Immuno suppressive include cyclosporin methotrexate, the brain cyclo force we made

1. IMMUNOSUPPRESSIVE AGENTS
IN
DERMATOLOGY
By- Dr. Deepika kothari
Moderator-Dr. Surendra Thalor Sir

2. • Immunosuppressant drugs are a class of drugs that suppress, or
reduce, the strength of the body’s immune system.
• Immunomodulatory drugs modify the response of the immune
system by increasing (immunostimulators) or decreasing
(immunosuppressives) the production of serum antibodies.

4. SYSTEMIC STEROIDS
• Most commonly used immunosuppressive and anti-
inflammatory drug.
Mechanism of action :
• There is passive diffusion of the glucocorticoids through the
cell membrane, followed by binding to soluble receptor
proteins in the cytoplasm.
• This hormone-receptor complex then moves to the nucleus
and regulates the transcription of a limited number of target
genes

6. Corticosteroids and transcription
factors
•Corticosteroids
increases
production of IxB
resulting in
decrease of free
NFkB.
•Corticosteroids
also directly bind
to free NFkB
inhibiting the
transcription
factor

7. INDICATIONS
• Severe dermatitis: Contact dermatitis (various forms), Acute
exacerbations of atopic dermatitis ; Photodermatitis ; Exfoliative
erythrodermas
• Bullous dermatoses
• Vasculitis: Cutaneous (various types); Systemic (various types)
• Autoimmune connective tissue diseases: LE ; Dermatomyositis ; Systemic
sclerosis; Morphea ;Eosinophilic fasciitis; MCTD ; Relapsing polychondritis
• Neutrophilic dermatoses: Pyoderma gangrenosum ; Sweet syndrome ;
Behçet disease ,etc
• Other disorders: Sarcoidosis; LP; Panniculitis ; Urticaria/angioedema ;
DRESS; Arthropod bites/stings ; LEPRA reactions

8. Adverse effects
SHORT TERM SIDE EFFECTS INCLUDE:
• Mood Changes, Anxiety, Insomnia
• Gastrointestinal Intolerance (E.G. Nausea, Vomiting)
• Hyperglycemia
• Fluid/Sodium Retention
• Increased Appetite, Weight Gain
• Acneiform Eruptions
• Increased Infections
• Amenorrhea
• Muscular Weakness, Muscle Effects
• Impaired Wound Healing

9. SIDE EFFECTS OF LONG TERM STEROID THERAPY:
• Osteoporosis And Osteonecrosis
• Gastrointestinal Side Effects
• Endocrine Side Effects-diabetes,hpa Axis
Suprression,cushing Syndrome
• Corticosteroid And Immunity Including Vaccinations
• Ophtalmologic Side Effects
• Cutaneous Side Effects
• Cardiovascular Side Effects
• Steroid Induced Myopathy
• Cognitive And Mood Side Effects

10. Monitoring
• BP (at 1 month and atleast every 2-3 months)
• Height and weight in children
• Ophthalmological examination for cataracts
and glaucoma
• Potassium, glucose and triglyceride levels (at 1
month and atleast every 2-3 months)
• Near time of cessation ( am cortisol levels)

11. METHOTREXATE-
• Methotrexate (4-amino-N10methyl pteroylglutamic acid) is
a potent competitive inhibitor of the enzyme dihydrofolate
reductase.
• First used by Gubner et al in 1951 for psoriasis , got USFDA
approval to be used in psoriasis in 1971.
Availability-
• Oral, IM, IV preparations available
• 2.5, 5, 7.5, 10, 15 mg tabs
• 15mg/ml, 25mg/ml injections
• IV MTX more tolerable due to high renal clearance
Regimes-
• Once weekly dose
• Three divided dose over 24 hour period
• MTX inhibits cell division at S phase (DNA synthesis) of the
normal cell cycle.

