Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Dermatology Update 2006

Whistler, British Columbia / October 25-29, 2006

According to Dr. Norman Wasel, Assistant Clinical Professor, University of Alberta, Edmonton, with traditional systemic therapies, physicians were taught that rotational therapy was the correct approach. However, he noted that there are serious inherent problems with this approach as there is no reason to stop an effective therapy, much less return to a previously ineffective one or one that had proven toxic in the past.

Continuous control over skin symptoms is also difficult using a rotational approach and patients worry about side effects from systemic therapies, including hepatotoxicity with methotrexate (MTX); skin cancer with UV light therapy; headache, hair loss and dryness with acitretin; and alterations in blood pressure and kidney function with cyclosporine.

Psoriasis Impairment and Treatment Goals

Since 2004, several biologics have been available in Canada for the treatment of psoriasis and psoriatic arthritis (PsA). Yet as Dr. Wasel noted, “Clinicians are still reluctant to use them in their practice”—often, as a poll of the audience here indicated, because they fear patients or their insurers cannot or will not pay for them. Delegates also expressed concern over adverse effects, which need to be measured against the real costs that moderate-to-severe psoriasis carries for both patients and the health care system. While it is always unnerving to introduce unknown compounds in practice, Dr. Wasel remarked that biologics are now an important aspect of his practice since complete clearance can be achieved as demonstrated with his experience with infliximab. When a patient presents with psoriasis, the aim now has become complete clearance, not just symptom improvement.

As discussed by Dr. Kristian Reich, Professor of Dermatology, Georg-August University, Göttingen, Germany, surveys of patients with psoriasis in both Europe and the US reveal that the mental and physical impairment in patients with moderate-to-severe psoriasis is comparable to other diseases, including diabetes, heart disease and cancer.

Because patients with significant psoriasis also report important losses in productivity, “we have under-estimated the effect that the disease has on the daily life of patients,” Dr. Reich remarked. It is also associated with multiple comorbidities, including PsA, alcohol abuse, depression, the metabolic syndrome and diabetes. “Overall treatment satisfaction is frequently low,” he added.

This, in part, may reflect the fact that psoriasis is often undertreated. In a recent survey carried out in over 1500 patients in Germany, approximately 20% had a severe Psoriasis Area and Severity Index (PASI) score (>20) and fewer than 50% of this patient group were receiving systemic therapies, Dr. Reich reported.

These findings argue in favour of establishing appropriate treatment goals for patients with severe psoriasis. Dr. Reich told the audience that appropriate treatment targets aim for a PASI 50 (50% improvement) and a Dermatology Life Quality Index (DLQI) <5. However, he suggested aiming for a DLQI of 0 or 1 and a PASI 75, indicating that with infliximab, this may be possible, as observed in EXPRESS I (European Infliximab for Psoriasis Efficacy and Safety Study) (Figure 1). From his study observations, a DLQI <5 corresponds to a PASI 75 response in a majority of patients. “I am also looking for long-term control, a treatment that has effects on nail and joint symptoms and a regimen that is convenient,” he stated. These goals are now largely attainable with at least some of the new tumour necrosis factor alpha (TNFa) inhibitors.

Figure 1. EXPRESS: Response Rates at Week 10

Infusion Network: Facilitating Treatment to Anti-TNFa Therapy

While there may be hesitancy to use the TNFa inhibitor infliximab due to a lack of familiarity in administering the agent, Dr. Reich considers that the infusion referral network is a unique opportunity for both patient and treating physician.

Dr. Kam Shojania, Director, Clinical Trials, Arthritis Research Centre of Canada, Vancouver, British Columbia, noted that the Remicade Infusion Network (RIN) thoroughly addresses infusion concerns, where a physician and nurse are on site and patients are pre-screened prior to each infusion session and monitored closely. Physicians also receive a post-infusion summary within 48 hours to stay abreast of their patient’s treatment course.

As Dr. Shojania told the audience, there are many sites across Canada where patients may access the RIN and there is no cost for the infusion itself. Physicians need to fill out a short form and the RIN coordinator takes care of everything else, including determining whether a patient has access to public or private reimbursement or is eligible for co-pay assistance. “The RIN is special because it is free for all infliximab patients, and the number one priority is safety,” she stated. “It is also very accessible, there are no wait times and it helps patients stay compliant to anti-TNF therapy.”

Biologics in Psoriasis: Data Review

Currently, there are five biologics available in Canada: infliximab, etanercept, alefacept, efalizumab and adalimumab. While not all are approved for use in psoriasis, Dr. Reich summarized outcome data from various trials evaluating the biologics for this condition.

Dr. Reich reviewed data from both EXPRESS I and EXPRESS II (Evaluation of Infliximab for Psoriasis Efficacy and Safety Study). Eighty per cent of patients receiving infliximab achieved a PASI 75 response at the end of induction (Figure 2), 25% had a PASI 100 response and 50% achieved a DLQI of 0. At one year, 60 to 70% of patients had retained that score. Dr. Reich also indicated that the EXPRESS I and II findings show greater efficacy when infliximab is given every eight weeks rather than on an as-needed ba
EXPRESS: Phase III

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In findings from a randomized, controlled trial of etanercept in psoriasis, Dr. Reich reported that between weeks 10 and 16, PASI 75 was achieved in 34% of patients with 25 mg twice a week and in 49% with 50 mg twice a week (Papp et al. Br J Derm 2005;152(6):1304-12). He observed that at one year, response rates to the high dose are approximately 60% and likely around 40% with the low dose.

