Maui Derm 2016 Highlights: Psoriasis

B. Strober, MD, PhD
C. Leonardi, MD
J. Gelfand, MD
A. Blauvelt, MD
A. Kavanaugh, MD
L. Stein-Gold, MD

Newer Biologic Therapies Show Promise for Psoriasis Relief:

There has been increased focus on the IL-23/IL-17 in psoriasis and its treatment. IL-23 is upstream (targeted by tildrakizumab, guselkumab, and BI 655066), IL-17 is in the middle of the stream (targeted by ixekizumab and secukinumab), and the IL-17 receptor is downstream (targeted by brodalumab).

Efficacy of new targeted treatment options for psoriasis:

  • Gesulkumab has shown excellent efficacy with PASI 75 scores approaching 80%.
  • Tildrakizumab has demonstrated excellent efficacy in a phase II trial. PASI 75 scores in this study ranged from 75-80% for different tildrakizumab doses.
  • BI 655066 has demonstrated remarkable efficacy after a single treatment with 54% of patients achieving and sustaining PASI 100 for 9 months.
  • Secukinumab has demonstrated excellent efficacy (PASI 75 scores in >75% of patients) and a rapid onset of action (3 weeks for a mean reduction of in PASI scores).
  • Ixekizumab has also demonstrated very strong efficacy (>80% of patients achieving PASI 75) and has a very rapid onset of action. It is also numerically superior to adalimumab for the treatment of PsA.

The number needed to treat (NNT) is number of patients who need a specific treatment to gain one additional good outcome (e.g., achievement of PASI 75). The best NNT is 1, where every patient experiences a benefit with the treatment The NNT for achievement of patient achieving PASI 75 is about 1 for both secukinumab and ixekizumab. They are 1.7 and 1.4, respectively, for PASI 90; and 3.6 and 2.8 for achieving PASI 100. These values are far lower (better) than those for non-biologic synthetic agents or TNF inhibitors. These new therapies mean that clearance is an achievable goal for patients with psoriasis.

There are many well-established comorbidities of psoriasis, including cardiovascular and metabolic disease. There is also increased mortality in patients with psoriasis (a 5-year reduction in lifespan). Patients with psoriasis are 30 times more likely to have a cardiovascular event than to develop melanoma. Your patients with psoriasis should be carefully evaluated for these very common conditions

Emerging comorbidities of psoriasis include chronic obstructive pulmonary disease, asthma, and chronic kidney disease. It is important to understand the entire spectrum of disease in each of your patients with psoriasis and ask questions that can uncover depression that may result from this burden.

A key question is how to identify patients with psoriasis likely to develop psoriatic arthritis (PsA). A good question to ask patients with psoriasis is, “Do you have joint pain or other joint symptoms that you want to do something about?”

Tapering therapy is an attractive approach to patient management in patients with PsA and rheumatoid arthritis (RA), but there is some evidence that stopping medication and restarting after a flare may not regain the efficacy attained prior to the treatment holiday.

It is important to understand that patients’ and physicians’ evaluation of the impact of their disease are very different and patient reported outcomes (PROs) are very important for determining “how patients do”.

Variables that significantly affect patients’ response to disease include gender and the portion of the body surface affected by psoriasis. Women are more adversely affected by psoriasis than men and the head and face are the most important parts of the body for influencing the patients’ perception of their disease severity.

It is important to keep in mind features of therapy that can affect real-world patient adherence, Maintenance regimens that are less complicated enhance the potential for increased patient adherence and successful outcomes.

Psoriasis 2015: More Pearls from Bruce Strober, MD, PhD

  • Hepatitis B serologies should be obtained prior to starting TNF inhibitors. Understanding the meaning of the various tests is important.
  • Continuous therapy with biologics more reliably guarantees persistent response.
  • Palmoplantar psoriasis is usually more difficult to treat, yet most effective psoriasis medications can be successful in at least 1/3 of patients.
  • Subcutaneous methotrexate demonstrates better bioavailability, tolerability, and efficacy when compared to oral methotrexate.
  • Ustekinumab is approved for the signs and symptoms of psoriatic arthritis, yet displays lesser efficacy for this disease than that of the TNF inhibitors.
  • All biologics have demonstrated efficacy for the treatment of nail psoriasis.
  • It is safe to use TNF-inhibitors in the context of hepatitis C infection.
  • Immunogenicity is one reason biologic therapies lose efficacy over time.
  • Biologic therapies have not been demonstrated to cause solid tumor malignancies at a rate greater than the baseline rate of patients with psoriasis.
  • Patients with a prior history of malignancy often can safely receive biologic therapies.
  • Live vaccines should only be administered to patients who are not currently receiving biologic therapies.
  • TNF inhibitors are thought to be safe to use during pregnancy and breastfeeding.

