Red, Scaly Rashes: Clinical Pearls

Matthew Zirwas, MD

What should we do with patients who present with red, scaly rashes? Dr Zirwas provides some of his clinical pearls from Maui Derm NP+PA Summer 2015…

  • Look behind the earlobes, under the jaw, and at the upper eyelids to distinguish between airborne contact dermatitis and photodermatitis;
  • Look for islands of sparing and ask if it started on the scalp when you’re considering pityriasis rubra pilaris;
  • With a widespread facial dermatitis, look for sharply demarcated red, scaly patches to diagnose seborrheic dermatitis, even if it isn’t in the normal distribution of seborrhea;
  • In cases of rosacea that don’t respond to treatment the way you expect, look for tiny, pinpoint pustules as a clue that demodex is the driving factor;
  • Dermatitis under a ring is essentially always irritant dermatitis from irritants trapped in the band. Fill in concavities on the inside of the band and only wear one ring per finger;
  • When the fingertips are the main place that is affected with a hand eczema, suspect friction with paper and keyboards as the most likely cause;
  • A rash under a bra-strap is most likely caused by symptomatic dermographism. Push-up bras with thin straps are most likely to cause problems.

Skin of Color: Clinical Pearls

Seemal Desai, MD

Here are some important takeaway messages from Dr Desai’s presentation on skin of color at Maui Derm Summer NP+PA:

  1. Erythema can be difficult to distinguish in patients with skin of color. Don’t be fooled by areas of violaceous hue, brownish discoloration, and bluish brown discoloration that can actually represent erythema and thus active inflammation. For example, in patients with psoriasis
  2. Progressive Macular Hypomelanosis is a condition commonly on the trunk, and can be seen in the distribution of tinea versicolor
  3. Treat acne vulgaris in patients with skin of color aggressively. These patients are more prone to post-inflammatory hyperpigmentation, which can be difficult to treat
  4. Inflammatory disorders such as sarcoidosis, cutaneous lupus, and infectious pathologies can mimic psoriasis in skin of color and vice-versa. Biopsy when in doubt
  5. First line therapy in the treatment of melasma consists of triple combination topical therapy, but second line therapy, including chemical peels should be considered for recalcitrant cases

Clinical Pearls: Nevus

Ashfaq Marghoob, MD

Here are some important takeaway points from Dr Marghoob’s presentation during the Pigmented Lesion session at Maui Derm NP+PA Summer 2015…

  • Globular nevi, reticular nevi, starburst nevi, homogeneous blue nevi are all biologically distinct subsets of nevi
  • Peripheral globular and starburst pattern correlate with the radial growth phase of dysplastic nevi and Spitz/Reeds nevi respectively
  • DN and Spitz nevi are markers for increased risk for developing melanoma
  • DN are markers for increased risk for melanoma and potential precursors to melanoma
  • Congenital nevi have a 1-5% risk for developing an associated melanoma
  • Screening for melanoma requires looking for lesions that are different, uneven in distribution of texture/color (ABCD), and/or changing
  • Dermoscopy improves the clinical sensitivity and specificity for cutaneous malignancy
Dr. Sheila Fallon-Friedlander

Infectious Diseases: Clinical Pearls

Sheila Fallon-Friedlander, MD

What do we need to know about infectious diseases in our pediatric patients?

  • Remember that not all “infections” in atopic dermatitis are bacterial. HSV can infect AD lesions and the hint is “monomorphous, punched-out”
  • Rashes in neonates instill fear in family & staff alike – always first determine if the child appears ill, then set your “DefCon level”   Concern for molluscum is Defcon 5,   HSV is Defcon 1
  • Diaper dermatitis is a frustrating disease that can be infectious. Remember these possibilities:
    • Candida
    • Staph
    • Strep
    • Molluscum
  • Diaper dermatitis is frequently NOT infectious
    • MCI (baby wipes) irritant derm
    • Dyes from “colorful” diapers
    • Zinc /metabolic deficiencies
    • LCH
  • Measles is still an infectious disease concern world-wide. The risks of the vaccine are far outweighed by risk from the disease
  • Recent studies have shown that the measles vaccine can actually stimulate immune responsiveness

Psoriatic Arthritis: Key Developments and Future Directions

Arthur Kavanaugh, MD

Dr Kavanaugh provides us with his clinical pearls on psoriatic arthritis (PsA)…

  • There is increasing evidence that early diagnosis and treatment of PsA results in improved outcomes
  • There exists a large gap and unmet need in PsA, with many patients not being evaluated by doctors or receiving appropriate therapy
  • Because skin manifestations usually precede joint involvement, often by years, Dermatologists play a key role in PsA diagnosis. However, this can present challenges.
  • New guidelines for PsA treatment are under development, and may provide some assistance to clinicians.
  • TNF inhibitors have allowed improved outcomes in PsA, and there continues to be great interest in optimizing therapy with these agents.
  • There is great interest in new targets and agents for the treatment of PsA. Recently revealed data with IL-17 inhibition show promise for treatment of all the various domains of PsA, including peripheral arthritis, skin and nail disease, enthesitis and dactylitis, and axial/spinal arthritis.
  • The IL-12/23 inhibitor ustekinumab was approved last year in PsA and has been shown to be effective across domains of disease.
  • The PDE4 inhibitor apremilast received FDA approval for PsA 3/21/14 and for psoriasis 9/23/14. Its use is increasing in the clinic, for diverse PsA patients. Safety is a particularly attractive feature of this drug.
  • Additional agents are in development for PsA.
  • Optimal management of PsA depends on the levels of activity and severity across the various domains of disease.

