Pemphigus: Current Therapy

Home , Paraneoplastic pemphigus, Pemphigus erythematosus, Resocortol

Veterinary Dermatology 2004, 15, 90–98

Blackwell Publishing, Ltd. Pemphigus: current therapy

WAYNE S. ROSENKRANTZ

Animal Dermatology Clinic, Tustin, CA 92780, USA

(Received 21 January 2003; accepted 6 June 2003)

Abstract Pemphigus is an autoimmune skin disease that can present in a variety of forms and can be a chal- lenging disease to manage and treat. An overview of the different forms of pemphigus and diagnostics are discussed including pemphigus foliaceus (PF), pemphigus erythematosus (PE), panepidermal pustular pemphigus (PPP), pemphigus vulgaris (PV) and paraneoplastic pemphigus (PNP). Emphasis on therapy is presented. Included are the most current commonly used therapeutics (glucocorticoids, azathioprine, chlorambucil and tetracycline and niacinamide); current alternative therapeutics (cyclosporin and tacrolimus and mycophenolate mofetil) and additional alternative therapeutics (cyclophosphamide, chrysotherapy, dapsone, sulfasalazine and intravenous immunoglobulin (IVIG) therapy).

Keywords: azathioprine, chlorambucil, chrysotherapy, cyclosporin, dapsone, glucocorticoids, mycophenolate mofetil, pemphigus, tacrolimus, tetracycline and niacinamide.

OVERVIEW OF DISEASE

Pemphigus is an autoimmune vesicobullous to pustular skin disease that is characterized by acantholysis or loss of adhesion between keratinocytes. In dogs and cats ﬁve forms are recognized: pemphigus foliaceus (PF), pemphigus erythematosus (PE), panepidermal pustular pemphigus (PPP), pemphigus vulgaris (PV) and paraneoplastic pemphigus (PNP).1–3 Pemphigus foliaceus (PF) is the most common form in dogs and cats (Fig. 1). It is seen at the author’s practices at an incidence of 2% of referral cases. Clinical lesions are variable and include pustules, crusts, erosions, ulcers and alopecia. However, clinical presentations may vary depending on the breed, triggering factors and the cyclical nature of the disease itself. Lesions include pustules, crusts, erosions, ulcers and alopecia. Some cases may remain localized to the Figure 1. Pemphigus foliaceus in a Chow Chow with classic facial head, face and pinnae, while others may generalize and erosions, ulcers and crusting. develop additional systemic symptoms. The foot pads can become involved and in some situations lesions can Labrador retriever. Many cases of PF attributed to be limited to the footpads. An idiopathic form is most chronic disease have often been treated with long-term commonly seen in chow chows, and akitas. It tends to drugs and may in reality reﬂect drug-induced cases.4 present with more generalized lesions often starting on Pemphigus erythematosus (PE) is considered to be a the face, nasal planum, pinnae and can spread to involve variant of PF is limited to the face and does not gener- the entire body. When generalized, limb oedema, fever alize. PE can look similar to PF histologically but may and lethargy are common. Pruritus is also more com- also show an interface dermatitis. This feature coupled mon in the generalized form. Some cases can be trig- with a combination of immunopathology of both PF gered by drug reactions or as a result of other chronic and lupus erythematosus as well as a positive ANA diseases such as allergic dermatitis. The drug-induced (antinuclear antibody) test in some cases, make this form is more common in the Doberman pinscher and form a possible cross over syndrome. However, this is controversial and may simply represent a localized form of PF. Collies and German shepherds may be pre- Correspondence: Wayne S. Rosenkrantz, 2965 Edinger Ave, Tustin, disposed. Photoaggravation may be a factor in PE. CA 92780, USA. E-mail: [email protected] Pemphigus vulgaris (PV) is a very rare form of pem- Reprints will not be available from the author. phigus accounting for less than 0.1% of the referral

