Psoriasis Update 2011: Psoriatic Arthritis (PsA)

Arthur Kavanaugh, MD

In this presentation, Dr Arthur Kavanaugh, of UCSD, discusses the newest concepts in the management and treatment of patients with psoriatic arthritis (PsA).

A major question still exists among healthcare professionals…Is methotrexate (MTX) effective among our PsA patients? Dr Kavanaugh states that in a room full of Rheumatologists, everyone would agree that MTX is effective; however, the data doesn’t necessarily indicate its effectiveness, as it is somewhat lacking.

For more information on the history and data around MTX, Dr Theodore Pincus recently published a study in Clinical and Experimental Rheumatology focusing on the use of MTX in various disease states, including skin disease and PsA.

There are very few studies utilizing MTX in psoriatic arthritis and little support for its use in PsA patients. There were a total of 4 double-blind, placebo-controlled randomized clinical trials in the published literature.

There is not a lot of support for MTX in patients with active PsA. A number of studies utilized higher doses of MTX; therefore, we can see a dose effect, (patients taking over 15mg/week of MTX) in patients with psoriatic arthritis, which shows that there is some benefit to its use.

The MIPA study, a 6-month, double-blind placebo-controlled trial, was based out of the UK. The entry criteria required one swollen joint. The researchers were able to recruit only 221 patients over the course of eight years.  There were lots of drop-outs and in conclusion the results were questionable as to the value of MTX in patients with active PsA. There are a few issues with this study and the researchers reported that healthcare providers need to see the full data and the question still remains:  is the 15mg dose of MTX really effective?

Dr Kavanaugh recently participated in a PsA panel that was organized through EULAR (European League Against Rheumatism), with the intent to develop guidelines for the management of PsA. The panel concluded that patients with active PsA should be on MTX before one would be given a biologic. This recommendation would be questionable to many US dermatologists, and, in turn, the EULAR panel did revise their statement to allow for patients in “exceptional” cases to be started on a biologic.  It is really up to the clinician and patient to decide on the appropriate therapy based upon the data, quality of life, benefits and risks.

Data do exist around the efficacy of TNF inhibitors plus MTX in Rheumatoid Arthritis patients; yet, the data are limited in patients with PsA.  A systematic review of the TNF inhibitors demonstrated a risk ratio response of about 11 for an ACR 50 and a risk ratio of 17 for a PASI 75.

Is there synergy when utilizing MTX plus a TNF inhibitor in PsA? It is known in Rheumatoid Arthritis patients, yet it is unknown among our PsA patients.

The RESPOND study compared MTX (15mg/week) to INF (5mg/kg)+ MTX (15mg/week) and showed that the patients in combination did better than those on MTX alone.

Assessing Psoriatic Arthritis

When assessing PsA, it is imperative that healthcare providers look at each patient individually. It is important to consider peripheral arthritis, and look at swollen joints and the composite scores; clinicians need to consider axial arthritis, quality of life, radiographs, skin disease and other issues such as dactylitis (swelling of the entire digit) and enthesitis.

The CPDAI (Clinical Psoriatic Disease Activity Index) is a new instrument for disease activity and various clinical domains of PsA. This has been borrowed from the GRAPPA group, and broken into its individual domains. When we have these tools, we can then begin discussing remission. It’s important to consider all of the different facets of this disease (skin, joints, spine dactylitis, etc…) The important thing to consider regarding patient management is that each patient has to be looked at individually, as it is not an algorithmic treatment/management strategy.

Video: Treatment Options for AKs

Evolving Landscape of Therapeutics for Actinic Keratoses (AKs)

George Martin, MD

George Martin, MD

Watch video of Dr. Martin’s full talk

At the podium during Maui Derm 2011, I discussed the evolving landscape of therapeutics for actinic keratoses (AKs).  In the US nearly 60% of “at risk” individuals over the age of 40 have at least 1 AK.  Therapy for AKs has resulted in over 5 million office visits with an estimated healthcare burden of over 1 billion dollars.

As healthcare initiatives examine and reward patient therapeutic “outcomes”, the clear lack of efficacy of cryosurgery as a “field therapy” for patients with numerous AKs will cause a shift in therapeutic algorithms toward field therapies.  However; field therapies, when performed according to the package insert, are associated with prolonged side effects that dramatically affect patient compliance.  As a result, small investigator initiated studies examining short course, combination and interval therapy in efforts to enhance patient compliance while maintaining efficacy are becoming more prevalent in the literature. Additionally new drugs such as the plant derived ingenol mebutate gel are ready to be brought to the marketplace and new formulations of existing drugs such as imiquimod 3.75%, which employs a more “user friendly” protocol compared to 16 weeks of twice daily 5% imiquimod, have been introduced.

