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.

FRONTLINE - Dermatology

October 7-11, 2009

Editorial Overview:

Neil H. Shear, MD, FRCPC, FACP

Chief of Dermatology, Sunnybrook Health Sciences Centre, Professor of Medicine, Pharmacology, Pediatrics and Pharmacy, University of Toronto, Toronto, Ontario

Psoriasis in all its forms affects an estimated 125 million individuals worldwide (National Psoriasis Foundation, 2007). Often pruritic and disfiguring, psoriatic lesions exact substantial physical and emotional tolls on affected patients. As many as 50% of patients with psoriasis have concomitant nail dystrophy (J Am Acad Dermatol 2007;57:1-27) and up to 30% may develop psoriatic arthritis (Derm Ther 2004;17:341-9) (Figure 1), which can interfere with activities of daily living and work performance and adversely affect quality of life (QoL).

Psoriasis patients have also a significantly higher prevalence of comorbid disease and nearly two times the overall level of comorbidity (Ann Rheum Dis 2005;64(suppl II ):ii87-ii90). As both psoriasis and cardiovascular disease involve underlying chronic inflammation, the risk of myocardial infarction is increased, the more so with increased severity of psoriasis (JAMA 2006;296(14):1735-41). As well, there is an increase in mortality with disease severity and comorbidities (Arch Dermatol 2007;143(12):1493-9).

Most treatment algorithms for psoriasis specify topical therapies as initial treatment, sometimes in conjunction with phototherapy (Expert Rev Dermatol 2009;4(1): 15-21). Up to 30% of patients have inadequate disease control with this initial strategy and require systemic therapies such as methotrexate (MTX), cyclosporine or acitretin. However, a substantial proportion of patients with psoriasis do not have adequate disease control with conventional systemic therapy. Other patients may experience adverse effects.

Expectations for Quality of Life

Given the adverse effects psoriasis has on QoL, patients demand and expect increased efficacy with faster onset of action and longer-lasting remissions as well as improved tolerability and safety. Over the last decade, the tumour necrosis factor-alpha (TNF-a) inhibitors have demonstrated greater efficacy with higher remission rates than conventional systemic therapy. Studies reported at the EADV congress covered a range of issues, including treatment effects on QoL, the relative efficacy of anti-TNF therapy and MTX and the feasibility of sequential use of TNF inhibitors.

Investigators in a multicentre European study assessed QoL in 751 patients with psoriasis and psoriatic arthritis and the impact of treatment with etanercept (Thaçi et al. Abstract P1160). Using the EuroQoL-5D questionnaire, the investigators found that baseline QoL was similar to that reported by clinically depressed patients and worse than scores associated with rheumatoid arthritis (RA). Treatment with either of two doses of the biologic resulted in improved QoL detected by the EuroQoL-5D three weeks into treatment. By week 24, QoL scores had improved to approximately five times the minimally important difference, defined as a change of =0.05 on the EuroQoL-5D score.

A multinational research group compared the effects of infliximab and MTX on QoL in patients with moderate to severe plaque-type psoriasis (Reich et al. Abstract 1187). The findings came from RESTORE 1, a multicentre randomized comparison of infliximab 5 mg/kg and oral MTX 15-20 mg weekly. Patients treated with the TNF-a inhibitor had significantly greater improvement in the Dermatology Quality of Life Index (DQLI) score at all time points: 10 weeks, -11.4 vs. -7.9, P<0.001; 16 weeks, -11.6 vs. -8.95, P<0.001; 26 weeks, -11.3 vs. -9.14, P=0.004. Assessment of QoL by the SF -36 health status questionnaire showed significantly greater improvement in the physical component with TNF-a inhibitor at 10 and 16 weeks (P<0.001, P=0.002) and a trend toward more improvement at week 26. Scores on the mental component of the SF -36 revealed significantly more improvement with the anti-TNF at week 10 (P=0.011) and a trend toward more improvement at weeks 16 and 26.

Figure 1.

The results of these studies are consistent with those of previous trials showing that improvement in QoL parallels the improvement in skin plaque activity during treatment with TNF-a inhibitors.

Anti-TNF and MTX Therapy

Clinicians have long recognized MTX as one of the most potent systemic therapies for psoriasis. The emergence of TNF-a inhibitors as a treatment option for psoriasis naturally led to questions about the relative efficacy of the two types of therapy. The recently completed RESTORE 1 trial provided much-needed comparative data (Barker et al. Abstract FC06.8).

