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we all know, the T-cell inhibitors, alefacept and efalizumab, once both approved for the treatment of psoriasis, were withdrawn from the market due to lack of use and serious infections (PML), respectively.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

Psoriasis Update–Current Therapies: Clinical Pearls

Bruce Strober, MD, PhD

Below are some important clinical pearls from Dr Strober’s update on psoriasis:

  • 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.
  • Data from the clinical trials of apremilast for the treatment of psoriasis do not convincingly support the contention that treatment with this drug causes depression and/or suicide.
  • Multiple independent registry studies show ustekinumab having the best durability of use, with patients remaining on this drug longer than other biologic and systemic drugs.
  • Rates of hospitalized infectious events are very low and fairly comparable between the various modalities, systemic and biologic, used to treat psoriasis.

Emerging Therapies in Psoriasis: Clinical Pearls

Bruce Strober, MD, PhD

What’s new in the field of psoriasis? Dr Strober provides us with some clinical pearls…

  1. TNF-inhibitors cause weight gain.
  2. Ustekinumab does not cause weight gain.
  3. IL-23 inhibitors block p19 and are more specific than IL-12/23 inhibitors, which block p40.
  4. Apremilast achieves PASI75 in approximately 30% of patients after 16 weeks.
  5. IL-17 pathway inhibitors achieve PASI75 in approximately 80% of patients after 12-16 weeks.
  6. IL-17 pathway inhibitors may slightly increase the risk of mucocutaneous candidiasis.
  7. JAK kinase inhibitors will require monitoring for liver function, renal function, lipids and creatinine phosphokinase.
  8. JAK kinase inhibitors might increase the risk of varicella zoster infection.
  9. Apremilast treats psoriatic arthritis.
  10. Apremilast does not need laboratory monitoring.

 

 

 

 

Psoriasis: Update on Emerging Systemic Therapies

Craig Leonardi, MD

At MauiDerm 2014, Dr  Craig Leonardi, Clinical Professor of Dermatology at Saint Louis University, presented us with the latest data on emerging systemic therapies for the treatment of psoriasis. According to Dr Leonardi, “the psoriasis space is going to move very quickly over the next year/year and a half…”

Dr Leonardi comments that many of our 2nd generation biologics were developed with these cytokines in mind (see below).

Screen Shot 2014-04-28 at 8.08.27 AM

 

Remember that drugs come and go and many fall by the wayside; what’s important to us, as practitioners, is finding the best medicine for our patients.

Certolizumab Pegol (CZP)

CZP is a peglyated Fab fragment. It was initially approved for Crohn’s disease and subsequently approved for the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. In 2005, there was a large phase II psoriasis trial of 176 patients with 10 percent BSA and PASI 12. It was conducted in Germany and France to look at CZP for the treatment of psoriasis. There were three treatment arms: 200mg sc qeow, 400mg sc qmonth, and placebo. PASI 75 results demonstrated 75 percent, 83 percent and 7 percent, respectively. PGA results (clear-almost clear) showed 53 percent, 72 percent and 2 percent, respectively among all treatment arms. There were no unexpected safety issues. This data tell us that CZP is both efficacious and safe for the treatment of moderate to severe plaque psoriasis. The fact that it is approved for PsA is also important to patients with PsO/PsA. This data was presented in 2007 at the American Academy of Dermatology and published as a paper in 2012. It appears that currently, UCB, the maker of CZP, has again taken an interest in this medication, as there is some development effort and we should be seeing a psoriasis trial quite soon.

Targeting the IL-12/23 Pathway

Both ustekinumab (IL-12) and briakinumab (IL-23) block the shared p40 subunit. When you block IL-12, you down-regulate a set a cytokines from the Th1 pathway, including INFy, IL-2 and TNF-alpha.  When you block IL-23, you down-regulate IL-17 alpha, IL-17f, IL-6, TNF-alpha, IL-21 and IL-22.

Function of Th17 Effector Cytokines

IL-17a

•Expressed by memory NK and T cells

•Increased in psoriatic skin

•Subcutaneous injection à neutrophilia

•Enhances inflammation

•Enhances angiogenesis

IL-22

•Expressed in high levels by Th17 cells

•Increased in psoriasis (skin and plasma)

•Levels correspond to disease activity

•Induces keratinocyte hyperproliferation (in vivo, in vitro)

•Stimulates keratinocytes to secrete antimicrobial peptides

Ustekinumab is a high-performing drug for psoriasis patients. The data at week 28 in both the PHOENIX 1 and PHOENIX 2 studies, show about 70-79% of patients are achieving a PASI 75; this is a huge achievement for these patients.

