Management of psoriasis.pptx (Recent advances)

Psoriasis is an inflammatory skin disease that is associated with multiple comorbidities and substantially diminishes patients' quality of life. Topical therapies remain the cornerstone for treating mild psoriasis. Therapeutic advancements for moderate to severe plaque psoriasis include biologics that inhibit TNF-α, p40IL-12/23, IL-17, and p19IL-23, as well as an oral phosphodiesterase 4 inhibitor.

1. MANAGEMENT OF PSORIASIS DR.MOHNISH SEKAR

2.  Group of common, chronic inflammatory and proliferative conditions of the skin a/w systemic manifestations in many organ systems . The most characteristic lesions  red , scaly, sharply demarcated, indurated plaques present particularly over the extensor surfaces and scalp. Morphological variants are common . INTRODUCTION

3. Clinical forms of psoriasis (based on morphology or natural history) • Plaque psoriasis (psoriasis vulgaris) • Acute guttate psoriasis • ‘Unstable’ psoriasis • Erythrodermic psoriasis • Pustular psoriasis • Atypical forms of psoriasis Other specified forms of psoriasis (based on age or precipitants) • Linear and segmental psoriasis • Psoriasis in childhood and old age • Photoaggravated psoriasis • Drug‐induced or exacerbated psoriasis • HIV‐induced or exacerbated psoriasis Psoriasis affecting specific sites • Scalp psoriasis • Follicular psoriasis • Seborrhoeic psoriasis ( sebopsoriasis ) • Flexural psoriasis (inverse psoriasis) • Genital psoriasis • Non‐ pustular palmoplantar psoriasis • Nail psoriasis • Mucosal lesions • Ocular lesions

4. ASSESSMENT OF DISEASE SEVERITY

5. MANAGEMENT Treatment depends upon: Age , gender, occupation, general health and resources.  T ype , extent, site, duration and natural history of the disease . Treatment should be appropriate to disease severity and importance in that individual  Cognitive– behavioural therapy has shown a significantly greater reduction in psoriasis severity compared to pharmaceutical therapy alone

6.  Known co‐morbidities, for instance psoriatic arthritis and cardiovascular disease should be actively looked for and treated.  Lifestyle and behaviours that contribute to general health and treatment responsiveness such as weight management and smoking cessation should be addressed .

7. For physicians, response to treatment should be recorded objectively using appropriate severity scores such as PASI and PGA. It is useful to consider treatment in two phases: induction of remission, and subsequent maintenance of remission. In inducing remission , 75% reduction in PASI from baseline (PASI 75)  minimum response criterion for severe plaque psoriasis in clinical trials. With the availability of higher efficacy treatments, this standard is rising to PASI 90, or preferably a low absolute PASI (e.g. PASI <3)

8. TOPICAL THERAPY

9. When the epidermis is hyperproliferative , vitamin D3 inhibits epidermal proliferation I t induces normal differentiation by enhancing cornified envelope formation and activating transglutaminase . I t also inhibits several neutrophil functions. Due to their therapeutic efficacy and limited toxicity, calcipotriene ( calcipotriol ) and other vitamin D3 analogues have become a first-line therapy for psoriasis .

10. Calcipotriol Calcipotriol (50 μg /g)  effective and safe in children when administered in amounts up to 45 g/week/m2 Side effects of calcipotriol  local irritation (20 % of patients) particularly troublesome on the face Hypercalciuria and hypercalcaemia It is prudent to restrict the amount of calcipotriol (50 μg /g) ointment to less than 100 g or 50 g/m 2 per week, and to monitor serum and urinary calcium levels should these doses be exceeded

11. Combining calcipotriol monotherapy morning + potent topical corticosteroid ( halobetasol ointment) evening x 2 weeks was superior to either drug used twice daily. C alcipotriol 50 μ g/g + betamethasone dipropionate 0.5 mg/g  licensed for treatment Calcipotriene monotherapy  ~60% reduction of PASI after 8 weeks of treatment Calcipotriene and betamethasone dipropionate are combined  ~70% reduction in PASI has been observed

12. Calcipotriol ointment  enhances the efficacy of PUVA and UVB phototherapy As UVA partly inactivates calcipotriol and UVB is absorbed by calcipotriol , it is recommended that calcipotriol is not applied immediately prior to phototherapy exposures . Topical calcipotriol ointment when combined with PUVA is UVA sparing and calcitriol is UVB sparing in combination. Calcipotriol 50 μg /g ointment used in combination with methotrexate enables lower cumulative doses of methotrexate to be used.

