PULSE THERAPY IN DERMATOLOGY very helpful.pptx

pulse therapy

1. PULSE THERAPY IN DERMATOLOGY PRESENTER- DR SEEMA MEENA(JR) MODERATOR- DR ASHA NYATI MAAM

2. INTRODUCTION Pulse therapy means administration of supra-pharmacologic doses of a drug in an intermittent manner to enhance the therapeutic effect and reduce the side effect. First reported use of pulse administration of corticosteroids is attributed to Kountze and Cohn; used to prevent renal graft rejection in 1973. Later used for treatment of lupus nephritis in 1976 and in steroid resistant nephritic syndrome. Pulse therapy (PT) was first described by Pasricha and Ramji in 1981.first used DCP for Reiter’s disease 1982-first used for pemphigus, systemic sclerosis[1989],pyoderma gangrenosum[1990]. Pulse therapy for pemphigus has revolutionized the therapy for pemphigus from mere control of the disease to probable cure.

3. LAYOUT: Rationale of pulse therapy Corticosteroid pulse therapy DCP Pulse therapy and modifications Oral mini pulse Topical steroid pulse Cyclophosphamide pulse therapy Pulse therapy with antifungals Azithromycin pulse therapy Pulse therapy for psoriasis

4. RATIONALE FOR USE OF HIGH DOSE INTRAVENOUS GLUCOCORTICOIDS Aim of pulse therapy - Getting quicker and stronger efficacy Decreasing the need for long-term use of steroids. The paradox - Administration of high dose steroids is used to achieve the steroid sparing effect. Toxicity- Less than that seen with daily oral prednisone. Corticosteroids given as pulses-Produce an immediate profound anti-inflammatory effect.

5. Faster clinical recovery from symptoms than with oral therapy. The clinical improvement last about 3 weeks after one pulse. No prolonged suppressive effect on the hypothalamic-pituitary axis . Pulse steroid therapy may provide symptomatic relief in inflammatory diseases. It might not change the long term course of any specific disease. Continued use of pulses at 1 month intervals led him to a remarkable recovery and a fairly useful life for the next 10 years

6. DRUGS USED FOR PULSE THERAPY IN DERMATOLOGY : Corticosteroids Other immune suppressants (like cyclophosphamide, azathioprine,Methotrexate etc) Antifungals Antibiotics

7. T he agent most commonly used for corticosteroid pulse therapy is methylprednisolone (MP) and dexamethasone . Methylprednisolone Dexamethasone It is an intermediate acting (biological half life of 12-36 hours). It is a fluoridated glucocorticoid, is a long acting agent (biological half life of 36-72 hours). Is a potent, antiinflammatoryagent (potency 1.25 times compared to prednisolone), It is 6.7 times more potent than prednisolone and more potent anti-inflammatory than methylprednisolone

8. A low tendency to induce sodium and water retention (relative glucocorticoid to mineralocorticocoid effect 6:1) Quicker penetration of the cell membrane. It has negligible mineralocorticoid effect with almost no sodium retaining tendency, and a small equipotent volume Slower penetration of the cell membrane.low protein binding. Methylprednisolone is administered at a dose of 20-30 mg/kg per pulse; Dexamethasone is administered at a dose of 4-5 mg/kg (100-200 mg) per pulse. Costlier Cheaper than methylprednisolone.

9. MECHANISM OF ACTION Cellular effects of glucocorticoids are mediated by genomic and various nongenomic mechanisms. Depending on the concentration of steroids used - Effect seen is as follows:

10. At low concentrations (genomic effect ) GC form complexes with cytosolic GC receptors (GCR) Form GCR complex activates the MAPK [   mitogen-activated protein kinase ] signalling pathway activated GCR complex moves to the nucleus activates the GC‑responsive element results in anti‑inflammatory and i mmunosuppressive effects

11. At high concentrations (genomic and nongenomic effects) GC intercalates with the cell membrane GCR Causing rapid immunosuppression via apoptosis and induction of lipomodulin which inhibits prostaglandins and leukotrienes At high doses steroids inhibit nuclear factor kappaB via “ transrepression ” (direct interaction of GC with transcription factors).