The study involved 858 patients with moderate to severe psoriasis, characterized by a mean baseline Psoriasis Area and Severity Index (PASI ) score =12 and =10% involvement of body surface area. Patients were randomized 4:1 to receive infliximab 5 mg/kg or MTX 15-20 mg/week. Patients who did not achieve a PASI 50 response by week 16 switched therapy. The primary outcome was the proportion of patients who achieved PASI 75 resp
re 2).

Figure 2.

<img3715|center>

Investigators reported that 78% of infliximabtreated patients had PASI 75 responses by week 16 compared with 42% of the MTX group and PASI 90 response rates were reported by 55% and 20%, respectively (both P<0.001). As early as week 2, 38% of the TNF -a inhibitor-treated patients had PASI 50 responses compared with 9% of the MTX patients (P<0.001). After 10 weeks, 74% of the TNF -a inhibitortreated patients had PASI 75 responses compared with about 30% of the MTX patients (P<0.001).

Further evidence of the biologic’s greater efficacy came from the finding that almost 30% of MTX patients switched to the TNF -a inhibitor at 16 weeks because of inadequate disease control. Of the patients who switched, about three-fourths subsequently achieved PASI 75 responses.

No unanticipated safety events were observed in the study. Similar rates of adverse events were reported with the biologic and the DMARD at 72% and 67%, respectively, with serious adverse events occurring at 7% and 3%, respectively. Discontinuation due to liver abnormalities occurred in 1% to 2% of patients in each group. Infusion-site reactions led to discontinuation of 4% of patients in the TNF -a inhibitor group.

For years, MTX has provided relief from psoriasis for patients who did not achieve adequate responses with topical therapy, phototherapy or a combination and remains a good option for many patients. However, a substantial proportion of patients with psoriasis do not achieve adequate disease control with MTX. Often patients feel that any improvement is an acceptable treatment goal as available treatment options frequently result in only moderate improvement. However, in light of the biologic era, it is important that physicians expect PASI 75 responses in the majority of their patients. If by week 12 to 16 such results are not attained with conventional treatment, use of a biologic should be considered.

Results of this study provide reassurance that psoriasis patients switched from MTX to a TNF -a inhibitor have a very good chance of achieving a positive response and the opportunity for more patients to even achieve at least 90% clearance (PASI 90) is increasing. In RESTORE 1, 57% of infliximab-treated patients met criteria for PASI 90 response compared with 1% in the placebo group (P<0.0001).

Additional evidence that patients who achieve an inadequate response with MTX often respond to treatment with a TNF-a inhibitor came from an openlabel extension phase of CHAMPION (Comparative Study of Adalimumab vs. Methotrexate and vs. Placebo in Psoriasis Patients) (Papp et al. Abstract P1225). Inadequate responders (<PASI 50) to MTX were eligible to continue treatment with adalimumab. After 24 weeks of treatment with the anti-TNF, PASI 75/90/100 responses of 79%, 52% and 31%, respectively, were achieved.

Evaluation of PASI 90 response rates reflected the growing interest in the potential of TNF-a inhibitors to achieve complete response or clearance of psoriasis skin lesions. The potency of these biologic agents relative to other psoriasis treatment options has made complete clearance a realistic therapeutic goal, more so than at any previous point in time.

Psoriasis-related Nail Disease

About 50% of patients with psoriasis have psoriatic nail disease (Figure 1, 3). In EXPRESS (European Infliximab for Psoriasis Efficacy and Safety Study), 82% of patients had nail disease at baseline (J Am Acad Dermatol 2008;58:224-31). Long-term anti- TNF
ed to clearance of nail disease in 45% of patients.

Figure 3.

<img3716|center>

Nail response has been presumed to parallel the response of psoriasis skin lesions, but few published data are available to support that view. Knowing when concurrent skin response and nail clearance can be expected might help promote adherence to longterm therapy. EXPRESS investigators retrospectively analyzed data from the trial to clarify the association between skin and nail response to long-term anti- TNF therapy (Winkelman et al. Abstract P1220).

The analysis included 378 patients with moderate or severe psoriasis. They were randomized to placebo or infliximab 5 mg/kg and followed for a year. Of 305 patients assigned to the TNF-a inhibitor, 240 had nail psoriasis of which 186 were still on the biologic at study end. All but one of the patients on infliximab had nail evaluations at week 50.

