Biologic Therapies for 2013: Do We Use Them Enough?

Psoriasis is a chronic autoimmune disease affecting approximately three percent of the US population. A better understanding of its underlying pathophysiology has led to breakthrough biologic therapies that have revolutionized our treatment algorithms.

Biologic drugs are biologically active large proteins that are capable of modifying an immune response. These drugs can no longer be considered new, as TNF-alpha antagonists have been used to treat patients for more than 10 years. More than two million patients worldwide, with a variety of autoimmune diseases, have been dosed with these drugs. Therefore, psoriasis patients benefit not only from their efficacy, but also from the accumulation of long-term safety data. A newer treatment blocks the p40 subunits of interleukins (IL) 12 and 23, also resulting in impressive efficacy with five-year safety data now published.¹

Psoriasis as a Systemic Disease

Over the last decade we have begun to understand that psoriasis is not just a disease of epidermal hyperproliferation, but also a systemic autoimmune disease. When clinicians see a patient with a characteristic butterfly facial eruption of systemic lupus, we immediately think about treating the skin eruption and everything else is going on systemically. We now feel the same is true with our psoriasis patients, and we need to have the same thought process when evaluating them. In addition to ascertaining severity of disease and quality of life, we must also look for associated comorbidities.

Psoriasis is partially mediated by Th-1 helper cells. This results in elevated pro-inflammatory cytokines such as TNF-alpha, IL-6, IL-12, interferon-gamma, and leptin. A more recent discovery was the identification of an activated Th-17 helper cell, which causes an increase in IL-17, IL-20, IL-22 and IL-23. These immune mediators result in a systemic autoimmune disease. Elevated TNF-alpha increases leptin and decreases adiponectin (an insulin sensitizer), which could influence insulin resistance, metabolic syndrome, and the appearance of nonalcoholic fatty liver disease. ² Metabolic syndrome is three times more prevalent in the psoriasis versus the general population.

Although several expert groups have proposed different diagnostic criteria for metabolic syndrome, they all include the same core components. It is defined by central obesity along with any two of the following five criteria: elevated blood pressure, elevated fasting plasma glucose, previous diagnosis of type 2 diabetes, elevated triglycerides, or low HDL. Non-alcoholic fatty liver disease in psoriasis patients is associated with obesity and metabolic syndrome. In a UK population-based cohort observational study, patients with severe psoriasis had a hazard risk of 1.46 for type 2 diabetes and were more likely to need treatment with oral medications.³ The Nurses Health Study, during a 14-year follow-up, confirmed that increased adiposity and weight gain are strong risk factors for incident psoriasis in women.⁴

Psoriasis itself is a risk factor for cardiovascular disease, even after adjusting for other risk factors such as smoking, diabetes, hypertension, lipid abnormalities, age, and sex. In a UK general practice database, there was a 6.2 percent increase in major adverse cardiac events (MACE) over 10 years in the severe psoriasis population compared to the general population.⁵ The risk of myocardial infarction (MI) associated with psoriasis is greatest in young patients with severe disease.⁶ Elevated plasma osteopontin levels are also associated with psoriasis and is another unfavorable cardiovascular risk factor.⁷

Other known comorbidities associated with psoriasis include depression in 15 to 25 percent of patients, sleep disorders, and ocular diseases, such as anterior uveitis which occurs in seven to 20 percent of patients with psoriasis. Psoriasis patients are at increased risk for other autoimmune diseases, such as inflammatory bowel disease with an odds ratio (OR) of 2, and celiac disease (OR 2.7).⁸ Other diseases such as vitiligo, pernicious anemia, and Hashimoto’s thyroiditis are also seen more frequently. A retrospective cohort study showed psoriasis patients have an OR risk of 1.6 to develop one other and OR 1.9 to develop two other autoimmune diseases.⁹

What Evidence Do We Have Biologics Can Improve Comorbidities?

