**9. Adjuvant treatment of pemphigus**

Immunosuppressive therapy for pemphigus includes azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporin and dapsone. Adjuvant agents with immuno‐ modulatory activity that have also been used in pemphigus include calcineurin inhibitors, epidermal derived growth factor and tetracycline antibiotics. The main role of these immu‐ nosuppressive medications is to function as a steroid-sparing agent. As they generally have a slow mode of onset, approximately 4-6 weeks, they are used in maintenance therapy rather than in the initiation of disease control. However, their role needs to be further elucidated as there has been only limited number of randomized controlled trials with most of the literature derived from case series reports.

mycophenolate mofetil in 33 patients with PV and 7 patients with PF [64]. The primary outcome was complete healing of all lesions. This study concluded that mycophenolate mofetil and azathioprine demonstrated similar efficacy. Safety profiles were similar as was corticosteroidsparing effects. There were less severe side effects observed in the mycophenolate group but this was not statistically significant. Many non-randomized trials have supported the use of mycophenolate mofetil in the treatment of pemphigus [65]-[69]. The majority of patients in these trials had PV. Mycophenolate mofetil is generally well tolerated; lymphopenia, gastro‐ intestinal symptoms and infections are the most common side effects. Currently it is a relatively expensive medication, often precluding its off-label use. The drug is usually commenced at dose of 1 g per day in adult patients, and if required, increased in 500-mg increments up to

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Cyclophosphamide is an alkylating agent that disturbs DNA synthesis and cell division. Cyclophosphamide interferes with DNA integrity and function inducing cell death in rapidly proliferating tissues including lymphocytes. This provides the basis for their therapeutic and toxic properties. Several randomized trials have assessed cyclophosphamide in treatment of pemphigus. Chrysomallis et al. used oral cyclophosphamide in patients with PV whose disease was limited to oral involvement [71]. Twenty-eight patients were divided into 3 groups and given corticosteroids alone, corticosteroids with cyclophosphamide or cyclosporine. No difference in remission was seen when cyclophosphamide was compared with corticosteroids alone, and at 5 years, all patients had their disease controlled with a low dose corticosteroid regimen. The more recent study by Chams-Davatchi et al. described above and comprising entirely of patients with PV concluded that there was no difference in remission rates following pulsed intravenous cyclophosphamide therapy [59]. A randomized control trial that included 6 patients with PF as well as 16 with PV compared pulsed cyclophosphamide with dexame‐ thasone and daily cyclophosphamide with methylprednisolone plus azathioprine [72]. No difference in disease control was observed for the cyclophosphamide group compared to the azathioprine group after 2 years. Several non-randomized case series have utilized pulse

Given the lack of superiority of cyclophosphamide over other regimes in randomized trials and its well-described serious side effect profile, the authors recommend that its use be restricted for the treatment of severe or refractory cases of PF, where alternative agents such

Cyclosporin is a calcineurin inhibitor that prevents dephosphorylation of nuclear factor of activated T cells (NFAT) preventing its translocation into nucleus and as a consequence the T cells fail to respond to specific antigenic stimulation. Cyclosporin also increases expression of TGF- beta, a potent inhibitor of IL-2–stimulated T-cell proliferation. A randomized trial compared oral methylprednisolone alone with oral methylprednisolone plus cyclosporin in 33 newly diagnosed patients, 29 with PV and 4 with PF [76]. The patients were followed for

doses of 2-3 g per day [70].

cyclophosphamide with variable outcomes [73]-[75].

as rituximab or IVIg are not available.

**9.4. Cyclosporin**

**9.3. Cyclophosphamide**

#### **9.1. Azathioprine**

Azathioprine is a purine antimetabolite that is cleaved to 6-mercaptopurine, which in turn is converted to additional metabolites that inhibit *de novo* purine synthesis. Cell proliferation is inhibited and as a consequence a variety of lymphocyte functions are impaired. Azathioprine is commonly used to treat pemphigus; a survey of dermatologists in 2003 showed it was the most commonly prescribed adjuvant agent used to treat PV [57]. It has even been used as monotherapy in mild cases [58]. In a recent randomized trial conducted by Chams-Davatchi et al, 120 new patients with PV were treated for over one year with one of four regimens. These regimes were prednisolone alone, prednisolone plus azathioprine, prednisolone plus intrave‐ nous cyclophosphamide and prednisolone plus mycophenolate mofetil [59]. Azathioprine reduced the cumulative dose of prednisolone compared with prednisolone alone however remission rates were similar. Side effects were similar between the two groups. Thus in this trial, which included only patients with PV, azathioprine reduced the cumulative corticoste‐ roid dose but not the rate of remission. More recently, a non-randomized study compared high dose oral prednisone daily (1.5 mg/kg/daily) versus low dose oral prednisone (40 mg on alternate days) plus azathioprine (100 mg/daily) in 36 patients with oral PV [60]. Both treat‐ ments resulted in high rates of clinical remission; the monotherapy group showed a reduced mean time to remission but this group was associated with an increased rate of treatmentassociated adverse events Other non-randomized trials using azathioprine are have generally shown favourable outcomes in PV [61],[62].