13. TOPICAL CORTICOSTEROIDS Potent and very potent topical corticosteroids are most effective topical monotherapies . 1 st line topical treatment on cost effectiveness ground Mild to moderate potency corticosteroids  treatment of choice on the face and neck, flexures and genitalia, and also used in unstable,erythrodermic and generalized pustular psoriasis Potent & very potent potency corticosteroids  scalp and palmoplantar psoriaisis

14. INTRALESIONAL Intralesional corticosteroid infiltrates intradermally into localized small resistant plaques, for instance on the backs of the hands and knuckles. I n the treatment of psoriasis of the fingernails , the nail fold can be injected, but results are often disappointing and painful.

15. Topical corticosteroids are associated with a lower incidence of short‐term local adverse events than other topical treatments  lack of irritancy  do not stain skin or clothing  ease of application.  Frequently combined with other topical agents to counteract irritancy.  It is prudent to limit the use of potent topical corticosteroids to stable plaque psoriasis.  Potent topical corticosteroids tend not to induce a lasting remission, unlike tar or dithranol which have the potential to do so.

16. DITHRANOL O riginally extracted from the bark of the araroba tree . A ntiproliferative and pro‐apoptotic effects on keratinocytes. It also reduces neutrophil and lymphocyte migration Ingram regimen ; in‐patients were treated with a tar bath, suberythemogenic UVB and then dithranol in Lassar’s paste applied to plaques, Starting at a concentration of 0.05–0.1% and increased cautiously to reduce irritation up to a maximum concentration of 4%

17. It is effective when applied five times weekly. Dithranol produces brown staining of the skin which resolves about 2 weeks after therapy is completed. It is not generally useful for facial or flexural psoriasis due to significant irritation

18. COAL TAR Coal tar is the byproduct of coal distillation and contains hydrocarbons. Goeckerman regimen  A pplied on an in‐patient basis for 24 h in combination with suberythemogenic doses of UVB M odified Goeckerman regimen using coal tar  A pplied for 5 h/day in combination with narrow‐band UVB ( NBUVB).  D ecreased serum levels of inflammatory cytokines(anti inflammatory ) & antipruritic  Mutagenic potential, tar is contraindicated in pregnant or lactating women

19. TOPICAL RETINOIDS Topical tazarotene , an acetylene retinoid that selectively binds retinoic acid receptor (RAR)-β & γ  D ecrease epidermal proliferation and it inhibits psoriasis-associated differentiation (e.g. transglutaminase expression & keratin 16 expression)  Manufactured in cream and gel formulations applied once or twice daily .  Main drawback  local irritation at the site of application hence frequently alternated with a potent topical corticosteroid  Probably best reserved for thick recalcitrant plaques of psoriasis.

20. TOPICAL CALCINEURIN INHIBITORS  Tacrolimus & pimecrolimus  E ffective for psoriasis affecting the face, neck, flexures and genitalia  M ay be effective under occlusion for psoriatic plaques at other sites.  Advantage  unlike topical corticosteroids they are selective , unlikely to be absorbed systemically and do not produce skin atrophy making them more suitable for long‐term use.

21. PHOTOTHERAPY Phototherapy with narrow‐band UVB  recommended first line therapy for most patients with moderate to severe psoriasis NB‐UVB causes cutaneous immunomodulation partly by increasing Vitamin D and similar to PUVA induces apoptosis of T cells and reduces epidermal hyperproliferation Recent studies also indicate that induction of keratinocyte apoptosis is involved in remodelling and resolution of hyperplastic psoriatic epidermis in response to NB‐UVB

22. E rythema is maximal at 48–72 h and this fact coupled with the dose–response curve for NB‐UVB suggests that treatment should be given three times weekly initial dose based on  skin phototesting and the determination of the MED or on skin phototype . Patients ’ estimation of their skin phototype may be inaccurate so MED phototesting is preferred

23. PUVA PHOTOTHEARAPY P soralens & long‐wave ultraviolet radiation (UVA 320–400 nm). Psoralens bind to DNA and when activated by UVA cause permanent DNA damage resulting cell death  R educes keratinocyte hyperproliferation , D ecreases antigen‐presenting cells in the dermis,reduces angiogenesis and causes T‐cell apoptosis with associated clearance & remission of psoriasis. Psoralens commonly used are  8‐methoxypsoralen (8‐MOP ),  5‐methoxypsoralen (5‐MOP )  T rioxypsoralen (T‐MOP ).  Psoralens are used either topically or orally in combination with UVA.

