Biological Response Modifiers & Psoriasis

The new biologics for psoriasis and psoriatic arthritis—weighing the risks

The long search for effective ways to alleviate the itching, scaling, and inflammation of plaque psoriasis has brought a range of treatments to bear on the problem. Some sufferers of psoriasis have frequented the therapeutic waters of the Dead Sea in Israel, or the Blue Lagoon in Iceland. They have sat among the fishes—the species Garra rufa to be exact—in the mineral springs of Kangal, Turkey, whose gentle feeding removes scales of plaque while the geothermal mineral waters provide their own therapeutic touch. For the overwhelming majority of psoriasis sufferers travel to such exotic places is not an option, and they have sought relief through phototherapy and topical preparations, ranging from coal tar and salicylic acid to low-, medium—or high-potency topical steroids. According to patient polling done in 2006 by the National Psoriasis Foundation (NPF), over half of respondents (55%, n=239) requested topical treatments of their dermatologists to treat their disease symptoms.

Those with moderate to severe psoriasis who have not found relief through these treatments have in recent years had available "systemic" remedies, compounded drugs affecting the entire immune system. Acitretin, a vitamin A derivative and oral retinoid; cyclosporin, a T-cell suppressor; and methotrexate, a folic acid antagonist, are three such systemics that are administered either orally or through injection. According to the same NPF survey, 22% requested systemics as their remedy of choice.

There are as many as 7.9 million psoriasis sufferers in the US, according the National Institutes of Health. And according to the American Academy of Dermatologists, anywhere from 5% to 42% of these have a potential to develop psoriatic arthritis , a potentially debilitating inflammation of the joints and connective tissues of psoriasis patients. It is well known that an autoimmune reaction in these people is at the root of their psoriasis. It is not known whether this response is initiated by something inherent to the skin cells ( keratinocytes ) themselves, or by an immune system dysfunction generating the T-cells and other immune factors that proliferate in the inflammation response. In the skin plaque form of the disease, an over-proliferation of skin cells rapidly rises from their site of origin in the basal layer through the epidermis to build up on the surface as a plaque of immature cells. In normal skin, turnover of skin cells occurs in 28 to 30 days; in psoriasis, the cycle occurs in 3 to 4 days. Psoriasis is an autoimmune disease, but what is the initial cellular stimulus that causes the autoimmune response? Research is ongoing.

Overriding the immune response—how the new systemics work

As one of several autoimmune/inflammatory diseases, the trend in systemic treatments over the last decade has been to target factors in the inflammation response underlying chronic psoriasis. These relatively new treatments, known as "biologics" (shorthand for biological response modifiers ), act directly on the immune cells that regulate and participate in the inflammation response. As modifiers of the immune system, they have shown potential for both marked relief from the inflammation and discomfort of psoriasis, but also the significant dangers inherent with tinkering with our body's first-line defense mechanisms against foreign microbes and infections.

TNF- a inhibition. Manufacturers of the compounds in this biologics class of drugs use recombinant DNA technology [ßLink to named anchor tag = "recombinantdna" above H2 heading in Enbrel/Humira article] to create novel hybrids of human anti-human antibodies —HAHA's—some of which are designed with an affinity for human tumor necrosis factor alpha (TNF-a). An important cytokine, or signaling protein, TNF-a has as one of its many natural functions the regulation of systemic inflammation by controlling pro-inflammatory factors that result from injury, infection, or an autoimmune disorder. It has been shown in an animal model that a proliferation of TNF-a can lead to a proliferation of T-cells, which in turn results in additional immune responses, inflammation and rapid skin turnover. A treatment with the ability to bind up excess TNF-a moderates inflammation, thereby interrupting a cycle that generates plaque formation and the itch and soreness of psoriasis. In doing so, however, the treatment also compromises a first-line defense strategy by inhibiting the beneficial functions TNF-a performs in the course of a normal immune response. Many patients have found varying degrees of relief from their symptoms through these treatments. A significant number have suffered the consequences of a compromised immune system that resulted in life-threatening fungal and bacterial infections, tuberculosis, and even death in some cases.

Inhibition of T-cell activation. TNF-a inhibition is one strategy used by this class of drugs. Another strategy uses the recombinant protein alefacept (trade name Amevive ) to inhibit T-cell activation, thereby interrupting the inflammation pathway. This recombinant protein is engineered to incorporate the binding portion of the human leukocyte function antigen-3 (LFA-3) onto the constant portion of human IgG antibody, our smallest but most common type of antibody. LFA-3 binds to a cell adhesion molecule on the surface of T-cells, thereby inactivating T-cells and moderating the autoimmune response.

And yet another recombinant humanized IgG antibody, efalizumab ( Raptiva ), binds human CD11a, the alpha chain portion of the gene called lymphocyte function-associated antigen 1 , also inhibiting T-cell activation. Raptiva, however, was pulled from the market beginning in April 2009, and as of June 2009 no longer available because a small number of patients developed progressive multifocal leukoencephalopathy , a fatal central nervous system disorder. This may serve to highlight the very significant risks this class of drugs poses to those using them. All three strategies suppress the immune response by different means, and while providing measurable relief for many, they are not administered without potentially life-threatening consequences.