12. Structure- Dose-
• 0.3mg/kg/week
• Max benefit at 10-25mg
/week
• Max dose 30mg/week
Response-
• Initial response 1-4 weeks
• Therapeutic benefit in 2-3
months.
• Antineoplastic dosage
range;30-40mg/m2/week
to 100-
12000mg/m2/week

13. Mechanism of action - • MTX affect the proliferation of
lymphocytes & blocks migration of
activated T cells
• Because of inhibition of DNA
synthesis in immunologically
competent cells , suppression of
primary and secondary antibody
responses occurs. There is no
significant effect on delayed-type
hypersensitivity.
• anti-inflammatory effects are
mediated by excess accumulation
of adenosine due to AICAR
transformylase and ecto 5′
nucleotidase interaction
• Adenosine binds to A2A receptor
in endothelial cells, inhibiting
apoptosis, neutrophil chemotaxis,
and release of TNFα, IFNγ, IL-12,
IL-6

14. Uses-
 FDA-approved dermatologic indications
• Psoriasis
• Sezary syndrome
 Off-label dermatologic uses
• Proliferative dermatoses- Pityriasis rubra pilaris ,Pityriasis lichenoides
,Reiter’s disease
• Immunobullous dermatoses -Pemphigus vulgaris, Bullous pemphigoid,
Epidermolysis bullosa acquisita
• Autoimmune connective tissue diseases –Dermatomyositis, Subacute
cutaneous lupus erythematosus, Systemic lupus erythematosus, Systemic
scleroderma
• Vasculitis – Leukocytoclastic vasculitis, Cutaneous polyarteritis nodosa,
Behcet’s disease, Kawasaki disease, Pyoderma gangrenosum
• Dermatitis -Atopic dermatitis,
• Other dermatoses -Sarcoidosis, Keloids, Keratoacanthomas (intralesional),
Mycosis fungoides, Chronic idiopathic urticaria

15. Indications of MTX use in psoriasis-
• Erythrodermic psoriasis
• Psoriatic arthritis: not responsive to conventional
therapy
• Pustular psoriasis: generalized or
debilitating localized disease
• Psoriasis that adversely affects ability to maintain
employment
• Extensive, severe plaque psoriasis: not responsive
to conventional therapy (usually > 20% surface
involvement)
• Lack of response to phototherapy (PUVA and UVB) or
systemic retinoids

16. Contraindications-
Absolute
• Pregnancy
• Lactation
Relative
• Unreliable patient – including excessive alcohol intake
(>100 g/week)
• Decreased renal function (dosage must be reduced, avoid
in patients on dialysis)
• Metabolic: diabetes mellitus or obesity
• Hepatic disease: abnormal liver function tests, active
hepatitis; NASH, cirrhosis
• Severe hematologic abnormalities Active infectious disease
or history of serious infection (eg-TB)
• Immunodeficiency syndrome: hereditary or acquired

17. Adverse effects-
• Gastrointestinal- nausea, anorexia, diarrhoea, vomiting
• Hematological- pancytopenia (more with dapsone ,
sulfonamides)
• Hepatotoxicity- risk increased with alcohol and retinoids
• Teratogenic and abortifacient
• Cutaneous- hyperpigmentation, alopecia
• Renal toxicity- only in high doses (with sulfonamides,
phenytoin , tetracyclines, chloremphenicol, probenecid)
• Erythema recall phenomenon
• MTX osteopathy
• Pulmonary- pneumonitis
• Lymphoma rarely

18. Monitoring guidelines-
• CBC & LFT every week for 4 weeks and then decrease frequency to
every 4 weeks
• RFT once or twice yearly
• Chest X ray annually
• Liver biopsy-first biopsy at 3.5 to 4 g total dose of mtx and
subsequent after 1.5-2 g accumulated dosage in low risk patients,
• consider baseline biopsy in high risk patients and After every 1g
dosage accumulation and every 6 months grade III A liver biopsy
changes
• To be stopped if
-TLC <3500 cumm
-platelet counts- <100000 cumm
-liver transaminase increases twice the upper limit

19. Acute methotrexate toxicity-
Causes
• Accidental overdose
• Drugs causing increased concentration in body
• Acute renal failure
• Hypoalbunimea
Clinical features-
• long standing chronic plaque psoriasis,
• Sudden onset of erosions on plaques and oral ulcers
Management-
• Folinic acid 10 mg/m2 according to BSA every 6 hourly
Leucovorin or(N5formyl-tetrahydrofolate: folinic acid) a fully reduced,
functional folate coenzyme bypasses the inhibition of dihydrofolate
reductase enzyme.
• Alkalization of urine by NaHCO3
• Myelosuppression – G-CSF