Psoriasis 2015: Pearls from Bruce Strober, MD, PhD

  • Apremilast achieves PASI 75 in approximately 30% of patients after 16 weeks of therapy.
  • Apremilast has FDA-approval for the treatment of both psoriasis and psoriatic arthritis.
  • Apremilast is associated with a >5% weight loss in between 10-20% of treated patients.
  • Secukinumab is the FDA-approved biologic medication with currently the highest level of clinical efficacy of all the self-injectable medications.
  • A side effect of secukinumab is oral candidiasis, which is usually mild and occurs in up to 5% of patients.
  • Secukinimab therapy should be used with caution in patients with inflammatory bowel disease.
  • IL-23 inhibition is a future mechanism of action for psoriasis therapy that shows very high efficacy in early clinical trials.
  • Ixekizumab is an IL-17 inhibitor that promises the highest level of efficacy of its class.
  • Tofacitinib inhibits JAK kinases and likely will be an oral drug approved for psoriasis. The only question is which dose, 5 or 10 mg, will be approved.
  • Secukinumab, ustekinumab and apremilast, like TNF inhibitors, are able to treat psoriatic arthritis to varying levels of efficacy. The TNF inhibitors remain the gold-standard therapies for psoriatic arthritis, though.

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.

Psoriasis 2015: Clinical Pearls

Bruce Strober, MD, PhD

Dr Strober provides us with some important takeaway points from his psoriasis lecture…

  • Apremilast achieves PASI 75 in approximately 30% of patients after 16 weeks of therapy.
  • Apremilast has FDA-approval for the treatment of both psoriasis and psoriatic arthritis.
  • Apremilast also has been shown to provide improvement for nail and scalp psoriasis, and the reduction of pruritus.
  • Apremilast is associated with a >5% weight loss in between 10-20% of treated patients.
  • Secukinumab is the FDA-approved biologic medication with currently the highest level of clinical efficacy of all the self-injectable medications.
  • A side effect of secukinumab is oral candidiasis, which is usually mild and occurs in up to 5% of patients.
  • IL-23 inhibition is a future mechanism of action for psoriasis therapy that shows very high efficacy in early clinical trials.
  • Tofacitinib inhibits JAK kinases and will be an oral drug approved for psoriasis.
  • Tofacitinib increases the risk for varicella-zoster.
  • Both secukinumab, apremilast and tofacitinib are all drugs that variably treat psoriatic arthritis.

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

Psoriasis Update: Current Therapies

Bruce Strober, MD, PhD

At Maui Derm 2015, Dr Strober led the psoriasis panel with a discussion on current therapies.

Apremilast

Apremilast, an oral phosphodiesterase type 4 inhibitor, was approved for psoriatic arthritis in March, 2014 and subsequently approved for the treatment of moderate-to-severe psoriasis in September, 2014. The data for apremilast rests on two major Phase III studies, ESTEEM 1 and ESTEEM 2. Patients with moderate to severe plaque psoriasis (PASI = 12, BSA =10%, sPGA =3) were randomized 2 to 1 to apremilast 30 mg twice daily or placebo. At week 16, all placebo patients switched to apremilast 30 mg through week 32. At week 32, all patients who achieved PASI-75 were randomized (1:1, blinded) to continue apremilast or receive placebo. Upon PASI-75 loss, patients who were re-randomized to placebo resumed apremilast treatment.

The efficacy (PASI 75 achievement at 16 weeks) of apremilast in either study (ESTEEM 1/ESTEEM 2) is somewhere around 29% to 33% and placebo is around the 5% to 6% range. Apremilast demonstrated an acceptable safety profile and appeared to be well tolerated for up to 52 weeks.

