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Sunday, March 25 - The Recognition, Evaluation and Treatment of Psoriasis

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The Recognition, Evaluation and Treatment of Psoriasis
0006-0000-18-010-L01-P | .1 CEU |
Joel Wagner, PharmD

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Sunday, March 25 - The Recognition, Evaluation and Treatment of Psoriasis

  1. 1. Joel Wagner Pharm. D. Clinical Professor/Emeritus Professor Thomas J. Long School of Pharmacy and Health Sciences No Conflicts of Interest to Disclose The Recognition, Evaluation, And Treatment Of Psoriasis
  2. 2. Goals and Objectives  The purpose of this presentation is to help pharmacists develop the skills to be able to recognize psoriasis, evaluate the severity of psoriasis, and to develop a treatment regimen for psoriasis dependent upon the severity of psoriasis lesions.
  3. 3. Learing Objectives  Recognize the major lesions associated with psoriasis.  Classify psoriasis based upon the type of psoriasis and the severity of the lesions.  Develop a treatment regimen for psoriasis based upon the severity of the lesions.  Explain the mechanism of action for the medications used for the treatment of psoriasis.  State the major side effects of medications used for the treatment of psoriasis.
  4. 4. The Basics
  5. 5. What is Psoriasis?  Psoriasis is a chronic, lifelong, relapsing, inflammatory skin disorder with predominately skin and joint manifestations  The most common age of onset is usually in the patient’s 20s or in the patient’s late 40s and 50s  Psoriasis has a strong genetic component with about 30% of the patients having a close relative with the disease  Psoriasis is often psychologically more serious than the severity of the lesions might indicate.
  6. 6. Evaluation of Psoriasis Severity  There are several ways to determine the severity of psoriasis.  Extent of BSA covered by psoriasis lesions  Psoriasis Area and Severity Index (PASI)  Dermatology Quality Of Life Index (DQOLI)
  7. 7. BSA and Psoriasis Severity Severity of Psoriasis Extent of Psoriasis Lesions Mild psoriasis Lesions on <5% of BSA Moderate Psoriasis Lesions on 5-10% of BSA Severe psoriasis Lesions on >10% of BSA
  8. 8. Psoriasis Area and Severity Index (PASI)  PASI is an assessment that combines the BSA that is covered with psoriasis lesions and an assessment of severity of several parameters of psoriasis lesions  Each parameter is given a number from 0 to 4 with 0 indicating that the parameter is absent and 4 indicating very severe disease  Parameter numbers are then put into a formula
  9. 9. Calculation of PASI  Results of the parameter evaluation is placed into the following formula:  PASI = 0.1(Rh +Th +Sh )Ah + 0.2(Ru +Tu +Su )Au + 0.3(Rt +Tt +St )At + 0.4(Rl +Tl +Sl )Al
  10. 10. PASI Scoring Severity of psoriasis PASI Mild Psoriasis < 5 Moderate Psoriasis > 8 Severe Psoriasis >10
  11. 11. PASI and Studies  The PASI is usually used to assess the effectiveness of treatment.  In many recent clinical trials, success is measured by the proportion of people receiving treatment who achieve a “PASI 75”.  This means that there is a 75% reduction in the PASI from the start to the end of the clinical trial.
  12. 12. Dermatology Quality Of Life Index  Psoriasis can cause a patient to have reduced self-esteem and loss of confidence  Psoriasis can cause a patient to have anxiety and depression  Psoriasis can cause stigmatization  Psoriasis can be emotionally devastating to a patient
  13. 13. Answers to Questions Score Very much 3 A lot 2 A little 1 Not at all 0 Not relevant 0 DQOLI Scoring
  14. 14. Meaning of DQOLI Scores Score Meaning 0-1 No effect at all on patient's life 2-5 Small effect on patient's life 6-10 Moderate effect on patient's life 11-20 Very large effect on patient's life 21-30 Extremely large effect on patient's life
  15. 15. Lesions of Psoriasis  The characteristic lesions of psoriasis are large erythematous plaques covered with thick silvery scale
  16. 16. What is a Plaque?  A solid, relatively large, slightly raised, flat-topped, lesion that looks different from the surrounding skin  May cover large areas of the body.
  17. 17. Psoriasis Plaque and Scale Thick Scale Plaque
  18. 18. Psoriasis Plaque and Scale Plaque Scale
  19. 19. Psoriasis Plaque and Scale
  20. 20. Psoriasis Plaque and Scale
  21. 21. Distribution of Lesions
  22. 22. Recognition of Psoriasis  Psoriasis can look like several other skin diseases.  Which of the following are pictures of patients who have developed psoriasis?