#### **9.2. Mycophenolate mofetil**

Mycophenolate mofetil is a prodrug and its active drug, mycophenolic acid, inhibits inosine monophosphate dehydrogenase, an important enzyme in guanine nucleotide synthesis. Lymphocytes are highly dependent on this pathway and are selectively inhibited by myco‐ phenolate mofetil [63]. In the randomized trial by Chams-Davatchi et al, no difference in remission was observed for mycophenolate mofetil when compared to prednisolone alone [59]. In this same study no difference in remission was demonstrated between azathioprine and mycophenolate mofetil. The steroid sparing effect of mycophenolate mofetil was inferior to azathioprine. Beissert et al. compared oral methylprednisolone plus azathioprine with mycophenolate mofetil in 33 patients with PV and 7 patients with PF [64]. The primary outcome was complete healing of all lesions. This study concluded that mycophenolate mofetil and azathioprine demonstrated similar efficacy. Safety profiles were similar as was corticosteroidsparing effects. There were less severe side effects observed in the mycophenolate group but this was not statistically significant. Many non-randomized trials have supported the use of mycophenolate mofetil in the treatment of pemphigus [65]-[69]. The majority of patients in these trials had PV. Mycophenolate mofetil is generally well tolerated; lymphopenia, gastro‐ intestinal symptoms and infections are the most common side effects. Currently it is a relatively expensive medication, often precluding its off-label use. The drug is usually commenced at dose of 1 g per day in adult patients, and if required, increased in 500-mg increments up to doses of 2-3 g per day [70].

## **9.3. Cyclophosphamide**

**9. Adjuvant treatment of pemphigus**

derived from case series reports.

118 Skin Biopsy - Diagnosis and Treatment

shown favourable outcomes in PV [61],[62].

**9.2. Mycophenolate mofetil**

**9.1. Azathioprine**

Immunosuppressive therapy for pemphigus includes azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporin and dapsone. Adjuvant agents with immuno‐ modulatory activity that have also been used in pemphigus include calcineurin inhibitors, epidermal derived growth factor and tetracycline antibiotics. The main role of these immu‐ nosuppressive medications is to function as a steroid-sparing agent. As they generally have a slow mode of onset, approximately 4-6 weeks, they are used in maintenance therapy rather than in the initiation of disease control. However, their role needs to be further elucidated as there has been only limited number of randomized controlled trials with most of the literature

Azathioprine is a purine antimetabolite that is cleaved to 6-mercaptopurine, which in turn is converted to additional metabolites that inhibit *de novo* purine synthesis. Cell proliferation is inhibited and as a consequence a variety of lymphocyte functions are impaired. Azathioprine is commonly used to treat pemphigus; a survey of dermatologists in 2003 showed it was the most commonly prescribed adjuvant agent used to treat PV [57]. It has even been used as monotherapy in mild cases [58]. In a recent randomized trial conducted by Chams-Davatchi et al, 120 new patients with PV were treated for over one year with one of four regimens. These regimes were prednisolone alone, prednisolone plus azathioprine, prednisolone plus intrave‐ nous cyclophosphamide and prednisolone plus mycophenolate mofetil [59]. Azathioprine reduced the cumulative dose of prednisolone compared with prednisolone alone however remission rates were similar. Side effects were similar between the two groups. Thus in this trial, which included only patients with PV, azathioprine reduced the cumulative corticoste‐ roid dose but not the rate of remission. More recently, a non-randomized study compared high dose oral prednisone daily (1.5 mg/kg/daily) versus low dose oral prednisone (40 mg on alternate days) plus azathioprine (100 mg/daily) in 36 patients with oral PV [60]. Both treat‐ ments resulted in high rates of clinical remission; the monotherapy group showed a reduced mean time to remission but this group was associated with an increased rate of treatmentassociated adverse events Other non-randomized trials using azathioprine are have generally

