Retinoids

Retinoids in dermatology, isotretinoin, tretinoin, Acitretin, retinoids teratogenecity

1. Presenter : Dr. Sanjay Singh Dermatology, AIIMS Retinoids in Dermatology

2. History Structure Natural Retinoids and carotenoids Mechanism of Retinoids Classification of synthetic Retinoids Effects of Retinoids on Human Skin Brief description of Individual Drugs and side effects Retinoid Teratogenecity Newer Retinoids

3. What are Retinoids? All synthetic & natural compounds that have biologic activity similar to Vitamin A.

4. HISTORY First dermatologic use of vitamin A : in 1943 by Staumfjord for Acne Vulgaris In 1962 : Therapeutic effectiveness of Topical Tretinoin : Disorder of Keratinisation by Stuttgen . In 1969 : first topical application of tretinoin for acne vulgaris : by Kligman & colleagues. In 1972 : Bollag discovered : Etretinate & Acitretin.

5. IN 1982 : Isotretinoin first approved by FDA : severe nodulocystic acne . IN 1987 : Etretinate approved by FDA : for Psoriasis . In 1998 : Etretinate phased out by Roche & replaced by its acid metabolite : Acitretin. In 1999 : Bexarotene approved : for CTCL . In 1999 : Alitretinoin approved by FDA : for Kaposi Sarcoma

6. STRUCTURE Cyclohexenyl Ring Conjugated Side Chain Polar Terminal Group

7. All classes of Retinoids : basic sructure of Vit A with modifications 1 st gen. Retinoids 2 nd gen. Retinoids 3 rd gen Retinoids Change of Polar end group & polyene side chain Replacing cyclic end group of Vit A with subsituted & non subsituted ring systems. Cyclization of polyene side chain.

8. NATURAL RETINOIDS Daily requirement: 0.8-1mg/ 2400-3000IU FUNCTIONS : Retinal (as 11-cis &11-trans isomer) : in Visual function Retinol : in Reproduction Retinoic acid : in Epithelial differentiation & normal growth

9. CAROTENOIDS Organic pigments : Naturally occurring in chlorophyll & chromoplast of plants . They are not biologically active until converted to one of the retinoids in the body . 1 mol. Of β carotenes = 2 mol. of retinal . Found in vegetables and fruits . Ex : Carotene α, Carotene β, Lutein, Lycopene, Zeaxanthin

10. Mechanism of Action RA is predominantly in ATRA form . Serum transport by Albumin. Intracellular transport to nucleus is by : CRABP. CRABP 1 : modulates level of RA in various tissues . CRABP 2 : main form in human epidermis .

11. Retinol

12. RETINOID RECEPTORS Belongs to Steroid thyroid hormone receptor superfamily Exists as α , β , γ types Human skin mainly contains RXR γ & RAR α

13. BASIC PRINCIPLES: RETINOID RECEPTORS RARs and RXRs are ligand-dependent transcription factors that regulate gene expression in two ways : Upregulate expression of genes by binding to RARE located in the promoter region of target genes Downregulate expression of transcription factors such as AP1 .

14. The RARs and RXRs always exist as dimers in vivo . The RARs always exist as heterodimers complexed with RXRs. RXRs can exist as homodimers or as heterodimers with RARs or a variety of other nuclear receptors (VDRs and T3Rs) . Provide a mechanism for cross - talk between hormone signalling pathways.

15. CLASSIFICATION OF RETINOIDS

16. Non-Aromatic Retinoids Tretinoin ( all-trans retinoic acid ) Isotretinoin ( 13-cis retinoic acid ) Alitretinoin ( 9-cis retinoic acid ) All-trans Retinoyl B- glucornide Fenretinide Ist GENERATION

17. Monoaromatic Retinoids Etretinate Acitretin Motretinide 2 nd GENERATION

18. Polyaromatic Retinoids Bexarotene Tazarotene Tamibarotene ( Am-80) Arotinoid sulfones Adapalene : D erivative of naphthoic acid with retinoid-like properties , does not fit precisely into any of three generations . 3 rd GENERATION

19. Seletinoid G Arotinoid Etretin Seletinoid G classified as fourth generation retinoids by some authors. Newer retinoids

20. Biological Diversity Sebolytic Synthesis of Dermal Matrix Anti-inflammatory Epithelial differentiation Morphogenesis Angiogenesis Melanotropism Immunomodulation