  23. 23. Picture 1  Does this patient have psoriasis? a. Yes b. No This patient has nummular eczema
  24. 24. Picture 2  Does this patient have psoriasis? a. Yes b. No
  25. 25. Picture 3  Does this patient have psoriasis? a. Yes b. No This patient has pityriasis rosea
  26. 26. Picture 4  Does this patient have psoriasis? a. Yes b. No This patient has tinea corporis
  27. 27. Picture 5  Does this patient have psoriasis? a. Yes b. No  This is a trick question.  Although this lesion looks like tinea corporis, it is a psoriasis variant called inverse psoriasis.
  28. 28. Variants of Psoriasis  Plaque psoriasis  Inverse or Flexural Psoriasis  Guttate Psoriasis  Nail psoriasis  Pustular psoriasis  Erythrodermic Psoriasis  Psoriatic arthritis
  29. 29. Plaque psoriasis  Most common type of psoriasis consists of erythematous plaques covered in thick scale.
  30. 30. Inverse or Flexural Psoriasis  Consists of erythematous patches located in the skin folds in the axillae, inguinal area, that is usually moist with very little if any scale
  31. 31. Guttate Psoriasis  Small drop-like pink papules covered in fine scale  Maybe triggered by a previous streptococcal infection  The precise mechanism whereby streptococcal infections induce psoriasis is not currently known.
  32. 32. Nail psoriasis  Nails may exhibit pitting, onycholysis, subungual hyperkeratosis, or the oil-drop sign Oil Drop Sign Oil Drop Sign Pitting Onycholysis
  33. 33. Pustular psoriasis  Rare type of psoriasis where pustules can be generalized or located on the palms of the hands and/or the soles of the feet  Maybe caused by treating plaque psoriasis with systemic corticosteroids or coal tar
  34. 34. Erythrodermic Psoriasis  Erythrodermic psoriasis is a rare, particularly inflammatory form of psoriasis  Widespread, fiery, erythema and exfoliation of the skin characterize this form.  Exfoliation often occurs in large "sheets" instead of smaller scales
  35. 35. Psoriatic Arthritis  Joint pain, inflammation, and swelling are symptoms of the disease.  When occurs in the hands, patient may describe their symptoms as having “sausage-like fingers”.
  36. 36. Pathophysiology of Psoriasis  Psoriasis is a T-cell mediated immune disease with accompanying dysregulation of the inflammatory process.  A overactive, deregulated inflammatory process, results in a large production of various cytokines such TNF-α, interferon-gamma, and interleukin-12, interleukin-23,and interleukin 17A  The effect of an abnormal production of cytokines and the infiltration of the skin with a large number of activated T-cells, results in keratinocyte proliferation.  Keratinocyte proliferation results in the characteristic lesions associated with psoriasis.
  37. 37. Normal Epidermal Cell Cycle  New cells are always being formed in the basal cell layer and migrate upward towards the stratum corneum  As the move towards stratum they become filled with keratin and their organelles disappear  When cells reach stratum corneum they die and are ultimately shed  Takes 4 weeks for cells to migrate from the basal cell layer to the stratum corneum Keratinocyte s Stratum Corneum Dead and filled with keratin
  38. 38. Psoriasis Skin Cell Cycle  Epidermal cell cycle is accelerated  Entire cell cycle takes place in 3-4 days rather than 4 weeks  Cells move so rapidly that they do not have time to differentiate and mature properly  Epidermal cells build up on the stratum corneum and form large silvery scale Greatly accelerate d cell cycle Thick Scale Nucleated cells
  39. 39. Symptoms Associated with Psoriasis  About 50% of patients have itching.  Rarely itching can be severe  Psoriatic arthritis is associated with joint inflammation, swelling, and pain.  The major problem with the disease is the rather unpleasant appearance of the skin that, in many cases, is psychologically damaging to the patient.
  40. 40. Clinical Course  Has unpredictable periods of exacerbation and remission  There is no known cure  Patients may improve during summer and worsen in cold, dry times of the year.
  41. 41. Factors That Improve Psoriasis  Exposure to sunlight
  42. 42. Factors That Worsen Psoriasis  Mental Stress  Dry winter weather  Smoking  High alcohol intake  Certain medications
  43. 43. Drugs That May Worsen Psoriasis Drugs that commonly make psoriasis worse Drugs that rarely make psoriasis worse -blockers Clonidine Lithium Carbonate Digoxin Indomethacin Amiodarone Naproxen Fluoxetine Chloroquine Carbamazepine Hydroxychloroquine Valproic acid Quinidine Ibuprofen (maybe)
  44. 44. Psoriasis in this Presentation  For the remainder of this presentation we will be discussing plaque psoriasis which is the most common form of psoriasis.  About 80% of patients with psoriasis develop plaque type psoriasis  Treatment of psoriasis is based the severity of the disease.