Mycophenolate mofetil is a prodrug and its active drug, mycophenolic acid, inhibits inosine monophosphate dehydrogenase, an important enzyme in guanine nucleotide synthesis. Lymphocytes are highly dependent on this pathway and are selectively inhibited by myco‐ phenolate mofetil [63]. In the randomized trial by Chams-Davatchi et al, no difference in remission was observed for mycophenolate mofetil when compared to prednisolone alone [59]. In this same study no difference in remission was demonstrated between azathioprine and mycophenolate mofetil. The steroid sparing effect of mycophenolate mofetil was inferior to azathioprine. Beissert et al. compared oral methylprednisolone plus azathioprine with

Cyclophosphamide is an alkylating agent that disturbs DNA synthesis and cell division. Cyclophosphamide interferes with DNA integrity and function inducing cell death in rapidly proliferating tissues including lymphocytes. This provides the basis for their therapeutic and toxic properties. Several randomized trials have assessed cyclophosphamide in treatment of pemphigus. Chrysomallis et al. used oral cyclophosphamide in patients with PV whose disease was limited to oral involvement [71]. Twenty-eight patients were divided into 3 groups and given corticosteroids alone, corticosteroids with cyclophosphamide or cyclosporine. No difference in remission was seen when cyclophosphamide was compared with corticosteroids alone, and at 5 years, all patients had their disease controlled with a low dose corticosteroid regimen. The more recent study by Chams-Davatchi et al. described above and comprising entirely of patients with PV concluded that there was no difference in remission rates following pulsed intravenous cyclophosphamide therapy [59]. A randomized control trial that included 6 patients with PF as well as 16 with PV compared pulsed cyclophosphamide with dexame‐ thasone and daily cyclophosphamide with methylprednisolone plus azathioprine [72]. No difference in disease control was observed for the cyclophosphamide group compared to the azathioprine group after 2 years. Several non-randomized case series have utilized pulse cyclophosphamide with variable outcomes [73]-[75].

Given the lack of superiority of cyclophosphamide over other regimes in randomized trials and its well-described serious side effect profile, the authors recommend that its use be restricted for the treatment of severe or refractory cases of PF, where alternative agents such as rituximab or IVIg are not available.

#### **9.4. Cyclosporin**

Cyclosporin is a calcineurin inhibitor that prevents dephosphorylation of nuclear factor of activated T cells (NFAT) preventing its translocation into nucleus and as a consequence the T cells fail to respond to specific antigenic stimulation. Cyclosporin also increases expression of TGF- beta, a potent inhibitor of IL-2–stimulated T-cell proliferation. A randomized trial compared oral methylprednisolone alone with oral methylprednisolone plus cyclosporin in 33 newly diagnosed patients, 29 with PV and 4 with PF [76]. The patients were followed for 4-6 years and the investigators concluded that the combination regimen of corticosteroids and cyclosporin provided no additional benefit over corticosteroids alone. Side effects, including hypertrichosis, hypertension and renal dysfunction, were more common in the cyclosporin group. The randomized controlled study by Chrysomallis et al. in newly diagnosed PV limited to oral involvement found no difference in remission or relapse rates between the cyclophos‐ phamide and cyclosporine (5 mg/kg) groups [71]. Again, adverse events were more common in the cyclosporin group and included hypertrichosis and renal impairment. A case series reported successful the successful treatment of 6 patients with recalcitrant PV [77].

role of methotrexate in treatment of pemphigus. The most recent study [83] treated 9 patients with chronic active PV, who were unable to successfully wean their prednisolone dose. They were treated with a mean dose of 12.5 mg per week of methotrexate. Prednisolone was discontinued in 6 of the 9 patients within 6 months of commencing methotrexate. There were minimal adverse effects reported in the study. A recent review of the English literature revealed that 111 (82%) of 136 pemphigus patients responded to methotrexate [85]. However, meaningful conclusions are limited by the lack of randomized trials, varying doses and schedules of treatment, and insufficient information on clinical progress including the lack of

Thus methotrexate may be useful as a steroid sparing agent but further trials are required

Only: <sup>A</sup>*causal* relationship has not been established with malignancy. Skin cancer

and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including pimecrolimus 1% cream.

> ∙ baseline visual acuity testing (for macular degeneration) by an Ophthalmologist

∙ FBC; G6DP levels; LFT's

∙ thiopurine methyltransferase (TPMT) assay (determines risk of bone marrow aplasia)

∙ FBC; LFT's; E/U/C

**Pre-Therapeutic Investigations**

∙ Tb, HIV, HBV, HCV Systemic:

∙ hypertension, psychosis, diabetes mellitus, weight gain,

cataracts

atrophy

Oral Mucosa: ∙ candidiasis, mucosal

∙ annual baseline visual acuity testing ∙ FBC and LFT's weekly for first 4 weeks; thereafter, only if indicated

∙ FBC weekly for first 8 weeks; thereafter monthly

**Monitoring Adverse Reactions**

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hypertension, psychosis, diabetes mellitus, weight gain, cataracts Oral Mucosa: candidiasis, mucosal atrophy

irritation, pruritis and erythema on application

UV (sun) light–initiated lichenoid cutaneous reactions

Note: slow onset of action of up to 3 months

severe adverse reaction with xanthine oxidase inhibitors of which the most potent is allopurinol (Progout® Zyloprim®)

before recommending methotrexate as an initial steroid-sparing agent.

