Saturday, December 31, 2005

Psoriasis -- An Overview of the Causes, Incidence, and Current Treatment

This tutorial on psoriasis, was part of a client-sponsored report looking at potential applications for a new (then) diode laser. It was completed and presented to the client in March 1994.

Irving J. Arons
Ophthalmic and Medical Laser Consulting Group
Arthur D. Little

Background

Psoriasis is a non-contagious, chronic skin disorder characterized by sharply defined scaly lesions on the skin. The patches are at first discrete but may subsequently become enlarged and produce a silvery white surface scale. The surface scales come off easily and are shed constantly, but those below the surface are quite adherent. When forcibly removed, they may reveal small punctate areas of bleeding known as Auspitz's signs.

The lesions or plaques may cover large areas of skin and merge into each other. Often the lesion appears in the same place on both right and left sides of the body. Lesions range in size and shape from individual to individual.

Although heredity seems to play a role, the basic cause of the disease is unknown. The hyper proliferation of the epidermis may result from a primary or secondary defect in the mechanism that regulates epidermal cell division.

It is thought that some type of biochemical stimulus triggers the abnormal cell growth that characterizes psoriasis. A normal skin cell matures in 28 to 30 days, while a psoriatic cell moves to the top of the skin in 3 to 4 days. The excessive skin cell that are produced "heap up" and form the elevated, red, scaly lesions that characterize the disease. The white silvery scale that covers the red underlying plaque is composed of dead cells that are continually being cast off. The redness of the underlying plaque is caused by the increased blood supply necessary to feed the area of rapidly dividing skin cells.

Skin injury, emotional stress, and some forms of infection are thought to trigger the episodes. For example, psoriasis will sometimes appear at a surgical incision or may follow a drug reaction or streptococcal throat infection.

Since the etiology of the disease is unknown, there is not at this time a known cure for the disorder. However, there are treatments that temporarily clear the plaques and significantly improve the skin appearance in most cases. Psoriasis treatments are aimed at slowing the excessive cell division. Treatment-induced remission can last from a few weeks to a year or more.

Incidence of the Problem

According to published reports, the disorder affects between 0.5% to 2.8% of the world's population (about 2% of the 276 million Americans, or between 5 to 6 million people in the United States), with nearly equal frequency in men and women. In the U.S., the treatment of psoriasis accounts for about 10% of physician visits for consultation or treatment.

Psoriasis is evaluated in terms of the extent of body surface affected and its location on the body. A case of psoriasis is considered mild when less than 10% of the body surface is involved. Ten to 30% coverage is considered a moderate disorder, while more than 30% coverage is considered a severe case.

Psoriasis may involve only a small are of the body and yet have a severe impact on the person's ability to function. Psoriasis of the palm of the hand or sole of the foot can be severe enough to be physically debilitating. For most people, psoriasis remains limited to one or two patches on the skin, most commonly on the scalp, elbows, trunk, and lower extremities.

In 1992, it was estimated that between 4 and 8 million people in the U.S. spent about $600 million for various drugs and related therapies, none very effective. Most of the expenditures were made by the approximately 400,000 people with severe psoriasis, who spend between $1000 to $3000 annually on treatments. About 200,000 new cases of psoriasis are diagnosed annually. About 5% to 7% of patients with psoriasis contract psoriatic arthritis, an inflammatory arthropathy that may damage the joints, especially in the hands and feet.

Current Methods of Treatment

The aim of treatment is to clear the skin of the psoriatic lesions for periods of time. Occasionally, psoriasis will go into a spontaneous remission of its own without treatment and, sometimes, a treatment that works to keep the psoriasis in check will stop working. The psoriasis simply becomes resistant, and a new type of treatment has to be tried.

There is a wide spectrum of treatment options available. Although all of the treatments are known to be effective for some patients, none are effective for all. In other words, response to a treatment will vary from individual to individual. Consequently, it is useful to try a spectrum of therapeutic choices to find the one that is most effective. Frequently, a physician will rotate a patient through a variety of therapies to avoid or minimize long-term side effects from any one therapy.