Pemphigus: current therapy 91 cases in a dermatology specialty practice.5 It is the disruption. The release of the protease, urokinase most severe form of pemphigus and is characterized plasminogen activator (uPA) is thought to convert by vesicles or blisters that usually ulcerate. The most plasminogen to plasmin which damages the inter- common location of lesions is the oral cavity, axilla, cellular adhesion.10,18,19 Complement may be involved groin, flank, mucocutaneous junctions (lips, nostrils, in some cases, but may just be an enhancing factor as eyelids, nail beds, genitals and anus) and foot pads. lesions can occur in its absence.20 One of the most cur- These cases may present with marked salivation and rent thoughts is a disruption in the regulation of the halitosis and are often depressed and anorectic. This assembly and disassembly of the desmosomes by the form requires the most aggressive forms of combination binding of the autoantibodies.1 therapy. Panepidermal pustular pemphigus (PPP) has been described based on the presence of pustules found at all OVERVIEW OF DIAGNOSTIC METHODS levels within the epidermis and follicle epithelium. PPP may simply represent a variant of PF, PE or pemphigus The hallmark of the pemphigus complex is the histo- vegetans (Hallopeau type) a variant of PV.6 Clinically logical presence of acantholysis. In PF either intraepi- there is predominance for facial lesions but generalized dermal or intrafollicular acantholytic pustules are disease can occur. Lesions are short-lived pustules that present. These pustules are most common in the cor- rupture and leave a thick adherent crust. neal, granular or upper spinous cell layers. In PE sub- Paraneoplastic pemphigus (PNP) is a very rare form corneal to intraspinous acantholytic pustules are also of pemphigus that has been associated in a limited present, but a lichenoid-interface dermatitis is usually numbers of dogs with lymphoma and in one case a present. In PV the acantholysis is at the suprabasalar Sertoli cell tumour. Histopathologically, these lesions level which can occur in the oral mucosa, epidermis or appear to be a mixture of PV and erythema multiforme follicular outer root sheath. In PPP intraepidermal (EM).7 pustules can be seen at all levels of the epidermis and follicular outer root sheath down to the level of the suprabasal layer. Eosinophils may be more abundant AETIOLOGY – PATHOGENESIS in this form. In PNP there are similar changes as seen with PV, but in addition to the suprabasal cleft forma- The aetiology of pemphigus is not known in most tion, apoptotic cells and vacuolar degeneration is cases. The development of autoantibodies may result present. from an abnormal immune regulation or abnormal Immunopathology, both direct and indirect immuno- antigen stimulation. There is a strong genetic predispo- fluorescence, has improved tremendously and has not sition in both humans and dogs. In humans certain only aided in the diagnosis of pemphigus but the HLA types and ethnic groups seem to be predisposed pathogenesis of the disease. In many cases, antikerati- to PF.8,9 Certainly the akita and the chow chow appear nocyte autoantibodies can be demonstrated. However, to fall into this category, having PF more frequently immunopathology should always be correlated with than other breeds. Infectious agents, such as viruses the clinical and routine histopathology findings. In PF have been suspected in certain regionalized outbreaks. the pattern of immunofluorescence is ‘chicken-wire’ Of specific interest is the PF seen in humans in South involving all of the suprabasal layers.1 The autoanti- America (fogo selvagem) where an insect vector (black bodies are usually of the IgG type with some cases flies), virus or local heat, humidity and tannin decom- having IgA and IgM. Complement may sometimes be position are suspected as predisposing factors.10–12 It is present. In the dog, desmoglein 1 (Dsg 1) 150 kDa is interesting to compare this form of PF in humans with the autoantigen that is targeted.1 In PE, the antikerat- what is seen in the dog. There are many similarities inocyte fluorescence is the same as in PF, however, between the two when the clinical lesions are com- there is a linear deposition of immunoglobulins and/or pared.4 Drug induced or association with chronic complement similar to what is seen in lupus erythema- skin disease has also been reported in humans and tosus. A positive ANA can also be detected in 50% of dogs.8,10,13,14 The possibility of ultraviolet light irradi- cases.21 In PV there is also membrane fluorescence of ation exacerbating acantholysis also exists.14,15 the keratinocytes of all suprabasal epidermal layers, The exact mechanism for the development of acan- which may extend to the basal cell membranes.21 The tholysis is not completely understood. The patient’s major PV antigen in the dog is desmoglein 3 (Dsg 3) autoantibodies bind to one of two members of the 130 kDa.19 The immunopathology of PPP is identical cadherin group (cell to cell adhesion molecules). In PF to that of PF and PNP is the same as PV. the binding is to Dsg 1 and to Dsg 3 in PV.16 Calcium Other clinicopathology includes the presence of has been shown to be very important for the adhesion acantholytic cells on routine cytology and variable of cadherins.17 The binding of the autoantibody to changes on complete blood counts and chemistry lab- the cadherins results in activation of intracellular oratory screens. Many pemphigus cases can have mod- pathways, which in turn leads to the disruption of inter- erate to marked leukocytosis and neutrophilia, mild cellular adhesion. This results in the acantholysis. nonregenerative anaemia, mild hypoalbuminemia and There are many different possible causes for this mild elevations in globulins.