FDA warnings—drugs of last resort

The FDA has paid very close attention to these treatments because significant illness and deaths have occurred in the population of patients that receive these types of drugs. Labeling for one particular member of this group, the TNF-a inhibitor adalimumab ( Humira , by Abbott Labs) is required to prominently display the following, or similar, warning:

Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), fungal infections, and other opportunistic infections, have been observed patients receiving HUMIRA. Some of these infections have been fatal. Anti-tuberculosis of patients with latent tuberculosis infection reduces the risk of reactivation in patients receiving treatment with HUMIRA. However, active tuberculosis has developed in patients receiving HUMIRA whose screening for latent tuberculosis infection was negative.

Patients should be evaluated for tuberculosis risk factors and be tested for latent infection prior to initiating HUMIRA and during therapy. Treatment of latent tuberculosis infection should be initiated prior to therapy with HUMIRA should monitor patients receiving HUMIRA for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection.

The FDA stringently requires that marketing materials and labeling prominently contain warnings such as this, and stipulates clearly that most, if not all, members of this class of drugs only be prescribed:

• to those who have moderate to severe symptoms;
• are candidates for systemic or phototherapy;
• and when other systemic therapies are medically less appropriate...

...as determined by the prescribing physician. At this time, these could be considered "last resort" treatments as dermatologists are strongly advised to, prior to prescribing them, carefully screen patients for latent tuberculosis or other affinities to infection; to prescribe them only after other treatments have failed or been shown ineffective; and to monitor patients closely for signs of infection, nervous system problems, blood problems, signs of cancer, or lupus-like symptoms throughout the course of treatment. (To read more about the biological response modifiers, see our page on Humira and Enbrel.

New biologics in development

The development of new biological response modifiers is the subject of ongoing research funded through the National Institutes of Health, and through grants from the National Psoriasis Foundation funded with the help of major donations from pharmaceutical companies such as Abbott and Wyeth. As is currently the case with many lines of basic research, public/private relationships abound—especially, as in this case, where the market for a given class of treatment is valued at well over a billion dollars annually.

Where are the experimental dollars going? Recent research is showing what roles T-helper 17 cells (Th-17), a novel subset of T-cells, and interleukin-23 (IL-23), may play in the pathogenesis of psoriasis and similar autoimmune diseases. IL-23 is shown to be a key master cytokine, or signaling protein, that stimulates the production of Th-17 cells within the dermis of psoriasis patients. An overproduction of IL-23 by keratinocytes and dendritic cells stimulates Th-17 within the dermis to produce IL-17A, a pro-inflammatory factor, and interleukin-22 (IL-22), another pro-inflammatory. IL-22 in turn, may be a key driver of keratinocyte hyperproliferation , the rapid turnover of skin cells endemic to psoriasis.

IL-17A has also been implicated in a pathway that generates in psoriatic skin lesions elevated amounts of cathelicidin (LL-37), a naturally occurring antimicrobial protein that normally defends against foreign microbial invaders. Research suggests LL-37 may be involved in the dysfunctional "self-recognition" at the bottom of this and other autoimmune diseases.

New biologics that inhibit the functions of IL-23, or interfere with the LL-37 pathway are being examined. Ustekinumab (trade name Stelara ) is a monoclonal antibody treatment that targets IL-23. Stelara has been approved for use in Europe and Canada and is close to approval in the US (as of June 2009), but carries similar safety warnings as earlier immunosuppressive biologics. In a recent 36-week trial of 124 patients, ustekinumab significantly reduced signs and symptoms of psoriatic arthritis and diminished skin lesions compared with placebo. Beyond this, how effective the LL-37 pathway inhibitor might be, or its long-term risk-to-benefit ratio in the treatment of psoriasis has not been widely reported.

Strengthening the immune system—still an option

In conclusion, while topical preparations are the preferred mode of treatment for people with psoriasis, those with moderate to severe psoriasis for whom topical or systemic treatments have proven less than effective are turning to the class of drugs known as biological response modifiers. Although these new drugs have shown positive results for some people with plaque psoriasis, there are extraordinarily high stakes associated with strategies that modify our fundamental immunity defenses. Clearly, very significant risks are associated with the use of these treatments for this reason, and patients looking for relief must weigh very carefully the risks versus the benefits before embarking on this course of treatments.

For the millions of psoriasis sufferers worldwide looking for relief, the mineral springs and gently feeding Garra rufa may not be on their itinerary, or even a desirable or effective treatment to this highly individualized disease. But all psoriasis patients stand to benefit from the systemic benefits of a deliberate and healthy diet, nutritional supplements to counter inflammation and shore up immunity, removing foods that aggravate their condition, a conscious reduction of stress in one's life, and the avoidance of unhealthy lifestyle choices. Some patients have found these strategies sufficient for reducing, if not completely eliminating, their inflammatory symptoms. At minimum, they provide a good starting point from which to try any number of treatments and find lasting, effective relief.

(For an overview of psoriasis treatment developments, links and descriptions of different forms of psoriasis, and information on the DermaHarmony approach to psoriasis, see our article on the history of psoriasis .)