12. GENOMIC EFFECTS NON GENOMIC EFFECTS Overall, effects of corticosteroid pulses appear to include down regulation of activation of immune cells and pro inflammatory cytokine production.

13. DERMATOLOGICAL INDICATIONS OF CORTICOSTEROID PULSE THERAPY Dermatologic diseases Commonly indicated in Pemphigus vulgaris Bullous dermatitis herpetiformis Severe psoriasis Alopecia totalis Infrequently used in Severe Stevens-Johnson syndrome Pyoderma gangrenosum Vitiligo with rapidly progressive disease Exfoliative dermatitis

14. Others : 1. Autoimmune blistering disorder. 2. Systemic sclerosis. 3. Systemic lupus erythematosus. 4. Dermatomyositis. 5. Toxic epidermal necrolysis (TEN). 6. Lichen planus. 7. Alopecia areata. 8. Sarcoidosis. 9. Systemic vasculitis

15. Administration of Intravenous High dose Corticosteroids Medication used Methylprednisolone (20-30 mg/kg) or dexamethasone (4-5 mg/kg). The reason for administration of dexamethasone in dextrose instead of normal saline is because steroids cause hypernatremia and hypokalemia . Route and method of administration The corticosteroid preparation is dissolved in 150-500 ml of 5% dextrose and infused intravenously, slowly over 2-3 hours.

16. Precautions 1 . Before starting therapy A informed consent detailed clinical history and examination to look for any concomitant disease or side effects of the previous treatment. [CBC]complete hemogram ( hemoglobin , total leukocyte and platelet counts and erythrocyte sedimentation rate), blood sugar, blood urea, serum creatinine, serum glutamate transaminases, serum sodium and potassium, urinalysis, X-ray of the chest, and electrocardiogram. Expert advice was obtained from the concerned specialist if there was any concomitant disease (but homeopathic and Ayurvedic drugs were not allowed). T he patient should be free from systemic infections. Minor upper respiratory tract, gastrointestinal, or skin infections are not a contraindication to pulse therapy.Blood pressure must be under control ,In elderly patients, cardiac assessment should be done Direct immunofluorescence (DIF) and histopathological examination help in the diagnosis of pemphigus. However, DIF specifically helps in monitoring disease activity and for prognosis and hence should be recorded before initiating pulse therapy. Patients on all types of pulse therapy were advised to follow contraception till all three phases of pulse therapy

17. 2. During and after therapy : Monitor pulse, respiratory rate, and blood pressure every 15–30 min In case of an arrhythmia[ palpitation,chest discomfort, sob,fainting episodes] ], the infusion is discontinued. Electrocardiography and electrolytes are measured, and abnormalities are corrected. On day 2 of cyclophosphamide infusion, the patient is advised to empty the bladder half hourly during infusion until 2 h after the infusion Check regular blood levels of sugar and electrolytes daily.

18. THE REGIMEN DCP or the dexamethasone-cyclophosphamide pulse (DCP) therapy regimen, [DCP therapy has the potential to effect lifelong recovery from these diseases] Dexamethasone-azathioprine pulse (DAP): Cyclophosphamide is replaced by daily oral azathioprine. No bolus dose of azathioprine is given during the pulse Dexamethasone-methotrexate pulse (DMP): Cyclophosphamide is replaced by 7.5 mg of oral weekly methotrexate (three doses of 2.5 mg at 12 h apart), during the three phases of pulse therapy Rituximab is also given for pemphigus according to the rheumatoid arthritis protocol as 2 doses of 1 g, 2 weeks apart and according to the lymphoma protocol as 375 mg/m 2  weekly for 4 weeks.