Approximately 30% of patients achieved a PASI 75 at the end of efalizumab induction according to trial results (Gordon et al. JAMA 2003; 290(23):3073-80). A study of longer-term use suggested that approximately 50% of patients achieved a PASI 75 after one, two and three years of treatment, “although this study was somewhat problematic because co-administration of other therapies was allowed,” Dr. Reich reported.

In a phase III trial evaluating alefacept in psoriasis, 54 out of 507 patients achieved a PASI 75 (Lebwohl et al. Arch Dermatol 2003;139(6):719-27). “If we have patients in whom we cannot reach our treatment goals with classical drugs, we should not hesitate to move on to a biologic,” Dr. Reich stated, adding that while the effects of all of the TNFa antagonists “are pretty similar” when treating joint symptoms, “there is a true difference with regard to their effects in skin disease” (Figure 3).

According to Dr. Richard Langley, Associate Professor of Medicine, Dalhousie University, Halifax, Nova Scotia, early findings have shown good response rates with adalimumab, noting that use of this compound in psoriasis appears promising.

With more than 1 million patients treated with biologics and more than 700,000 who have been given infliximab, most of the safety issues have been addressed. Dr. Reich concluded that data to date supp
biologics.

Figure 3. Efficacy of Systemic Therapies in Psoriasis

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Safety Aspects and Treatment Strategies

Biologics have demonstrated a relatively low risk for end-organ toxicity compared to other agents such as MTX. Nevertheless, safety issues have been raised with respect to the TNFa antagonists, in particular re-activation of tuberculosis (TB), heightened risk of infection and increased risk of malignancy, notably lymphoma. As discussed by Dr. Brian Feagan, internal medicine specialist (clinical epidemiology and gastroenterology) and Professor of Medicine, Epidemiology and Biostatistics, University of Western Ontario, London, isolated cases of TB began to appear as the use of TNFa blockers broadened and they typically occurred in patients from Eastern Europe, the Middle East and Southeast Asia where TB is endemic.

Dr. Feagan recommended that prior to initiating any TNFa treatment, patients should undergo screening for latent TB by chest X-ray, a purified protein derivative (PPD) skin
story including place of birth (Figure 4).

Figure 4. Algorithm for TB Testing: European-based Recommendations

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“The risk of TB occurs within the first six months of therapy so you need to be hypervigilant with regard to signs of infection early on in the course of therapy,” Dr. Feagan advised.

Opportunistic infections have also been reported for all TNFa inhibitors and recipients living in high-risk areas should be monitored closely. TNFa blockade should be continued when a mild infection develops, stopped if a serious infection such as diabetic foot ulcer develops and not initiated in patients presenting with an active infection.

From the outset, TNFa inhibitor use has been suspected of increased malignancy. However, recent data from a Swedish registry of TNFa inhibitor users do not support an increased risk of solid tumour malignancies with any of the biologics.

In contrast, the incidence of lymphoma may be two to three times higher with TNFa blockade based on data from the rheumatoid arthritis trials. Consequently, presenters here at the scientific sessions recommend that patients with a prior history of lymphoma should not receive treatment with any of the TNFa blockers, although treatment appears to be less risky in patients who have had a prior solid organ tumour.

Psoriatic Arthritis

Dr. Wayne Gulliver, Chairman, Division of Dermatology, Memorial University of Newfoundland, St. John’s, discussed PsA, which likely affects between 200,000 and 300,000 patients in Canada alone. “Most people have skin lesions well before their arthritis,” he noted, “and the consequences of inflammation include ossification, ankylosis and tumour-like changes of affected bones.”

Increased production of TNFa is a key event not only in the pathophysiology of the skin but of the joints as well, bringing inflammatory cells into the joint that contribute to their destruction. As he explained, all agents that target TNFa “work relatively well and are about the same” in the joints, although not, he reiterated, in the skin.

Dr. Gulliver addressed the audience, “The question now is: if we treat psoriasis early and aggressively, can we prevent the development of PsA and other comorbidities we see in association with psoriasis?” He and co-investigators are conducting ongoing research from a large Newfoundland database of psoriatic patients in an effort to answer this question.

Questions and Answers

The following question-and-answer session was conducted with Dr. Wayne Gulliver, Chairman, Division of Dermatology, Memorial University of Newfoundland, St. John’s; and Dr. Richard Langley, Associate Professor of Medicine, Dalhousie University, Halifax, during the scientific sessions.

Q: Why do you think cardiovascular comorbidities are so often seen in psoriatic patients?

Dr. Gulliver: If you look at the immunology of psoriasis, obesity and acute myocardial infarction, they are almost identical, so it does not surprise me that all these diseases occur together. I am fairly convinced that having psoriasis is an independent risk factor for cardiovascular events, including hypertension, hyperlipidemia and diabetes. Now when I see a patient with psoriasis, I check their blood pressure, their sugar levels and their lipids and I treat the whole patient, not just their skin.

Q: Can you vaccinate patients who are taking a TNFa inhibitor?

Dr. Langley: You can vaccinate patients with a killed vaccine and still achieve an adequate humoral response but not with a live vaccine. Live vaccines are contraindicated in this setting. But before I start patients on a TNFa blocker, I try to get them to go to their GP and make sure their vaccinations are up to date.