Screen Shot 2014-04-28 at 8.08.38 AM

New Development Efforts

Ustekinumab was recently approved for the treatment of PsA, based upon its efficacy data with regards to an ACR 20 response at week 24.

Screen Shot 2014-04-28 at 8.08.46 AM

However, when you compare these numbers with the other TNF antagonists, ustekinumab does not appear to work as well in PsA. It remains to see how our rheumatology colleagues will regard this drug over time. It may be used as a second- or third-line drug for PsA.

Screen Shot 2014-04-28 at 8.08.52 AM

 

3rd Generation Biologics

There is a down-stream effect from anti-IL-23 blockade feeding into IL-17 and down-regulating IL-22. Many pharmaceutical companies have been studying this pathway; there are two, possibly three, IL-23 inhibitors currently in trial, there are two anti-IL-17 inhibitors, an IL-17 receptor antagonist, and there was an IL-22 blocker that came and went…this is a very rich developmental pathway with many promises.

IL-17 Antagonists

The phase II studies of secukinumab (Novartis) a human IgG1 monoclonal IL-17A antibody demonstrated that the 150mg and 300mg doses were statistically significant as compared to placebo at week 12. This is an incredibly high-performance drug, i.e., in the 300mg dose, between 80 and 90 percent of these patients were achieving a PASI 75. According to Dr Leonardi, “this is absolutely remarkable when you think about the world of chronic inflammation”.

The results of secukinumab’s pivotal phase III data was released this fall at EADV.  Dr. Leonardi reported that the ERASURE study evaluated secukinumab doses of 150 mg and 300 mg in a placebo controlled study.  PASI-75 response rates in the secukinumab groups reached a peak at week 16 (80% – 90% range).  IGA scores of “clear or almost clear” were reported in the 60% to 75% of patients. Treatment benefit was maintained through week 52 on q4 week injections following an induction period. Other phase 3 trials included the FIXTURE study included etanercept as an active control.  In this comparator study patients showed a more rapid response to secukinumab vs etanercept (3 vs 8 wks) to achieve a PASI 50 and greater number of patients achieving PASI 90 (72.4% vs 41.5%). The third secukinumab Phase 3 trial SCULPTURE compared fixed-interval q4 weeks maintenance dosing with an “retreatment-as-needed” regimen. Data from follow-up to week 52 showed fixed interval therapy with SEC 300 mg and 150 mg q4wks sustained significantly greater PASI 75, 90 and 100 clearance rates over 1 year compared to “retreatment-as-needed”. “Retreatment as needed” is not a good regimen for any biologic”, says Dr. Leonardi.

We haven’t seen any of the safety results from the secukinumab phase III trials; however, the drug was well tolerated overall according to the phase II data according to Dr. Leonardi.

Ixekizumab (Lilly), is another anti-IL 17 monoclonal antibody, is another high-performance skin-clearing drug based upon its phase II data. Studies looking at 10, 25, 75 and 150 mg demonstrated that at the two highest doses, 80 percent of patients were at the PASI 75 range. There were no serious adverse events in this trial and the drug had a “remarkable safety profile” according to Dr. Leonardi.

The biostatisticians at Lilly, the makers of ixekizumab, utilized Youden’s Index to create a sensitivity and specificity assay. They determined that if they looked at the PASI 50 response at week four, they could make accurate predictions on the chances of success downstream. The likelihood of achieving PASI 75 and PASI 90 correlated with the PASI 50 response.

Brodalumab (Amgen) is an anti-IL-17 receptor antibody, which blocks not only Il-17A but also IL-17E and IL-17C.  It is another high-performance drug for the treatment of psoriasis. The phase II studies, which were completed some time ago, demonstrated positive efficacy results along with a good safety profile. The long-term maintenance of clinical response with brodalumab has been demonstrated through week 96 of an open-label extension study. The one caveat with this open-label extension study is that it is an observed analysis, not an intent-to-treat approach to the data. Remember that the patients who came out of the trial are those who are not doing well so as you move through the trial, the population will continue to improve.

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Positive results were also seen with sPGA over 96 weeks.

