Psoriasis Update: 2012 Part 1

Craig Leonardi, MD

IL-12/23 Safety Issues

Cardiovascular Safety in Psoriatics Using Biologic Drugs.  Does a Signal Exist in the IL12/23 Pathway?

Case Report MACE in a Ustekinumab-Treated Psoriasis Patient

  • 47 year old construction worker
    • Caucasian male
    • Weight: 290 lbs
    • Negative Hx: DM, HTN, Tobacco
  • Psoriasis
    • 20 yr history
    • 15% BSA; PGA: M-S; DLQI: 12
    • No evidence of PsA
    • Past Tx: MTX, Etanercept, Infliximab, Golimumab
  • Current PsO Tx
    • Ustekinumab 45mg x 4 doses à 90mg x 2 doses
    • MTX 15mg SC QWk
    • Folic Acid 1mg QD
    • ASA 81mg QD (* This is something that Dr. Leonardi uses as add-on therapy)
  • Anterior wall MI
    • Normotensive
    • HgB A1C: 6.2
    • LDL-Chol: 108
    • Ejection Fraction: 45%
  • Two stents were placed

The Cardiologist commented: “Young for this type of event given his health status”

The question lies…what is it about this patient and his health status and the drug that he is currently taking, does it give him any protection about MACE events that can occur?

The answer is: no one knows right now and this is a hot debate that we all try to answer as best as we can…

Psoriasis patients have a wide and rich subset of many of the components of the Metabolic Syndrome such as diabetes mellitus, hyperlipidemia, coronary heart disease, and arterial hypertension that has been shown in much of the data.

We know from Dr. Joel Gelfand and colleagues, that our patients with psoriasis are at increased risk for myocardial infarction.

Methotrexate Reduces Incidence of Vascular Diseases in Psoriatics

  • Retrospective VAMC cohort study
    • 7615 patients with psoriasis
    • 6707 patients with rheumatoid arthritis
  • Covariates included age, sex, DM, HTN, dyslipidemia, and certain medications
  • MTX-treated pts had decreased vascular disease risk
    • Better: Low dose vs high dose
    • Best: Combination MTX and folic acid

From the Rheumatologists we have been following patients for many years….

So in treating RA patients with a TNF inhibitor, one could reduce cardiovascular events.

PsO: Risk of MI with anti-TNF therapy

This was a Kaiser Permanente psoriasis cohort of more than 24,000 patients. Patients had an ICD-9 of 696.1 (psoriasis) or 696.0 (PsA) for more than 3 prior visits and no MI prior to 2004 at the start of the study. The anti-TNF cohort was defined as receiving an anti-TNF for greater than 2 consecutive months. The oral/phototherapy cohort was anti-TNF-naïve, received oral/phototherapy for more than 2 consecutive months, and the “mild” cohort received no anti-TNF, oral therapy or phototherapy.  The researchers conducted a multivariate analysis using cardiac risk factors too look at a comparison between anti-TNF and other systemic therapy.

IL12 and 23 Blockade: A New Approach to Treating Psoriasis and Psoriatic Arthritis

There are new therapies currently available to Dermatologists, ustekinumab has been available for about 2 ¼ years; however, it is still a relatively new product. Both ustekinumab (IL-12) and briakinumab (IL-23) both block the p40 subunit.

When you block IL-12, you down-regulate a set a cytokines from a Th1 pathway, including INFy, IL-2 and TNF-alpha.  When you block IL-23, you down-regulate IL-17 alpha, IL-17f, IL-6, TNF-alpha, IL-21 and IL-22.

Function of Th17 Effector Cytokines

IL-17a

  • Expressed by memory NK and T cells
  • Increased in psoriatic skin
  • Subcutaneous injection à neutrophilia
  • Enhances inflammation
  • Enhances angiogenesis

IL-22

  • Expressed in high levels by Th17 cells
  • Increased in psoriasis (skin and plasma)
  • Levels correspond to disease activity
  • Induces keratinocyte hyperproliferation (in vivo, in vitro)
  • Stimulates keratinocytes to secrete antimicrobial peptides

 