∙ Active infectious diseases: Tb, HIV, HBV,

∙ pre-existing retinopathy ∙ psoriasis ∙ porphyria ∙ G6PD deficiency

∙ recent use of live vaccines

∙ pregnancy (Category D) (including partner of male patient) ∙ concomitant allopurinol

HCV

consistency of the length of follow up.

**Medication Dose Contra-indications**

prednisolone: (1) ½-1 mg per kg/ bodyweight of the patient for 4 days (or longer in pemphigus) with rapid taper until clinical remission occurs (2) < 7.5 mg/daily

Topical Application

thin layer to affected mucosa twice daily

> 200-400 mg (once daily)

1.0-2.0 mg per kg bodyweight/daily (once daily)

Corticosteroids ("steroids")

Calcineurin-Inhibitors: pimecrolimus (Elidel®)

Lysosomotropic Amines: hydroxylchloroquine (Plaquenil®)

azathioprine (Imuran®)

The randomized trials have not supported the use of cyclosporine at a dose of 5 mg/kg for the treatment of new onset pemphigus and side effects are relatively common. Further random‐ ized controlled trials are required to determine its benefit in recalcitrant disease.

#### **9.5. Dapsone**

Dapsone has anti-inflammatory and antimicrobial actions. Its immunomodulatory action is incompletely understood but several actions have been described including prevention of the respiratory burst from myeloperoxidase, suppression of neutrophil migration by blocking integrin-mediated adherence, inhibition of adherence of antibodies to neutrophils, and reduction of eicosanoid release. Most studies utilising dapsone have been performed in patients with PV. A randomized controlled trial performed in 19 patients, all with PV, compared dapsone with placebo [78]. Patients were in the maintenance phase after glucocor‐ ticoids and/or cytotoxic agents (azathioprine, mycophenolate or methotrexate) were used to achieve remission. Doses of dapsone were increased to 150 mg per day and then to a further 200 mg per day if tolerated. The trial was performed over 1 year, and the main outcome measured was reduction of prednisolone to doses of 7.5mg/day or less. Five of the 9 patients in the placebo group achieved the main outcome compared with 3 out of 10 in the placebo group. The difference was not statistically significant although there was a trend favouring dapsone as a steroid sparing agent. A retrospective study in 9 patients with PV suggested that dapsone reduced steroid dependence in these patients [79]. Another study reported improve‐ ment in 5 of 9 cases of superficial pemphigus treated with dapsone [80]. A recent meta-analysis comprising 55 patients with pemphigus revealed that 32 patients with PV and 14 patients with PF responded to dapsone [81].

The side effects of dapsone observed in these studies include methaemoglobinaemia, haemol‐ ysis and agranulocytosis. [81],[82] Patients should be tested for glucose-6-phosphate dehy‐ drogenase deficiency prior to commencing this agent. Dapsone at best may have a role as a steroid sparing agent in the maintaining remission in pemphigus but cannot be recommended in treatment of acute disease.

#### **9.6. Methotrexate**

The antimetabolite methotrexate is a folic acid analogue that competitively inhibits dihydro‐ folate reductase and has multiple immunosuppressive actions including suppressing lym‐ phocytes in the skin [83],[84]. A small number of non-randomized trials have investigated the role of methotrexate in treatment of pemphigus. The most recent study [83] treated 9 patients with chronic active PV, who were unable to successfully wean their prednisolone dose. They were treated with a mean dose of 12.5 mg per week of methotrexate. Prednisolone was discontinued in 6 of the 9 patients within 6 months of commencing methotrexate. There were minimal adverse effects reported in the study. A recent review of the English literature revealed that 111 (82%) of 136 pemphigus patients responded to methotrexate [85]. However, meaningful conclusions are limited by the lack of randomized trials, varying doses and schedules of treatment, and insufficient information on clinical progress including the lack of consistency of the length of follow up.

