PULSE THERAPY IN DERMATOLOGY.pptx

PULSE THERAPY IN DERMATOLOGY

1. PULSE THERAPY IN DERMATOLOGY PRESENTED BY DR PDIANGTY GIRI PG 2 ND YEAR PGIMS ROHTAK

2. Introduction Pulse therapy was first introduced by Pasricha and Ramji in 1984 The first reported use of pulse administration of corticosteroids is attributed to Kountz and Cohn who used it to prevent renal graft rejection in 1973.

3. DEFINITION Pulse therapy means the administration of suprapharmacologic doses of drugs in an intermittent manner to enhance the therapeutic effect and reduce the side effects . MEDICATIONS USED T he agent most commonly used for corticosteroid pulse therapy is methylprednisolone (MP) and dexamethasone.

4. DIFFERENCES BETWEEN METHYLPREDNISOLONE 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

5. 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 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.

6. 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.

7. 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.

8. 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: At low concentrations (genomic effect)

9. GC form complexes with cytosolic GC receptors (GCR) Form GCR complex activates the MAPK signalling pathway activated GCR complex moves to the nucleus activates the GC‑responsive element results in anti‑inflammatory and i mmunosuppressive effects

10. 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).

11. Indications for High Dose Intravenous Steroid 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

12. 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

13. CONTRAINDICATIONS Systemic infections, including fungal sepsis Uncontrolled hypertension known hypersensitivity to the steroid preparation. Absolutely contraindicated in pregnant, lactating, and unmarried patients

14. Protocol for High Dose Intravenous "Pulse" Steroids Administration ADMINISTRATION OF INTRAVENOUS HIGH-DOSE CORTICOSTEROIDS Medication used Methylprednisolone (20-30 mg/kg) or dexamethasone (4-5 mg/kg) Route and method of administration The corticosteroid preparation is dissolved in 150-200 ml of 5% dextrose and infused intravenously, slowly over 2-3 hours.

15. Precautions A. Before starting therapy Free from any systemic infections before administration of corticosteroids. Minor upper respiratory tract, gastrointestinal or skin infections are not a contraindication. Blood pressure must be controlled. Obtain total and differential white cell counts, blood level of sugar, urea, creatinine, sodium and potassium.

16. During and following therapy Record of heart rate, respiratory rate and blood pressure every 15-30 minutes. If an arrhythmia is suspected, the infusion is discontinued; an ECG and blood levels of Na, k, ca and mg are obtained and abnormalities are rectified. Careful screening for occurrence or exacerbation of infections. Estimate blood levels of sugar and electrolytes every other day.

17. THE REGIMEN DCP regimen or the dexamethasone-cyclophosphamide pulse (DCP) therapy regimen DOSE - 100 mg dexamethasone dissolved in 500 ml of 5% glucose as a slow intravenous drip over 2 hours repeated on 3 consecutive days. On the second day, the patient is also given 500 mg cyclophosphamide in the same drip. The reason for administration of dexamethasone in dextrose instead of normal saline is because steroids cause hypernatremia and hypokalemia .

18. This constitutes one DCP. DCPs are repeated at exactly 28 day intervals counted from the first day of the pulse. In between the DCPs the patient receives only 50 mg cyclophosphamide orally per day.

19. PHASES OF DCP The DCP regimen is administered in four phases . Phase I - Patient may continue to develop recurrences of clinical lesions in between the DCPs and on conventional daily doses of oral corticosteroids or additional dexamethasone pulses . Phase II- Patient remains completely alright clinically but receives 9 more DCPs with 50 mg cyclophosphamide orally per day. Phase III- DCPs are stopped and the patient receives only 50 mg cyclophosphamide orally per day for the next 9 months. Phase IV- The treatment is stop and followed up for the next 10 years to look for a relapse if any.

20. INDICATION All pemphigus patients deserve to be treated with this regimen irrespective of whether they are having severe or mild disease.

21. Precautions 1 . Before starting therapy: Should be free from systemic infections. Blood pressure must be under control. Counts, blood sugar, urea, creatinine, electrolytes, and urine routine should be done. In elderly patients, cardiac assessment should be done. Direct immunofluorescence (DIF) and histopathological examination help in the diagnosis of pemphigus. DIF specifically helps in monitoring disease activity and for prognosis and hence should be recorded before initiating pulse therapy.

22. 2 . During and after therapy: Monitor pulse, respiratory rate, and blood pressure every 15–30 min In case of an arrhythmia, the infusion is discontinued. Electrocardiography and electrolytes are measured, and abnormalities are corrected. Check regular blood levels of sugar and electrolytes daily. On day 2 of cyclophosphamide infusion, the patient is advised to empty the bladder half hourly during infusion until 2 h after the infusion.

23. DCP CAN BE GIVEN TO There are almost no contraindications. 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.,

24. 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 . Active tuberculosis- Give pulse therapy along with the anti-tubercular treatment. Viral warts and molluscum contagiosum - Treated concomitantly along with the pulse therapy.

25. CONTRAINDICATIONS Severely infected lesions or there is a serious infection elsewhere. The start of the pulse therapy can be delayed for a week or two till the infection has been brought under control. The only contraindication - pregnancy and lactating mother . This is also not an absolute contraindication; the pulse therapy is only to be postponed till the patient has delivered her baby and stopped feeding the child.