  45. 45. Goals of Treatment  Minimize or eliminate the visible signs of psoriasis  Alleviate pruritus  Reduce the frequency of flare-ups  Screen for and manage lifestyle factors that may trigger exacerbations  Avoid or minimize adverse effects from treatments used  Maintain or improve the patient’s quality of life
  46. 46. Case 1: History  Wendy Nelson is a 22-year-old healthy woman with a new diagnosis of psoriasis.  The patient reports psoriasis lesions localized to her knees with no other affected areas.  She has not tried any therapy.  She has had no major illnesses or previous hospitalizations.  The only symptoms that she is having is slight pruritus
  47. 47. Picture of Patient in Case 1
  48. 48. Case 1: Question 1  Into which severity class would place this patient? a. Mild psoriasis b. Moderate psoriasis c. Moderate to severe psoriasis d. Severe psoriasis
  49. 49. Computerized PASI Calculator
  50. 50. Case 1: Question 2  With of the following would you begin treatment for this patient? a. Biologic response modifier b. Medium to high potency topical corticosteroid c. Low potency topical corticosteroid d. Systemic corticosteroids e. Methotrexate
  51. 51. Primary Treatment of Mild Psoriasis Mid to High Potency Topical Corticosteroids Calcipotriene Tazarotene Topical Lactic, Glycolic, or Salicylic Acid (to help remove thick scale) Coal Tar Adjunctive Therapy Moisturizers Aveeno Cetaphil Cleanser Sunscreens Stress Reduction Treatment Algorithm for Mild Psoriasis
  52. 52. Adjunctive Therapy
  53. 53. Approach to Treatment  No single topical agent is ideal for plaque psoriasis  Several medications are often used concurrently in a combined approach.  Using a rotational therapeutic approach in which different topical agents are used sequentially over time in the same patient is the standard of care
  54. 54. Initial Treatment of Mild Disease  Topical corticosteroids are the treatment of choice  Topical corticosteroids are more effective when used with occlusion which allows for better drug penetration.  In general, the effects of topical therapy should become evident within the first 2-3 weeks of use.  Clearing of scale is usually observed first, followed by flattening of the treated plaques.  Resolution of erythema may take 6-8 weeks.
  55. 55. Treatment Guidelines  Treatment is initiated with a medium to high potency (Group III-IV) topical corticosteroid  Ultra high-potency corticosteroids are reserved for the treatment of lesions that are refractory to less potent steroids.  Ointments are preferred over other bases.  Occlusion increases the effectiveness of topical corticosteroids  Generally hydrocortisone is ineffective for treatment of psoriasis
  56. 56. Advantages of Corticosteroids  Rapid onset  Good effect on inflammation  Good at decreasing erythema  Good at rapidly reducing pruritus
  57. 57. Disadvantages of Corticosteroids  Give very good initial response but tolerance occurs and becomes less effective with continued treatment  This is due to down-regulation of steroid receptors in the skin  Continual application of potent topical corticosteroids for longer than 4 weeks maybe associated with the development of side effects
  58. 58. Case 1: Question 3  What are the side effects associated with the long-term continuous application of high potency topical corticosteroids? a. Development of HPA axis suppression. b. Development of steroid psychosis. c. Development dermal atrophy. d. Development of osteoporosis. e. Development of cataracts.
  59. 59. Dermal Atrophy  Any topical corticosteroid may cause dermal atrophy  Must be applied regularly to the same site for a sufficient period of time  Low potency agents may be used for many months before changes occur  More potent corticosteroids reduce the time necessary to induce dermal atrophy
  60. 60. Case 1: Question 4  What are the characteristic skin lesions associated with the development of dermal atrophy? a. Development of telangiectasia. b. Development of ecchymoses. c. Development of striae. d. Development of prominent underlying veins. e. All of the above.
  61. 61. Telangiectasia  Fine, irregular red lines produced by capillary dilation
  62. 62. Telangiectasia
  63. 63. Ecchymoses  A red-purple discoloration of the skin  Cause is vascular wall destruction and deterioration of the collagen and elastin fibers in the skin
  64. 64. Ecchymoses
  65. 65. Striae
  66. 66. Striae
  67. 67. Prominent Underlying Veins
  68. 68. Prevention of Dermal Atrophy  Once a good response has been achieved with topical corticosteroid, they are used in rotational therapy with calcipotriene or tazarotene.  Rotational therapy reduces development of steroid tolerance and decreases development of dermal atrophy
  69. 69. What is Calciprotriene?  Calcipotriene is a topical vitamin D3 analog  Binds to vitamin D3 receptors in the skin and reduces keratinocyte proliferation  Usually applied one or twice daily  Brand name is Dovonex 0.005%
  70. 70. Advantages of Calciprotriene  No tolerance  Not associated with dermal atrophy  Effective alone for long-term maintenance therapy  Used in rotational therapy with topical corticosteroids to reduce incidence of tolerance and dermal atrophy
  71. 71. Disadvantages of Calciprotriene  Onset of action is slow and may take several weeks to get good clinical response  Agent is irritating especially when applied to groin and facial regions
  72. 72. Is it effective?  Marked improvement occurs in 60% of patients  Most studies indicate that calcipotriene used by itself is not as quite as effective as the use of topical corticosteroids  Major value of calcipotriene is in rotational therapy along with corticosteroids to help reduce development of dermal atrophy.