24. Oral PUVA therapy 8‐MOP is usually given at a dose of 0.6 mg/kg 2 h before UVA therapy although it may be dosed according to the BSA . As the skin reacts to PUVA by developing pigmentation and epidermal hyperplasia , increasing doses are required. Twice‐weekly treatment and the average number of treatments to clearance  18 .

25. Twice‐weekly PUVA is as effective as three times weekly PUVA. Initial dose of UVA is calculated as 70% of the minimal phototoxic dose and 20 % increments are given until erythema occurs. Scrotum and genital skin are more sensitive to the development of PUVA induced skin cancers and should be protected from irradiation

26. ADVERSE EFFECTS E rythema , maximal at 72–96 h, Blistering  usually dose & skin phototype dependent. Neurogenic pruritus (PUVA itch )  fairer skin types & dose related sensation crawling under the skin that affects both psoriasis and normal looking skin. Increased incidence of non‐melanoma skin cancer b oth BCC and SCC (relative risk of cutaneous SCC starts to increase after 250 treatments in a lifetime . Cataract formation Teratogenecity

27. Systemic therapy In general, systemic treatment  more extensive disease not responsive to topical therapy or phototherapy M ain systemic treatments in current clinical practice are methotrexate, cyclosporin , acitretin and FAEs C hoice of suitable agent depends on variables P erson’s age Plans for conception Presence of psoriatic arthritis or other co‐morbidities P attern of activity and current severity of their psoriasis

28. METHOTREXATE D erivative of aminopterin an analogue and antimetabolite of folic acid . FDA approved in the treatment of psoriasis At present, the drug  treatment of moderate or severe psoriasis, including psoriatic arthritis I ndicated as an element of combined therapy with other immunosuppressive drugs, primarily in combination with biologics.

29. MECHANISM OF ACTION Inhibits dihydrofolate reductase I nhibition of reduction of dihydrofolic acid to tetrahydrofolic acid Inhibition of the activity of thymidylate synthase, component for the synthesis of purines and pyrimidines , and thus for the synthesis of DNA (occurs during S phase of cell cycle) Inhibition of growth and cell death ( apoptosis) limits epithelial hyperplasia, reinforces the apoptosis of activated T cells, and inhibits the chemotaxis of neutrophils, decreasing the synthesis of proinflammatory CKs such as TNF-α & IL-1

30. Indications of MTX in psoriasis

31. C urrent recommended dose of MTX  7.5–25 mg/week. The preferred dosage regimen is once weekly in three divided doses at 12 h intervals ( Weinstein's regimen). If the oral route is unavailable, the drug can be administered in a single weekly dose of 2.5–25 mg subcutaneously, intramuscularly or intravenously. Therapy can be initiated at low doses (e.g. 7.5 mg/week) and gradually increased. Alternatively, the maximum dose can be prescribed from the start of treatment.   Minimum period of 4–8 weeks is recommended before drug discontinuation or dose modification is introduced ,corresponds to the time which is typically needed to achieve a full therapeutic effect

32.   Primary purpose of folic acid supplementation is to prevent adverse reactions of the hematopoietic system and lessen hepatotoxicity . Folic acid supplementation has also been demonstrated to reduce a range of symptoms including nausea and mucosal ulcerations. The role of folic acid in lowering the risk of pulmonary fibrosis has not been proven The widely recommended dose of folic acid is 15 mg per week, administered a minimum of 12 h (usually 24–48 h) after the last dose of MTX . Another option is to use 5 mg of folic acid daily (except for MTX days)