19. DCP or the dexamethasone-cyclophosphamide pulse (DCP) therapy regimen.

20. Cyclophosphamide is an alkylating agent which was first synthesized as a derivate of nitrogen mustard. It is used as an immunosuppressant , primarily metabolized by the liver. It is a PRODRUG activated in the liver by conversion through cytochrome P450 to 4-hydroxy cyclophosphamide . Its immunosuppressive properties due to the metabolite Chloracetaldehyde produced after side chain oxidation of Cyclophosphamide. Oral Bioavailability is 74%. Peak Plasma level 1 hour. It distributed throughout the body including CSF . The half-life of the drug from 2 to 10 hours. Hepatic metabolisms is the route of elimination of Cyclophosphamide. 70% drug is excreted in the urine as inactive compounds

21. MOA It has the ability to form strong electrophiles that form covalent linkages to electron rich groups of DNA. The active metabolite is phosphoramide mustard, which undergoes cyclization to the reactive aziridium intermediate, which in turn alkalizes the DNA . The result is irreparable damage to the DNA and subsequent apoptosis of the cell. Cyclophosphamide highly toxic to the rapidly dividing cells . It is toxic to the cells in all phases of the cell cycle.

22. Aims & Advantages of DCP therapy To gain greater efficacy of the drug and fast response. To achieve a steroid sparing effect. To avoid the need for long-term use of systemic steroids acute arrest of disease activity. faster healing of the lesions. Reduce duration of hospital stay. Decreases chances of HPA axis suppression. direct correlation with disease severity. More DCPs were required to achieve an initial control in severe disease

23. PHASES OF DCP THERAPY: DCP THERAPY CONSISTS OF 4 PHASES (explained for pemphigus group of disorders). PHASE 1 PHASE 2 PHASE 3 PHASE 4

24. PHASE 1 The DCP comprised of 100 mg dexamethasone dissolved in 500 mL of 5% glucose given as an intravenous infusion over approximately two hours, repeated on 3 consecutive days. On the second day, 500 mg of cyclophospamide added to the dexamethasone infusion -- ONE DCP . Patients are unmarried or those who have not yet completed their family and want to have more children, have to be given only dexamethasone pulses (DPs) and not DCPs. Repeated every 28 days from the first day of the drip till no new lesions appear between pulses. During this phase the patient continue to develop recurrences of clinical lesions in between the DCPs . Interval 50 mg cyclophosphamide daily along with interval oral steroids,antibiotices to achieve quicker clinical recovery. skin and mucous membrane lesions subside completely and the additional medication complete stop. PHASE 1 R epeated DCP , the recurrences would become progressively milder and ultimately go into a state of complete clinical remission the patient is considered to have entered phase II . Existing lesions reduced in number and healing phase. No new lesion appear. C omplete tapering of the oral betamethasone and other drugs . Duration: not fixed.

25. PHASE 2 Continue DCP every 4 weeks and daily cyclophosphamide 50 mg for 9 months . The patients should remain completely free of any pemphigus lesions. Pemphigus lesions recur, the patients should be reverted back to phase I and given more treatment until they achieve complete clinical remission. It should be consid er complete patients remain completely free of any pemphigus lesions for a continuous period of nine months. In case of doubt, it is preferable to give a few more DCPs rather than risk a relapse in the future.

26. PHASE 3 Only oral cyclophosphamide 50 mg daily given for next 9 months. PHASE 4 A chieve complete remission, All treatments are withdrawn. Pt kept in monthly follow up for relapse if any. Duration- Life long (at least 10 years). T otal duration of treatment comes to approximately two years

27. DCP in various conditions DCP therapy can be given to patients of all ages. Doses have to be reduced to half for children below the age of 12 years. Can be given to patients having diabetes mellitus, hypertension, hyperacidity , osteoporosis, tuberculosis, etc.,

28. But each patient must receive additional appropriate treatment for the concomitant disease whenever necessary. Diabetic patients - Give10 units of soluble insulin for every 500 ml bottle of 5% glucose dissolved in the same drip in addition to the routine treatment for diabetes. Hypertensive patients - Monitor the blood pressure regularly and adjust the treatment for hypertension . Viral warts and molluscum contagiosum - Treated concomitantly along with the pulse therapy .