  73. 73. What is Tazarotene?  Tazarotene is a topical retinoid used to slow skin cell growth.  Tazarotene has multiple effects on keratinocyte differentiation and proliferation that contribute to psoriasis, however, the exact mechanism of action is unclear.  When applying tazarotene, it is normal for psoriasis plaques to become very red and irritated before clearing.  Combination of topical corticosteroid and tazarotene will help reduce erythema and irritation.  Usually applied once daily
  74. 74. Is it effective?  A PASI 75 was achieved in 48-63% of patients after 8 weeks of treatment in two studies.  The major side effect in these studies was moderate to severe erythema and irritation.  Irritation seem to be mitigated somewhat when tazarotene was combined with a topical corticosteroid.
  75. 75. Example of Rotational Treatment  After good initial response with topical corticosteroids has been achieved, use in rotational therapy with calcipotriene or tazarotene  Use topical corticosteroids for 2 weeks on and then 1 week off  Use calciprotriene during week off corticosteroid  After complete control is achieved, calcipotriene or tazarotene can be applied once (tazarotene ) or twice daily (calcipotriene) without the application of a topical corticosteroid  Continue to apply moisturizers and use other adjunctive treatment measures
  76. 76. Other Treatments  Coal Tar  Keratolytic therapy  Salicylic acid, lactic acid, or glycolic acid help to remove scale and to increase penetration of drugs into skin
  77. 77. Coal Tar  Used in the treatment of psoriasis for more than 100 years, although the use of tar products for treatment of localized psoriasis has decreased over time in the U.S.  Often poorly tolerated by patients because of cosmetic issues, including staining of clothes, skin and a tar odor.  Many problems with compliance  Other potential adverse events include irritant contact dermatitis, folliculitis, and photosensitivity.
  78. 78. Keratolytic Therapy  Helps to break up thick scale and improve penetration of corticosteroids and other topical medications into psoriasis plaque  Salicylic, lactic, and glycolic acid  Used to help breakup thick scale  5% salicylic acid and 12% lactic acid most commonly used
  79. 79. Case 2: History  Roberta Silvers is an 50-year-old healthy female with a diagnosis of psoriasis.  She has had a previous history of psoriasis on her elbows and knees that has been well controlled with the use of topical betamethasone and calcipotriene.  She now presents at the dermatology clinic with psoriasis lesions on her scalp. The patient complains of mild pruritus .
  80. 80. Picture of patient in Case 2
  81. 81. Case 2: Question 1  Which of the following topical corticosteroids would be the treatment of choice for this patient? a. Clobetasol 0.05% Cream b. Triamcinolone 0.1% Cream c. Desonide 0.05% cream d. Hydrocortisone 1% cream
  82. 82. Potency of Corticosteroids  Areas of the body that have thin skin are much more susceptible to the development of dermal atrophy with topical corticosteroids  Selection of which topical corticosteroid to use corticosteroid potency is determined by the part of the body that the corticosteroids is applied.  Can use super potent corticosteroids on areas of the body with thick skin.  Must use lower potency corticosteroids on areas of the body with thin skin
  83. 83. Summary of Topical Therapy Medication Use in Psoriasis Side Effects Topical Corticosteroids Used in chronic plaque psoriasis Dermal atrophy Calcipotriene Used in chronic plaque psoriasis in combination with topical corticosteroids. Skin irritation, and photosensitivity Tazarotene Used in chronic plaque psoriasis in combination with topical corticosteroids. Very irritating with severe erythema Salicylic or lactic acid Used in chronic plaque psoriasis to help reduce scale and soften plaque. Skin irritation Coal Tar Used in Chronic Plaque Psoriasis Skin irritation, smelly, and stains skin and clothing. Compliance a problem
  84. 84. Summary Treatment Algorithm for Mild Psoriasis First Line Treatment Calcipotriene orIn rotational therapy with Tazarotene Plus Stress Reduction Moisturizers CetaphilAveeno Sunscreens Keratolytics Alternative Treatment Coal Tar Supplemental Therapy Plus Topical Corticosteroids Plus Topical Corticosteroids
  85. 85. Case 3: History  John Ewing, a 52-year-old mailman, presents to a dermatology clinic in rural Florida with concerns about the worsening of his plaque psoriasis.  The patient has had psoriasis for 3 years.  However, the patient’s psoriasis lesions have become progressively worse over the past 4 months. The disease began on his elbows about one year ago and has recently appeared on his knees.  He is worried about what people may think about the appearance of his skin especially since he usually wears shorts while working.  He was diagnosed 6 months ago with bipolar disorder for which he was placed on lithium carbonate at a dose of 300mg po TID. He is currently under the care of a psychiatrist for this illness.  One year ago the patient’s private physician prescribed triamcinolone 0.1% ointment to be applied to the lesions on both of his elbows twice daily. The patient states that he has been using the ointment continuously for the past year.  In addition, the patient tells you that for the past 4-5 months, he has been using triamcinolone 0.1% ointment on his knees as well as his elbows.