20. AZATHIOPRINE-
• Azathioprine was synthesized in 1959 from its parent
drug 6-mercaptopurine (6-MP), and became drug of
choice for organ transplantation during the 1970s
• Peak levels 1–2 h
• Bioavailable 88%
• Half-life 5 hours
• Therapeutic effect take 2-3 month to develop
• Metabolism
-Thiopurine methyltransferase -inactive metabolites
-Xanthine oxidase - inactive metabolites
-HGPRT - active purine analogue

21. • Azathioprime dosage after pre TPMT testing
-low values- not used to prevent severe
myelosuppression
-intermediate values- 1mg/kg
-high values- 2-2.5mg/kg

22. Mechanism of action-
-6-TG’s structural similarity to the
endogenous purines allows it to
be incorporated into DNA and
RNA,
-Hence inhibiting purine
metabolism and cell division.
-Azathioprine also affects T- and
B-cell function and antigen-
presenting cell function and
numbers.
-T-cell-mediated function is
depressed, and antibody
production is diminished in the B
cell.

23. Uses-
FDA-approved indications (none specific to dermatology)
• Organ transplantation
• Severe rheumatoid arthritis
Off-label dermatologic uses
• Immunobullous dermatoses- Bullous pemphigoid, Pemphigus vulgaris, Cicatricial
pemphigoid18
• Vasculitis - Leukocytoclastic vasculitis, Wegener’s granulomatosis, PAN
• Neutrophilic dermatoses -Behçet’s syndrome, Pyoderma gangrenosum
• Autoimmune connective tissue diseases- Systemic lupus erythematosus, DLE,
Dermatomyositis, Relapsing polychondritis
• Dermatitis and papulosquamous dermatoses - Contact dermatitis, Atopic
dermatitis, Lichen planus , Psoriasis,
• Photodermatoses - Polymorphous light eruptions,CAD,
• Sarcoidosis (especially pulmonary features)
• Erythema multiforme (persistent)
• Chronic graft-versus-host disease

24. Contraindications-
Absolute
• Hypersensitivity to azathioprine
• Low TPMT level
• Pregnancy
• Active clinically significant infections
Relative
• Allopurinol use – prescribe azathioprine
cautiously with significantly reduced dose
• Prior use of alkylating agents (increased
malignancy risk)

25. Side effects-
• Malignancies – Cutaneous SCC ,Lymphomas
• Myelosuppression (correlates with low TPMT activity)-
Neutropenia , Agranulocytosisand pancytopenia
• Infections- Human papilloma virus, herpes simplex
• Teratogenicity
• Hypersensitivity syndrome- morbilliform, purpura,
erythema multiforme, urticaria, angioedema,
erythema nodosum
• Gastrointestinal- Gastritis, Pancreatitis ,Hepatic
Transaminase elevations , Severe hepatocellular
toxicity (rarely)

26. Monitoring guidelines-
• Clinical evaluation
• Discuss the risk/benefit profile and adverse effects with patient.
• Discuss birth control/abstinence if women of child bearing potential
• Elicit history of prior alkylating agents or current use of allopurinol
• Laboratory
-Pregnancy test
-Complete blood count (CBC)
-Serum chemistry profile
-Urine analysis
-Tuberculin skin test
• Special tests- TPMT assay dose according to enzyme activity.
Follow-up
• Clinical evaluation – Annual complete physical examination for lymphoma
and SCC
• Laboratory - CBC
- LFT
biweekly for the first 2 months, every 2–3 months thereafter

27. CYCLOPHOSPHAMIDE-
• Alkylating agent Derived from nitrogen mustard
• Causes cross-linking of DNA, leading to cell death by
apoptosis
• Cell cycle non specific
• Metabolism in liver by cytochrome P450
• Bioavailability- 75%
• Peak levels in 1-2 hours and half life is 5-9 hr
• Therapeutic effect evident after 4-6 weeks
• Dose 1-1.5mg/kg (adjuvant)
• Parenteral pulse dose – 10-15 mg in 200 ml of 5% dextrose
infused over an hour.
• Advised to drink 3 litres of water and void frequently.