I presented the work of Prof. Eggert Stockfleth of Charite Hospital in Berlin who has published compelling molecular data on the role of human papilloma virus (HPV) 21 as a co-carcinogen along with UV.  The role of HPV 21 is analogous to the role of certain oncogenic HPV sub-types in cervical cancer.  HPV 21 has been found in 95% of AKs and 100% of cutaneous SCCs in Prof. Stockfleth’s study. Tumour-inducing effects of HPV 21 have been attributed to its production the viral protein E6.  E6 interacts with pro-apoptotic Bak-protein and the p53 protein resulting in inhibition of apoptosis.   A vaccine directed against the HPV 21 is in early stages of development. Because of the increased risk of SCC development in organ transplant patients  (>20x the rate of SCC development compared to non-immunocompromised individuals) the efficacy of pre-operative immunization in preventing AKs and SCC in this high-risk group will be studied first.

Figure 1: Fluorokinetic Analysis

Figure 1: Fluorokinetic Analysis

ALA PDT has come a long way from its lengthy 14 – 18 hr. incubation times in efforts to become user friendly.  However, I presented data that the shorter 1-hour ALA incubation times may have sacrificed significant efficacy for convenience.  Based on fluorokinetic data on the accumulation of the photosensitizer protoporphyrin IX (PpIX) inside AKs following ALA application (Figure 1) and patient observation, we now regularly treat patients using a minimum of 3-hour ALA incubation period to allow more PpIX accumulation inside AKs.  In patients with “stubborn” AKs we pre-treat with 5-FU daily for 7 days on the face and 10 days on the scalp and extremities followed by PDT using 1 – 3 hour incubations.  Lastly, for the patient with extensive AKs on the face and scalp who I never seem to get close to clearing, pretreating with 3.75% imiquimod for 1 week followed by ALA PDT using a 3 hour incubation has produced remarkable sustained clearance not achieved in either ALA PDT alone or in combination with 5-FU.

Figure 2: Therapeutic "Downtime"

Figure 2: Therapeutic “Downtime”

I addressed the issue of pharmaco-economics involving our currently available field therapies.   Medicare insurance covers the cost of ALA PDT, which is a decision factor for cash strapped seniors unable to afford the several hundreds of dollars for topical field therapies.   In terms of downtime for working individuals, ALA PDT affords the least amount of downtime (generally 1 week) compared to other field therapies (Figure 2).

5-FU remains a cornerstone of  field therapy in most our practices.  I was noted that phase III data on 0.5% 5-FU showed that 1 week of daily use of 0.5% 5-FU cleared nearly 75% of individual AKs.    I think that it is time that we should re-examine the scorched earth policy of 4-week 5-FU therapy!

Figure 3: AK of the Lip

Figure 3: AK of the Lip

What’s been overlooked for actinic chelitis?   3% diclofenac gel applied twice daily for 3 months is particularly effective for this problem. It is very tolerated and results in excellent clearance data with over 80% of individual lesions clearing and patient satisfaction was rated as very high.  (Figure 3) For those patients not wishing at least 2 weeks of downtime following any of the current modalities ranging from PDT, CO2 laser resurfacing, 5-FU or imiquimod this is a tolerable option that allows people to continue socializing.  Recent data on 3% diclofenac has shown significant long-term clearance during the phase IV study involving 1-year follow-up evaluations.

The evolution of imiquimod therapy for the treatment of AKs has undergone an evolution since the introduction of 5% imiquimod applied twice weekly for 16 weeks.  While the efficacy of this regimen is significant, the tolerability and patient compliance is wanting.  In Europe the use of 5% imiquimod 3-times weekly 4 weeks followed by a 4-week rest period and repeated produces excellent clinical and histologic clearance long term (1 year) clearance but is once again associated with significant patient downtime.  Limiting therapy to only 4 weeks results in only <30% clearance compared to two cycles that result in approximately an 85% clearance.  The introduction of 3.75% imiquimod applied daily for 2 weeks-2 weeks off- 2 weeks on has resulted in better patient tolerance and impressive individual lesion clearance (>80%). Long-term complete clearance (1 year) data for those phase III study patients initially completely clearing was 40%. In light of the role of HPV 21 as a co-carcinogen responsible for the development of AKs and cutaneous SCCs, the use of imiquimod as an immune modulator used either alone or in combination would seem to have a therapeutic advantage.

Finally, ingenol mebutate 0.015% gel when applied for 3 consecutive days during phase III studies, produced very nice and consistent clearance data (80% range) as a field therapy for the head area (face and scalp).  The 3-day topical therapy had excellent patient compliance, which is a major challenge for other field therapies.  Downtime following ingenol mebutate was on average 2 weeks.  It will be interesting to see how this drug will be used as a field therapy because of the inability to “titrate” its response following application.  Likely most of us will begin using it a “limited area” field therapy. However the future seems very bright for this latest pending addition to our therapeutic toolbox.