Interleukin 23

Remember that the p19 subunit is NOT shared; therefore, an anti-P19 molecule will block just IL-23. Tildrakizumab, a novel anti-IL23p19 monoclonal antibody, demonstrated good results in a 16-week phase IIB trial. There were four doses at weeks 0 and 4 (5mg, 25mg, 100mg, and 200mg) versus placebo.  PASI 75 was achieved in 35, 65.5, 67.1, and 76.2 percent of patients, respectively versus 4.9 percent in the placebo arm and PASI 90 was achieved in 11.9, 24.4, 38.2, and 51.2 percent of patients versus 2.2 percent in the placebo arm. Tildrakizumab appears to be generally safe and well tolerated.

Small Molecules

Apremilast (Celgene)is a novel, small molecule that inhibits PDE-4. It has a variety of immunosuppressive effects, in that it reduces TNF-alpha, IL-2, IFN-γ and several leukotrienes. In Phase III studies (ESTEEM I and II), apremilast (30 mg BID) has achieved a PASI 75 rate of 33 percent. Importantly, scalp, nail and pruritus scores were superior in the apremilast patients compared to controls. Phase III results also demonstrated greater improvements from baseline Dermatology Quality of Life Index versus placebo.  The majority of adverse events (AEs) were not serious and included mild gastrointestinal side effects: nausea 16% and diarrhea 19%.

According to Dr. Leonardi, apremilast also has phase III PsA results that are statistically significant versus placebo although not quite as robust as the TNF inhibitors.  (FDA approval for apremilast for the treatment of PsA was announced during the winter AAD).

Tofacitinib (Pfizer), a novel, oral JAK inhibitor approved for the treatment of rheumatoid arthritis, is currently being investigated as a treatment for psoriasis among other indications. At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25% (2mg), 40.8% (5 mg) and 66.7% (15 mg), compared with placebo (2%). It appears to work about as good as methotrexate. Of note, in rheumatoid arthritis, the FDA approved only the 5mg dose. The phase II safety data reported five serious adverse events (SAEs), three of which (atrial fibrillation, pyelnephritis, and urosepsis) occurred in one patient on the 2mg BID dose. There was a mild increase in Hgb levels that was greater in the 15mg BID group. There was a transient decrease in PMNs in the 5mg and 15mg BID groups and there were dose-related increases in both HDL and LDL. In the rheumatoid arthritis trials, the FDA found that the numerical increase in malignancy incidence over time was of particular concern and is consistent with a scenario where increasing exposure to tofacitinib increases the risk of malignancies. The FDA also stated that opportunistic infections, including TB, were “not uncommon.” In the RA program, 14 out of 15 patients who died due to infection were on tofacitinib. There were 34 patients with opportunistic infections, all of whom were on tofacitinib. Despite the immunological differences between rheumatoid arthritis and psoriasis patients, this is remarkable data and something that we, as dermatologists, need to pay particular attention to.

Conclusions

In conclusion, we can see an explosion of new biologics in the marketplace with most of the drugs targeting the IL-23 pathway. We still have an unresolved issue with regards to major adverse cardiovascular events (MACE).  Some feel that there is a signal at the IL-12/23 blockade level, it will be interesting to see if the MACE signal populates the IL-17 blockers…there may be more information coming out on that.  We are also seeing a wide variety of novel small molecules demonstrating moderate to robust efficacies and the safety profiles for some of these products are promising.  There has also been a move to explore the JAK inhibitor in a topical formulation to treat psoriasis.

Psoriasis patients are now the “model” of choice for chronic inflammatory disease and we are getting these drugs earlier now than ever before.  Remember that many of the drugs have fallen by the wayside for efficacy and/or safety issues. We need to select drugs that are good for our specialty and for our patients. As dermatologists, we need to consider that short- and long-term safety issues do exist; however, the benefit/risk ratio appears to be favorable overall.

Our treatment paradigm has shifted from a stratified approach, i.e., patients must fail the previous “step” of therapy before initiating a more “aggressive” therapy to an approach whereby the choice of therapy depends upon individual patient characteristics.