Treatments for psoriasis can be divided into three categories: topical agents (potions, lotions, and creams that are topically applied to the psoriatic lesions); phototherapy (the use of ultraviolet light, either with or without a light activating agent); and internal medications (pills and injections). Generally speaking, treatments for psoriasis usually involve a 1-2-3 approach. As a first step, the topical agents are tried, and if not effective or appropriate because of the severity of the lesions, the second level of treatment, the use of phototherapy is recommended. The use of drugs is usually reserved for only the most severe or non-responsive cases, primarily because of the additional risk of potential side effects.

a. Topical Agents

The topical agents used in step 1 include topical steroids, for mild to moderate cases; coal tar; anthralin; moisturizers; bath solutions; non-prescription medications; and sunbathing. The steroids are simple to apply and cosmetically elegant in that they do not stain skin or clothing and have no offensive odor. Coal tar is an old remedy but is usually unpleasant to use since it can have an unpleasant odor and can stain clothing. Coal tar is sometimes used in conjunction with ultraviolet B phototherapy, and is sometimes used along with sunbathing. The tar makes the skin more sensitive to light and must be used cautiously when combined with sunbathing.

Anthralin is a topical compound that also has been used for many years to treat psoriasis. It can be irritating to normal skin, and somewhat like coal tar, can cause skin to stain. Moisturizers can give some sufferers relief, although they are generally not as effective as other therapeutics. However, they can produce an acceptable cosmetic result and help with itching. Keeping the skin moist every day helps to reduce inflammation and maintain skin flexibility.

Bathing or soaking in water can be beneficial in keeping psoriatic skin comfortable, if not improved in appearance. Adding oil to the bath water can help, especially if followed by the application of a moisturizer. Non-prescription medications that can be purchased in the drug store generally help by moisturizing and soothing the lesions. Natural ingredients such as jojoba, oils and vitamins are frequently used. Plus there are medications that contain small amounts of coal tar and/or ingredients that may eliminate the scaling of psoriasis.

Finally, it is well documented that the UV light exposure during sunbathing can clear psoriasis lesions. Ultraviolet light B (commonly referred to as UVB) is found in natural sunlight, and exposure on a regular basis can help to eliminate lesions or at least decrease their activity. The only drawback to sunbathing is the possible development of skin cancer, apparently more prevalent today, possibly because of a reduction in the ozone layer in the air that absorbs most of the UVA light that can cause cancer.

b. Phototherapy with UV Light

Step 2 therapy involves phototherapy, or the use of ultraviolet light on a controlled basis. By exposing the psoriatic skin to UVB light, both stubborn and unmanageable lesions either widespread over the body or on a localized basis can be effectively treated. The light is administered by placing the patient into a light box or exposing the psoriatic skin to a light source or panel. The optimal exposure time to ultraviolet light differs for different parts of the body. Typically, the elbows and shins require much more light than the trunk or back.

There is another source of phototherapy called PUVA that involves the use of an internal medication called psoralen and UVA light, thus the acronym PUVA. The most common administration of psoralen is via an ingestible pill or oral medication, followed a short time later by exposure to UVA light. PUVA can also be done by a topical treatment rather than systemically, by "painting" a psoralen preparation (either in an ointment or lotion form) onto the affected body area. It can also be applied by soaking the affected body parts such as the hands or feet in a solution containing psoralen. The UVA light is applied via a light box, with appropriate protection given for the eyes. PUVA treatment is more labor intensive and poses a higher risk of burning the skin, and therefore, requires close medical supervision and meticulous modulation of the light dose. Moreover, PUVA treatment has been shown to cause a sixteen fold increase in the risk of squamous cell carcinoma.

As noted earlier, when psoriasis is resistant to one of the standard therapy methods, a combination of therapies may be used. For example, a low dose of an internal medication may be used with either PUVA or UVB treatment. Using several different therapies may also decrease the likelihood that a patient becomes resistant to a particular therapy.

c. Internal Medications/Drugs

In the case of persistent or severe psoriasis, the physician may resort to step 3 therapy or the use of internal medications. These include methotrexate, etretinate (retinoids), hydroxyurea, sulfasalazine and cyclosporin A. These medications are among an array of prescription drugs that are used to treat psoriasis. All may have systemic side effects and their use must be monitored carefully.