10 Pearls from Dermatopathology

Whitney A. High, MD, JD, MEng

  1. Dermatopathology is one of two ABMS-recognized subspecialties in dermatology, and one may become fellowship-trained after first being a board-certified dermatogist or general pathologist.
  1. Biopsy use is increasing. In nine geographic areas of the USA, over the time period 1986-2001, the biopsy rate among those >65 years of age rose 5-fold and the melanoma rate rose 2.4-fold.
  1. There are mulitple steps involved in taking a specimen from a piece of “wet” tissue, in formalin, to an interpretable slide and to a typewritten report. These steps include:

Biopsy performed & fixed in formalin            Accessioned

Grossed                                                                Processed

Embedded                                                            Cut

Stained and coverslipped                                  Analyzed

Transcribed/typed/signed                                Transmitted back to the provider

  1. The dermatopathologist is examining but a small portion of your original sampling, and this must always be considered when one assesses the “representative nature” of the results.
  1. There is an old mantra in pathology: crap in = crap out. No dermatopathologist, regardless of skill or expertise, can weave a poor sample into an outstanding result.
  1. It is the clinician responsibility to secure a “representative biopsy,” and if this is not done, eventually this inadequacy will be discovered. Over the period of 1998-2005, the number of shaves increased, but the volume of a typical shaves decreased.
  1. The technique employed (shave, punch, excision) must be adapted to the clinical situation – there are no fixed rules that may be applied to every situation. This is why the clinician is being paid an “evaluation/management” code; to select a biopsy that is appropriate for the circumstances.
  1. A recent study of pigmented lesions showed the odds of misdiagnosis (overall and that associated with adverse outcome) were higher with a punch biopsy than with an excisional biopsy, whereas a shave biopsy was only weakly associated with misdiagnosis. (Ng et al. 2010)
  1. Situations where the biopsy technique should be carefully considered include suspected:

Verrucous carcinoma              Mycosis fungoides

bullous pemphigoid                 Immunofluorescence studies

Panniculitis                               Alopecia

Lymphoid proliferations        Pigmented lesions

  1. The pathology report itself should be carefully read and scrutinized to understand precisely what the dermatopathologist is trying to convey. Demographic data should be confirmed. The technique and specimen size should be verified. Data used by the dermatopathologist to formulate the diagnosis should be noted (i.e. step levels, immunostains, special stains, etc.). If questions still exist, a phone call should be placed to the dermatopathologist for expanded dialog.

Contact Dermatitis and Eczema Clinical Pearls

Matthew Zirwas, MD

Dr Zirwas provides us with important clinical pearls from his presentation on contact dermatitis and eczema…

  1. If a patient with facial dermatitis is patch tested with the TRUE Test, the likelihood that patch testing will get them better is 1%. (30% chance they have contact dermatitis x 20% chance it will accurately diagnose them x 50% chance they will remember their allergies x 50% chance they will be able to avoid them if they remember them = 1.5% chance they will get better).
  1. TRUE Test is great for diagnosing allergic contact dermatitis to common metals, rubber, and active ingredients in OTC and Rx products. It is very bad at diagnosing ACD to personal care products.
  1. If there isn’t somebody in your area who does comprehensive patch testing, at the very least you should add these ten allergens to the TRUE Test: Methylisothiazolinone 2000 ppm, Formaldehyde 2%, Propylene Glycol 100%, Fragrance Mix 2, Cocamidopropyl Betaine, Amidoaminde, Dimethylaminopropylamine, Hydroxyethyl methacrylate, Mixed dialkyl thioureas, Chloroxylenol.
  1. Patients can be accurately patch tested while on 10 mg of prednisone.
  1. Every allergen you tell someone they are allergic to decreases they chances they will remember what they’re allergic to by 50%. (Allergic to 0 allergens à100% chance of remembering, Allergic to 1 à50% likelihood of remembering, Allergic to 2 à 25% likelihood of remembering, Allergic to 3 à 12% chance of remembering what they are allergic to).