29. Modifications to Standard DCP Regimen

30. Superadded fungal infections must be controlled by proper usage of antifungal drugs and antibiotics Patient is advised to go for thorough cleaning of skin and scalp with soap and shampoo and maintenance of oral hygiene The modified Phase 2 will consist of bolus dose of dexamethasone (100 mg for 3 days) and cyclophosphamide (500 mg on day 2) for 9 months. The modified Phase 3 will consist of only bolus dose of cyclophosphamide 500 mg IV every 4 weeks for 9 months instead of oral daily 50 mg. Cyclophosphamide 500 mg on the second day of DCP, it is followed by an additional 5% dextrose of 500 ml, to prevent the urinary complications of Cyclophosphamide. Prevention of steroid-induced osteoporosis by administration of calcium supplementation (500 mg/day), Vitamin D (400 IU/day), and bisphosphonate (e.g., alendronate). Patients with oral lesions are encourage to clean the oral cavity with regular brushing of the teeth. topical corticosteroid gel on the oral ulcers three to 4 times/day especially after meals , ketoconazole 200 mg/day orally and 500 mg Ciprofloxacin or Cefadroxil twice daily. This change leads to the healing of oral lesions within 2–3 months Earlier patients received only monthly pulses of corticosteroids, some degree of recurrence of lesions between the pulses in the early stages of therapy, daily corticosteroids are added in the 1 st  few months. Patients with extensive active disease are also given interval pulses[MID PULSE ] of dexamethasone.

31. Modifications of DCP Therapy 1. Dexamethasone Azathioprine Pulse Therapy :-Cyclophosphamide is known to cause oligo/azoospermia and amenorrhea. so for unmarried patients who have not completed their family, cyclophosphamide was replaced by 50 mg of azathioprine daily during the first three phases. No bolus dose of azathioprine.

32. DMP(DEXAMETHASONE METHOTREXATE PULSE): cyclophosphamide replaced by 7.5 mg of methotrexate weekly (three doses 2.5 mg given in 12hrly intervals every weekend), for the 3 phases. Recommended for pts not responding to DCP\DAP after 12 pulses in phase1. Patients not completed family or wanting more child.

33. CONTRAINDICATIONS No contraindications of pulse therapy. Absolutely contraindicated in pregnant , lactating mother, pulse to be withheld till baby delivered and weaned off.Rx -daily small doses of steroids. Uncontrolled viral infection- HSV, HZV or any other viral infection can spread dangerously, DCP to be interrupted temporarily for a minimum period of 3 weeks the infection subsides. Patients who are unmarried . Patients not completed family or wanting more child. only dexamethasone pulses (DPs) and not DCPs

34. Adverse Effects Immediate (<7 DAYS) Specific to pulse Flushing (most common), Hiccups[T/t tab baclofen], Facial puffiness, Palpitation , diarrhea, polyuria, mental confusion Steroid related Dyspepsia, Epigastric pain, vomiting[PPI], Hypertension , acute psychosis, cardiovascular complications ( <24 hours) and sudden death, electrolyte imbalance Rare Shivering, soreness of mouth, conjunctival congestion, diffuse rash, limb edema, breathlessness

35. DELAYED(> 7 DAYS) Specific to pulse Generalized weakness (most common), Headache, insomnia , arthralgia, arrythmia (can occur >3days) Steroid related Blurring of vision (cataract), hypertension, diabetes mellitus, Osteoporosis, HPA suppression (not clinically severe), hirsutism, moon facies, Increased susceptibility to infections(bacterial, viral & fungal infections.) Reactivation of tuberculosis (in some pts) Electrolyte imbalance

36. Due to cyclophosphamide : Hematological toxicity Bone marrow suppression. Decrease in leucocyte count. Thrombocytopenia occurs less frequently. Diffuse hyperpigmentation ,Hair loss, Nail discolouration , Gonadal failure manifesting as amenorrhea at[30gm]/azoospermia [12gm]/disappearance of primordial follicle/atrophied uterus. Urological damage increased frequency, dysuria, urgency, microscopic haematuria, hemorrhagic cystitis, fibrosis of bladder, and bladder necrosis. increased rugosities of the bladder wall Carcinogenesis carcinoma of bladder,urinary tract, and carcinoma[85gm] of the renal pelvis and ureter.