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CURRENT TREATMENTS glucocorticoids can create atrophy, alopecia and localized pyoderma. Systemic absorption by percutaneous Therapy for all forms of pemphigus requires immuno- absorption or ingestion via licking is also a major con- suppressive or immunomodulating drugs. There are cern. Iatrogenic hyperadrenocorticism has been well variable responses to treatment with the different documented with potent glucocorticoids.23,24 The most forms of pemphigus recognized. As a result it is essen- common form of therapy used in pemphigus manage- tial that a diagnosis be made. ment is systemic glucocorticoids. In the author’s spe- Even with a specific diagnosis there appears to be cialty referral practices, 35% of the PF cases are some controversy regarding the treatment success and adequately controlled with only glucocorticoid ther- the ultimate long-term prognosis of canine pemphigus. apy. There are unlimited mechanisms as to why gluco- In general, PV tends to be a more aggressive disease corticoids are effective but it primarily relates to their and more difficult to treat and manage. Despite treat- profound effects on the humoral and cell-mediated ment many cases may still die. PF tends to warrant a immunity, phagocytic defences, and inhibition of better prognosis but in a recent report only 17/43 cases inflammatory mediators and suppression of autoanti- (39.5%) were alive at the end of a 6-year study. Of the body levels.25,26 Which form of oral glucocorticoid dogs that had died, 92% were dead by 1 year into treat- therapy is selected depends on the individual case ment. Of these cases, 87% were euthanized because of response and the side effects seen in that particular drug side effects.22 These results are different from patient. Most commonly, prednisone or prednisolone what is seen at the author’s practices. Currently, a large- is utilized at immunosuppressive dosages. Initial scale retrospective PF study is being conducted at the dosages at 2.2–4.4 mg kg−1 every 24 h can be used. If a author’s practices. An initial review of 31 cases with response is seen within 10–14 days this dosage is follow-up ranges from 1 to 5 years and a mean of reduced gradually on a daily basis over 30–40 days and 2.7 years, showed a survival rate of 22/31 (71%). Of the then lowered to an alternate day basis with the ultimate 9 cases (29%) that had died, 4/9 (44%) were euthanized goal of dosing at 1 mg kg−1 every 48 h or less. The at the end of 1 year because of either poor response to author prefers methylprednisolone (Medrol, Pfizer) therapy (2/4) or discontinuation of medications and to prednisone or prednisolone due to the reduced subsequent relapse after the owners discontinued mineralcorticoid effects resulting in less polyuria and drugs (2/4). The remaining 5/9 cases died because of polydipsia. In addition, there are some cases that will unrelated problems; heart disease (2), renal disease (1), respond more favourably to methylprednisolone than arthritis (1), old age (1). Many specialists and research- prednisone or prednisolone. The dosing and tapering ers consider PE, PEP and P vegetans benign variations regime is the same as for prednisone or prednisolone. of pemphigus that usually respond well to treatment Oral triamcinolone (Vetalog, Fort Dodge) or oral dex- and have less overall systemic manifestations.1,8 amethasone (Azium, Schering-Plough and generics) The author divides therapy into three categories: are alternative glucocorticoids that can be utilized in common therapeutics, current alternative therapeutics more refractory cases or in cases that have profound and additional alternative therapeutics. polyuria and polydypsia or other behavioural or per- sonality changes. These glucocorticoids are considered to be 6–10 times more potent than prednisone or COMMON THERAPEUTICS prednisolone. Starting immunosuppressive dosages for these drugs range from 0.2 to 0.6 mg kg−1 every 24 h Glucocorticoids for triamcinolone and 0.2–0.4 mg kg−1 every 24 h for More localized forms of PF and PE can be treated with dexamethasone. As with prednisone therapy these topical glucocorticoids. Occasionally, the author uses dosages need to be reduced gradually and eventually topical therapy in conjunction with systemic therapy tapered to an every 48–72 h basis. As these glucocor- on more persistent focal areas that remain active ticoids suppress the hypothalamic–pituitary–adrenal despite systemic treatment. When utilized a potent glu- axis for 24–48 h, it is optimal to give these drugs every cocorticoid is often needed initially and then if ade- 72 h for maintenance. However, the author has had quate response is seen switching to a less potent topical many cases do very well long-term on an every 48 h glucocorticoid is recommended. The author likes 0.1% basis as maintenance. Maintenance dosages range from amcinonide cream (Cyclocort, Lederle), fluocinonide 0.1 to 0.2 mg kg−1 every 48–72 h for triamcinolone and 0.05% cream (Lidex, Dermik) or 0.015% triamci- 0.05–0.1 mg kg−1 every 48–72 h for dexamethasone. nolone acetonide solution (GENESIS, Virbac) used In severe cases of pemphigus foliaceus or vulgaris, daily for 7 days then EOD for 7 days and if an ade- the author has, on occasion, given shock dosages of quate response is seen switching to a 1–2% hydrocorti- prednisolone sodium succinate (10 mg kg−1 IV) or dex- sone cream or ointment (Hytone, Dermik and other amethasone (1 mg kg−1 IV).4 This can be performed as generics) on an as-needed basis is recommended. Some a one time treatment or given two days consecutively. 1% hydrocortisone gels and sprays may also be helpful This can be followed with a modification of other oral in long-term management (Corticalm, Cortispray glucocorticoid therapy. This form of therapy has a DVM Pharmaceuticals, Resicort, Virbac). Persistent higher incidence of gastrointestinal ulceration, in par- use (daily for 14 days or longer) of more potent topical ticular gastric haemorrhage. Concurrent use of gastric