Both demonstrating positive effects…

Ustekinumab is a high-performing drug for psoriasis patients. One can see, by the data that at week 28, about 71-79% of patients are achieving a PASI 75; this is a huge achievement for these patients. Looking at briakinumab (ABT874), this product seemed to enable patients to achieve at PASI 75 within twelve weeks of treatment. Unfortunately, attached to this positive response was also a safety signal, specifically MACE events that is categorized as cardiac, stroke or death by cardiovascular reasons. There were five MACE events in treated arm and none in the placebo arm. There were also some other troubling issues such as six malignancies, all of which were squamous cell (2 were internal and 4 cutaneous), and again, none in the placebo group and there were five serious infections to one in the placebo arm.  There was an imbalance to MACE events, malignancies and infections as compared to placebo. This is problematic as with malignancies as to the fact that no one knows as to why the cancer issues showed up some early in this trial.  MACE events are very significant as it defies the conventional thought regarding systemic inflammation and cardiovascular disease—we expect that when inflammation is decreased, the cardiovascular status should improve; however, with that in mind, when looking back at the ustekinumab SAEs that occurred within the first twelve weeks, one can see an imbalance in the placebo versus the treated arms. One can see angina, stoke, congestive cardiomyopathy (and death), and CABG. Dr Leonardi points out that angina and coronary artery bypass are not necessarily MACE events, they would not actually qualify. All in all, between the phase II and phase III trials for ustekinumab there were five MACE events, an equal number to that of the briakinumab events.

What about infection rates?

When you’re looking at a subset of the drugs or patients who are doing well, you see positive results; however, that’s the not the case for the patients who are not doing well on drug.

Summary of MACE Events in Randomized Controlled PSO Trials (meta-analysis)

Dr Leonardi, along with a group of other concerned dermatologists, statisticians, cytokine biologists and cardiologists convened for a meeting. The goal of this meeting was to analyze the data from the published studies regarding the MACE events that occurred among these patients. The group was able to tabulate the data that exist among the IL-12/23 drugs and the TNF antagonists.

When looking at the data, one can see that there was one case of MACE reported in an adalimumab trial and there was another MACE event reported in an etanercept trial (one on treatment; one on placebo in the TNF antagonist trials). When looking at the IL-12/23 drugs, there are ten versus zero; that is a pretty compelling number.  Many argue that this is due to an unhealthy status of the patients; however, this is not seen with the placebo arm, so that question still remains.

What are the statistics?

*There was no statistical significance among the TNF trials

In both drugs, we see a flurry of activity and then it flattens out over time; therefore, the kinetics of both drugs seems to be similar.

We expect MACE events to DECREASE when systemic inflammatory diseases are treated. Why are we seeing a paradoxical increase in MACE events?

Dr Leonardi’s hypothesis tells us that when we look at serum p40 subunit levels following a single dose of ustekinumab, they peek at about 3-3 ½ weeks, and then they settle down over a 32-week period. Therefore, one can see an increase in drug concentration and in binding of the ligand, p40, during the initial period. The target for this drug is in the tissue (inflamed) skin; i.e., it is expected to pull p40, presumably in the form of IL-12 or IL-23, into the serum and perhaps it interacts with an atherosclerotic plaque. It could also be an increase in IL-12 or IL-23 delivery, indirectly, to atherosclerotic plaques. Literature also suggests that p40 subunits can also have a form of bioactivity if they dimerize. It is also possible that it is an expected biologic activity of the drug. It is unlikely; however, that it is due to patient selection bias, as it is not apparent in patients taking placebo.

Conclusions

IL 12/23 Antagonists: Possible Next Steps

  • Obtain complete datasets from Abbott, Centocor
  • Time-to-event details
  • Patient details (risk factors, basic demographics)
  • Pharmacokinetic profiles
  • All ischemic non-MACE events
  • Analysis of p40, IL12, IL23 serum levels during long term therapy
  • Routine and frequent safety updates (especially in relevant psoriasis populations)
  • Determine whether a pattern of comorbidities exists
  • FDA, EMA input based on review of both datasets

Ustekinumab: Recommendations for Use (Dr Leonardi’s Approach)

  • Consider all options when selecting a biologic tx
  • Know that psoriatics typically have multiple cardiac risk factors
  • Consider starting with low (45mg) dose regardless of pt weight
  • Consider adding ASA 81mg QD
  • Await further analysis (FDA, EMA, Abbott, Centocor)
  • Remember that all new drugs are ‘new’

 IL 12/23 Blockers and CV Risk? (Dr Leonardi’s Opinion)

Pros

  • Probable class effect demonstrated in 2 drugs
  • Equal number of MACE events in 1st 12 weeks (DBPC)
  • Increased rate of MACE in the early part of trials
  • Rate of MACE appears to decrease over time
  • Peak serum concentrations of drug correspond to MACE activity (ustekinumab)

Cons

  • Unanticipated finding
  • P= 0.11
    • Not significant at traditional levels (0.05)
    • Underpowered study for CV events
    • 11% probability that results (10 vs 0) is “by chance”

 

 

 

 

 

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.

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.