  86. 86. Picture of patient in Case 3
  87. 87. Case 3: Question 1  Which of the following are factors that may have contributed to the exacerbation of this patient’s psoriasis? a. Increased mental stress b. The almost continuous application of topical corticosteroid resulting in tolerance c. The administration of lithium carbonate d. All of the above
  88. 88. Case 3: Question 2  What treatment can be given to this patient that will help to clear his psoriasis exacerbation? a. Discontinue the lithium carbonate. b. Apply betamethasone 0.05% to the lesions twice a day. c. Administer biologic response modifiers. d. Begin phototherapy. e. Begin systemic corticosteroids.
  89. 89. Treatment of Unresponsive Mild Psoriasis or Moderate Psoriasis Topical Agents + Phototherapy Phototherapy UVB Narrow Band UVB PUVA (Psoralens and UVA) Treatment Algorithm for Unresponsive Mild or Moderate Psoriasis
  90. 90. Phototherapy  Three major types of phototherapy  UVB radiation  Narrow band UVB radiation (NB-UVB)  UVA radiation in combination with orally administered methoxsalen (PUVA)  Works by slowing down dermal hyper- proliferation
  91. 91. UV Therapy for Arm
  92. 92. UV Therapy for Hands and Feet
  93. 93. Whole Body UV Therapy
  94. 94. UVB Phototherapy  The patient is exposed to UVB radiation for 30-60 seconds or until the skin turns pink. When the patient skin no longer turns pink with 30-60 second exposures, the exposure time can be increased to a maximum of 2 minutes per session  Typical UVB radiation treatment is for three to five days a week for two or three months  Commonly used as narrow band UVB (311nm) radiation.
  95. 95. Photochemotherapy (PUVA)  Photochemotherapy (PUVA) is the combination of UVA + methoxsalen (Oxsoralen)  Used for widespread, unresponsive cases of psoriasis  PUVA is administered 2 to 3 times a week beginning with 1 minute exposures and slowly increasing exposure time to 2-3 minutes
  96. 96. Methoxsalen (Oxsoralen)  Methoxsalen is activated by UVA radiation and acts to photo-damage DNA  Results in decreased cellular proliferation  Adult methoxsalen dose is 30-70mg (depending on weight) given 90-120 minutes before exposure to UVA radiation
  97. 97. Is UV Therapy Effective?  UV phototherapy is extremely effective for treating moderate-to-severe plaque psoriasis.  The major drawback of this therapy is the time commitment required for treatments and the accessibility of the UV equipment.  Nearly 90% of patients achieve improvement or marked improvement within 20 - 30 treatment sessions.
  98. 98. Combination UVB Radiation  UVB is commonly combined with topical corticosteroids, calcipotriene, tazarotene, coal tar, or petrolatum  Most patients complain about the unpleasant odor when coal tar is added to UVB treatment.
  99. 99. Phototherapy Concerns  Short-term problems include skin redness and itching  Long-term side effects include skin aging and perhaps the development of skin cancer.
  100. 100. Phototherapy Concerns  Although UVB has a theoretical risk of photocarcinogenesis, the risk is significantly higher with PUVA and is dose related.  A meta-analysis reported a 14-fold increase in the incidence of squamous cell carcinoma in patients receiving high-dose PUVA when compared with low-dose PUVA.  SCC of the male genitalia particularly elevated.
  101. 101. Phototherapy Concerns  PUVA may also increase the risk of basal cell carcinoma and possibly melanoma.  This may occur as long as 10 years after the first treatment.  Therefore the use of phototherapy or photochemotherapy is contraindicated in patients with a history of melanoma or multiple non-melanoma skin cancers.
  102. 102. Case 4: History  John Lapper is a 58-year-old male with a long history of psoriasis who presents to the dermatology clinic with psoriasis plaque and scale on his elbows, knees, scalp, external auditory meatus, and his back.  The patient has been dealing with psoriasis on his elbows and knees for at least 5 years. He tells you that these lesions go through periods of exacerbation and remission.  The patient tells you that the lesions on his elbows and knees are currently on the severe side but the lesions have been this severe in the past but they always abate with treatment.  The patient has been using clobetasol cream on and off for 3 years and has been using clobetasol continuously on his knees and elbows for at least 3 months without much response. The patient is worried because past exacerbations of his disease never lasted this long.  The main reason that the patient comes to the clinic today is because he recently developed severe psoriasis lesions on his scalp, in his ears, and on his back. He has not had psoriasis in the places before and it distresses him greatly.