26. 3) Patients who are unmarried. 4) 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.

27. SIDE EFFECTS OF DCP Immediate ( Less than 7 days) Flushing ( most common) Anorexia Bad taste in the mouth Myalgia, feeling of weakness and tiredness Headache Dysgeusia (altered taste) Nausea Insomnia Fever Arthralgia, irritability Vomiting, hiccups, epigastric pain, loose motion

28. DELAYED (more than 7 days) Oral candidiasis ( most common) Weight gain Furuncles Hypertension Diabetes mellitus Amenorrhea Cataract Septicemia Cushingoid habitus, generalised pruritus Diffuse scalp hair loss Oligomenorrhea,osteopenia

29. ELECTROLYTE IMBALANCE Hyperglycemia Hypocalcemia Hypernatremia Hyponatremia Hypokalemia Increase serum alkaline phosphatase Increase SGOT/PT Leucocytosis/ leucopenia Eosinophilia

30. Modifications Oral antibiotics and antifungals to control superadded infections which delay the healing of lesions. Addition of daily oral steroids to control the disease activity during Phase 1, with progressive tapering as lesions heal. “Intermittent pulse” may also be given at shorter intervals (fortnightly) if disease is very severe. .. Individualization of the duration of Phase 2 and 3 based on IF results. The relapse rate is 13–27% if DIF is negative at the end of treatment but increases to 4–100% if DIF is positive.

31. To replace a daily dose of cyclophosphamide of 50 mg in Phase 3 with a bolus dose of 500 mg every 4 weeks. Cyclophosphamide‑induced hemorrhagic cystitis is prevented infusion of 500 ml of 5% dextrose on day 2 of IV cyclophosphamide Bladder toxicity is reduced by administration of IV mesna during IV doses of cyclophosphamide. The dose of mesna is equivalent to cyclophosphamide dose in 5 divided doses over 24 hr.

32. Prevention of steroid‑induced osteoporosis by administration of calcium supplementation (500 mg/day), Vitamin D (400 IU/day), and bisphosphonate (e.g., alendronate) In patient of diabetes instead of 5% dextrose replace it by normal saline infusion.

33. Controversies Patients with diabetes were given pulse in 5% glucose hyperglycemia. Unmarried patients and in complete families were given 50 mg cyclophosphamide daily gonadal failure (cumulative dose of 30 g and 12 g in women and men) 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, however, cephalosporins aggravate pemphigus.

34. 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.

35. Modifications including regimens other than DCP 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.

36. 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. DAP is recommended for unmarried patients who have not completed their family. DMP is recommended for patients not responding to DCP/DAP after 12 pulses in Phase 1.

37. OTHER FORMS OF PULSE THERAPY 1. Cyclophosphamide pulse therapy Cyclophosphamide 500 mg pulses are given in 500 ml of 5% dextrose solution slowly intravenously. These pulses are given monthly for 12 months and 2 monthly for further 6 pulses. Close monitoring of kidney and bladder function was done. This form of pulse therapy has been tried in other conditions like lupus nephritis, serious central nervous involvement in lupus erythematosus and Wegener’s granulomatosis.

38. 2 .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-Pulse therapy: 250 mg twice a day for 1 week of each month over 3 months. Itraconazole-Pulse therapy: 200 mg twice daily 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-450 mg once weekly until nail is normal or acceptably improved against dermatophytes (treatment often requires 6 to 9 months

39. 3. Isotretinoin therapy for acne vulgaris 1 mg / kg / day of isotretinoin is administered for 7- 10days every month. 4. Pulse therapy in 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).

40. Oral mini pulse 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. Used in the treatment vitiligo and in other dermatological conditions such as lichen planus, alopecia areata, nail dystrophy, infantile periocular hemangioma .

41. Drug used for omp are Betamethasone Dexamethasone Methylprednisolone Prednisolone

42. The management of unstable or generalized vitiligo with OMP

43. Treatment of LP with OMP dose

44. The management of extensive and recalcitrant alopecia

45. Side effects of oral mini -pulse therapy Long term use of corticosteroids can cause adrenal suppression, avascular necrosis, osteoporosis and growth retardation. Since oral mini pulse is administered in intervals, fewer side effects are reported than daily use of low- dose corticosteroids. OMP do not lead to adrenal suppression. The most common side effect was weight gain. Epigastric discomfort and acne flare up were other complaints

46. References Thappa DM. Current treatment of onychomycosis. Indian J Dermatol Venereol Leprol 2007;373-6. Abraham A, Roga G, Job AM. Pulse therapy in pemphigus: Ready reckoner. Indian J Dermatol 2016;61:314-7. Viswanath V, Vasani R.Viva questions from the IJDVL. Indian J Dermatol Venereol Leprol 2015;81:226-3 Pasricha JS. Pulse therapy as a cure for autoimmune diseases. Ind J Dermatol, Venereol, Leprol 2003 ; 69(5): 323 – 28 Mittal R, Sudha S, Murugan S, Adikrishnan , Shobana S, Anandan S. Pulse therapy in dermatology. Sri Ramachandra J Med 2007;1:44-6. Vasaghi A, Kalafi A ,Reza M. Oral mini -pulse steroid therapy in the treatment of dermatological diseases: review of the literature. Egyptian Dermatology Online Journal 2014; 10 (2): 1.

47. Thank you