21. EFFECTS on KERATINIZATION Different keratin profile on cultured keratinocytes and in vivo human skin In Vivo level of Keratin 1, 2, 10 decreases and Keratin 4,6,13,16,17,19 increases . Induces heparin binding (HB)- EGF, TGF α and amphiregulin

22. Reduction of tonofilaments , ￬ corneocyte adhesiveness, impaired permeability barrier, ￪ TEWL Normalise hyper-proliferative epidermis Clinical desquamation and peeling

23. Inhibits Proinflammatory cytokines and enzymes of Phagocytosis ￪ cell surface antigens of T cells and NK cells Inhibition of Transcription factor AP-1 ￬ Neutrophil migration , leukotriene B4 mediated chemotaxis , NO, TNFα levels Psoriasis : ￪ IL6 , IL8, ICAM1 IMMUNOLOGIC & ANTIINFLAMMATORY EFFECTS

24. EFFECT ON SEBACEOUS GLAND ACTIVITY Isotretinoin >> tretinoin > acitretin >> other retinoids 90 % ￬ in sebaceous gland size by ￬ ing proliferation of basal sebocytes 70-90 % ￬ in sebum production Altered sebum composition : ￬ TGs, wax/ steryl esters, FFA Squalene normal or mildly ￬ ￪ free sterols, cholesterol, ceramides

25. ANTITUMOUR EFFECTS Retinoid induced apoptosis : Regulation of expression of apoptosis linked gene products: BCL-2, tissue transglutaminase Activation of tumour suppressor genes, viz. p21, p38, p53 ￪ Caspase proteolytic activity Restoration of RAR β activity in premalignant oral lesions Suppress production of COX 2 and PGE 2 , whose activity is upregulated in transformed cells

26. EFFECTS ON INTERCELLULAR MATRIX COMPONENTS Physiological conc : promote wound healing ￪ MPS, collagen, fibronectin & GAG, ￬ collagenase Supraphysiologic conc : inhibit wound healing ￬ fibroblast prolif , ￬ collagen 1 & 3, ￬ GAG

27. EFFECTS ON EMBRYONIC DEV & MORPHOGENESIS Vit A & retinoids needed for formation of face, heart, eye, limb, & nervous system All RAR agonists – strong teratogens All RXR agonists – low to absent teratogenic response Retinoids not binding to RAR/RXR – likely non teratogenic

28. INDICATIONS OF RETINOID THERAPY FDA APPROVED TOPICAL RETINOIDS Acne Vulgaris Tretinoin , Adapalene , Tazarotene Photoageing Tretinoin , Tazarotene Psoriasis Tazarotene Cutaneous T-cell lymphoma Bexarotene Kaposi Sarcoma Alitretinoin

29. FDA-approved Oral Retinoids Psoriasis 1. Pustular psoriasis (localized and von Zumbusch ) 2. Erythrodermic psoriasis 3. Severe and recalcitrant psoriasis Acitretin Acne Nodulocystic acne Recalcitrant acne with tendency for scarring Isotretinoin Cutaneous T-cell lymphoma Bexarotene

30. INDICATIONS Non FDA approved Off Label Uses Follicular Disorders Acne-related conditions Rosacea Hidradenitis suppurativa Dissecting cellulitis of scalp

31. Disorders of Keratinization Pityriasis rubra pilaris Ichthyosis spectrum Keratodermas Darier’s disease Inflammatory Dermatoses Chronic hand eczema Lupus erythematosus Lichen planus - oral erosive, palmoplantar Lichen sclerosus et atrophicus

32. Chemoprevention of Malignancies Premalignant conditions Syndromes with increased risk of cutaneous malignancy Transplantation patients Frequent BCC or SCC Kaposi’s sarcoma

33. TRETINOIN All-trans-retinoic acid 1st retinoid introduced into clinical use – nearly 4 decades ago, for topical Rx of acne vulgaris MOA : By reducing microcomedone formation Decreasing cohesiveness of follicular corneocytes Increasing keratinocyte autolysis Availiable topically as : .01% to 0.1% as cream, gel, solution forms

34. New microsphere preparation: 4x potent, faster response, better tolerated Available in 0.1 % & 0.04% ADVANTAGES : Decrease irritation by slowing release of drug. Enhance efficacy by targeting delivery to sebaceous follicle

35. Photodamaged skin : ￪ Basal & granular layer thickness. ￬ Melanocy tic activity, even distribution of melanin. ￪ glycosaaminoglycan secretion into intercellular space . ￪ synthesis of collagen and elastin Improvement in skin smoothness and tightening of skin in 2 to 4 weeks Decreased fine wrinkles and mottled hyperpigmentation at 2 to 4 months Coarse wrinkles require at least 6 months of therapy .