Immunotherapy Update

Keith T. Flaherty, MD

At Maui Derm 2015, Dr Flaherty, a medical oncologist at Massachusetts General Hospital, reviewed updates in melanoma therapy for advanced disease and how these drugs have impacted clinical care. As we try to build on targeted therapy based on our current knowledge of pathways, we ask ourselves what will be the role of combinations and/or precision medicine-type immune therapy matching strategies. Of note, the therapies discussed are investigated in the metastatic setting first, and as dermatologists, we are considering their use in the adjuvant setting.

Ipilimumab

Ipilimumab was the first entry into the field in terms of a positive phase III trial. Ipilimimab at 3mg/kg, with or without gp100, was given every three weeks for four treatments. Based on the data, there’s no question that ipilimumab outperformed the gp100 vaccine alone. This outcome, at the level of overall survival, demonstrated the efficacy needed to warrant the approval of ipilimumab.

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Ipilimumab was already a ten-year old therapy for which metastatic melonama patients were taking the drug for a few months course of treatment and who are still alive and well. Dr Flaherty states that we knew, when these results emerged, that there may be a truly, durable, lasting effect.

There is a cost to this type of treatment in terms of adverse events (AEs). All of the toxicities associated with this drug come from autoimmune attack(s) affecting the skin, large intestine, endocrine glands, or hepatic autoimmune injury. Why these tissues and not others? There are several theories, but not a firm understanding. If you focus on the ipilimumab monotherapy group, you can look at those who had severe autoimmune toxicity, i.e., you have to stop giving the drug and/or give high-dose corticosteroids to stop the autoimmune reaction. This occurs about 10 percent of the time. Everything short of this autoimmune toxicity appears, in short, in mild or moderate form and basically goes away without any immunologic intervention.

Phase III MDX010-20 Study:  Most Common irAEs (Grades 3-5) Over Entire Study

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The idea is that we think we’re unmasking normal tissue tolerance, but in a largely reversible way. About two thirds of patients who receive ipilimumab have some form of autoimmune toxicity, only about 10 percent have enough of it that it creates a truly life-threatening scenario for which we need to intervene. Not all of the toxicities manifest at the same time. Dr Flaherty feels that in major melanoma programs, we have become quite comfortable with regards to counseling patients as far as what to look out for and when to call with suspected reaction(s). Dr Flaherty believes that ipilimumab is a therapy that can absolutely be safely administered.

The other phase III trial that corroborated the effects of ipilimumab looked at patients taking ipilimumab (10mg/kg) plus decarbazine (850 mg/m2) or dacarbazine (850 mg/m2) plus placebo at weeks one, four, seven, and ten, followed by dacarbazine alone every three weeks through week 22. This trial was similarly positive with the addition of ipilimumab. The difference, as shown below, was really not very different from that of the ipilimumab versus vaccine trial.

First-line Ipilimumamb/DTIC vs DTIC: OS

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The toxicities of the two-drug approach were modestly worse. When the FDA looked across the two data sets, they didn’t feel that the addition of chemotherapy was synergistic; therefore, they went with the previous study and approved ipilimumab as a monotherapy for metastatic melanoma.

In clinical practice, you can look at the pooled data set (below) and feel comfortable counseling patients that they have about a 20 percent chance of walking away with the diagnosis of metastatic melanoma by receiving this treatment (four doses over three months) with time-limited risk of toxicity.

Ipilimumab Analysis:  Pooled OS Analysis

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We have learned that if you “cherry-pick” patients and only treat those with lower disease burden, the rate may be as high as 30 percent.

The PD-1 Pathway

What is the role of the PD-1 pathway in suppressing anti-tumor immunity? How might we think about deploying antibodies that try to intercept this negative immune regulator? We can target on either the PD-1 side or the PD-L1 side [with antibodies]. Scientifically, we would anticipate that this would alleviate the negative influence that the expression of this immune marker on tumor cells can produce in terms of silencing T-cells directly. There was a belief that PD-L1 target is actually safer than PD-1 targeting because you don’t disrupt PD-L2/PD-L1 interactions that a PD-1-blocking antibody would and there is some clinical evidence that this may be true.

Pembrolizumab

Pembrolizumab was FDA-approved in the late summer of 2014. In the pivotal, randomized study, patients who had received ipilimumab and/or a BRAF inhibitor, if they were BRAF mutant, were randomized to receive pembrolizumab 2mg/kg IV every three weeks (ongoing), pembrolizumab 10mg/kg IV every three weeks (ongoing) or chemotherapy. This was a trial that was aiming to show that patients who had exhausted the available therapies could benefit from treatment with pembrolizumab. This data set addresses the unmet need of patients who don’t get a benefit from ipilimumab.

Primary End Point:  PFS (RECIST v1.1 Central Review)

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The data (above) is impressive when looking at pembrolizumab compared to chemotherapy at the level of progression-free survival. This is clearly a positive study and very important data for patients who had exhausted all of the other treatment options. It is true; however, that this therapy does not work for all patients and about half of patients will still experience disease progression. The number of patients who have objective responses, again these are patients who have not exhausted all other options, appears to be about 20-25 percent.