28. Mechanism of action-
-prodrug is biologically
inactive
-the primary metabolites
form covalent bonds
with the nucleophilic
centers of DNA.
-alkylation causes DNA
cross-linking, abnormal
basepair formation,
-Damage overwhelms
cellular repair
mechanisms, and
mutagenesis,
carcinogenesis, and cell
death result.
-greater effect upon B
lymphocytes than T
lymphocytes.

29. Uses-
FDA-approved indications
• Non-dermatologic: some lymphoma and leukemia, multiple
myeloma, neuroblastoma, ovarian cancer, breast
carcinoma, retinoblastoma
• Dermatologic:-mycosis fungoides
Dermatologic uses (‘off label’)
• Immunobullous disease Bullous pemphigoid, Cicatricial
pemphigoid, pemphigus
• Vasculitis/vasculitides- Churg–Strauss syndrome,
Leukocytoclastic vasculitis, Microscopic polyangitis, PAN,
Wegener’s granulomatosis
• Neutrophilic dermatoses – Behçet disease, Erythema
elevatum diutinum, Pyoderma gangrenosum
• Autoimmune connective tissue disease- Dermatomyositis,
Scleroderma, Severe cutaneous lupus

30. Contraindications-
Absolute
• Drug allergy (conflicting reports of cross-reaction
with clorambucil)
• Depressed bone marrow function
• Lactation
• Pregnancy (teratogenic) category D
• Prior history of bladder cancer
Relative
• Active infection
• Impaired hepatic metabolism
• Impaired renal function

31. Side effects-
• Genitourinary- Bladder fibrosis, contracture,
vesicoureteral reflux, Dysuria, urgency, microscopic
hematuria ,Hemorrhagic cystitis (5–41%) by acrolein
• Carcinogenesis- Bladder carcinoma, Leukemia,
Lymphoma, SCC
• Gastrointestinal - Anorexia, stomatitis, hepatotoxicity,
hemorrhagic colitis ,Nausea, vomiting, diarrhea
• Hematologic- pancytopenia
• Reproductive- Amenorrhea, Azoospermia (improved
with testosterone) ,Ovarian failure
• Dermatologic- Alopecia (anagen effluvium),
Pigmentation of skin and nails Pigmented band on
teeth (irreversible) ,Urticaria or bullous eruptions

32. Monitoring guidelines-
• CBC and urine analysis
-weekly for a month
-every 2 weeks for 2 months
-monthly with stable dose
• discontinue if WBC<4000 ,platelets<100000 and
RBC in urine
• LFT-
-Every month for 6 months
-every 3 months

33. CYCLOSPORINE-
• isolated from the soil fungus Tolypocladium inflatum gams
• Neutral cyclic peptide (11 amino acids)
• family of calcineurin inhibitors and it was initially approved
by the FDA in 1983 to reduce the risk of organ transplant
rejection
• Bioavailability- 30-35%
• peak concentration levels- 2 to 4 hours
• metabolized in the liver by cytochrome P450 3A4
• main route of excretion bile.
• 2 formulations sandimmune and neooral.
• Starting Dose 5mg/kg in recalcitrant psoriasis
• 2.5-3 mg/kg in atopic dermatitis
• Duration of therapy 3-6 months

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

35. Uses-
US FDA-approved indications
• Psoriasis
• Severe Recalcitrant psoriasis
• Disabling psoriasis (including localized versions such as hand and foot psoriasis)
• Atopic dermatitis (in other countries)
Other dermatologic uses
• Papulosquamous dermatoses- Lichen planus
• Bullous dermatoses- Pemphigus, Pemphigoid, Epidermolysis bullosa acquisita
• Autoimmune connective tissue diseases- Dermatomyositis, Lupus erythematosus,
Scleroderma
• Neutrophilic dermatoses- Behçet’s disease, Pyoderma gangrenosum
• Atopic dermatitis
• Alopecia areata ,Lichen planopilaris
• Granulomatous dermatoses- Granuloma annulare, Sarcoidosis
• Disorders of keratinization- Pityriasis rubra pilaris
• Photosensitivity dermatoses - Chronic actinic dermatitis
• Persistent papular acantholytic dermatosis- Purpura pigmentosa chronica, Reiter’s
syndrome
• Urticaria- Chronic urticaria, Cold urticaria, Solar urticaria