  103. 103. Pictures of Psoriasis Case 4
  104. 104. Case 4: Question 1  What would be the treatment(s) of choice for this patient? a. Potent topical corticosteroids b. Topical corticosteroids plus phototherapy c. Systemic corticosteroids d. Biological Response Modifiers e. Phosphodiesterase 4 (PDE-4) inhibitors f. Methotrexate or Cyclopsorine
  105. 105. Unresponsive Moderate or Severe Psoriasis Topical + Systemic Agents Immunosuppressants Biologic Response Modifiers Phosphodiesterase -4 Inhibitor Treatment Algorithm for Unresponsive Moderate or Severe Psoriasis
  106. 106. Immunosuppressants  Methotrexate  Cyclosporine
  107. 107. TNF-α Inhibitor IL-12/IL-23 Inhibitor IL-17A Inhibitor Etanercept (Enbrel) Ustekinumab (Stelara) Ixekizumab (Taltz) Infliximab (Remicade) Guselkumab (Tremfya) Secukinumab (Cosentyx) Adalimumab (Humira) Brodalumab (Siliq) Certolizumab (Cimzia)* Golimumab (Simponi)* Biological Response Modifiers * Indicated only for psoriatic arthritis
  108. 108. Phosphodiesterase -4 Inhibitor  Aprimlast (Otezla) (PDE-4)
  109. 109. TNF-α Inhibitors  Dysregulation of TNF-α production is associated with various inflammatory conditions including psoriasis.  Elevated TNF-α levels are seen in both the affected skin and serum of patients with psoriasis  Elevated TNF-α levels have a significant correlation with psoriasis severity.  TNF-α Inhibitors lower concentration of TNF-α in skin.
  110. 110. Case 4: Question 2  What are the concerns when a patient is receiving TNF-α Inhibitors a. Bone marrow depression b. Hepatotoxicity c. Renal impairment d. Increased risk of infections e. Increased risk of developing a malignancy f. Development of congestive heart failure
  111. 111. TNF-α and Infections  One concern is an increased risk of infections, most commonly upper respiratory tract infections,  Less commonly new-onset or reactivation tuberculosis and fungal infections such as histoplasmosis, cryptococcosis, aspergillosis, and candidiasis.  In adults, the rate of serious infections was 4.6 per 100 patient-years among TNF-α recipients as compared with 3.1 per 100 patient-years among control-treated recipients.
  112. 112. TNF-α and Demyelinating Disorders  A second concern is the development or worsening of autoimmune diseases such as peripheral and central demyelinating disorders including multiple sclerosis.  The recommendation is not to use TNF-α antagonists in people with demyelinating diseases and to stop treatment if neurologic symptoms suggestive of demyelinating disease develop.
  113. 113. TNF-α and Demyelinating Disorders  Symptoms of developing demyelinating disorders include:  Loss or reduction of vision in one eye with painful eye movements.  Double vision.  Ascending sensory disturbance and/or weakness.  Problems with balance, unsteadiness, or clumsiness.
  114. 114. TNF-α and Malignancy  A third concern is the potential increased risk of malignancies such as lymphoma, melanoma, and non-melanoma skin cancer.  In adults, the observed rate of lymphomas was approximately 0.11 per 100 patient- years during controlled and uncontrolled portions of clinical trials.  This rate is approximately 3-fold higher than expected in the general population.
  115. 115. TNF-α and CHF  There is a concern about CHF, although this has now become controversial because of conflicting studies demonstrating both worsening and improvement of CHF.  The current recommendation from the American Academy of Dermatology is that TNF-α inhibitors be avoided in patients with severe CHF.  Those patients with milder CHF should have their TNF-α inhibitors withdrawn at the onset of new symptoms or worsening of preexisting CHF.
  116. 116. Are TNF-α Inhibitors Effective?  Studies have shown that TNF-α inhibitors produce rapid and dramatic results which can be sustained with continued use in patients with moderate-to-severe psoriasis.  In addition, studies have shown that TNF-α inhibitors in combination with potent topical corticosteroids, produced significant improvement in PASI when compared to using each medication by itself.