Experimental Techniques Under Development

a. Biotechnology/Drug Approaches

There are extensive R&D efforts underway by many companies in exploring a variety of approaches to develop new agents for the treatment of autoimmune and inflammatory disorders such as psoriasis and rheumatoid arthritis. To date none has produced effective therapies. Most novel drugs are in the preclinical or very early clinical stages with few results reported. According to a recent article in a trade journal, more than 75 companies are investigating more than 100 drug approaches for these ailments. Some of the major efforts include the following:

Non-steroidals

Prodrug G-201 from Genta (San Diego, CA) is a topical treatment for skin inflammation, which combines salicylic acid with a mucolytic deblocking agent. In animal studies the prodrug was more effective than the combined effect of its constituents. In a preliminary human study, G-201 greatly reduced UV light induced inflammation. The company has recently completed a Phase I clinical trial of the prodrug.

Immunosuppressive Agents

Human studies of oral Cyclosporin A to treat psoriasis have been underway for nearly 9 years. Thousands of patients with severe psoriasis have been treated worldwide with a 98% success rate. Efficacy has been established, as has the relative safety for up to two years of therapy, but long-term safety is of concern because experience is still limited.

FK-506 from Fujisawa, a macrolide antibiotic that inhibits the lymphocyte production of IL-2, IL-3, IL-8 and interferon gama, supposedly has an immunosuppressive activity of 100 times greater than cyclosporin A. However, serious toxicities, including neurotoxicity, hypertension, and hypomangesmia are of concern. Fujisawa is developing FK-507 that supposedly retains the effectiveness of FK-506 without its deleterious side effects.

Cytokines -- Inhibitors and Release Modifiers

TGF alpha and interleukins are cytokines that also act as inhibitors and release modifiers. Genta, in collaboration with researchers at University of Michigan, are in preclinical study of TGF alpha that may inhibit cell proliferation in a psoriasis cell culture. Several companies are experimenting with various interleukins as cell receptor modifiers. Synergen (Boulder, CO) entered into Phase I/II clinical trials in late 1992 with an IL-1 receptor antagonist for treatment of psoriasis.

Non-Systemic Antiproliferative Agents

Antiproliferative agents act by controlling over proliferation of keratinocytes and immune cells associated with psoriasis. Systemic methotrexate is used for the treatment of severe psoriasis, but no topical formulation of methotrexate is approved for use in the United States. Genta, Matrix Pharmaceutical (Menlo Park, CA), and Advanced Polymer Systems (Redwood City, CA) are developing drug delivery systems that will enhance the penetration of systemic drugs like methotrexate through the skin.

Cellular Adhesion Inhibitors

Cellular adhesion molecules are targets for treating immune-mediated diseases. During periods of hyperimmune activity, particular members of this protein family are expressed on surfaces of endothelial cells where they act as anchors for various types of immune cells circulating in the blood, including white blood cells. Once anchored to endothelial cells, white blood cells can migrate between them, leaving blood vessels and traveling into tissues and organs to propagate the inflammatory response, causing acute and chronic tissue damage and disease. Several companies are targeting drugs that will inhibit various cell adhesion molecules from attaching to the endothelial cells.

Retinoids

During the past two decades, retinoids have revolutionized dermatologic practice, especially in the treatment of acne. Some psoriasis conditions also react favorably to treatment with retinoids, such as etretinate and acitretin, the latter a second generation monoaromatic retinoid.

Monoclonal Antibodies

In collaboration with SmithKline Beecham, Idec Pharmaceuticals (La Jolla, CA) is developing a so-called primatized anti-CD4 antibody for the treatment of rheumatoid arthritis and other autoimmune diseases, including psoriasis. These engineered antibodies are similar to human antibodies, and it is hoped that they will be useful for long-term therapy of chronic diseases. FDA has approved an IND for testing this new MAb.

b. Phototherapy/Laser Approaches

There appears to be at least two valid laser-based approaches for attacking the blood supply feeding the hyper proliferating cells associated with psoriatic plaques: the use of photodynamic therapy (PDT) and selective photothermolysis of the blood vessels.

In the PDT approach, the theory is that either an exogenous or endogenous photoactivatable compound is either intravenously injected or topically applied to the diseased skin. The compound becomes concentrated in either or both the hyperproliferating cells and/or the blood vessels, and is then activated by laser light to selectively destroy the diseased tissue or blood vessels from within.