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Within these studies, subanalyses were performed looking at nail, scalp and palmoplantar psoriasis based on the NAPSI, ScPGA, and PPPGA. Apremilast demonstrated significantly greater response rates versus placebo for psoriasis affecting the nails, scalp, and palmoplantar areas among patients with NAPSI ≥1 (n=266), ScPGA ≥3 (n=269), or PPPGA ≥3 (n=42) at baseline, respectively. This data demonstrates reduced severity in nail, scalp, and palmoplantar psoriasis at week 16, and observed improvements up to week 32. Keep in mind that the patients in this study with palmoplantar psoriasis were seen in the context of also having moderate-to-severe psoriasis; these are not patients with bona fide, stand-alone palmoplantar psoriasis.

Overall, the drug appears to do well on various parts of the body, much like our other good psoriasis medications.

When you’re discussing apremilast with your patients, there are two side effects that seem to appear to be most troublesome—diarrhea and nausea. Over the course of the study, approximately one in six patients experienced diarrhea or nausea; however, probably fewer than five percent of patients found it intolerable and very few patients discontinued this drug due to either side effect.

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Most commonly, these side effects occur during the first one to two months of therapy. There are no real “studied” approaches to minimizing these side effects; however, after the first of couple of months, the side effects did tend to wain.

Apremilast: Effects on Itch

Psoriasis patients have reported itching as the most bothersome symptom of psoriasis. (Lebwohl MG, JAAD. 2014) A pooled analysis of VAS of itch from ESTEEM 1 and 2 demonstrated improvements in pruritus with apremilast as early as week 2 and maintained through week 32. The reduction of itch in many patients precedes the clearing of their skin.

Additional Considerations with Apremilast

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As previously noted, apremilast demonstrated an acceptable safety profile and was generally well tolerated for up to 52 weeks with no new or unexpected safety findings. In Dr Strober’s opinion, you should perform baseline labs prior to starting any medicine for moderate-to-severe psoriasis. This is, in part, due to the fact that you may have to switch drugs if they do not respond to the initial therapy. Current data show no indication for a need for laboratory monitoring with apremilast, as no organ- or system-specific toxicities have been detected.

One of the two warnings on the label for this drug is the risk for depression or thoughts of suicide. Another pooled analysis of the ESTEEM 1 and 2 trials studied psychiatric disorders and depression with the use of apremilast. There is a slight increase in frequency of depression with the patients on apremilast versus placebo (1.2 % to 0.5%). Based on an analysis of clinical trials of apremilast and the published literature on psoriasis, there is no evidence of an increased risk of psychiatric events, including suicide, with the use of apremilast. The rate of depression was comparable to the background rate in the psoriasis population. People often ask about this issue, but Dr Strober feels that depression and mood effects of apremilast are possible, but are relatively rare. This should be discussed with the patient at the baseline visit, and followed prospectively.

One important way of looking at the data is to consider how the drug affects the population overall with regards to symptoms of depression. The PHQ-9, a patient-reported questionnaire, has been very well accepted, according to the medical community, as a very reliable, subjective means to detect depression. Using the PHQ-8, a similar study lacking one question found in the PHQ-9, invesigators found that psoriasis patients receiving apremilast achieved significant improvements in the PHQ-8 total score compared to those receiving placebo—indicating that their depressive symptoms may improve over the course of therapy.

Weight loss is another warning in the apremilast label. While weight loss has been observed in the ESTEEM trial (approximately one in five to six patients), there were no significant clinical consequences observed from the weight loss. The average weight loss over one year of therapy across all study subjects receiving apremilast is about four pounds. When discussing this drug with your patients, this is an issue that should be mentioned. Weight loss did appear to level off over time and it was not correlated with diarrhea/nausea. One cannot predict who will experience weight loss, and this side effect affects patients of both high and low BMI. Of note, only two patients in the clinical studies discontinued apremilast because of weight loss.

Drug Survival

Dr Strober concluded his presentation by discussing a few posters that have been presented over the past year regarding drug survival. According to Dr Strober, “one of the biggest failings of the medicines that we use for psoriasis is that they don’t always keep working.”

Which drugs do the best when looking at analyses?

There are three different analyses out there and they’re all corroborating one another. The first study (van den Reek and colleagues) aimed to describe one-year drug survival for adalimumab, etanercept, and ustekinumab in a daily practice psoriasis cohort. The other objective was to introduce the concept of ‘happy’ drug survival defined as DLQI≤5 combined with being ‘on-drug’ at a specific time-point. 249 patients were included in the study. The patients were asked how ‘happy’ they were over a course of time, i.e., 1. remained on the drug and; 2. DLQI was reduced to less than or equal to five.