33. ADVERSE EFFECTS Nausea , vomiting, mucosal ulcers, loss of appetite Hepatotoxicity (small elevation of aminotransferases level is common, but it is uncommon to have liver steatosis , fibrosis, and cirrhosis when taking a low dose of methotrexate. Over a long duration of treatment, ultrasound scanning and liver biopsy are required to ascertain the level of liver damage). Pulmanory toxicity  pneumonitis Hematologic effects  Pancytopenia Malignancy induction  lymphoma & lymphoproliferative disorders Reproductive side effects  potent teratogenic and abortifacient Category X drug

34. Recent modalities to diagnose liver fibrosis Serum aminoterminal peptide of pro‐collagen III (PIIINP) Transient elastography ( Fibroscan )

35. ACITRETIN Acitretin  metabolite of etretinate which was the first retinoid used in the treatment of psoriasis . Acitretin binds to nuclear receptors of the steroid superfamily, which includes the vitamin D receptor.  reduces keratinocyte proliferation and also reduces Th17 cells with a concomitant increase in regulatory T cells. Not an immunosuppressant  considered in clinical situations where other systemic medications are contraindicated, such as active malignancy. Combination therapy with systemic retinoids and phototherapy is more effective than monotherapy with either modality

36. CURRENT RECOMMENDATION: Instituting low-dose (25 mg) acitretin 2 weeks prior to the initiation of phototherapy . If skin-type dosing is used, the initial dose of UV light and subsequent increments should be adjusted downward to accommodate the acitretin effect. Alternatively , if a patient is on a stable dose of UV, the UV dose should be lowered by 30– 50% approximately 7 days after starting acitretin .

37. Adverse effects

38. CYCLOSPORINE Cyclosporine  immunosuppressant drug widely used in organ transplantation to prevent rejection. It was isolated from the soil fungus tolypocladium inflatum gams FDA approved for psoriasis in 1997

39. Mechanism of action Mechanism of action Inhibit production of IL-2 by inhibiting calcineurin Calcineurin inhibition leads to reduced activity of the transcription factor NFAT-1 Inhibits IFN-γ production by T-lymphocytes Binds to steroid receptor associated heat-shock protein 56 Resultant clinical effects Decreased T-cell proliferation upon activation Reduced HLA DR-positivity; reduced keratinocyte proliferation Inhibits transcription of proinflammatory cytokines such as GM-CSF, IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, TNF- α

40. Adverse effects Renal  Renal dysfunction Cardiovascular  Hypertension Neurologic  Tremor,Headache,Paresthesia , hyperesthesia Mucocutaneous  Hypertrichosis Gingival hyperplasia Gastrointestinal  Nausea , abdominal discomfort Diarrhea Musculoskeletal  Myalgia , lethargy, Arthralgia Laboratory abnormalities Hyperkalemia Hyperuricemia (occasionally precipitates gout) Hypomagnesemia Hyperlipidemia

41. Current recommendation Cyclosporine is employed as an intermittent short-term therapy . The dosage is 2.5 to 5.0 mg/kg of body weight for up to 10 to 16 weeks. Tapering of the drug is recommended to prevent relapse

42. Cyclosporine monitoring guidelines Baseline Examination: Complete history and physical examination (to rule out active infections, malignancy) Two baseline blood pressures at least a day apart Laboratory Baseline serum creatinine levels (two baseline creatinine values at least a day apart) Other baseline renal evaluation – BUN, urinalysis with microscopic examination (optional) C BC and liver function tests (especially SGOT/AST and SGPT/ALT ) Fasting lipid profile – triglycerides, cholesterol, HDL cholesterol Other laboratory tests: magnesium (may decrease), potassium (may increase) uric acid (mainly relevant for patients at risk for gout).

43. Follow-up Examination : Re-evaluate the patient every 2 weeks for 1–2 months, then every 4–6 weeks while on cyclosporine Blood pressure checked at each visit Laboratory Laboratory surveillance every 2 weeks for the first 1–2 months, then monthly while on cyclosporine Renal function – serum creatinine, BUN, urinalysis CBC and liver function tests (especially SGOT/AST and SGPT/ALT ) Lipids – triglycerides, cholesterol Other laboratory tests – magnesium, potassium, uric acid

44. Oral sequential therapy

45. Fumaric acid esters Mechanism of action  Reduction of glutathione with subsequent decrease in Th1 cytokine production including IL‐12 and IL‐23, and a corresponding increase in Th2 cytokines such as IL‐4.  FAE also cause altered Langerhans cell function and reduction in NF‐ Κ b production , with subsequent decreased TNF‐α and IL‐8 levels.