The data showed that 138 of the 185 infliximabtreated patients had PASI 75 responses at week 50. Among those who had achieved at least PASI 90, the median improvement in the target nail Nail Psoriasis Severity Index (tnNA PSI) and the number of nails affected (NNAIL ) was 100%. The proportion of patients who had full nail clearance at week 50 with PASI 75 and PASI 90 responses was 56% and 62%, respectively.

Results of this analysis show that nail clearance and response improved in parallel with skin response at one year in patients with moderate or severe psoriasis. Clinicians may find this information useful when counselling patients about expectations of anti-TNF therapy for psoriasis and associated nail disease.

Ethnicity and Response to Anti-TNF Therapy

Global economic development and greater mobility have increased the need to consider therapeutic consistency across ethnic groups in clinical decisionmaking. A presentation at the EADV congress examined the issue in an evaluation of anti-TNF therapy in Middle Eastern patients with psoriasis (Dayem HA, Omar MF. Abstract P1269).

The study included 22 patients with moderate to severe plaque psoriasis, treated with infliximab 5 mg/kg at baseline and weeks 2, 6, 14 and 22. The primary end point was PASI 75 response at 10 weeks. Nail response (NA PSI ), quality of life (DQLI ) and physician global assessment (PGA ) also were among the outcomes of interest.

The authors reported that 16 of 20 (80%) evaluable patients achieved PASI 75 responses by week 10. Additionally, eight patients (40%) achieved PASI 90 and two patients (10%) achieved PASI 100 scores, indicative of complete clearance. At week 24, response rates were 85% for PASI 75, 65% for PASI 90 and 25% for PASI 100. The 10-week NA PSI results showed that 43% of patients had at least 75% improvement in nail disease, increasing to 86% at week 24. The average DQLI improved by 12.6 points at week 10 and by 13.5 points at week 24. PGA data showed that 75% of patients were clear or almost clear by week 10, increasing to 80% at week 24.

Results of this study are consistent with those from other evaluations of TNF-a inhibitors in different populations of patients with psoriasis. Moreover, nail disease, QoL and physician assessment all improved in parallel with the clearance of skin disease.

Treatment of Palmoplantar Psoriasis

Psoriasis of the palms and soles often proves resistant to conventional means of treatment. Although a majority of patients with psoriasis have palmoplantar involvement, few studies of anti-TNF therapy have focused specifically on response in the palms and soles.

A small randomized clinical trial limited to 24 patients whose psoriasis included palmoplantar involvement was presented (Bissonnette et al. Abstract P1159). Patients had a baseline palmoplantar PASI score of at least 8 and at least 10% involvement of the palms and soles. They were randomized to infliximab 5 mg/kg or placebo at baseline and weeks 2 and 6. Patients initially treated with placebo received infliximab at weeks 14, 16 and 20.

After 14 weeks, 33.3% of patients in the anti-TNF group had achieved PASI 75 responses and 66.7% met criteria for PASI 50 responses. In contrast, 8.3% of placebo-treated patients had PASI 75 and PASI 50 responses at week 14 (P=0.009 for PASI 50). Surface area involvement decreased by 53.6% in the infliximab group compared with 4.5% in the placebo group (P=0.002). After 26 weeks, the average affected surface area of the palms and soles had declined by 69.2% in patients initially treated with the biologic; PASI 75 response rate was 58.3%.

Though small, this study provides prospective data showing that infliximab can significantly improve difficult-to-treat palmoplantar psoriasis.

Expanding Armamentarium

While these findings add to the consistency in the efficacy of anti-TNF therapy for psoriasis, other presentations at the EADV provided an insight into a new class of agents to treat psoriasis.

Expressed in psoriatic lesions are the interleukins (IL) 12 and 23 which share the p40 subunit. A new class of agents has emerged that targets IL-12/23. As the first agent in this class, ustekinumab has demonstrated similar response rates irrespective of age at diagnosis, disease duration, concomitant psoriatic arthritis or baseline PASI score, physician assessment, extent of body surface area affected or QoL score. Analysis of clinical characteristics also showed no major variations in response by treatment history, including phototherapy and previous psoriasis medications (Reich et al. Abstract P1222). Another study by Menter et al. (Abstract P1157) evaluating ABT-874, another agent targeting IL-12/23, demonstrated that after 12 weeks of treatment half of patients achieved 90% clearance compared to placebo. These agents add support to the goal of achieving and maintaining high response rates.