Of note, your average patient, when he/she enters a clinical study for moderate to severe psoriasis, has a DLQI in the 10 to 13 range. If you are able to bring those patients to less than or equal to five, then you are achieving a measurable and clinically significant improvement in quality of life.

In this study, at baseline, the majority (n=115, 73%) was considered ‘unhappy’ and the minority ‘happy’ (n=42, 27%). The percentage of ‘happy’ on-drug patients increased to 79% after 1 year. In summary, ustekinumab showed better overall drug survival compared to etanercept and a trend towards better overall drug survival compared to adalimumab. Why do we suppose we may see these results? We must keep in mind that in these studies there is no randomization. Secondly, does the frequency, setting and method of administration make a difference? With ustekinumab, a subcutaneous medication commonly is administered in the office every 3 months. This set of features may allow patients to stay on drug longer. We should also consider whether or not the DLQI is a valid means to measure happiness and drug survival.

A multicenter, longitudinal, observational study, PSOLAR, evaluated persistency, i.e., treatment longevity, of biologics for psoriasis. While this study was funded by Janssen Biotech as part of the post-marketing surveillance for ustekinumab, it is important to note that over seven hundred patients were on drugs other than ustekinumab.

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Again, this was not a randomized study, and patients were “channelled” to the various therapies based on “real world” clinical decision making. The results show that the persistence of ustekinumab therapy in PSOLAR was significantly better than anti-TNF therapies in biologic- naïve and experienced psoriasis patients, with lower rates of stopping/switching and higher median days on therapy.

In a third study, the researchers aimed to describe and compare the drug survival of different biologic (infliximab, etanercept, adalimumab,and ustekinumab) and systemic drugs (acitretin, cyclosporine, and methotrexate) in moderate-to-severe psoriasis by analysing data from the BIOBADADERM registry. 1956 patients were included in the analysis (1240 on biologics and 1076 on classic drugs) with a median follow-up time of 3.3 years. When looking at the demographic data, you can see age differences across the board as well as widely varying PASI scores. Patients with more severe disease appeared to be going on infliximab with other less severe patients going on other biologics or even acitretin.

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Over half of these patients were on prior therapy. There were 2,209 discontinuations during the study time with the main reason being a lack of efficacy (36.4%), followed by remission of the disease (27.2%). In Europe, sometimes patients are treated until remission and then they stop drug. This is not something that we necessarily do here in the United States. The results of this study demonstrated that biologics, especially ustekinumab and infliximab, showed a superior drug survival than classic agents. In conclusion, the number of patients with moderate-to-severe psoriasis in continuous therapy decreases with time for all the systemic drugs included in the cohort, both classical systemic drugs and biologics. There seem to be a high number of factors that influence drug survival rates in psoriasis treatment making survival studies prone to bias and not necessarily the best approach to evaluate drug efficacy and safety in this specific setting, especially when comparing different drugs.

Nevertheless, ustekinumab, across three different studies carried out in very different geographic settings and with different methodology, demonstrated the most durability among the various agents used psoriasis treatment. Whether this is artefact or real may be validly debated.

 

 

 

Psoriatic Arthritis: Key Developments in 2014

Arthur Kavanaugh, MD

At Maui Derm 2015, Dr Kavanaugh, a Rheumatologist at the University of California, San Diego, presented some of the important developments in psoriatic arthritis (PsA) from 2014.

The diagnosis of PsA remains a challenge. Data from the Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey looked at 3,426 patients with psoriasis and/or PsA. Among those patients, 712 (20.8%) had PsA. (Lebwohl MG, et al. J Am Acad Dermatol. 2014;70:871-881.) According to the survey, the average was five years between PsA signs and symptoms and diagnosis. What symptoms do we need to recognize in these patients? In this survey, symptoms included:

  • Joint pain in knees (41%), fingers (26%), hips (19%), back/spine (18%), ankles (19%), and wrists (16%)
  • Pain or swelling in heels (45%) and “sausage digits” (31%)

Approximately 16% of these patients did not see a healthcare provider in the past year, and most of the PsA patients in the survey were not treated by a rheumatologist. These results imply a huge unmet need as many psoriatic patients are going untreated. We may need to think about the realization of PsA at the primary care level so that these patients can be referred to rheumatologists or dermatologists for appropriate treatment.