  117. 117. Treatment with Adalimumab 16 weeks PASI 75 0 Weeks
  118. 118. Treatment with Adalimumab 0 Weeks 28 weeks PASI 75
  119. 119. Treatment with Adalimumab 28 weeks PASI 75 0 Weeks
  120. 120. Interleukin Inhibitors  Ustekinumab and guselkumab are monoclonal antibodies that selectively bind and inhibit IL-12/23  IL-12 and IL 23 are cytokines that play a role in the pathogenesis of psoriasis
  121. 121. Interleukin Inhibitors  Secukinumab, ixekizumab, and brodalumab are monoclonal antibodies that selectively bind and inhibit IL-17A, which is a proinflammatory cytokine  Elevated concentrations of IL-17A are found in psoriatic plaques.  Treatment with these medications reduce epidermal neutrophils and IL-17A concentrations in psoriatic plaques.
  122. 122. Case 4: Question 3  Are the concerns with using interleukin inhibitors similar to those of using TNF-α inhibitors? a. Yes. b. No. c. Well maybe, possibly, sometimes.
  123. 123. Interleukin Inhibitors and Infection  All interleukin inhibitors may increase the risk of infection.  During placebo-controlled clinical trials, infections were reported in 28.7% of patients treated with secukinumab compared to 18.9% of patients in the placebo group.  During the entire secukinumab treatment period studied (up to 52 weeks for most patients), infections were reported in 47.5% of patients, and serious infections were reported in 1.2% of patients.
  124. 124. Interleukin Inhibitors and Malignancy  Long-term treatment with a TNF-α inhibitor may increase the risk for malignancy in patients with psoriasis.  When compared to TNF-α inhibitors, malignancy rates did not increase with long-term ustekinumab treatment.  The observed malignancy rate in treatment with interleukin inhibitors was consistent with the expected rate in the general US population in the SEER database (Surveillance, Epidemiology, and End Results)
  125. 125. Case 4: Question 4  Does this mean that the administration of interleukin inhibitors do not increase the risk of developing a malignancy? a. Yes b. No c. Well maybe, possibly, sometimes d. I don’t know
  126. 126. Interleukin Inhibitors and Malignancy  My opinion is that it is to early to say that interleukin inhibitors don’t increase the risk of developing a malignancy.  They are just too new and more experience is needed with the medications before we can come to a conclusion.
  127. 127. Interleukin Inhibitors and Depression  Brodalumab (but not other interleukin inhibitors) carries a black box warning because of an observed risk of suicidal ideation and behavior.  In clinical trials, four completed suicides occurred in the brodalumab-treated group  Currently brodalumab has restricted availability under a Risk Evaluation and Mitigation Strategy (REMS).
  128. 128. Interleukin Inhibitors and Crohn’s Disease  Those interleukin inhibitors that inhibit IL-17A (secukinumab, ixekizumab, and brodalumab) may exacerbate Crohn’s disease  While those interleukin inhibitors that inhibit IL-12 and IL-23 (ustekinumab and guselkumab) attenuate Crohn's disease
  129. 129. Are Interleukin Inhibitors Effective?  Interleukin Inhibitors provide a rapid response that is seen within 2 weeks of initiating treatment.  Two large randomized placebo-controlled trials demonstrated clinical efficacy of ustekinumab, with approximately 70% of patients achieving a PASI 75% after two doses and maintaining the response for 1 year with continued treatment.
  130. 130. Are Interleukin Inhibitors Effective?  Treatment with ustekinumab also showed significant improvements not only in skin-related QOLI, but also in symptoms of anxiety and depression.  Ustekinumab was significantly more efficacious than etanercept in clinical trials.
  131. 131. Are Interleukin Inhibitors Effective?  In the VOYAGE 1 trial, 7 of 10 patients treated with guselkumab achieved a PASI 90.  Similar results were shown in the VOYAGE 2 trial that included patients who did not respond to adalimumab.  Guselkumab also demonstrated effectiveness in patients who had an inadequate response to ustekinumab.
  132. 132. Treatment with Ustekinumab
  133. 133. Treatment with Secukinumab
  134. 134. Treatment With Guselkumab
  135. 135. Recommendations for BRMs  The current recommendations for the use of BRMs is as follows:  BRMs are indicated for treatment in patients who require systemic therapy and who have failed on traditional treatment with methotrexate and cyclosporine.  My opinion is that BRMs (especially interleukin inhibitors) are rapidly becoming treatment of choice for severe psoriasis (PASI>10) or in those patients whose psoriasis has a large impact on physical, psychological, or social functioning.
  136. 136. Apremilast (Otezla)  Apremilast is an oral phosphodiesterase-4 (PDE4) inhibitor.  By inhibiting PDE-4, apremilast prevents the degradation of cAMP which suppresses production of pro-inflammatory cytokines and increases production of anti-inflammatory mediators.  Apremilast offers a novel mechanism of action by acting at an earlier point in the inflammatory cascade than biologic response modifiers.