4-6 years and the investigators concluded that the combination regimen of corticosteroids and cyclosporin provided no additional benefit over corticosteroids alone. Side effects, including hypertrichosis, hypertension and renal dysfunction, were more common in the cyclosporin group. The randomized controlled study by Chrysomallis et al. in newly diagnosed PV limited to oral involvement found no difference in remission or relapse rates between the cyclophos‐ phamide and cyclosporine (5 mg/kg) groups [71]. Again, adverse events were more common in the cyclosporin group and included hypertrichosis and renal impairment. A case series

The randomized trials have not supported the use of cyclosporine at a dose of 5 mg/kg for the treatment of new onset pemphigus and side effects are relatively common. Further random‐

Dapsone has anti-inflammatory and antimicrobial actions. Its immunomodulatory action is incompletely understood but several actions have been described including prevention of the respiratory burst from myeloperoxidase, suppression of neutrophil migration by blocking integrin-mediated adherence, inhibition of adherence of antibodies to neutrophils, and reduction of eicosanoid release. Most studies utilising dapsone have been performed in patients with PV. A randomized controlled trial performed in 19 patients, all with PV, compared dapsone with placebo [78]. Patients were in the maintenance phase after glucocor‐ ticoids and/or cytotoxic agents (azathioprine, mycophenolate or methotrexate) were used to achieve remission. Doses of dapsone were increased to 150 mg per day and then to a further 200 mg per day if tolerated. The trial was performed over 1 year, and the main outcome measured was reduction of prednisolone to doses of 7.5mg/day or less. Five of the 9 patients in the placebo group achieved the main outcome compared with 3 out of 10 in the placebo group. The difference was not statistically significant although there was a trend favouring dapsone as a steroid sparing agent. A retrospective study in 9 patients with PV suggested that dapsone reduced steroid dependence in these patients [79]. Another study reported improve‐ ment in 5 of 9 cases of superficial pemphigus treated with dapsone [80]. A recent meta-analysis comprising 55 patients with pemphigus revealed that 32 patients with PV and 14 patients with

The side effects of dapsone observed in these studies include methaemoglobinaemia, haemol‐ ysis and agranulocytosis. [81],[82] Patients should be tested for glucose-6-phosphate dehy‐ drogenase deficiency prior to commencing this agent. Dapsone at best may have a role as a steroid sparing agent in the maintaining remission in pemphigus but cannot be recommended

The antimetabolite methotrexate is a folic acid analogue that competitively inhibits dihydro‐ folate reductase and has multiple immunosuppressive actions including suppressing lym‐ phocytes in the skin [83],[84]. A small number of non-randomized trials have investigated the

reported successful the successful treatment of 6 patients with recalcitrant PV [77].

ized controlled trials are required to determine its benefit in recalcitrant disease.

**9.5. Dapsone**

120 Skin Biopsy - Diagnosis and Treatment

PF responded to dapsone [81].

in treatment of acute disease.

**9.6. Methotrexate**

Thus methotrexate may be useful as a steroid sparing agent but further trials are required before recommending methotrexate as an initial steroid-sparing agent.



pimecrolimus ∙binds to the cytosolic protein cyclophilin of T-lymphocytes and the complex of cyclosporin (or other calcineurin-inhibitor) and

⇩ cytokine production (e.g.: Tumour Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), Interferon-gamma (IFN-γ))

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP) into which is rapidly broken down (in vivo).

Lipophilic weak base that passes easily through plasma membranes to accumulate in acidic vesicles, such as the lysosomes of the

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∙ 6-MP readily crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, including the main

∙ thioinosinic acid inhibits many pathways in nucleic acid biosynthesis causing damage to deoxyribonucleic acid (DNA), through

∙ this action is restricted to the cells involved in determination and amplification of immune response; the B and T lymphocytes as they are unable to source alternate or extrinsic nucleotides being entirely dependent for their proliferation on de novo synthesis

Mycophenolic acid (MPA) is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) which inhibits the de novo pathway of guanosine nucleotide synthesis but without incorporation into the cell's DNA: ∙ MPA has more potent cytostatic effects on T and B lymphocytes than on other cells because these cells are entirely dependent

for their proliferation on their *de novo* synthesis of purines, whereas other cell types can utilise salvage pathways

∙ depletion of guanosine nucleotides also leads to the inhibition of glycosylation of the adhesion molecules on lymphocytes

∙ Dapsone interferes in chemotactic-mediated migration of neutrophils and neutrophil function by: (1) inactivating the function of the G-protein (Gi type) that initiates the signal transduction cascade common to chemotactic stimuli; (2) the cytokine mediated adherence of neutrophils to the vascular endothelial cells; and (3) inhibits neutrophil MPO-mediated iodination and cytotoxicity and eosinophil peroxidise, thereby, dapsone suppresses neutrophil recruitment and protects cells from neutrophil- and