Two different doses were investigated in this study (2 mg/kg Q3W and 10mg/kg Q3W). Because there was no difference in efficacy, the lower dose, which is modestly safer, was the regimen that was approved. The toxicity is identical in type with ipilimumab. This type of immune therapy produces the same autoimmune reactions in terms of the affected organs and tissues. The issue is that the severity is clearly lower than that of iplimumab.

AEs of Clinical Interest for Pembrolizumab

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If you look at the Grade 3 and Grade 4 AEs (above), notice how there are only a few autoimmune toxicities in the approved pembrolizumab group (2mg/kg).

For our patients, this is a drug that can be effective and a bit less dangerous in terms of autoimmune toxicities.

Nivolumab

Nivolumab, another PD-1 antibody that was approved in December 2014, was studied in patients who had not received prior therapy. Patients were randomized to nivolumab (3 mg/kg IV every two weeks) plus placebo or placebo plus dacarbazine (1000 mg/m2 IV every three weeks). The thought here was that if you were going to conduct a clinical trial that was chemotherapy controlled, you couldn’t include BRAF-mutant patients because you wouldn’t offer them decarbazine as a front-line “cytotoxic” therapy. Patients in this study were stratified based on PD-L1 status.

This drug has a huge impact in terms of overall survival.

Primary Endpoint:  Overall Survival

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The data demonstrate a one-year overall survival rate of 73 percent. Many practitioners look at the evidence and would like to get PD-1 antibodies in the front-line. Currently, these drugs are approved for second- or third-line.

Progression-free survival clearly improved as well with nivolumab. These are immune therapies, but they have a clear impact on tumor burden as well. About sixty percent of patients have some demonstrable tumor effect.

When you see a response, the likelihood that the response is going to be durable through six and twelve months of follow-up is very likely.

PD-L1 status is an interesting biomarker to which we should pay attention. The overall survival outcome for patients whose tumors express PD-L1 on their surface does better than the control group and the overall population. (see below)

OS by PD-L1 Status*

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It is fairly clear that we can do some enrichment by using PD-L1 on the tumor as a biomarker.

Combination Therapy

In the medical oncology metastatic melanoma field, there is a lot of research around the concept of combining PD-1 and CTLA-4-blocking antibodies. Tumor responses in patients receiving nivolumab plus ipilimumab demonstrated that approximately 90 percent of patients responded after a follow-up of about 13 months.

Cli

There is still a group of patients who remain refractory, even to two-drug therapy. This phase I data ultimately launched a large phase III trial and we expect to see the data in June of this year (2015). The combination regimen cannot be given at the full dose of each drug; at least one of the therapies has to be attenuated. The data in the phase III trial is not quite as robust; however, we look forward to hearing the results in June.

When you look at the best available data with PD-1 monotherapy (pembrolizumab), this is actually not bad (below). Dr Flaherty feels that it is still unclear as to whether combination therapy is lifting us to a new plateau. We need more evidence to support that. Regarding safety, in patients who were taking combination therapy at the doses that were taken into the phase III trial, there was a sixty percent rate of severe (Grades 3 and 4) autoimmune toxicity. The results from the phase III data will help us to determine whether or not this combination therapy can be clinically useful.

Pembrolizumab Change in Tumor Size

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Adjuvant Therapy

There is some preliminary evidence on adjuvant therapy as we only have an interim result from a trial looking at ipilimumab monotherapy versus placebo in 951 patients with high-risk, stage III, completely resected melanoma. The primary endpoint was recurrence-free survival. If you focus on hazard ratio, there is about a 25 percent improvement. The question is whether or not this drug is really doing something more effective in the adjuvant setting than it would otherwise do in the overt metastatic setting. This is not clear—we need to see more data, more follow-up, and more overall survival evidence to know if this is a therapy that should be moved to the high-risk, resected setting. This therapy can have significant toxicity consequences, so we do have reason to be concerned.

Toxicities are substantial in the adjuvant setting. Notice the rate of Grade 3 and 4 toxicities. (below) This is the same drug that has a ten to twelve percent toxicity rate in the overt metastatic setting, but more in the adjuvant setting—partly because of the higher dose.

Safety:  Immune-related Adverse Events

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There were treatment-related deaths in this trial. This is not something that we can take lightly.

Vaccines

From 2010 to 2015, in the metastatic melanoma field, we have run about twelve phase III trials and they have all been positive, except for the most recent of the vaccine trials, a MAGE-3 peptide. Prior to this, we have had three peptide vaccine trials suggesting a detriment in overall survival. We still have not found a way to deploy these therapies. Dr Flaherty states that many of us are hopeful that either by using some biomarker selection strategy or, more likely, using these agents with immune checkpoint antibodies, we may be able to find utility in steering immune responses towards specific epitopes. Currently, there are no ongoing phase III trials.