36. Sunscreen use is necessary

37. ISOTRETINOIN 13-cis-retinoic acid No affinity for RAR/RXR First retinoid for systemic use Initially evaluated for icthyotic disorders in the 1970’s, found to be very effective in nodulocystic acne

38. B est agent for acne vulgaris : targets all pathogenic factors of acne Rapid and early improvement in the inflammatory lesions (pustules ) Closed comedonal acne & microcystic acne are less responsive

39. Important indications Nodulocystic acne Inflammatory acne with scarring Acne with psychological distress Gram-negative follicullitis Pyoderma faciale Severe rosacea

40. Standard dosing recommendations 1 mg/kg/d for 4 to 5 months Start at 0.5 mg/kg/d and increase gradually to 1 mg/kg for 4 to 5 months . Acne fulminans - Prednisolone 0.5–1 mg/kg/d Acne flare - Prednisolone 0.5–1 mg/kg/d Gram-negative folliculitis - 0.5–1 mg/kg/d Acne rosacea/rosacea - 10 mg/d for 4 months

41. Prospective , observational, intervention study 116 participants, 12-month follow-up survey High-dose  isotretinoin  treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris . Blasiak RC, Stamey CR, Burkhart CN et al . JAMA Dermatol . 2013 ;149(12 ):1392-8 . Lower-dose treatment group (<220 mg/kg) High-dose group ( > 220 mg/kg) p value Relapse rate 47.4 % 26.9 % 0.03 Retinoid dermatitis 31.6 % 53.8 % 0.02 Cheilitis and xerosis 100 % 100 % Other adverse effects > 0.05

42. 80 participants Three-year study period High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life . Cyrulnik AA, Viola KV, Gewirtzman AJ et al. Int J Dermatol . 2012 ;51(9 ):1123-30. Mean daily dose Average time Duration Cumulative dose Relapse 1.6 mg/kg/day 178 days 290 mg/kg 10 patients (12.5%)

43. No progressive accumulation of drug in skin on chronic administration . Absorption enhanced when taken with food.

44. Acitretin Hence recommended period of contraception lengthened from 2mnths to 2 yrs in Europe & 3 yrs in USA Effectiveness : Higher doses [ 50 & 75mg] > Low doses [ 10 & 25mg ] Initial response : 4-6 weeks Full benefit : 3-4 month Acid metabolite of etretinate Acitretin Etretinate Less lipophilic Highly lipophilic Elimination half life 2 to 4 days ≥ 120 days > 98 % eliminated 2 months > 98 % eliminated 2 or more years Small amounts converts converts to Etretinate , accelerated in presence of Ethanol Metabolized to Acitretin

45. Acitretin and Psoriasis Regimens : Plaque Psoriasis 0.3 – 1.0 mg/kg/d for 4–12 wks Combination with PUVA or UVB 0.3 - 0.5mg/kg for 6 wks Erythrodermic Psoriasis Start at 0.3 mg/kg/d and ↑ to 0.5–0.6 mg/kg/d for 3 month . Maintainance required for upto 6 months. Pustular Psoriasis Start at 1 mg/kg/d ↓ to 0.5–0.6 mg/kg/d over 3 to 6 month. Maintainance required for upto 6-12 months

46. Better efficacy in combination Rx : UVB, PUVA , topical Rx ( steroids, anthralin , vit D) Comb with MTX not recommended Benefit on psoriatic arthritis not established unlike etretinate

47. Disorders of Keratinization Good to excellent efficacy Rapid response, long term Rx req Best results: lamellar icthyoses Lower doses in bullous icthyosiform erythroderma , darier’s disease : prevents disease flare Low dose retinoid therapy (< 1mg/kg/d ) with acceptable remaining disease activity preferable

48. BEXAROTENE It selectively binds RXRs . Metabolised by CYP3A4 , so chances of drug interactions more . Used in CTCL refractory to atleast one prior systemic therapy. Dose : 300mg/m2 daily Tablets : 10mg & 75mg Single daily dose with meal

49. Initial dose : 300 mg/m2, ￪ to 400 mg/m2 Response seen within 4 weeks Response better in early stage disease (54% vs 45 %) Remission gen durable, relapse rate: 28 % Therapy may be cont. indefinitely based on clinical response Unlike other retinoids, very little renal elimination – extreme caution in liver insuff .