∙ in antibody mediated diseases, dapsone appears to interfere in the adherence of neutrophils to the auto-antigenic antibodies (IgA and IgG) bound to the various target sites in the basement membrane zone, so protecting the epithelial cells from

Antimetabolite cytotoxin. Methotrexate (MTX) competitively inhibits the enzyme *dihydrofolate reductase* and so prevents the regeneration of intermediates (such as tetrahydrofolate) essential for the synthesis of purines and thymidylate so preventing DNA

∙ actively proliferating tissues such as the bone marrow stem cells, dermal epithelium, and lymphocytes (as well as the oral

for their proliferation on their *de novo* synthesis of purines, whereas other cell types can utilise salvage pathways

∙ MTX has more potent cytostatic effects on T and B lymphocytes than on other cells because these cells are entirely dependent

cyclophilin inhibits calcineurin, which normally induces the transcription of interleukin-2. ⇩ lymphokine production and interleukin release (further reducing the function of effector T-cells)

hydroxylchloroquine (Plaquenil®)

azathioprine (Imuran®)

mycophenolate (CellCept®, Myfortic®)

dapsone (Dapsone®)

methotrexate (Methoblastin®) inflammatory cells and acts by:

⇩ stimulation of the toll-like receptors ∙ prostaglandin antagonist

active nucleotide: thioinosinic acid.

incorporation of this "false" purine thio-analogue.

further interfering in their immune functions

neutrophil-derived cytolytic agents

synthesis:

of purines, whereas other cell types can utilise salvage pathways.

Dapsone is effective in dermatoses with abnormal neutrophil accumulation

eosinophil-mediated injury by directly inhibiting the generation of toxic, oxygen-derived radicals.

⇩ release of prostaglandins and leukotrienes and so blocks their inflammatory effects

mucosal cells) are in general more sensitive to the effects of MTX

⇩ antigen presentation by the antigen-presenting cells (APC's)


#### Pemphigus Vulgaris and Pemphigus Foliaceus http://dx.doi.org/10.5772/56423 123


mycophenolate (CellCept®, Myfortic®)

dapsone (Dapsone®)

methotrexate (Methoblastin®)

Rituximab (Mabthera®)

corticosteroids (" 'steroids)

cyclosporine tacrolimus

max 2 g/day (once daily or divided dose)

122 Skin Biopsy - Diagnosis and Treatment

maintenance dose: 50-100 mg daily (≥ 300 mg daily

*WEEKLY ONLY*

until adequate response is achieved

> 375 mg/m<sup>2</sup> (body surface area) once weekly

for 4 weeks or 2x 1.0g -500 mg ivi infusions over two weeks

∙ pregnancy (Category

∙ HIV, HBV, HCV ∙ FBC and LFT's weekly

∙ FBC, G6DP levels, LFT's ∙ HIV, HBV, HCV

FBC, LFT's, E/U/C HIV, HBV, HCV

**(A)**

reacting with certain corticosteroid responsive genes of sensitive cells in many tissues:

Profound, generalised inhibitory effects on inflammatory processes and cells achieved by the control of protein synthesis by

⇩ production of acute inflammatory mediators, especially eicosonoids, postaglndins and leukotrienes. (corticosteroids increase the production of a polypeptide – *lipocortin,* that in turn inhibits phospholipase A2 the enzyme responsible for the mobilising

⇩ production and numbers of circulating immune-competent cells: e.g.: neutrophils, macrophages, T and B lymphocytes

⇩ activity of macrophages and fibroblasts involved in the chronic stages of inflammation – leading to decreased inflammation

for first 4 weeks; thereafter, only if indicated

∙ FBC, LFT's weekly for the first month, monthly for six months and semiannually thereafter

∙ FBC weekly for first 8 weeks, thereafter monthly

∙ Tb, HIV, HBV, HCV ∙ infection progressive multifocal

malignancy risk eg skin cancer, lymphoma; infection; progressive multifocal leucoencephalopathy; bone marrow depression

dose related haemolysis, especially in G6DP deficient patients; agranulocytosis; toxic hepatitis and cholestatic

hepato/ nephrotoxicity; ulcerative stomatitis; bone marrow depression; immunesuppression

leucoencephalopathy

(PML)

jaundice

D)

10 to 25 mg/ ∙ pregnancy (Category D) ∙ liver/renal impairment ∙ HIV, HBV, HCV ∙ immune-deficiency; ∙ concomitant retinoinds

> ∙ Murine(mouse) protein hypersensitivity

**Medication Actions**

arachniodonic acid from cell membranes)