 

MauiDerm News Editor- Judy Seraphine

 

Psoriatic Arthritis Update

Arthur Kavanaugh, MD

Dr Arthur Kavanaugh is a Rheumatologist and a Professor of Medicine at the University of California, San Diego. At MauiDerm 2014, he provides the practicing dermatologist with an update on PsA and the latest treatment advances…

The reported estimates of the prevalence of PsA among psoriasis patients have been highly variable, i.e., six percent to 42 percent. It is currently estimated that between 20 and 30 percent of psoriasis patients also have PsA. In addition, psoriasis precedes PsA in over 85-90 percent of the cases, though we’re not sure why. Dr Kavanaugh believes that in 20 to 30 years, we may have that answer. In 2012, there were an estimated 1,600,000 PsA patients in the United States. Of those patients, about 485,000 were diagnosed and only about 345,000 received treatment. Now that we have treatment available, Dr Kavanaugh feels that healthcare providers will be seeing more of these patients. As dermatologists, it is important to remember that PsA is a serious condition; approximately 20 percent of patients with PsA will develop destructive, disabling arthritis. PsA results in radiological damage in up to 47 percent of patients at a median interval of two years. Remember that other comorbididites often exist among PsA patients; these include, metabolic syndrome, CAD, uveitis, IBD, impaired function and quality of life, and economic implications.

Recent data presented at the 2013 American College of Rheumatology, suggest that a delay in the diagnosis of PsA correlates with poor patient outcomes. A study of 283 PsA patients, fulfilling the CASPAR criteria, demonstrated that even a six-month delay from symptom onset to the first visit with a rheumatologist contributed to the development of peripheral joint erosions, sacroiliitis, and worse long-term physical function.

Diagnostic Criteria for PsA (CASPAR)

The diagnostic criteria for PsA includes an established inflammatory articular disease (joint, spine, or entheseal), plus three or more points from the following five categories:

  • Psoriasis
    • Current-psoriatic skin or scalp disease present today (2 points)
    • History-a history of psoriasis
    • Family history-history of psoriasis in a first or second degree relative
    • Nail Changes-typical psoriatic nail dystrophy
    • A negative test for RF-by any method except latex (preferably ELISA or nephlemetry)
    • Dactylitis
      • Current-swelling of a current digit
      • History –history of dactylitis
      • Radiological evidence of juxta-articular new bone formation-ill-defined ossification near joint margins (but excluding osteophyte formation) on plain X-rays of hand or foot

The CASPAR criteria are very sensitive and very specific; but, in the clinic, the question lies as to whether or not the patient has inflammatory arthritis. That is a tougher question and we don’t have a perfect answer for that. Several questionnaires and screening tests have been developed for this, such as the Psoriasis Epidemiological Screening ProjecT (PEST), Toronto Psoriatic Arthritis Screen (ToPAS), and Psoriatic Arthritis Screening and Evaluation (PASE). All of these instruments did relatively well in the development studies; however, remember that with these screening tests come trade-offs. The more sensitive an answer is, the less specific it is and vice versa. There is no perfect questionnaire and how they perform is based upon how you define them. The difficulties are the oligoarticular and differentiating osteoarthritis from inflammatory arthritis. The utilization of more sensitive imaging (ultrasound and MRI) can help to determine what is inflammatory versus what isn’t inflammatory.

GRAPPA PsA Treatment Recommendations

The chart below outlines the GRAPPA treatment recommendations; however, these guidelines are currently being updated to incorporate some of the newer treatment modalities.

Screen Shot 2014-03-20 at 3.04.49 PM

 

Treatment choices are based on the severity of the different domains.

Clinical Pearl-PsA requires a clinician to really listen to the patient, examine the patient, and formulate and appropriate treatment plan with the patient.

We know that the data on the TNF blockers for the treatment of PsA is very positive for both joint symptoms and skin symptoms. Currently, we even have data that demonstrate the effects of TNF blockers on issues that are important to the patient, such as nail involvement, enthesitis, and dactylitis. In the past, we didn’t have we didn’t have quantifiable ways to measure these, but now we do.

Data also demonstrate that TNF inhibitors slow down the damage to the bone. Getting patients under good control allows them to be functional and go about doing the things they do in their daily life.

Certolizumab Pegol

Certolizumab Pegol (CZP) was approved for the treatment of PsA in September of 2013 and is the fifth TNF inhibitor available for the treatment of PsA. The RAPID-PsA study is important to us, as clinicians, because the researchers looked at switching, i.e., may have failed a previous TNF inhibitor.  The phase III results of the 24-week, double-blind, placebo-controlled study showed that the ACR20 response at week 12 was significantly higher in the CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (58.0% and 51.9% vs. 24.3%) and PASI75 response at week 24 for patients with ≥ three percent psoriasis body surface area at baseline (61.6% randomized set) was 62.2 percent with CZP 200mg Q2W and 60.5 percent with CZP 400mg Q4W versus 15.1 percent with placebo.  This data demonstrate that CZP is effective in PsA, including patients with prior TNF inhibitor exposure. This is very important for our patients who may not have responded to previous therapy. This data as also been confirmed in other registries; therefore, indicating that switching from one TNF inhibitor to another in PsA is a viable option.