Conclusions

Ipilimumab was the first-in-class immune checkpoint inhibitor and has demonstrated survival advantage. Long-term follow-up clearly supports survival impact with only three months of therapy. PD-1/PD-L1 is considered “best-in-class” based on higher response rates and better disease control; however, the percentage rate of long-term survivors is unknown. The combination of ipilimumab/nivolumab suggests synergistic toxicity and the question remains regarding synergistic efficacy. The adjuvant role of therapy is still not defined as we only have interim data for ipilimumab at the higher dose.

 

 

 

 

Systemic Treatment of Psoriasis: What’s New?

Written by Judy Seraphine, MSc–Maui Derm News Editor

The field of psoriasis, especially with regards to systemic therapy, is ever evolving. In this presentation, Dr Craig Leonardi discusses what’s new as far as treatment for psoriasis and what we need to know for this first quarter of 2015.

Inventory of Biologics with Utility in Psoriasis

As we all know, the T-cell inhibitors, alefacept and efalizumab, once both approved for the treatment of psoriasis, were withdrawn from the market due to lack of use and serious infections (PML), respectively. Our attention has shifted to managing cytokines rather than affecting T-cells directly. This approach has led us to more successful research.

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Our second-generation biologics (adalimumab, etanercept, infliximab, and certolizumab) all target TNF-alpha. Ustekinumab, an IL-12/23 antagonist is a third generation biologic with which most of us are familiar.

There are a growing number of new and emerging biologics for the treatment of psoriasis. Guselkumab, tildrakizumab, and another therapy under development by Boehringer-Ingelheim all target IL-23. Secukinumab (approved February 2015), ixekizumab, and brodalumab target IL-17.

New Development Efforts

Certolizumab-Pegol (CZP)

CZP is a pegylated Fab fragment that was initially approved for the treatment of Crohn’s disease in 2008. In 2009, it was approved for the treatment of rheumatoid arthritis and in 2013, CZP received approval for both active psoriatic arthritis and ankylosing spondylitis. The phase II psoriasis trial of 176 patients demonstrated positive efficacy results with no unexpected safety issues. Patients were randomized to CZP 200 mg queow, CZP 400 mg qmonth, or placebo.

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(Ortonne JP, et al. J.Am.Acad.Dermatol. 56[Suppl 2], AB6. 2007; Reich K, Ortonne JP, Gottlieb AB, et al. Br J Dermatol. 2012:167:180-190.).

Several years later, the company started a phase III program in psoriasis. Dr Leonardi feels that if you have patients with significant psoriatic arthritis and you are running out of TNF antagonists, you may want to consider CZP.

IL-23

Remember that ustekinumab is an antibody that targets the p40 subunit. When it does that, it hits both IL-12 and IL-23 because the p40 subunit is shared. Targeting IL-12 and IL-23, causes a rich set of downstream effects, including down-regulation of Th1, Th17, and Th22 immunocytes. We will also see a decrease in the production of cytokines in the skin, especially IL-17a, IL-17f, and TNFα.

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These features are suggestive of the psoriasis phenotype, so this is a good approach to targeted therapy.

Ustekinumab

In the phase III studies, PHOENIX 1 and PHOENIX 2, ustekinumab 45 mg and 90 mg, at 28 weeks, achieves a PASI 75 in 71%, 79%, 70% and 79% of patients, respectively. (Leonardi CL, Kimball AB, et. Al.. Lancet. 2008; 371:1665-74.)

What about the newer drugs, guselkumab, tildrakizumab, and BI-655066 that selectively block IL-23? These drugs selectively target the IL-23 p19 subunit, which is not shared with IL-12, thereby allowing them to function as IL-23 selective monoclonal antibodies.

Guselkumab

The phase II trial demonstrates that this novel anti-IL-23 p19 subunit monoclonal antibodiy is a significant drug. Several doses were used and compared not only to placebo, but also to adalimumab. At week 12, four of the doses showed a PASI 75 between 75% and 81% indicating that this is a high performance drug. Regarding adverse events, three serious infections, one malignancy and three MACE events were reported. There were no anaphylactic reactions or serum sickness-like reactions. (Callis Duffin K., et al. AAD 2014. P8353)

Tildrakizumab

Tildrakizumab is a novel anti-IL23p19 monoclonal antibody. Unlike usetekinumab, it blocks IL23 and not IL12. In phase 2 trials, at week 16, 76.2% of patients achieved a PASI-75 and 52.2% of patients achieved a PASI-90. All doses (5 mg, 25 mg, 100 mg, 200 mg) were statistically significant at PASI-75 compared to placebo. Common adverse events included nasopharyngitis and URTI. Overall, the drug appears to be generally safe and well tolerated. (Thaci D P1537 EADV 2013)

Boehringer-Ingelheim 655066

BI 655066 is a novel anti-IL23p19 monoclonal antibody given as a single subcutaneous injection. The phase 2 study results demonstrated a PASI-75 in 87% of patients and PASI-90 in 58% of patients at week 12. Thirty-three percent of patients remained clear after 66 weeks. (Krueger J. EADV 2014). This is a very early phase 2 study, and lot more work will likely be done.