Patients with autoimmune diseases such as psoriasis are known to live about four years less than the general population. As stated previously, this is related to an increase in MACE events. But if we can reduce systemic inflammation with biologic drugs, it makes intuitive sense that the associated comorbidities should also decrease. Studies also indicate that biologics reduce these risks. Two large studies in RA show TNF-alpha inhibitors do reduce first CV events.^10,11

Etanercept (Enbrel, Amgen/Pfizer) has been shown to lower pro-inflammatory markers such as CRP and IL-6 and increase adiponectin in patients with psoriasis, psoriatic arthritis (PsA), and metabolic syndrome.¹² Leptin is a protein made by fat cells that tells the brain “you’re full” so you stop eating. Leptin levels are elevated in overweight people due to leptin resistance. The brain does not get this signal, so the person eats even more, which becomes a vicious cycle leading towards obesity. Leptin levels however, are decreased with adalimumab (Humira, AbbVie) or infliximab (Remicade, Janssen).¹³ In obese patients with metabolic syndrome, etanercept over a six-month period improved fasting glucose and increased the ratio of high molecular weight to total adiponectin.¹⁴

Solomon, et al. showed that in RA or psoriasis, TNFalpha antagonists and hydroxychloroquine, but not methotrexate or other non-biologic disease modifying anti-rheumatic drugs (DMARDs), decreased the incidence of diabetes.¹⁵ In a Danish database over a three-year period, the incidence rates of MACE events in severe psoriasis patients were reduced with use of biologic drugs, with hazard ratio (HR) of 0.28 versus 0.65 with methotrexate. In this group 80 percent of the patients were treated with TNF-alpha antagonists and 20 percent with IL-12/23 inhibitors.¹⁶

Wu, et al. published a retrospective cohort of Kaiser patients with psoriasis and PsA. The HR of MI was 0.5 compared to the topical cohort. Therefore, half the number of patients in the TNF-alpha treated groups had cardiac events compared to the number treated only with topical agents.¹⁷ Burmester, et al. published a long-term safety analysis of over23,000 patients on adalimumab from global clinical trials with six different autoimmune diseases. Patients were treated for up to 12 years. For treated subjects with rheumatoid arthritis (RA), ankylosing spondylitis, and psoriasis, the observed number of deaths was less than expected in an age-and sex matched population. However, in PsA and Crohn’s disease studies, the observed number of deaths was similar to the number expected in the reference general population.¹⁸ This improvement in mortality rates for the psoriasis population is likely related to the overall reduction in inflammation resulting in reduced MACE events. Although several studies show a clear effect on lipids is not evident with the TNF-antagonists, these drugs may improve cardiometabolic risk through its net anti-inflammatory effect.¹⁹

Depending on the study, PsA can occur in up to 40 percent of psoriasis patients. TNF-alpha antagonists significantly improve the symptoms of disease and can prevent irreversible joint destruction.²⁰ Ustekinumab (Stelara, Janssen) also has a moderate clinical effect in reducing ACR scores in early studies. In the Phase 3, multicenter PSUMMIT I study, ustekinumab significantly reduced signs and symptoms of PsA at week 24.²¹

Conclusion

A National Psoriasis Foundation survey concluded that more than one third of psoriasis patients with moderatesevere disease were not adequately treated. Biologic drugs have dramatically improved our ability to treat this systemic disease and should therefore be considered more widely for patients with moderate to severe disease. We have seen mounting evidence that these therapies also improve quality of life and reduce associated comorbidities.

The combined effect of improved insulin sensitivity along with a reduction of pro-inflammatory mediators likely has the net effect of interrupting the inflammatory cascade linking psoriasis with metabolic syndrome and MACE events. Although these drugs have potential side effects, numerous studies prove both efficacy and lack of cumulative toxicity.

Importantly, biologics should only be used in conjunction with educating our psoriasis patients about the known cardiovascular risk factors. Patients should also be encouraged to address modifiable behavioral changes, such as avoiding smoking or excessive alcohol consumption, in addition to maintaining a healthy diet and sufficient exercise. Not only can we now improve quality of life in our psoriasis patients with biologic therapy, but we can also possibly increase longevity by reducing systemic inflammation and cardiac risk factors.