In PsA, we don’t know whether a TNF inhibitor plus methotrexate (MTX) is additive or synergistic. In Rheumatoid Arthritis, there is data that demonstrate that even a dose of MTX as low as 10mg gets you synergy. This is something that as a practitioner, you need to negotiate with your patients.

What about obesity and weight loss?

Currently, the data on obesity are very strong and very consistent. We know that PsA patients have shown an increased prevalence of obesity. A study by Di Minno and colleagues demonstrated that within 12 months of starting a TNF inhibitor, patients with PsA achieved minimal disease activity (MDA). The prevalence of obesity was lower in the group achieving MDA.  Patients who lose weight and then begin a TNF inhibitor have a much better chance of doing well, than those who are obese. When you look at the CORRONA database, a study of 392 patients starting a TNF inhibitor showed that only obesity was significantly associated with the discontinuation of treatment. This tells us that patients who are obese do not do as well on therapy and have more disease activity. This is true not only for fixed-dose treatment, but weight-based treatment, such as infliximab, as well. Obesity is inflammatory and this is a very dramatic effect. In fact, it has changed the way Dr Kavanaugh approaches his patients regarding discussing the importance of weight loss.

Biosimilar (CT-P13)

A randomized, double-blind, phase III study of 606 patients demonstrated the clinical equivalence of CT-P13 to infliximab when co-administered with MTX in patients with active rheumatoid arthritis. The results were maintained after the switch from infliximab to CT-P13 from weeks 52 to 104.  CT-P13 received a favorable opinion by the EMA and is now available in Europe.  CT-P13 was studied in rheumatoid arthritis and ankylosing spondylitis and because it was clinically equivalent it received approval for all of the indications for which infliximab is approved.  The FDA has not yet weighed in on how it will approach biosimilar approvals; however, they are here and this is coming. Cost is a major issue, i.e., they could be available at 20-25 percent less than the branded products.

Emerging Therapies

We know that TNF inhibitors work well in GI disease, skin disease, rheumatoid arthritis, etc.. Dr Kavanaugh points out that we have made a somewhat switch from “bench to bedside” to “bedside to bench.” He states that “we are dissecting these diseases by our therapies” with hopes to find more specific treatments for specific groups of patients with these distinct diseases.

Ustekinumab (USK) was approved for PsA in September of 2013. The PSUMMIT trial included 615 adult PsA patients with active disease despite DMARD and/or NSAID therapy. Patients were randomized to receive USK 45 mg, 90 mg, or placebo at weeks 0, 4, and q12 weeks thereafter. At week 16, patients with less than five percent improvement in tender joint count and swollen joint count entered blinded early escape (placebo to USK45 mg; USK 45 mg to 90 mg; 90 mg to 90 mg).  Stable concomitant MTX use was permitted but not mandated. Patients treated with prior anti-TNF agents were excluded. The primary endpoint was an ACR20 response at week 24. A significantly greater proportion of USK-treated patients (versus placebo) had an ACR20 response at week 24. Significant improvements were also observed with USK 45mg and 90 mg for ACR50/70 responses and DAS28-CRP responses at week 24 versus placebo. Through week 16, adverse events were similar between patients receiving USK and placebo with infections being the most common AE. No malignancies, serious infections, tuberculosis, opportunistic infections, or deaths occurred through week 24.  PASI 75 response at week 24 also demonstrated positive efficacy among the USK 45mg and 90mg doses versus placebo.

The PSUMMIT 2 study looked at USK in patients with active PsA who were previously treated with an anti-TNF agent. This data show some improvement in ACR 20/50/70 and demonstrate that it is safe and could be modestly effective for PsA TNF inhibitor-experienced patients.

Dr Kavanaugh and his colleagues, utilizing an integrated data analysis of two phase III randomized, placebo-controlled studies, also demonstrated that USK inhibits radiographic progression in patients with active PsA.