Summary

A strong rationale exists for use of anti-TNF therapy in psoriasis. A decade of clinical evaluation and experience in clinical practice has established the safety and efficacy of TNF-a inhibitors in the treatment of appropriately selected patients. Overall, the agents have a favourable safety profile. Collectively, the TNF-a inhibitor class offers an effective therapeutic option for a physically and emotionally injurious disease that often proves difficult to control with conventional methods. The potential to achieve complete response or clearance of psoriasis skin lesions has become an even more realistic objective with anti-TNF therapy and with the addition of agents targeting IL-12/23.

The following difficult-to-treat cases show how physicians obtained significant results with the use of a TNF-a inhibitor.

Case 1

Presented by Dr. Ulrich Mrowietz, University of Kiel, Germany

T he patient is a 45-year-old male who is 183 cm tall and weighs 82 kg (body mass index 24.5). He has had psoriasis since age 19. Familial history is unknown. He is HLA-Cw6-negative. The appearance of skin lesions is typical of psoriasis vulgaris or plaque-type psoriasis, a mix of inflammatory and hyperproliferative disease. His comorbidities are not known but he is a smoker. He is not taking any medications. He has used all available topical agents without success and has undergone several courses of phototherapy (UVB and bath PUVA). Neither acitretin nor MTX at doses up to 20 mg/week improved his disease status. The patient could not tolerate fumarates and cyclosporine caused unacceptable increases in blood pressure. PASI score of 18.2 is indicative of severe, ongoing psoriasis.

Q: On the basis of the information presented, what do you think is an attainable treatment goal for this patient? PASI 50, PASI 75, PASI 90, complete skin clearance or complete skin and nail clearance?

A: A third of audience respondents chose PASI 50. The remaining two-thirds of responses were evenly divided among the four other options.

Dr. Mrowietz: The patient’s extensive history of unsuccessful therapy identifies him as being in treatment failure at presentation. In deciding how to proceed with therapy, several factors should be taken into account. Some measure of disease severity is required to obtain an accurate assessment. Extent of body surface area involvement and the intensity of local signs are two possibilities. Lesion location should be considered, particularly the presence of nail or scalp involvement. Disease duration is another key consideration, and this patient has a 25-year history of therapy that has been unresponsive to multiple prior therapies. Other factors that should be considered include possible joint involvement, activity and tolerability of prior therapies, associated symptoms and comorbidities, and input from the patient regarding the disease’s impact on QoL. Taking into account all these factors, two treatment options emerge: combination therapy and use of a biologic agent. Given the recalcitrant nature of the patient’s disease, long-term maintenance therapy will almost certainly be required to keep the psoriasis in check. In reviewing his treatment history, a combination containing phototherapy, such as PUVA, comes to mind. However, use of phototherapy is limited to brief treatment periods. This patient requires ongoing therapy, which leads to consideration of biologic agents, particularly TNF-a inhibitors, which offer a majority of patients with psoriasis the potential for long-term disease control. Results of the EXPRESS study, a large placebo-controlled clinical trial of infliximab in psoriasis, illustrate the therapeutic potential that can be offered to patients (Reich et al. 2005). Almost 60% of patients achieved a PASI 90 response by week 10, and the response wa
4. In follow-up to week 50, more than 70% of patients treated with the biologic maintained a PASI 75 response.

<img3717|center>

Commentary by Dr. Shear

In the past, moderate improvement was an acceptable treatment goal of psoriasis therapy because available treatment options frequently resulted in no more than moderate improvement. Non-skin manifestations received little attention and disease burden was not necessarily a consideration in deciding therapy. The availability of TNF-a inhibitors has changed expectations. Most patients can achieve a PASI 75 or PASI 90 after 10 to 16 weeks of therapy, and that should be the expectation. Additionally, the physician and patient should anticipate improvement or clearance of nail disease, associated morbidities and QoL. Longterm management warrants greater consideration because biologic therapy offers the potential for longterm disease control. Management strategies for psoriasis should focus on achieving all treatment goals.

Case 2

Presented by Dr. Alexandra Ogilvie, University of Erlangen, Germany

A 52-year-old male patient presents with a 25-year history of psoriasis. Initially, nail disease was the only manifestation, but the disease evolved into plaque psoriasis, which has persisted for 22 of the 25-year history. Since three years ago, the patient has distal interphalangeal predominant (DIP) arthritis in three joints. The patient’s only comorbid condition is hypertension, which is managed with an ACE inhibitor. Current psoriasis therapy is MTX 15 mg/week. The patient’s treatment history includes topical therapy with class II-III steroids, calcipotriol, coal tar and anthralin. Phototherapy (UVA/UVB and oral PUVA) led to substantial but short-lived improvement in skin lesions. Prior systemic therapy consisted of acitretin which was discontinued because of elevated liver enzymes.