Among those with PsA in the MAPP survey, the majority of patients were not on therapy (28%) or on topical therapy (31%). Of the patients surveyed who had ever used biologic therapy (including those with psoriasis or PsA), 45% had discontinued treatment.

The literature suggests that only half of patients with PsA are diagnosed, and only half of the diagnosed patients receive drug treatment. This is something that we can and must do better.

In rheumatology, Dr Kavanaugh comments that we are still fighting the historical viewpoint that PsA is not as bad as rheumatoid arthritis (RA). But, if you take people who have polyarticular disease, you will see that they are every bit as severe as the RA patients.

It has been shown that a delay in the diagnosis of PsA correlates with worse outcomes for patients. In a study of 283 patients fulfilling CASPAR criteria from a single Irish center, the mean lag from symptom onset to seeing a rheumatologist was about one year. This study demonstrated that if the patient didn’t get to the rheumatologist within 6 months, he/she had 4 times the chance of already having joint damage. Even a short delay in diagnosis is associated with increased morbidity. (Haroon M, et al. Ann Rheum Dis Epub 27 Feb 2014)

Diagnosis

Diagnosis of PsA can be a bit tricky. Among the patients with psoriasis, who are the 25%-30% of patients who have PsA? Because skin symptoms often precede joint symptoms, dermatologists play an important role in the early diagnosis of PsA.

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Psoriatic Arthritis Screening and Evaluation (PASE)

  • Dermatology or shared clinic
  • 15 questions in subscales
  • No skin and nail assessment

82% sensitive; 73% specific

Toronto Psoriatic Arthritis Screening Questionnaire (ToPAS)

  • Dermatology, rheumatology, family medicine clinic
  • 11 questions and pictures
  • Skin and nail assessment

87% sensistive; 93% specific

Psoriasis Epidemiology Screening Tool (PEST)

  • Community and hospital clinic
  • 5 questions plus joint exam
  • Skin and nail assessment

97% sensistive; 79% specific

 

Treatment of PsA

TNF inhibitors have dramatically changed our overall approach to the management of PsA. They remain the main focal point of how we treat patients with moderate-to-severe disease activity.

What’s new with TNF inhibitors? One very important consideration is that of biosimilars. There is a biosimilar infliximab that is widely used in Europe. It was studied in RA and a small study was also conducted in ankylosing spondylitis; however, its approval was across the board for all of infliximab’s indications. An etanercept biosimilar that was studied in psoriasis was just approved in Korea for all six etanercept indications.

What about the relationship between serum concentration and efficacy? Vogelzang and colleagues studied serum adalimumab concentrations and clinical response in 103 PsA patients treated with 40 mg over 28 weeks measured by ELISA. The researchers found that adalimumab concentrations of 5-8mg/L achieved optimal clinical benefit in PsA as previously seen in RA.

What about remission? Can we taper or discontinue therapy? According to Dr Kavanaugh, the short answer is that we really don’t know. Studies in PsA have shown that the possibility of reaching a drug-free remission is low and discontinuation of DMARD therapy is not recommended. (Araujo E G et al. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-204229) An observational cohort study of the PsA patients in the CORRONA registry also looked at stopping TNFi therapy and the data can be interpreted a number of different ways. There were some patients who were able to stop therapy and still do well and others flared around or just before two years after stopping therapy. The challenge is identifying the patients who will do well. There are dozens of studies in RA that are looking at this issue. The trouble is, we cannot compare from study to study because there are so many different variables to consider such as the tapering plan, the “target” for remission, duration, prior/concomitant therapy, disease activity, definitions of failure, length of follow-up, efficacy of retreatment, sequelae of flares, predictors of response, study design, motivation, and specific biologic target/agent. (Yoshida K, et al. Ann Rheum Dis 2014;73:e5; Kavanaugh A, Smolen JS. Clin Exp Rheumatol 2013;31(Suppl.78): S19–S21)

Immunologic Targets in PsA

What about other pathways? Even though we’re doing much better than we were in years past, there is still an unmet need until we can cure everyone.