  137. 137. Is Apremilast Effective  Two clinical studies, (ESTEEM 1 and ESTEEM 2) showed that patients treated with apremilast experienced significant, clinically meaningful improvement in plaque psoriasis at week 16 as measured by the PASI score.  Several other studies have shown that apremilast administered at a dose of 30mg twice daily produced a 75% improvement of PASI in 33-41% of patients when taken for 28 weeks.  Probably less effective than BRMs.
  138. 138. Apremilast Concerns  Surprisingly well tolerated.  No liver, kidney, or bone marrow toxicity.  No suppression of immune system.  Most common side effects are on the GI tract.
  139. 139. Common Side Effects with Apremilast Side Effect Incidence Diarrhea 7.7% Nausea 8.9% Vomiting 3.2% Abdominal pain 2.0%
  140. 140. Apremilast and Depression  Treatment with apremilast seems to be associated with an increase risk of depression.  During clinical trials, 1.3% of patients treated with apremilast reported depression compared to 0.4% on a placebo.
  141. 141. Take Away Points  Patients with psoriasis have a lifelong illness that may be very visible and emotionally distressing.  Diagnosis of psoriasis is usually based on recognition of the characteristic psoriatic lesion and not based on laboratory tests.  Therapy is generally guided by the severity of disease, advancing from topical agents to phototherapy to systemic agents as needed.  Treatment goals for patients with psoriasis are to minimize signs such as plaques and scales, alleviate symptoms such as pruritus, and to reduce the frequency of flare-ups.  BRMs have proven efficacy for psoriasis and are becoming first-line therapy especially for unresponsive moderate and severe psoriasis.
  142. 142. References  Hongbo Y, Thomas CL, Harrison MA, Salek MS and Finlay AY. Translating the science of quality of life into practice: What do dermatology life quality index scores mean? J Invest Dermatol 2005; 125:659-64.  Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: A phase III, multicenter, double-blind trial. Lancet 2005;366:1367–1374.  Papp K, Reich K, Leonardi CL. .Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73:37-49.
  143. 143. References  Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: A phase III, multicenter, double-blind trial. Lancet 2005;366:1367–1374.  Menter A. Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis—section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008;58:826–850.  Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol 2008;58:106–15  Mohan N., Edwards E. T., Cupps T. R., et al. Demyelination occurring during anti-tumor necrosis factor α therapy for inflammatory arthritides. Arthritis and Rheumatism. 2001;44(12):2862–2869
  144. 144. References  Matz H. Phototherapy for psoriasis: What to choose and how to use: Facts and controversies. Clin Dermatol 2010;28:73–80.  Stern RS. Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUVA) and ultraviolet B radiation: The photochemotherapy follow-up study. N Engl J Med 1990;322:1093–1097.  Lebwohl M, Leonardi C, Griffiths CEM, et al. Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (part I of II): Results from analyses of general safety parameters from pooled phase 2 and 3 clinical trials. J Am Acad Dermatol 2012;66:731–741
  145. 145. References  David Fiorentino et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. JAAD 2017: 77 issue 5: 845-854  Lebwohl MG, Kircik L, Callis Duffin K, Pariser D, Hooper M, Wenkert D, et al. A randomized study to evaluate the efficacy and safety of adding topical therapy to etanercept in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2013 May 1  Christopher E.M., Griffiths, M.D. Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis. NEJM 2010;362:118- 28.  Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis .Biochem Pharmacol. 2012; 15:1583- 90.
  146. 146. References  Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-Week results from a randomized, double- blind, placebo-controlled trial. Lancet 2008;371:1675–1684.  Sofen H, Wasel N, Yeilding N, et al. Ustekinumab improves overall skin response and health-related quality of life, in a subset of moderate-to-severe psoriasis patients with psoriatic arthritis: Analysis of PHOENIX 1 and 2. J Am Acad Dermatol 2011 Feb;64  Papp K, Reich K, Leonardi CL. .Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73:37-49.
  147. 147. References  Papp K et al. Malignancy rates in the ustekinumab psoriasis clinical trial program: Update with up to 4 years of follow-up and comparisons to the general United States population. JAAD 2012: 66, Issue 4, Supplement 1, AB19  Cather JC, Horn EJ. Apremilast in the treatment of moderate-to- severe plaque psoriasis: results from the ESTEEM studies. Clin. Invest. (Lond.) (2015) 5(9), 777–791  Krueger GG et al. The Safety and Efficacy of Tazarotene Gel, a Topical Acetylenic Retinoid, in the Treatment of Psoriasis. Arch Dermatol. 1998;134(1):57-60.
  148. 148. References  Reich K, Armstrong AW, Foley P, Song M, Wasfi Y, Randazzo B, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017 Mar. 76 (3):418-431.  Langley RG, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: Results of the randomized, double-blind, Phase 3 NAVIGATE trial. Br J Dermatol. 2018; 178(1):114-123

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