IL-17

Secukinumab

Secukinumab was approved in the United States for the treatment of psoriasis on January 21, 2015. Langely and colleagues published what Dr Leonardi refers to as “masterful” manuscript in the New England Journal of Medicine in 2014. As a clinician, if you would like to completely understand secukinumab, this publication may be extremely beneficial to you. (Langley R, et al. N Engl J Med. 2014;371:326-338.)

Secukinumab (300 mg and 150 mg) demonstrates a much faster response rate in achieving a (PASI-50), in 3 weeks and 4 weeks respectively, when compared to that achieved by etanercept in 7 weeks. Like many physicians, Dr Leonardi sees his patients at one-month into the experience. With a drug like secukinumab, you will understand at that visit whether or not it is going to achieve the results that we expect. We can see a PASI-75 in over 80% of patients at week 12 and continuing through week 52 with this drug.

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There are no significant safety issues associated with secukinumab. One of the fascinating things that we have seen is the FDA’s independent analysis of this drug.

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FDA Briefing Document. Dermatologic and Ophthalmic Drugs Advisory Committee Meeting October 20, 2014 Background Package for BLA 125504 Cosentyx (Secukinumab)

Figure 1 (above) is plotting clear/almost-clear response versus serum concentration of drug. The FDA is modeling where they expect/what percent of patients will achieve clear/almost-clear based on concentrations of the drug. They have four real data points on the graph and the rest is a dosing model. This is the first time that Dr Leonardi has seen the FDA predict a response based on serum concentration. This gives us a more informed way of using the medicines that we prescribe, especially the more expensive ones. In figure 2 (above), the FDA was looking at the dosing on the left side and suggested that patients would be better served, the heavier weighted patients, if they went with the 450 mg dose—a dose that had never been tested. The FDA was so unconcerned with the safety profile of secukinumab that they urged the company to run the drug harder than they already have. This reflects a dramatic shift in the FDA as far as the approach to this drug, psoriasis, and the severity of the disease.

The labeling for secukinumab is also interesting. Remember, they are not so much concerned with safety with this drug. “Recommended dose is 300 mg by subcutaneous injection at Weeks 0, 1,2,3, and 4 followed by 300 mg every 4 Weeks. For some patients, a dose of 150 mg may be acceptable.” Some feel that the insurance industry may challenge the 300 mg dosing. With these therapies, maybe they are saying for whatever reason you have, you may want to alter the dose. Dr Leonardi feels that this is good because we should be able to use expensive resources in ways that are creative and best for our patients, our specialty, and for society.

Ixekizumab

Phase 3 data for this drug will likely be available in March 2015. Phase 2 data have shown that this is a very high-performance drug with a high percentage of patients achieving PASI-90. The drug is exceedingly well tolerated with no serious adverse events reported. (N Engl J Med 2012;366:1190-9) The scientists at Eli Lilly looked at the predictive value of PASI-50 for predicting PASI-75 response. This analysis showed that there was good overall sensitivity (83%), specificity (87%), PPV (90%), and NPV (77%). This is showing that if your patient, treated with ixekizumab, achieved PASI-50 response they would go on to achieve PASI-75 by week 12. This is important—think about when you might be seeing your patient for the first time.

This class of drugs shows significant clearing and increased patient and physician satisfaction.

Brodalumab

Phase 2 data for brodalumab shows positive efficacy results.

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This drug was again well tolerated and demonstrates a favorable safety profile.

One study looked at long-term maintenance of clinical response with brodalumab therapy and found that the vast majority of patients did quite well over a 96-week period. (N Engl J Med. 2012 Mar 29;366(13):1181-1189)

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Psoriatic Arthritis (PsA)

Based on Dr Leonardi’s understanding of the literature, the TNF antagonists are the standard drugs of choice for the treatment of psoriatic arthritis. When looking at adalimumab, etanercept, and infliximab, the ACR 50 responses were 39, 37, and 41, respectively. (Mease P, et al. Presented at: ACR; October 14-19, 2004; San Antonio, Tex. (Abstract L6-521);Enbrel package insert. Amgen;Antoni C, et al. Ann Rheum Dis. Published Online First January 27, 2005. doi: 10.1136/ard.2004.032268.) Looking at ustekinumab 45 mg and 90 mg, we see a significantly less response rate with an ACR 50 of 24.9 and 27.9, respectively. (Kavanaugh A, et al. ACR2012. Abstract 2562.)

Secukinumab released its phase 3 PsA results at the American College of Rheumatology in November 2014. In this study, the patients received IV secukinumab for the first three doses and then changed over to subcutaneous secukinumab. Using this scheme, we can see ACR 50 response rates similar to those of the TNF antagonists. (See graph below)

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Again, the IL-17 antagonists are finding their way in rheumatology as well.