 

Anti-IL12/23p40 Antibodies in the Treatment of Psoriasis and Psoriatic Arthritis

Craig Leonardi, MD

The much anticipated introduction ustekinumab (Stelara®) for the treatment of moderate to severe psoriasis came about in 2010.  This fully humanized monoclonal antibody directed against the p40 subunit of IL 12 and 23 has demonstrated in phase II and III studies that it is a “high performance” drug: fast acting, long duration of action and great efficacy.  However, according to Craig Leonardi, MD, a principal investigator for ustekinumab, there appears to be a potential cardiovascular safety signal which came in the form of MACE events (Major Adverse Cardiovascular Events ie myocardial infarction, stroke and sudden death).  These MACE events appear to be a “class effect” as it is also found in the other anti p40 antibody briakinumab, which is in phase III development.  When both phase II and III data were analyzed for both anti-IL12/23 blockers there were 10 MACE events in the 3,100 drug treated patients and none in the 1,400 placebo treated control group. Because these studies are not powered to demonstrate statistical significance of this small but finite signal none was found.   It should be noted that MACE events do not encompass other cardiovascular signals such as angina, coronary bypass surgery or TIAs. The incidence of these non-MACE events is unknown.  This MACE safety signal has not found in the numerous trials involving thousands of moderate to severe psoriasis patients who received anti-TNF therapies who presumably have the same metabolic risk factors for MACE events.  Comparator groups such as those found in the Framingham study population really do not apply. Drug study populations preselect for healthy patients.  The placebo-controlled group is still the best comparator group and there were at least 1,400 patients in that group for both.

Dr Leonardi pointed out that MACE events occur early in the course of the drug therapy, usually within the first 8 months and level off.  Speculation regarding a mechanism for the MACE events would likely involve some form of plaque disruption. There is some independent investigational data that demonstrate a significant rise (a 13-fold increase) in serum p40 levels at week 12 which decrease back to baseline by 8 months after injection of these anti- p40 molecules.  This finding seems counter intuitive to what one would expect after introducing an antibody against p40 cytokines.   The elevation likely comes from an intracellular reservoir that enters into the serum over a period of time. Interestingly, the course of p40 subunits in the serum roughly parallels the development of MACE events. It is known that p40 can dimerize and become pro-inflammatory which if we continue on our speculator path could lead to plaque disruption and a MACE event.

Briakinumab’s application to the FDA for approval has been pulled and in July of 2011 Abbott halted all clinical trials involving briakinumab pending further evaluation of MACE events. Additionally there are many questions to be answered including regarding briakinumab’s early SAE’s such as infections  cutaneous and systemic squamous cell carcinomas reported in the first 28 weeks following the introduction of the drug in study patients.

Unlike the history behind TNF inhibitors which had long-term safety profile in the rheumatology and gastrointestinal field the IL 12/23 blockers are new and dermatology specific. In light of the current cardiovascular signal where does ustekinumab fit in our therapeutic tool box for psoriasis patients?

Dr. Leonardi’s Recommendations:  It should be understood that this is a “class effect” of the IL 12/23 blockers not observed in analysis of TNF inhibitor safety data.  Consider all options when selecting a biologic therapy.  Patients with moderate to severe psoriasis typically have cardiac risk factors.  Consider starting with a low dose regardless of the patient’s weight.  Although there is not data to support its use consider starting a patient on 81 mg of ASA.  Await further analysis of the safety data. Unlike the anti TNF therapies that came to us from rheumatology and gastroenterology, the IL 12/23 blockers have no point of reference.  Scientific analysis of the p40, IL 12 and IL 23 serum levels during long term treatment.

To add to Dr. Leonardi’s recommendations, in my patients with early signs of psoriatic arthritis such as enthesitis (inflammation of the insertions of ligaments and tendons into bone) with possible early join involvement I still favor the use of anti-TNF therapy when considering a biologic agent because of their longstanding efficacy in psoriasis patients with early signs of psoriatic arthritis.

Post Maui Derm Footnotes:

Since Dr. Leonardi’s presentation a paper co-authored by Dr. Leonardi discussing this potential safety signal among antii-IL 12/23 antibodies was published in JAMA (JAMA Aug 24/31 Vol 306 No. 8 (864 -871).  The article concluded: “Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/IL-23 antibodies or anti–TNF treatments. This study may have been underpowered to identify a significant difference.”

Centocor recently released Stelara’s 4-year safety data, which did not demonstrate any new safety signals. This comes as good news particularly when one considers that the appearance of Raptiva’s (efalizumab) safety signal (PML) occurred at year 4.