Interleukin-17A has been found to be a unique pathway in immune-mediated diseases, i.e., psoriasis and psoriatic arthritis. The human monoclonal antibody, secukinumab, selectively neutralizes IL-17A and has demonstrated very positive ACR responses at week 24 when compared to placebo in the FUTURE 1 study. (Mease P, et al. ACR Annual Meeting. Nov 14-19, 2014; Boston, MA; Oral 953)

What about patients who have been on the TNF inhibitors? Those patients can be more difficult, but they’re the ones who we really want to know about as we typically utilize TNF inhibitors first. As we have previously seen with the ustekinumab data and other RA studies, the people who are naïve to TNF inhibitors did better overall than those who had previously been on TNF agents; but, the responses were still good.

IL-17 also has a positive impact on joint damage, in that it inhibits radiographic progression with treatment. This is very impressive data as these studies are becoming harder and harder to conduct for ethical reasons.

The PASI 75 and 90 responses through week 52 also demonstrate strong evidence for the use of secukinumab. Patients were receiving either secukinumab 10 mg/kg IV + 150 mg SC or secukinumab 10 mg/kg IV + 75 mg SC. At week 52, 76.9% and 65.7% of patients, respectively achieved a PASI 75.

In the FUTURE 2 study, there was no IV loading dose; they studied secukinumab subcutaneously only. When looking at the positive ACR responses at week 24, we can see very little difference between secukinumab 300 mg versus 150 mg.

However, we do see a difference in dosing when looking at TNF naïve versus TNF exposed patients. In the FUTURE 2 study, patients were receiving secukinumab 300 mg, 150 mg, 75 mg or placebo. Among the TNF naïve patients, 38.8%, 44.4%, and 24.6%, respectively achieved an ACR 50. Among the TNF exposed patients who achieved an ACR 50, the results were 27.3%, 18.9%, and 5.9%, respectively.

Ustekinumab, an IL-12/23 inhibitor, was approved in September 2013 for the treatment of PsA. In addition to demonstrating clinical efficacy, ustekinumab has also shown the ability to stop X-ray progression. (Kavanaugh, A et al. Ann Rheum Dis. 2014 (Epub 2014 19 Feb)

Cytokine-based Disease Taxonomy

We’re now learning many different facets of disease and Dr Kavanaugh believes that we will begin discussing responses to these different targets more than we ever have before. Interestingly, IL-17A appeared to have no clinical efficacy in RA and may have even worsened the crohn’s disease.

Intracellular Signaling

The two-year data for Apremilast, which will be presented at EULAR in June 2015, shows that 86% of the patients stayed on drug and about 20% achieved an ACR 70 response.

The earlier data for apremilast, while not quite as robust as that of the TNF inhibitors, still shows good clinical ACR response rates.

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Among patients receiving apremilast 20 mg BID and 30 mg BID, 34% and 51%, respectively, achieved a PASI 50 and 18% and 21%, respectively, achieved a PASI 75. Some patients do very well with this drug. The safety and tolerability issues with apremilast are very important for patients, as most adverse events are either mild or moderate and there is no need for laboratory monitoring.

In conclusion, Dr Kavanaugh feels that the future of PsA is very bright. We have lots of therapies on the horizon. GRAPPA is currently in the process of updating the PsA guidelines so as to incorporate some of the newer data.

 

 

 

 

More Clinical Pearls on Psoriasis

Joel Gelfand, MD

What about common comorbidities associated with psoriasis? Dr Gelfand highlights important clinical pearls…

  • The risk of comorbidities generally increases with the severity of psoriasis, patients with more severe disease have a 5 year reduction in life expectancy
  • Well established comorbidities associated with psoriasis include Heart Attack, Stroke, CV death, Metabolic syndrome, Diabetes, Psoriatic arthritis, Mood Disorders (anxiety, depression, suicide), Crohn’s Disease, and T cell lymphoma (rare)
  • Emerging comorbidities associated with psoriasis include Sleep apnea, Nonalcoholic steatohepatitis (NASH), Chronic obstructive pulmonary disease (COPD), Adverse infectious disease outcomes, Chronic and end stage renal disease, Peptic ulcer disease
  • Perform a skin biopsy if the diagnosis is not certain or if the patient is not responding appropriately to treatment. Connective tissue diseases and cutaneous T cell lymphoma can mimic psoriasis and may be exacerbated by psoriasis treatments
  • Putting a patient on an immune suppressive medication? Be sure to consider age appropriate cancer screening and vaccinations to lower the risk of complications