In the direct laser approach, an appropriate wavelength and pulse duration is selected so that the light energy is selectively absorbed within the hemoglobin of the blood, raising the temperature and destroying the capillaries feeding the hyperproliferating cells.

1) PDT

According to our research, there are at least four companies developing photoactivatable compounds that are currently under evaluation as a potential treatment for psoriasis. As shown in Table 1, the five photosensitizers differ in chemical makeup, how they are applied, and in the wavelength needed for activation. Those compounds that are activated at the lower wavelengths may not be as effective as those activated at the higher wavelengths as the longer wavelengths usually can penetrate deeper into the skin, and the blood vessels feeding the hyperproliferating cells are typically deeper into the dermal layers because of the "heaped up" effect of the proliferating cells. To our knowledge, only the Quadra Logic Technology' (QLT) benzoporphyrin derivative (BPD) and hematoporphyrin derivative (Photofrin), and the DUSA's 5-aminolevulinic acid (ALA) are currently in human clinical trials, with the PDT Systems' tin ethyl etiopurpurin (SnET2) in pre-clinical trials. The status of the Nippon Petrochemical's mono aspertyl chlorin e6 (NPe6) for treating psoriasis is unknown, although, it is reportedly in Phase I clinical trials for treating skin cancer and Kaposi's carcinoma.

A Phase I/II clinical trial of the QLT BPD compound for treating psoriasis has been underway at the Wellman Laboratory of Photomedicine in Boston since January 1993. According to QLT, "Preliminary research suggests that BPD may be effective in treating a variety of diseases that are characterized by rapidly dividing cells which are fed by an abnormal blood supply, such as...psoriasis...Based on our research experience with cancer, we believe that there is a common thread in the way BPD accumulates in diseased tissue." In a midyear review article, the Wellman group reported that six patients had been treated, "With the study answering some questions and raising others". Four patients treated at the lowest dosage of medication had some response and no toxicity observed. The therapy seems to "selectively damage the blood supply," and also have "some direct effects on cells". Since the proliferation of the disease is dependent on rapid development of new cells, curbing the blood flow -- a necessary component of cell replication -- could slow the disease's progression.

QLT's Photofrin is currently being evaluated for the treatment of portwine stains (PWS) and psoriasis at the Beckman Laser Institute and Medical Clinic in Irvine, CA. Encouraging preliminary clinical results on the treatment of PWS were reported by Dr. Stuart Nelson at the Biomedical Optics conference at OE/LASE in January 1993. At that time, it was noted that at least 25 patients were also being treated with Photofrin for psoriasis, but no results of that study had yet been reported on or published. It should be noted, however, that people treated with Photofrin retain prolonged photosensitivity to sunlight, a major drawback of this photosensitizer.

According to DUSA's first quarter 1993 report to shareholders, the company (now known as DUSA Pharmaceuticals) received FDA permission in February 1993 to enter into Phase I/II human clinical trials for the topical application of ALA to treat actinic keratoses and psoriasis on more than 100 patients at the University of California, Irvine, under the direction of Dr. Gerald Weinstein. (In addition, two other physician sponsored IDE studies using ALA to treat basal cell carcinomas have been under way for one to two years.) In October 1993, another article discussed the clinical trials being conducted with ALA. According to one of the team physicians at UCal/Irvine, the investigations of the drug's potential have been satisfactory. One of the reasons that ALA therapy is potentially useful for treating psoriasis is that it resembles current therapy, the use of psoralen and ultraviolet light (PUVA). The change to a different drug and a different light source for psoriasis therapy appears to be trivial. The effect of light exposure, however, is hoped to be considerably different, since PUVA has been shown to cause skin cancer, while PDT therapy is a treatment for cancer. The doctor reports that, "It is too early to make conclusions about the usefulness of the drug yet, but they hope to have data for presentation to the FDA by the end of 1993".

A news release from the company in December 1993, stated that results from the UCal/Irvine study were presented by Dr. Weinstein at the annual meeting of the Photomedicine Society in Washington, D.C. According to Dr. Weinstein, "Nine lesions per patient of fourteen psoriasis patients were treated with 10% to 20% ALA on selectively sensitized psoriatic plaques, with nearly 50% of treated sites having greater than a 50% improvement after only 4 weekly treatments".