46. Dosage recommendation Fumaderm is given according to a gradually increasing dosing schedule to a maximum dose of 240 mg three times daily . ADVERSE EFFECTS: DIARRHOEA FLUSHING EOSINOPHILIA LYMPHOPENIA PROTEINURIA TOLERANCE

47. Hydroxyurea MECHANISM OF ACTION Hydroxyurea impairs DNA synthesis  inhibition of ribonucleotide diphosphate reductase , an enzyme that reduces nucleotides to deoxynucleotides . Enzymatic inhibition limits the supply of DNA bases available for synthesis, resulting in strand breakage and cell death . M ost effective in cells with a high proliferative index, as it acts upon cells entering the S phase of the cell cycle and it is preferentially concentrated within leukocytes.

48. THERAPEUTIC GUIDELINES Typical doses range from 1 g to 2 g daily, usually as a divided dose, such that the amount consumed is typically 20–30 mg/kg daily Older patients and those with renal impairment are more susceptible to toxicity, and should receive starting doses of hydroxyurea of only 500 mg/day.

49. Adverse effects

50. Apremilast Mechanism of action

51. Therapeutic dosage The recommended dose of apremilast in adults for psoriasis and psoriatic arthritis is 30 mg twice daily taken orally . The treatment is started with 10 mg morning dose with a daily increment of 10 mg until day 6 when the recommended dose (30 mg bid) for adults is reached which is continued at the same dose thereafter

52. Adverse effects D iarrhea, Headache, Nausea Nasopharyngitis Upper respiratory tract infections .

53. Monitoring guidelines Body weight should be recorded prior to the initiation of treatment and monitored regularly . P retreatment assessment of renal function is recommended and the dose of apremilast has to be modified in severe renal impairment . B aseline and 3 monthly monitoring of complete hemogram , liver enzymes, and serum creatinine.

54. Biological therapy Mechanism of action

55. Adalimumab The onset of treatment response in psoriasis is rapid, being significant at 2 weeks

56. IL‐12/IL‐23 p40 inhibitors USTEKINUMAB Initial : Inject 90mg SQ on Day 0, And then inject 90mg SQ on Day 28. Maint : then inject 90mg once every 12 weeks. LABARATORY WORKUP TB ( mantoux ) prior to starting and every year while on Stelara and BCG vaccines should not be given during treatment with Stelara or for one year following d/c . CONTRAINDICATION Clinically significant hypersensitivity to Stelara or to any of the excipient

57. IL‐17 inhibitors Brodalumab I xekizumab Secukinumab

58. TOFACITINIB DOSE  5-10MG twice daily

59. ADVERSE EFFECTS

60. References Ighani A, Georgakopoulos JR, Yeung J. Tofacitinib for the treatment of psoriasis and psoriatic arthritis. G Ital Dermatol Venereol . 2020 Aug;155(4):400-410. Sonthalia S, Aggarwal P. Oral tofacitinib : Contemporary appraisal of its role in dermatology. Indian Dermatol Online J 2019;10:503-18 Gupta AK, Cernea M, Lynde CW. Tofacitinib in the Treatment of Rheumatoid Arthritis and Chronic Plaque Psoriasis. Skin Therapy Lett . 2017 Mar;22(2):1-7 . Rajagopalan M, Mital A. Biologics use in Indian psoriasis patients. Indian Dermatol Online J 2016;7:489-97 Afra T P, Razmi T M, Dogra S. Apremilast in psoriasis and beyond: Big hopes on a small molecule. Indian Dermatol Online J 2019;10:1-12 Bubna AK. Apremilast : A dermatologic perspective. Indian J Drugs Dermatol 2016;2:75-82 Pai VV, Phadke D, Shukla P, Naik K. Fixed tapering dosage of acitretin in patients with psoriasis: A short-term analysis of clinical efficacy and its effects on biochemical parameters. Indian J Dermatol 2019;64:213-6 Katz HI, Waalen J, Leach EE. Acitretin in psoriasis: an overview of adverse effects. J Am Acad Dermatol . 1999 Sep;41(3 Pt 2):S7-S12 .

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