36. Contraindications-
Absolute
• Significantly decreased renal function
• Uncontrolled hypertension
• Hypersensitivity to CsA or any ingredients in formulation
• Clinically cured or persistent malignancy
• Cutaneous T-cell lymphoma
Relative
• Age <18 years or >64 years Controlled hypertension
• Planning to receive a live attenuated vaccination
• On medications that potentiate renal dysfunction
• Active infection or evidence of immunodeficiency
• receiving , methotrexate, or other immunosuppressive
agents
• Pregnancy or lactation Pregnancy– Category C

37. Side effects-
• Renal dysfunction
• Cardiovascular - Hypertension
• Neurologic - Tremor , Headache, Paresthesia,
hyperesthesia
• Mucocutaneous- Hypertrichosis , Gingival hyperplasia
• Gastrointestinal- Nausea, Diarrhea
• Musculoskeletal- Myalgia, lethargy, Arthralgia
• Laboratory abnormalities- Hyperkalemia,
Hyperuricemia (occasionally precipitates gout)
,Hypomagnesemia , Hyperlipidemia

38. Monitoring guidelines-
• Blood pressure
• CBC
• LFT
• S.creatinine
• Fasting lipid profile
Every 2 weeks for 2 months
Then every 4 weeks
• S.creatinine if >30% baseline repeat in 2 weeks if not
normalised stop drug
• Blood pressure if >140/90 ,repeat in 2 weeks ,if not
normalised , reduce the dose by 30% or treat with calcium
channel blockers.

39. MYCOPHENATE MOFETIL-
• Prodrug to mycophenolic acid
• Derived from penicillium stoloniferum
• Morpholinoethylester of MPA
• Bioavailable 94%
• Protein bound 97%
• First peak in 1 hr second peak in 6 hrs
• Metabolised in liver by glucoronidation into MPA
• Excreted in urine in form of MPAG
• Dose 25-35mg/kg for T cell mediated diseases and 35-
55mg/kg for antibody mediated
• Induction and maintenance in lupus nephritis at 500mg
ODHS for a week.

40. Mechanism of action-
• MPA non-competitively
binds to and inhibits
inosine monophosphate
dehydrogenase
(IMPDH), the key
enzyme in the de novo
pathway.
• MMF has a much higher
affinity for the isoform
of IMPDH that is
expressed in activated
lymphocytes.
• Hence MMF is able to
target those
lymphocytes most
responsible for disease
sparing other organs and
cells

41. Uses-
FDA approved indications
• Renal, cardiac, and liver allograft rejection prevention
Dermatologic uses
• Dermatitis- Atopic dermatitis, Dyshidrotic eczema, Chronic actinic
dermatitis
• Psoriasis
• Bullous dermatoses- Pemphigus, Bullous pemphigoid, Cicatricial
pemphigoid, Paraneoplastic pemphigus, Epidermolysis bullosa
acquisita
• Autoimmune connective tissue diseases- SLE, Subacute and chronic
cutaneous lupus erythematosus, Diffuse systemic sclerosis,
Dermatomyositis
• Vasculitis- Wegener’s granulomatosis, Microscopic polyangiitis,
Churg–Strauss syndrome, Hypocomplementemic urticarial
vasculitis, Nodular vasculitis

42. Contraindications-
Absolute
• Pregnancy (teratogenic) category D
• Drug allergy
Relative
• Lactation
• Peptic ulcer disease
• Hepatic/renal disease
• Drugs that interfere with enterohepatic circulation
(cholestyramine)
• Azathioprine (concomitant administration increases
risk of bone marrow suppression)