50. TAZAROTENE 3 rd generation retinoid approved for : Psoriasis Acne vulgaris It is the first topical retinoid approved by FDA for t\t of psoriasis. Its active metabolite tazarotenic acid Availiable as : 0.o5 & 0.1 % cream

51. ADDITIONAL USE : In treatment of Photodamaged skin . Good evidence of improvement in both clinical & histological signs of photodamaged skin. A review of tazarotene in the treatment of photodamaged skin Ogden S, Samuel M, Griffiths CE. Clin Interv Aging. 2008;3(1):71-6.

52. ALITRETINOIN Binds to all types of retinoid receptors . Approved only for treatment of the skin manifestations of Kaposi Sarcoma . ￬ IL-6, growth factor for Kaposi sarcoma cells & altering expressions of virally encoded genes . Oral alitretinoin OD approved for : severe chronic hand eczema unresponsive to t/t with potent topical steroids . Drugs. 2009; 69(12) :1625-34

53. Derivative of napthoic acid Achieved by replacing the unstable double bonds of tretinoin with napthoic acid aromatic rings Chemical and sunlight stability and high lipophilicity Inspired by a need to ￬ S/E of tretinoin Lack of effect on CRABP I & II accounts for its better tolerability Adapalene

54. Marked anti-proliferative action : Comedolytic & anticomedogenic ≥ than tretinoin . Has immunoregulating activity : ↓ TLR2, inhibit cytokine prod by P . acne. Anti-inflammatory activity : blocks AP1 inflammatory pathway . Available as 0.1 % gel/cream

55. CONTRAINDICATIONS ABSOLUTE RELATIVE Pregnancy or woman who is likely to become pregnant Leukopenia Noncompliance with contraception Hypothyroidism (in bexarotene patients) Nursing mothers Moderate-to-severe cholesterol or triglyceride elevation Significant hepatic/renal dysfunction

56. SIDE EFFECT PROFILE

57. Relatively Common Minor Adverse Effects Due to Systemic Retinoids

58. HAIRS & NAILS

59. Potentially Serious Adverse Effects Due to Systemic Retinoids TERATOGENICITY Retinoic acid embryopathy Spontaneous abortions OCULAR Reduced night vision Persistent dry eyes Staphylococcus aureus infections LIPIDS Hypercholesterolemia Hypertriglyceridemia

60. BONE Diffuse interstitial skeletal hyperostosis [DISH] Osteophyte formation Osteoporotic changes in long bones Premature epiphyseal closure

61. GASTROINTESTINAL Pancreatitis (due to ↑↑ triglycerides) Inflammatory bowel disease flare HEPATIC Transaminase elevations Toxic hepatitis (rarely)

62. ENDOCRINE EFFECTS Hypothyroidism ( Bexarotene ) Diabetes mellitus (controversial) HEMATOLOGIC Leukopenia Agranulocytosis NEUROLOGIC Pseudotumor cerebri Arthralgia & Myalgia

63. Mucocutaneous Dry Lips 96 % Facial Dermatitis 55 % Dry Nose 51 % Dry skin, Pruritus, Desquamation 20-50 % Conjuctivitis 19 % Hair Loss 13% Impetiginization 7.5 % Photosensitivity 1-5 % Side effects of acne therapy and their management . Miller RA. J Cutan Med Surg2(suppl3 ):14-8 (1998).

64. Arthralgia and Myalgia 15 – 20 % Headache 5 – 16 % Impaired Night Vision Unknown

65. Isotretinoin & Depression : A controversy

66. Case-crossover study D : 1984 through 2003. 30,496 subjects in the initial cohort, 126 (0.4%) cases met inclusion criteria. Relative risk for those exposed to isotretinoin was 2.68 . Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study . Azoulay L, Blais L, Koren G, LeLorier et al. J Clin Psychiatry. 2008;69(4):526-32.