Choosing Highly Effective Drugs

Number Needed to Treat (NNT)

The NNT is the average number of patients who need to be treated to achieve one additional good outcome (e.g. the number of patients that need to be treated for one to benefit compared with a control in a clinical trial). It is defined as the inverse of the absolute risk reduction.

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You can see that we’re starting to cluster as we get to the bottom, whether you’re thinking about PASI numbers or NNT numbers. It really is quite remarkable. According to Dr. Leonardi, in the case of ixekizumab, the NNT is 1.1 meaning that if you treat 11 patients with Ixekizumab, 10 will achieve a PASI-75.

Do we really need biomarkers when clinical response is profound and fast?

We have been talking about biomarkers for years, but it’s quite likely that when a patient comes back after four weeks, we will have a good understanding of how he/she is going to respond to the various classes of therapy.

Small Molecules

Tofacitinib, an inhibitor of JAK 1 and 3, was recently approved at 5 mg BID for the treatment of rheumatoid arthritis. The data for psoriasis is positive, in that it is highly efficacious and is relative well tolerated. (Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol (2012) 167, pp 668–677)  Serious adverse events included atrial fibrillation, pyelonephritis, and urosepsis. Mild decreases in HgB levels were greater in the 15 mg BID group and transient decreases in PMNs were seen in the 5 mg and 15 mg BID groups. There were also dose-related increases in HDL and LDL. (Harness J, et al. EADV 2010: P558)

There were issues in the rheumatoid arthritis program that will be brought to attention despite the fact that RA and psoriasis are two completely different immunologic disorders. The FDA commented that the risk of malignancy appeared to increase in a dose and time dependent fashion and the data also suggest tofacitinib treatment is associated with an increased risk of serious infections, including opportunistic infection.

A Few Final Comments

The traditional psoriasis treatment paradigm was that of a stepwise progression, i.e., patients must fail the previous “step” of therapy before initiating more “aggressive” therapy. In today’s dermatology setting, psoriasis treatment is not stepwise. Choice of therapy depends on individual patient characteristics. We have a rich set of biologic agents and five more coming down the pipeline. As dermatologists, it’s time that we “rethink our goals.”

 

 

 

 

 

 

 

Update on Psoriasis Comorbidities

Joel M. Gelfand, MD, MSCE

Dr Joel Gelfand provides us with an update on the comorbidities often associated with psoriasis. Over the last decade, we have been able to identify factors that may contribute to comorbidities in psoriasis. Environmental risk factors include smoking and obesity. Scientists have also identified genes and loci associated with psoriasis, diabetes, and cardiovascular disease including PSORS2/3/4, CDKAL1, ApoE4, and TNFAIP32. We should also consider mediating factors such as pathophysiology, effects of treatment, and the psychosocial impact of psoriasis. (Azfar RS, Gelfand JM. Curr Opin Rheum 2008;20:416–422)

Currently, data suggest that we do have well-established comorbidities of psoriasis. These include:

  • Heart attack, stroke, cardiovascular death
  • Metabolic syndrome
  • Diabetes
  • Psoriatic arthritis
  • Mood disorders (anxiety, depression, suicide)
  • Crohn’s disease
  • T cell lymphoma (rare)

The risk of cardiometabolic disease in patients appears to increase with more severe disease. What does this mean clinically? As previously noted, patients with more severe psoriasis experience an increased risk of MI, stroke, cardiovascular death, and diabetes. There is an average of five years of life lost. The ten-year risk of a major CV event attributable to psoriasis is six percent. Literature suggests that the risk of cardiovascular disease in patients with severe psoriasis is comparable to the risk conferred by diabetes. Additionally, patients treated for severe psoriasis are 30 times more likely to experience MACE (attributable to psoriasis) than to develop a melanoma.

Research has also been conducted using UK-based data comparing cardiometabolic events in psoriasis versus rheumatoid arthritis (RA). We can see that patients with psoriasis have a higher rate of diabetes, but this is not seen with RA patients. There is something specific about psoriatic disease making one more prone to developing diabetes over time. (See Figure 1) These data also demonstrate that psoriasis patients treated with systemic or phototherapy have a similar increased risk of CV and all cause mortality compared to RA treated with disease modifying treatments.

 FIGURE 1

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Clinicians should recognize that metabolic problems start early and there is emerging pediatric data. The prevalence of the metabolic syndrome in pediatric psoriasis is 30 percent versus 7.4 percent in the control population.

The skin of patients with psoriasis has increased regulation/expression of cardiometabolic genes, more so than the up-regulation of inflammatory genes. This tells us that the skin itself may be the source of the abnormalities that we’re seeing.

We should also remember that psoriasis is more than just skin deep. Psoriasis is associated with increased vascular inflammation independent of traditional risk factors and equivalent to ten years of aging. Advanced FDG-PET/CT imaging demonstrated subclinical inflammation in the liver and joints.

How are we doing as healthcare providers?