37. COUNSELLING OF PATIENTS Strict adherence to T/t schedules Adequate hygiene (i.e. daily bath, oral care, sanitation habits) Timing of intake of oral cyclophosphamide Hydration Adverse effects of steroids and cyclophosphamide Advice should be given to follow the contraception till all 3 phases of pulse trerapy completed. Monitoring(blood glucose, urine reports prior to each pulse)

38. Limitations of DCP therapy Pt compliance is poor Frequent need of hospitalization Short follow up periods. major causes of relapse in the patients treated with the regimen (1) incomplete treatment, (2) irregular treatment, and (3) use of one drug instead of the two mentioned

39. Other Uses 1. SLE Severe lupus nephritis- treated with a combination of glucocorticoid and intravenous cyclophosphamide (induction therapy), followed by a period of less intensive maintenance therapy (often with Azathioprine). Intravenous CYP pulses are given in doses of 10–15 mg/kg body weight once every four weeks with or without dexamethasone.

40. 2. Pyoderma gangrenosum Pulsed IV corticosteroid therapy has been reported to be effective in cases refractory to oral steroids. It is recommended in PG refractory to other forms of treatment. 3. ENL Dexamethasone pulse therapy with Azathioprine is to be considered as daily steroid sparing regimen for recurrent ENL. It is given as 100 mg dexamethasone in 500 ml glucose IV infusion on 3 consecutive days every month along with 50 mg daily Azathioprine.

41. Propose the following suggestions for modifications in the protocol of pulse therapy: The total duration of treatment may be individualized according to the severity of the disease and response to therapy. So instead of a regimental approach of a total of 18 months for phases II and III, we may rely on a combination of the clinical severity index, immunofluorescence titers and promptness of response to therapy to decide whether to shorten the duration in quick responders and to extend it in slow responders The decision to stop pulse therapy after 18 months in phase II + III can be individualized depending on the results of immunofluorescence (IF) tests. This may decrease the relapse rates.

42. Serology by IIF can be replaced by ELISA for direct measurement of desmoglein 1 and desmoglein 3 antibodies. The bladder toxicity with bolus doses of cyclophosphamide reduces by concomitant administration of MESNA (sodium 2 mercaptoethane sulfonate) given intravenously, give on the day of administration of bolus cyclophosphamide. The usual dose is equivalent to the dose of cyclophosphamide , intravenously over 15-30 minute infusions in 5 divided doses over 24 hrs . It acts binding to the acrolein metabolite which is implicated in causing hemorrhagic cystitis and the subsequent development of transitional cell carcinoma of the bladder. fulminant disease not controlled addition of interval pulses and daily steroids, a different approach use of immunoablative high dose cyclophosphamide without stem cell rescue . This approach has been utilized with success in other autoimmune diseases like systemic lupus erythematosus, acquired aplastic anemia and more recently for paraneoplastic pemphigus..

43. Controversies Pulse therapy can result in cardiac arrhythmias and sudden death during and even days after pulse therapy; but patients are discharged within 3 days of hospitalization. Patients receive antibiotics especially cephalosporins in view of bacterial skin infection, until the skin lesions heal, however, cephalosporins aggravate pemphigus. Furthermore, long-term use of antibiotics can cause antibiotic resistance. Ramam found that antibiotics should be used until the infection clears and not until lesions heal.

44. No standardized objective method for assessing severity of disease before and after treatment. A study by Shahidi‑ Dadras et al ., a trial of pulse versus oral steroid therapy, therapeutic responses, remission, relapse, and complications were similar in both study groups.