67. Retrospective cohort study 5,756 patients ranging in age from 15 to 49 years Slight ↑ depression/suicide attempts during during and up to one year after treatment Trend towards improvement after 1 year H/o attempted suicide may not need to be a contraindication when considering treatment with isotretinoin Association of suicide attempts with acne and treatment with isotretinoin : retrospective Swedish cohort study. Sundström A, Alfredsson L, Sjölin-Forsberg G et al. BMJ. 2010 Nov 11;341

68. Nine studies met the qualifying criteria Studies comparing depression before and after treatment did not show statistically significant difference. Some, in fact, demonstrated a trend toward fewer or less severe depressive symptoms after  isotretinoin therapy. Depression and suicidal behavior in acne patients treated with  isotretinoin : a systematic review . Marqueling AL,  Zane LT . Semin Cutan Med Surg. 2005 Jun;24(2):92-102 .

69. MONITORING DURING SYSTEMIC RETINOID THERAPY

70. ISOTRETINOIN & ACITRETIN Clinical Examination Lab investigations : Serum or sensitive urine pregnancy test CBC Before Rx and 4-6 wks after onset of Rx LFT Repeat every 3 months Lipid profile KFT Special tests : X-ray wrists, ankles, thoracic spine Optha examination Follow up : monthly x 3 months, then 3 monthly BAD Guidelines 2010

71. BEXAROTENE TSH , T4 Follow up: 2 weekly x 4-8 weeks, then monthly x 3 months, then 3 monthly

72. TERATOGENECITY Prescribing Status of systemic Retinoids in Pregnancy – Category X

73. Major components Of Retinoid Teratogenecity

74. CRANIOFACIAL ABNORMALITIES

75. Agenesis of Cerebellar Vermis Abnormal Cortical Tracts CNS ABNORMALITIES

76. CARDIOVASCULAR ABNORMALITIES ASD VSD Hypoplastic or Interrupted Aortic Arch Septum

77. AUDITORY ABNORMALITIES Microtia Absent auditory canals Conductive hearing loss Sensorineural hearing loss Vestibular dysfunction OCULAR ABNORMALITIES Micropthalmia Optic nerve atrophy

78. BONE ABNORMALITIES Absent clavicle and scapula Aplasia/hypoplasia of long bones Short sternum Sternoumbilical raphe Absent thumb OTHER ABNORMALITIES Thymic aplasia or hypoplasia Anal and vaginal atresia

79. PREGNANCY MONITORING GENERAL REQUIREMENTS : 2 negative UPT or serum pregnancy tests Each month of therapy, patient must have negative urine or serum pregnancy test . Must commit 2 forms of contraception 1 mnth before & after Isotretinoin therapy . For patients with amenorrhoea , 2 nd test should be atleast 11 days after last act of sexual intercourse.

80. INVESTIGATIONAL RETINOIDS MOTRETINIDE Dev in Europe as topical med Less irritating & efficacious than tretinoin TEMAROTENE (Ro 15-0778) Some immunosuppressive activity like cyclosporine No sebosuppr , antikeratinizing property AROTINOID ETHYL ESTER Analogous to etretinate , oral agent Highly effective in Rx etretinate resistant DOK S/E profile similar to etretinate

81. GLUCURONIDE ANALOGS Topical agents, less Mucocutaneous S/E Unstable preparations AROTINOID SULPHONES Methyl sulphone – sumarotene Ethyl sulphone – etarotene Do not bind to RARs Topical – multiple actinic keratoses

82. FENRETINIDE Oral, dose: 200 mg/d Actinic keratoses , chemoprevention of BCC & oral leukoplakia Drug allergy and nyctalopia more frequent ALRT 1550 RAR selective retinoid Cervical carcinoma CD437 In the prevention or treatment of cutaneous carcinoma

83. Summary Retinoids : synthetic & natural compounds with biological activity of Vit . A. Vit . A & Carotenoids are needed for various biological functions. Various generation of synthetic retinoids have been developed by changing str. of Vit . A Tretinoin : very effective in mild to moderate grade acne. Adapalene : similar efficacy with less local adverse effects. Isotretinoin : highly effective in nodulocystic acne due to its significant sebosupp . effects : Higher doses for longer duration in resistant & severe acne.

84. Acitretin : very effective in disorders of keratinization, major drawback is recurrence after stoppage of therapy. Bexarotene : response in all stages of CTCL. : More side effects than other retinoids, managed with monitoring and dose reduction. Investigational retinoids : less side effects while maintaining efficacy