Overall, cardiovascular risk factors are under-screened and under-managed in patients with psoriasis. CDC US population data indicates poor screening rates for hypertension—only four percent of severe psoriasis patients receive screening for hypertension in the dermatology office versus 61 percent patients in the non-dermatology setting.

Should we treat psoriasis aggressively to lower the risk of CV disease?

The answer is that we really don’t know for certain. Observational data suggest that methotrexate and TNF inhibitors lower the risk of cardiovascular events. Data do not yet exist to determine a protective effect of phototherapy, apremilast, and ustekinumab on CV events. (Micha R et al. Am J Cardiol 2011;108:1362–1370; Barnabe C et al. Arthritis Care Res (Hoboken) 2011;63:522–529; Prodanovich S et al. J Am Acad Dermatol 2005;52:262–267; Wu JJ et al. Arch Dermatol 2012;148:1244–1250; Ahlehoff O et al. J Int Med 2013;273:197–204)

Emerging Comorbidities

Newer data suggest that following are also comorbid conditions associated with psoriasis:

  • Sleep apnea
  • Nonalcoholic steatohepatitis (NASH)
  • Chronic obstructive pulmonary disease (COPD)
  • Adverse infectious disease outcomes
  • Chronic and end-stage renal disease
  • Peptic ulcer disease

Moderate to severe psoriasis is also a risk factor for chronic kidney disease (CKD). Data suggest that there is nearly a two-fold risk of moderate to advanced CKD among psoriasis patients and a greater than four-fold risk of end stage renal disease requiring dialysis. Risks are independent of diabetes, hypertension, and nephrotoxic medication. The risk of CKD associated psoriasis is greater than the risk of CKD associated with diabetes and hypertension. (Wan J, Wang S, Denburg MR, Shin DB, Gelfand JM. Risk of moderate to advanced kidney disease in patients with psoriasis. BMJ 2013;15;347:f5961)

There are clear clinical implications that comprehensive care is required for patients with psoriasis as we shift from the old paradigm of “just a skin disease” to the new paradigm of “a systemic disease.”

Clinical Implications

Standard Screening Recommendations (US Preventative Services Task Force (HTN) 2007; American Diabetes Association Guidelines 2014 (Diabetes Care 2014;37:S5-S13); ACC/AHA 2013 Guideline on the assessment of CV risk)

  • Hypertension
    • Every 2 year if BP <120/80 mm Hg
    • Every year if BP 120 to 139/80 to 89 mm Hg.
  • Diabetes (Fasting plasma glucose, HbA1c, or OGTT)
    • Adults ≥ 45
    • Adults BMI ≥25kg/m2 who have one or more additional RFs
    • Repeat every 3 years
  • Cardiovascular risk assessment:
    • Traditional risk factors every 4-6 years in patients 20-79
    • Estimate 10 year risk in those 40 -79

Psoriasis and Cancer

We should remember to encourage patients to stay up-to-date on age appropriate cancer screenings, including cervical cancer, colon cancer, breast cancer, and lung cancer. (CDC guidance accessed 1/21/14Note: Earlier Screening recommended in those at high risk; Moyer VA et al Screening for lung cancer: US Preventative Services Task Force recommendation statement. Ann Internal Med.  doi:10.7326/M13-2771)

  • Cervical cancer: Pap smear (q 2-3 yrs ages 21-65)
  • Breast cancer: mammography (50-74, q 2 yrs)
  • Colon cancer: (50-75) fecal occult blood q year, flex sig q5 yrs, colonoscopy q10 yrs)
  • Lung cancer: Annual low dose CT screening for 55-80 with ≥30 pack year history and current smoker or quit within 15 years

Large, long-term follow-up studies are necessary to determine the risk of cancer with psoriasis treatments.

Psoriasis and Infection

It is important that we screen psoriasis patients for streptococcal infection with guttate flares. In severe psoriasis, it’s also important to test for HIV. Psoriasis patients who are undergoing immune suppressive treatments should stay up-to-date with all recommended vaccinations as well, including influenza, pneumonia, zoster, hepatitis B, and HPV. (http://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf)

Psoriasis and Mood Disorders

Healthcare providers should ask patients about depression and anxiety symptoms and monitor the impact of treatment on psychiatric symptoms as well as refer for treatment when appropriate. Some data suggest that cognitive behavioral therapies and meditation may modestly enhance the response to psoriasis treatment.

Psoriasis and PsA

Remember the importance of identifying the signs and symptoms of psoriatic arthritis, including:

  • Morning joint stiffness
  • Joint pain that improves with activity
  • Swollen, tender joints, dactylitis, enthesitis
  • Check X rays of affected joints and CRP
  • Co-manage with rheumatology, DMARDs

In conclusion, we have to look beyond the skin for our psoriasis patients. A comprehensive care approach is essential for our patients. Patients should be educated about the disease, treatment, and associated risk factors.

Maui Derm News Editor-Judy L. Seraphine, MSc