⇩ Complement activation

Calcineurin inhibitors:

and healing


**9.9. Topical agents**

*9.9.1. Epidermal growth factor*

*9.9.2. Topical corticosteroids (Clobetasol)*

*9.9.3. Topical calcineurin inhibitors*

**10. Novel therapies and strategies**

**10.1. Biological agents**

*10.1.1. Rituximab*

A double-blind randomized controlled study investigated the use of epidermal growth factor (EGF) on skin lesions of 20 patients with PV [94]. Topical epidermal growth factor 10 ug/g in 0.1% silver sulfadiazine cream was applied to skin lesions daily until lesions had healed and compared to the effect of applying 0.1% silver sulfadiazine (SSD) cream alone. Topical EGF

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A small study comprised of 4 patients with mild PF and 3 with mild PV were treated with the very potent topical corticosteroid, Clobetasol propionate 0.05%, as a sole agent [95]. The cream was applied to mucosal lesions and involved skin twice a day for at least 15 days, then progressively tapered. Control of disease was defined as healing of lesions was obtained, with a 75% decrease in the number of new lesions per week without the addition of systemic treatment. Disease control was achieved in all 7 patients, with cutaneous remission attained in 15 days, although mucosal regression occurring more slowly. In 4 patients, remission was maintained with topical corticosteroid alone for a mean 19-month follow up. In 3 patients, relapse occurred after 2-11 months, requiring systemic treatment. Another study is in progress

Tacrolimus and Pimecrolimus are non-steroidal immunomodulatory macrobactams that inhibit the enzyme, calcineurin, impairing the production and IL-2 and subsequent T-cell activation and proliferation [96]. A small number of case reports and case series suggest a useful role for Tacrolimus in mild PV and PF but further randomized controlled trials are required to clarify its role in this setting [97]-[99]. A recent double blind study of 11 patients with PV refractory to azathioprine and corticosteroids showed a marked response to pime‐ crolimus 1% by day 15 when compared to placebo using the epithelialization index [100].

Rituximab is a chimeric (human/murine) monoclonal antibody directed against CD20, a cell surface molecule specific to B cells. Although it was initially approved for use in B-cell non-Hodgkin's lymphoma, a growing number of reports have described the efficacy of rituximab for B-cell depletion in the treatment of autoimmune diseases [101]. The mode of action of rituximab in autoimmune diseases includes the removal of precursors of autoantibody-

appeared to hasten lesion healing by a median of 6 days compared to SSD.

comparing the effect of Clobetosol with placebo in pemphigus vulgaris.

B: ⇩ = decreased or reduced

**Table 2.** (A) Therapeutic Agents Useful in the treatment of Pemphigus, (B) Therapeutic Agents Useful in Treating of Pemphigus

#### **9.7. Gold**

Auad [86] performed a blinded placebo-controlled randomized trial on the utility of auranofin in 30 patients with PF. Nearly one third of the patients withdrew from the active treatment arm due to side effects. In the placebo group, a reduction in the mean corticosteroid steroid dose was evident. Other case series comprising patients with PV and/or PF have described similar findings [87]-[89]. The most recent study published showed that 62% of patients with PV achieved remission or halve their dose of prednisone during a period of 10 years of intramuscular gold therapy [90]. However, the mean time to halve the dose of prednisone was 3 months and 42% developed side effects blood dyscrasia, proteinuria and nephrotic syn‐ drome, cutaneous reactions and dizziness. These adverse effects in addition to the relatively long time to take effect as a steroid-sparing agent preclude its use in favour of other steroidsparing agents in the treatment of treatment of pemphigus.

#### **9.8. Tetracycline antibiotics and nicotinamide**

Tetracycline antibiotics with and without nicotinamide have been combined with other adjuvant agents as treatment for pemphigus. Several small non-randomized trials have shown varying results [91]-[93]. Minocycline given at a dose of 100 mg per day allowed the reduction of prednisolone in 6 out of 10 patients with pemphigus [91]. Tetracycline at a dose of 2 g per day for 1 month reducing to 1 g per day for 4 weeks enabled more rapid tapering of cortico‐ steroids in 13 patients with PV [93]. However the study by Alspoy found that a combination of tetracycline (2 g/d) and nicotinamide (1.5 g/d) for 2 months was not an effective alternative to the classic forms of therapy in 14 patients with pemphigus [92]. Further trials are needed before recommending these agents.