45. Oral Mini-pulse Therapy Oral mini pulse (OMP) is a type of pulse steroid therapy which is given orally in intervals to patients. It is more comfortable for patients to comply with than daily systemic steroid therapy . Pasricha used OMP in the treatment vitiligo for the first time and later it was used in other dermatological conditions . Used in diseases: vitiligo Lichen planus Alopecia areata Nail dystrophy Infantile peri ocular haemangioma Urticaria

46. Drug used for OMP Betamethasone Dexamethasone Methylprednisolone Prednisolone

47. The management of unstable or generalized vitiligo with OMP[ oral mini pulse might help arrest the disease progression ]

48. Treatment of LP with OMP dose

49. The management of extensive and recalcitrant alopecia

50. Side effects of oral mini -pulse therapy Long term use of corticosteroids can cause adrenal suppression, avascular necrosis, osteoporosis and growth retardation. OMP do not lead to adrenal suppression. The most common side effect was weight gain. Epigastric discomfort and acne flare up were other complaints

51. TOPICAL STEROID PULSE THERAPY : Topical Corticosteroid Pulse Therapy comprises of intermittent use of superpotent corticosteroids. Prolonged continuous therapy with such agents in patients with psoriasis results in certain side-effects e.g., telangiectasis, cutaneous atrophy, hypothalamic-pituitary-adrenal (HPA) axis suppression and tachyphylaxis, whereas intermittent therapy may achieve beneficial effects for maintenance of remissions with an advantage of diminishing the side effects and total cost of medication. Used for atopic dermatitis, bullous pemphigoid and at times in psoriasis. Used when there is limited body surface area involvement. Clobetasol(0.05%) weekly topical application with 3 consecutive application at 12 hour interval. (sat 11 am, sat 11 pm and sun 11am every week)

52. Azithromycin Pulse Therapy in acne vulgaris Macrolide (azalide analogous to Erythromycin), with an expanded spectrum of activity and improved pharmacokinetic features. Rapid uptake from the circulation and slow release. Stable in low gastric PH and there is no major drug interactions[ metabolization via hepatic pathways other than cytochrome P450], as compared with erythromycin. Good diffusion in all tissues and a broad spectrum, with efficacy against p. acne and other bacterial agents found in skin.  A bioavailability of 37% after a single 500 mg oral dose and a half-life of 2.3 to 3.2 days depending on the tissues have been reported for azithromycin Excellent tissue concentration- 10-100 times greater than corresponding plasma concentration and long elimination half life from tissue permits less frequent administration reduce dose.

53. DOSE: Azithromycin 500 mg once daily for 3 days per week or in cycles of 10 days for 12 weeks are the most commonly used regimens . Adverse effects : mild gastrointestinal discomfort and occurs less frequently than with other antibiotics. Azithromycin can be given in combination with iso-tretinoin and can be used in pregnancy and childhood(as compared with doxycycline ) Isotretinoin pulse therapy for acne vulgaris: 1mg/kg/day for 7-10days of every month.

54. As acne runs a variable course with fluctuations, long term therapy often needed. Therefore, drugs with relatively long half lives such azithromycin can be useful in increasing patient compliance It has an anti-inflammatory action that prevents the growth of P.acne Reduce the production of inflammatory [ IL-1α and IL-8 cytokines ]mediators and acting in immune modulation Useful in management of moderate to severe acne vulgaris.(inflammatory acne vulgaris)

55. Pulse therapy with antifungals Terbinafine, Itraconazole, fluconazole are used to treat superficial and deep fungal infections. These drugs are administered in weekly doses every month. Terbinafine- 250 mg daily for 3 months (continuous) or terbinafine, 500 mg daily for 1 week per month for 3 months (pulse)  Itraconazole-Pulse therapy: 200 mg twice daily [400mg/day]for 7 days per month, with the treatment repeated for 2 to 3 months (“pulses”) to treat fingernails and for 3 to 4 months to treat toenails Fluconazole- 400mg once a week for 1 month.for pityriasis versicolor.

56. PULSE THERAPY FOR PSORIASIS Methotrexate can be administered as a single weekly dose, or the weekly dose can be divided into three doses each at 12 hours interval (Weinstein-Frost regimen). Split dose decreases the chance of gastrointestinal upsets.

57. THANK YOU