporine may be best used in acute situations, followed by a switch to safer long-term treatments. Such an approach might include the initial use of cyclosporine to achieve rapid control followed by a transition to either acitretin or UVB phototherapy to maintain control.
|Table 9: Cyclosporine|
Although cyclosporine is quite safe and effective in short-term use, it is associated with long-term toxicity including hypertension and decreased renal function.[50,51] The prescribing dermatologist should be familiar with the 1998 consensus conference recommendations for monitoring cyclosporine therapy and delineates the numerous potential drug interactions. Among other interactions, increased renal toxicity may occur with nonsteroidal anti-inflamatories; increased cyclosporine levels may be seen with ketoconazole, cimetidine and macrolide antibiotics; and rhabdomyolysis may occur with HMG CoA reductase inhibitors.
Of all the oral agents for severe psoriasis, cyclosporine may be the safest for women who may become pregnant. Surprisingly, the FDA lists cyclosporine as a pregnancy category B drug.Other Treatments
Other immune inhibitors modulators such as hydroxyurea may be used. The advantage of hydroxyurea is that it may be used in place of methotrexate in patients with cirrhosis. Monitoring for bone marrow toxicity is necessary.
Mycophenolate mofetil (CellCept) may be a helpful adjunctive immune modulator in psoriasis. The initial dose is 1 g by mouth twice daily. Doses of up to 3 to 4 g/day may be needed. Neutrophil counts should be followed closely, as severe neutropenia may occur in 2% of patients.
Psoriasis is a multifaceted disease and its treatment generally requires the expertise of dermatologists. The National Psoriasis Foundation is a tremendous resource for patient education and advocacy in psoriasis care. To plan for acute and long-term control of localized psoriasis, combinations of topical corticosteroids and either calcipotriene or tazarotene are the most effective approaches. For generalized disease, UVB treatment provides the safest means of achieving long-term control of the disease. Acitretin is a very helpful adjunct for improving the efficacy of phototherapy. For patients with severe, refractory disease, methotrexate may be most effective, while cyclosporine may be most valuable for patients needing rapid, short-term improvement.
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