#### **9.9. Topical agents**

Rituximab (Mabthera®)

124 Skin Biopsy - Diagnosis and Treatment

B: ⇩ = decreased or reduced

Pemphigus

**9.7. Gold**

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody that binds specifically to the antigen CD20, a transmembrane molecule located on pre-B and mature B-lymphocytes, only. This non-glycosylated phosphoprotein is found on both normal (and malignant B cells), *but* not on haemopoietic stem cells, pro-B cells, normal plasma cells or other normal tissues:

∙ the depletion of circulating autoreactive B cells (for up to 12 months) and , presumably specific downregulation of dsg3-specific

∙ inhibits CD20 which regulates the early steps in the activation process for B-cell cycle initiation and differentiation

**(B)**

A: Tb = tuberculosis, HIV = human immune-deficiency virus, HBV = hepatitis B virus, HCV = hepatitis C virus, G6DP = glucose-6-phosphate dehydrogen‐

**Table 2.** (A) Therapeutic Agents Useful in the treatment of Pemphigus, (B) Therapeutic Agents Useful in Treating of

Auad [86] performed a blinded placebo-controlled randomized trial on the utility of auranofin in 30 patients with PF. Nearly one third of the patients withdrew from the active treatment arm due to side effects. In the placebo group, a reduction in the mean corticosteroid steroid dose was evident. Other case series comprising patients with PV and/or PF have described similar findings [87]-[89]. The most recent study published showed that 62% of patients with PV achieved remission or halve their dose of prednisone during a period of 10 years of intramuscular gold therapy [90]. However, the mean time to halve the dose of prednisone was 3 months and 42% developed side effects blood dyscrasia, proteinuria and nephrotic syn‐ drome, cutaneous reactions and dizziness. These adverse effects in addition to the relatively long time to take effect as a steroid-sparing agent preclude its use in favour of other steroid-

Tetracycline antibiotics with and without nicotinamide have been combined with other adjuvant agents as treatment for pemphigus. Several small non-randomized trials have shown varying results [91]-[93]. Minocycline given at a dose of 100 mg per day allowed the reduction of prednisolone in 6 out of 10 patients with pemphigus [91]. Tetracycline at a dose of 2 g per day for 1 month reducing to 1 g per day for 4 weeks enabled more rapid tapering of cortico‐ steroids in 13 patients with PV [93]. However the study by Alspoy found that a combination of tetracycline (2 g/d) and nicotinamide (1.5 g/d) for 2 months was not an effective alternative to the classic forms of therapy in 14 patients with pemphigus [92]. Further trials are needed

CD4(+ve) T-lymphocytes and the associated release of proinflammatory cytokines

ase, FBC – full blood count, LFT's = liver function tests, UV = ultraviolet light, E/U/C = electrolytes/urea/creatinine

mayre-establish immune homeostasis and tolerance

sparing agents in the treatment of treatment of pemphigus.

**9.8. Tetracycline antibiotics and nicotinamide**

before recommending these agents.

#### *9.9.1. Epidermal growth factor*

A double-blind randomized controlled study investigated the use of epidermal growth factor (EGF) on skin lesions of 20 patients with PV [94]. Topical epidermal growth factor 10 ug/g in 0.1% silver sulfadiazine cream was applied to skin lesions daily until lesions had healed and compared to the effect of applying 0.1% silver sulfadiazine (SSD) cream alone. Topical EGF appeared to hasten lesion healing by a median of 6 days compared to SSD.

#### *9.9.2. Topical corticosteroids (Clobetasol)*

A small study comprised of 4 patients with mild PF and 3 with mild PV were treated with the very potent topical corticosteroid, Clobetasol propionate 0.05%, as a sole agent [95]. The cream was applied to mucosal lesions and involved skin twice a day for at least 15 days, then progressively tapered. Control of disease was defined as healing of lesions was obtained, with a 75% decrease in the number of new lesions per week without the addition of systemic treatment. Disease control was achieved in all 7 patients, with cutaneous remission attained in 15 days, although mucosal regression occurring more slowly. In 4 patients, remission was maintained with topical corticosteroid alone for a mean 19-month follow up. In 3 patients, relapse occurred after 2-11 months, requiring systemic treatment. Another study is in progress comparing the effect of Clobetosol with placebo in pemphigus vulgaris.

#### *9.9.3. Topical calcineurin inhibitors*

Tacrolimus and Pimecrolimus are non-steroidal immunomodulatory macrobactams that inhibit the enzyme, calcineurin, impairing the production and IL-2 and subsequent T-cell activation and proliferation [96]. A small number of case reports and case series suggest a useful role for Tacrolimus in mild PV and PF but further randomized controlled trials are required to clarify its role in this setting [97]-[99]. A recent double blind study of 11 patients with PV refractory to azathioprine and corticosteroids showed a marked response to pime‐ crolimus 1% by day 15 when compared to placebo using the epithelialization index [100].