IL-17

Genovese, et al. studied brodalumab, an anti-IL-17RA in patients with PsA.  ACR20 was achieved at week 12 by 37 percent and 39 percent of patients in the 140- and 280-mg brodalumab groups, respectively, compared with 18 percent of placebo patients.  The percent of ACR20 responders (observed) increased at week 24 (44%, 51%, 64%, in prior placebo, prior 140 mg, and prior 280 mg groups, respectively). The percent of ACR50 responders (observed) across all groups increased from week 12 to week 24. There were improvements in other secondary endpoints such as DAS 28, CDAI, and several components of the ACR from baseline to week 12 that continued through week 24 in all treatment groups. Adverse events were similar among all treatment groups and placebo. This demonstrates that brodalumab is associated with significant clinical response with continued improvement from week 12 to 24 and further studies of brodalumab for treatment of PsA should be conducted.

Small Molecules

Apremilast, an inhibitor of PDE4, is currently under development for the treatment of PsA. Data from the PALACE 1 study are statistically significant for the apremilast group(s) versus placebo for both ACR 20/50/70 scores and PASI75. At week 24, significantly more apremilast 20 mg BID (36%) and 30 mg BID (45%) patients achieved ACR20 versus placebo (13%). There were also significant improvements in key secondary measures (physical function, psoriasis) with both apremilast doses versus placebo.

One of the major advantages of apremilast is its safety profile. Laboratory monitoring may not be needed with this drug.

Conclusions

Since the availability of biologics, the interest in PsA has increased exponentially. This is exciting for us, as healthcare providers, and very promising for our patients.  Lastly, remember the importance of tight control in early PsA. If patients are not responding the way you feel that they should be, then their management strategy needs to be modified. Data demonstrate that using a treat-to-target approach can significantly improve both joint and skin outcomes for newly diagnosed PsA patients.

 MauiDerm News Editor-Judy Seraphine

10 Most Important Take Home Points: Psoriatic Arthritis

Arthur Kavanaugh, MD

Dr Kavanaugh, a renowned Rheumatologist, provides the ten most important take home points in psoriatic arthritis to help practicing dermatologists…

  1. Psoriatic Arthritis (PsA) is common, occurring in about 20-30% of patients who have skin psoriasis. Patients almost always have psoriasis before developing PsA, sometimes by a decade or more. At present, we are unable to predict which psoriasis patients will go on to develop PsA.
  2. PsA is under-recognized, under-diagnosed and under treated. With more treatment options available, it is likely more PsA patients will be seen in the clinic and we will have more options for treating them.
  3. There is no single screening test or set of questions for determining which psoriasis patients have PsA. Sometimes it is hard for rheumatologists to tell. It is hardest for people with less abundant joint involvement (oligoarticular), and hardest to differentiate PsA from osteoarthritis (which can be inflammatory). Highly sensitive imaging techniques such as musculoskeletal ultrasound are sometime used.
  4.  Important areas of potential involvement for PsA, in addition to the skin and nails, include: 1) peripheral joints (e.g. small joints of the hands and feet,  of the wrists and ankles, the  knees, etc); 2) spine arthritis (essentially ankylosing spondylitis [AS] in a PsA patient),  3) enthesitis (inflammation of the insertion of tendons and ligaments into bone) and 4) dactylitis (swelling of an entire digit) Treatment depends upon the activity in these different areas.
  5. Greater understanding of the immunopathophysiology of PsA has led to the introduction of novel therapies, particularly TNF inhibitors . TNF inhibitors are the “go-to” biologic in PsA, and are sometimes used even before DMARDs.
  6. TNF inhibitors can be effective for all manifestations of PsA, although not all patients respond. Factors that affect response include obesity, which decreases the severity of disease as well as attenuates the response to treatment. Potentially tapering drugs, particularly biologics, is an area of increasing interest in rheumatology.
  7. Biosimilar TNF inhibitors have been approved in several countries worldwide, and a biosimilar infliximab received a favorable review from the European Medicinal Agency (EMA) and is almost certain to be introduced in European countries this year. Although the biosimilar was studies in RA and AS, it is likely to receive the full approval that the originator infliximab has, including psoriasis and PsA.
  8. Switching of TNF inhibitors can be effective in PsA. Many rheumatologists believe, although it is not proven, that TNF inhibitors and methotrexate offer synergistic benefit in PsA.
  9. Newer therapies for diseases like PsA, such as IL-12/23 inhibitors and IL-17 inhibitors, have been effective for some patients and are helping to define a novel approach to autoimmunity. Different than for the TNF inhibitors, autoimmune diseases seem to have varied responses to these other specific agents.
  10. Other new agents for PsA include oral inhibitors such as apremilast (a PDE4 inhibitor). The seemingly very good safety profile of apremilast has attracted particular attention.