43. Side effects-
• Carcinogenicity- Lymphoproliferative disorders, non-
melanoma skin cancer
• Gastrointestinal- Nausea, diarrhea, Anorexia, abdominal
cramps, vomiting,
• Genitourinary- Urgency, frequency, dysuria, burning, sterile
pyuria
• Infectious- Viral, bacterial, atypical mycobacteria, fungal,
Progressive multifocal leukoencephalopathy
• Hematologic- Dose-dependent reversible pancytopenia
agranulocytosis
• Neurologic- Weakness, fatigue, headache, tinnitus,
insomnia
• Teratogenicity- First trimester loss, external facial
abnormalities, anomalies of distal limbs, heart, esophagus,
kidneys

44. Monitoring-
• CBC
• RFT
• LFT
Every 2 weeks at dose escalation
Every 2 months when dose is stable.

45. INTRAVENOUS IMMUNOGLOBULIN-
• Derived from human plasma pool of >1000 healthy donors
• Comprised of IgG in major amounts and traces of others
• Peak immediate
• Half life- 3-5 weeks
• Distribution- 60% intravascular
• Dose 2g/kg/cycle 3 consecutive days slow infusion over 4
hours
one cycle every 3 weeks
• Clinical control in 4-6 months -> tapering done -> at end
point 2 infusions 16 weeks apart

46. Mechanism of action-
-the suppression of antibody production by
IgG binding via its Fc fragment to surface
receptors on B lymphocytes
-binds to C3 and C5 convertases, block
complement activation hence prevent
formation of the membrane attack complex
-IVIg binds to Fc receptors on macrophages,
subsequently downregulating these
receptors.
-downregulate the expression of co-
stimulatory molecules such as lymphocyte
function-associated antigen-1 (LFA-1) on
activated T cells, interfering with T-cell
activation
-Antibodies against the extracellular matrix
protein Arg-Gly-Asp may inhibit the cellular
adhesion and subsequent cellular migration
-anti-Fas-receptor antibodies, which block
molecular Fas ligand/Fas receptor
interactions and keratinocyte apoptosis

47. Uses-
Dermatologic uses
• Vasculitis- Kawasaki’s disease
• Autoimmune connective tissue disorders-Dermatomyositis,
Scleroderma, Systemic lupus erythematosus
• Autoimmune bullous dermatoses- Pemphigus vulgaris and
foliaceus, Bullous pemphigoid, Cicatricial pemphigoid,
Epidermolysis bullosa acquisita, Pemphigoid gestationis ,
Toxic epidermal necrolysis/Stevens-Johnson syndrome
• Other inflammatory dermatoses -Chronic autoimmune
urticaria, Atopic dermatitis
• Graft-versus-host disease
• Psoriasis
• Pyoderma gangrenosum

48. Contraindications-
Absolute
• anaphylaxis secondary to previous infusions
Relative
• Congestive heart failure (increased risk fluid overload)
• Renal failure (increased risk fluid overload)
• IgA deficiency (increased risk of anaphylaxis)
• Rheumatoid arthritis (increased risk of renal failure)
• Cryoglobulinemia (increased risk of renal failure)
• Pregnancy NOT a contraindication for IVIg therapy

49. Side effects-
 Infusion-related adverse effects –
• headache, myalgia,
• chills, flushing, fever,
• nausea or vomiting,
• low back pain,
• wheezing, chest pain,
• blood pressure changes, and tachycardia.
 Anaphylaxis in patients with IgA deficiency having anti-IgA
antibodies.
 Fluid overload and Rarely acute renal failure due to ‘osmotic
nephrosis’ in patients receiving sucrose-containing IVIg
preparations.
 Hematologic disorders, such as neutropenia and hemolysis
 Aseptic meningitis reported in up to 11% patients
 Thromboembolic events
 Infections from pooled human plasma.

50. Monitoring guidelines-
• Complete history and physical exam with emphasis on
cardiopulmonary and renal status
• Laboratory – Complete blood count (CBC)
– LFT
– RFT
– Immunoglobulin levels ( to exclude IgA deficiency
increases risk of anaphylaxis)
• Screen for rheumatoid factor and cryoglobulins (these patients are
at increased risk for renal failure from IVIg)
• Consider screening for hepatitis B and C , HIV.
• During infusions monitor blood pressure and heart rate frequently.
• Assess for signs of fluid overload – auscultate lungs and heart,
weigh the patient
• Laboratory – no specific follow-up laboratory testing required

51. Thank you.