As has been noted, ALA is applied topically to the skin, and because of its small molecular structure, easily penetrates the epidermis and causes an accumulation of a natural photosensitizer, protoporphyrin IX (PPIX) in some tissues. As in the case of Photofrin (porfimer sodium), light activation of PPIX causes the release of singlet oxygen that is toxic to cells in which it is contained. ALA is currently the only topical agent available for PDT treatment. While other photosensitizers may exist in cream or lotion form, none has yet been used successfully in topical applications. (Other photosensitizers, formulated for topical use, should begin clinical trials later this year.)

2) Direct Laser Intervention

Over the past ten years, several physical methods including the use of local hyperthermia, cryotherapy, dermabrasion, surgical removal, and the use of both argon and CO2 lasers have been used to treat psoriatic plaques, mostly unsuccessfully or without lasting effects. More recently, several researchers have attempted to use pulsed dye lasers hoping to achieve selective photothermolysis of the blood supply in the vasculature supporting the hyperproliferating skin cells. The experimental work reported by Hacker and Rasmussen was only partially successful. Although 57% of the 19 patients treated had a positive short term outcome, none achieved complete clearing of the psoriasis under the clinical parameters attempted. However, the pioneering, but unreported work of Dr. Adrianna Scheibner, an Australian physician, using both continuous wave and pulsed dye lasers to treat psoriasis was more encouraging. Beginning in 1983, Dr. Scheibner has treated some thirty psoriasis patients using the dye laser at 577 nm. In 28 of the 30 patients, she noted virtually complete clearing of plaques in areas subjected to the laser with essentially no reoccurrence in the treated areas over an average of 3 to 4 years followup. Untreated areas on the same patients continued to show signs of psoriatic plaque.

Although the latter results are considered encouraging, the work was not conducted as a rigorous study and never published (or peer reviewed), and the fluence level used was well above levels considered safe for scarring of normal skin. Thus, the results have shown that a safe, controlled study attacking the blood supply of psoriatic plaques with fluence levels below the damage level could lead to a successful modality for treating psoriasis. This is the approach taken by Star Medical.

3) The Star Medical Technologies Pulsed Diode Laser Approach

Using the model of selective photothermolysis, established using the pulsed dye laser to destroy abnormal blood vessels in the treatment of portwine stains, the company will use its pulsed diode laser system to interrupt the blood flow to psoriatic tissue by destroying the blood vessels feeding the hyperproliferating cells. Star Medical has chosen the 800 nm wavelength to achieve deeper penetration -- from 0.8 mm to 1.4 mm -- as compared to the 0.4 mm average penetration achievable with the 577 nm wavelength of the pulsed dye laser. The deeper penetration will allow access to the highly exaggerated papillary loop which can extend to depths of about 0.8 mm. The company believes that the destruction of the deep vessels is a key to a successful laser therapy for psoriasis. Further, the company has chosen a 5 ms pulse width which should enable the laser energy to destroy larger vessels (>50 microns). With the longer pulse, smaller vessels fed by the larger vessels are not directly destroyed by the laser energy as they can cool to surrounding tissue temperature, but they will be destroyed because the larger feeding vessels are destroyed. This is likely to lead to less damage to surrounding tissue structures concomitant with the heating of the vessels themselves. Previous research on the importance of pulse duration supports this view, concluding that longer pulses were preferable.

The diode laser at 800 nm was chosen for both the deeper penetration ability noted above and for the selectivity of absorbance in blood as compared to tissue. Experiments at the Wellman Labs have shown the blood absorption at 800 nm is 30 times higher than surrounding tissue. Thus, the 800 nm light is highly absorbed in the blood and can be used efficiently in selective destruction of blood vessels within the skin.

In the clinical trials, a fluence of 15 to 20 J/cm2 will be evaluated, which should be sufficient to heat the blood vessels in the skin to a depth of nearly 1 mm. A specially designed handpiece (described in Section IV) will be used to deliver single and multiple pulses of 6x6 mm spots of laser energy to the skin surface.

2 Comments:

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