Dr. Prussick has served as a consultant, speaker, trainer or investigator for Abbott, Allergan, Amgen, Gene Logic, Janssen, Leo, L’Oreal, Pharmaderm, Medicis and Medimetriks.

Ronald Prussick, MD is Director of Washington Dermatology Center, North Bethesda, MD and Assistant Clinical Professor, George Washington University, Washington, D.C.

Lisa Prussick, BSc is a master’s student at Tufts University School of Medicine in Boston, MA and is with Washington Dermatology Center, North Bethesda, MD.

1. Kimbell A, Papp K, Wasfi Y, et al. Long term efficacy and safety of ustekinumab in patients with moderate to severe psoriasis through 5 years of follow-up. Poster presented at the European Association of Dermatology & Venereology Annual Meeting, Verona, 6 June 2012. Poster P582.
2. Chen YJ, Wu CY, Shen JL, et al. Psoriasis independently associated with hyperleptinemia contributing to metabolic syndrome. Arch Dermatol. 2008;144(12),1571-5.
3. Azfar RS, Seminara NM, Shin DB, et al. Increased risk of diabetes mellitus and likelihood of receiving diabetes mellitus treatment in patients with psoriasis. Arch Dermatol. 2012; 148(9):995-1000.
4. Setty AR, Curhan G, Choi HK. Obesity, Waist Circumference, Weight Change, and the Risk of Psoriasis in Women. Arch Intern Med. 2007;167(15):1670-75.
5. Mehta NN, Yi DY, Pinnelas R, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med. 2011;124(8):775.
6. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-41.
7. Chen YJ, Shen Jl, wu CY, et al. Elevated plasma osteopontin level is associated with occurrence of psoriasis and is an unfavorable cardiovascular risk factor in patients with psoriasis. J Am Acad Dermatol. 2009;60:225-30.
8. Hsu LN, Armstrong AW. Psoriasis and autoimmune disorders: a review of the literature. J Am Acad Dermatol. 2012;67:1076.
9. Wu JJ, Nguyen TU, Poon KYT, Herrington LJ. The association of psoriasis with autoimmune diseases. J Am Acad Dermatol. 2012;67:924-30.
10. Jacobsson Lt, Turesson C, Gulfe A, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005;32(7):1213-18.
11. Dixon WG, Watson KD, Lunt M, et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-TNF therapy: Results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007;56(9):2905-12.
12. Bernstein LE, Berry J, Kim S,et al. Effects of etanercept in patients with metabolic syndrome. Arch Intern Med. 2006;166:902-8.
13. Kofoed K, Clemmensen A, Mikkelsen UR,et al. Effects of anti-tumor necrosis factor therapy on body composition and insulin sensitivity in patients with psoriasis. Arch Dermatol. 2012;148(9):1089-91.
14. Stanley TL, Zanni MV, Johnsen S,et al. TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab. 2011;96:E146-50.
15. Solomon DH, Massarotti E, Garg R, et al. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305(24):2525-31.
16. Ahlehoff O, Skov L, Gislason G, et al. Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study. J Intern Med. 2012;sep 11 (epub ahead of print).
17. Wu JJ, Poon KY, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;aug 20:1-7 (epub ahead of print).
18. Burmester GB, Panaccione R, Gordon KB, et al. Adalimumab: long-term safety in 23,458 patients from global clinical trials. Ann Rheum Dis. 2012;july 6 (epub ahead of print).
19. Strober B, Teller C, Yamauchi P, et al. Effects of etanercept on C-reactive protein levels in psoriasis patients and psoriatic arthritis. Br J Dermatol. 2008;159:322-30.
20. Mease PJ, Ory P, Sharp JT, et al. Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the adalimumab effectiveness in psoriatic arthritis trial (ADEPT). Ann Rheum Dis. 2009;68:702-9.
21. McInnes, IB , Kavanaugh A, Gottlieb AB, et al. Ustekinumab in patients with active psoriatic arthritis: Results of the phase 3, multicenter, double-blind, placebo- controlled PSUMMIT I study. Ann Rheum Dis. 2012;71(supp 3):107.