Q: Would involvement of nails, in addition to the skin, influence your choice of treatment?

A: An 86% majority of respondents said the presence of nail involvement would influence their treatment decisions.

Dr. Ogilvie: Nail involvement is a common manifestation of psoriasis and adds significantly to the disease burden. A highly visible manifestation, nail disease impairs function, confers a risk of secondary infection and frequently is treatment-resistant. Accumulating evidence suggests nail disease also is associated with the severity of psoriatic skin lesions. In a study involving 1500 patients with psoriasis, investigators grouped patients according to disease severity (mild, PASI<10; moderate, PASI 10-20; severe, PASI >20). About half of the patients had nail involvement. Comparison nail involvement and PASI scores revealed a near-linear relationship. The prevalence of nail involvement increased from 41.3% of patients with mild psoriasis to 61.2% of those with severe disease (Dermatology 2008;216:366-72). Some evidence suggests nail psoriasis is an early marker of psoriatic arthritis. Interrelationships among nail psoriasis, enthesitis and DIP arthritis point to the possibility of the nail as a window to the joint. A multivariate analysis of factors associated with psoriatic arthritis in 1600 patients with psoriasis revealed scalp lesions and nail dystrophy as two of the
conferring a hazard ratio for arthritis of 3 to 4, compared with patients who did not have those disease characteristics (Arthritis Rheum 2009;61:233-9).

<img3718|center>

Commentary by Dr. Shear

Evaluation of every patient with psoriasis should include a thorough assessment of nail involvement. Several tools for evaluating and monitoring psoriatic nail disease have been developed. Currently, the only validated instrument is the Nail Psoriasis Severity Index (NA PSI). Commonly used in clinical research, the NA PSI can be difficult to integrate into clinical practice. Several groups are developing nail disease assessment tools for use in clinical practice and a simpler validated instrument should be available in the near future. The availability of anti-TNF agents has provided additional impetus for incorporating nail disease into the evaluation and treatment of psoriasis. Unlike conventional systemic therapies, biologic agents have demonstrated the ability to achieve clearance of nail disease in a substantial proportion of patients with psoriasis and nail involvement (J Am Acad Dermatol 2008;58:224-3).

Case 3

Presented by Dr. Marina Papoutsaki, University of Rome Tor Vergata, Italy

T he patient is a 51-year-old female with a 33-year history of psoriasis and concomitant psoriatic arthritis for the past 25 years. Her treatment history includes topical and oral corticosteroids, keratolytics, vitamin D derivatives, MTX, acitretin and fumaric acid esters. Since 2002 she has been treated with cyclosporine, which has resulted in hypertension and recurrent basal-cell carcinoma.

Q: Would you manage this patient with long-term biologic therapy?

A: Respondents were equally divided, as 50% said they would initiate long-term biologic therapy and 50% said they would not.

Dr. Papoutsaki: The availability of biologic therapy has effectively raised the bar for psoriasis treatment goals. A majority of patients can attain PASI 75 or PASI 90 responses within 10 weeks after therapy. Complete clearance of skin lesions is attainable for many patients. Additionally, biologic therapy can improve difficult-to-treat nail and scalp lesions, reduce the impact of psoriasis-associated comorbidities (including joint involvement) and reduce the adverse effects of psoriasis on QoL. With biologic therapy, long-term maintenance of disease control with minimal safety issues is a realistic goal for every patient with psoriasis. A strategy to achieve that goal has been recommended for infliximab (Reich et al. Dermatology 2008;217:268-75). The strategy emphasizes ongoing monitoring of treatment response and adjustment of the therapeutic regimen to mainta
h the least possible risk to the patient. In my own clinical practice, patients with severe psoriasis have had complete clearance with the anti-TNF, which maintained its activity for five years or more.

<img3719|center>

Q: After achieving skin clearance with infliximab, would you continue treatment with it, switch to another biologic agent or stop all biologic treatment?

A: Three-fourths of respondents (74%) agreed that continuing infliximab would be the best course of action.

Commentary by Dr. Shear

As psoriasis is a chronic disease, there are compelling reasons to continue the medication. For one, relapses will occur when patients are taken off therapy. Also, retreatment after a prolonged hiatus is not always as successful as continued treatment. So if infliximab or the biologic used is working well, there is no reason to stop therapy.