Pemphigus: current therapy 93 protectants is usually recommended when this form of therapy is utilized. Side effects are common with long-term oral glucocorticoid therapy. The most common seen include: poor dull scaly hair coats, muscle atrophy, polyuria, polydipsia, polyphagia, weight gain, behavioural changes, panting and increased risk of infection. Sec- ondary bacterial skin and bladder infections are common. Demodicosis and dermatophytosis are also more frequent in dogs on chronic glucocorticoid therapy. Ongoing cases that ﬂare during their course of management should always be rechecked and screened for these secondary opportunistic infections. Other skin changes include atrophic skin, calcinosis cutis, atrophic scars, comedones and ‘milia’ follicular cysts. Figure 2. Poorly responsive case of generalized pemphigus foliaceus Less common side effects include: gastrointestinal to glucocorticoids. ulcerations, diarrhoea, and pancreatitis. Steroid hepat- opathy is a major concern and is one of the most important organs to monitor in long-term cases. Other endocrine concerns include the development of diabe- tes mellitus, adrenal gland suppression and reduced thyroid hormone production. Monitoring should include semi-annual complete blood counts, chemistry proﬁles, urinalysis and urine cultures. If cases are nonresponsive to glucocorticoids, fail to control on safe alternative day to every 72 h dosing or have undesirable side effects, alternative or concurrent immunosuppressive drugs are indicated.

Azathioprine therapy Azathioprine (Imuran, Glaxo Wellcome and generics) is the author’s favourite and ﬁrst choice immunosuppressive to use in canine pemphigus cases. The author Figure 3. Same case as Fig. 2 after 8 weeks of azathioprine and has not seen any differences with brand name or glucocorticoid dose reduction. generic therapy. It can be used as a glucocorticoid- sparing agent in cases when glucocorticoids cannot be reduced to safe long-term levels, used in combination with glucocorticoids or other immunosuppressives in more refractory cases, or as a sole therapy (Figs 2, 3). It is generally contraindicated in cats due to its more profound myelosuppression and potential for fatal reactions in cats. It is dosed at 1.5–2.5 mg kg−1 every 24–48 h. It is available is a 50 mg scored tablet. It is an antimetabolite that interferes with the synthesis of nucleic acids and is cytotoxic to T cells. It has its great- est effect on T-cell-dependent antibody synthesis. It has a slow onset of action and usually takes 4–8 weeks to see clinical effects. Adverse reactions primarily include myelosuppression (lymphopenia, anaemia and leukopenia) diarrhoea and increased susceptibility to opportunistic infections when used long-term (pyoderma, demodicosis and dermatophytosis) (Fig. 4). Figure 4. Secondary demodicosis and dermatophytosis from immuno- The diarrhoea that can be seen usually responds to suppression associated with azathioprine therapy. dosage reduction, although it can be severe (haemorrhagic) and require drug discontinuation. Less common complications include vomiting, hepatotoxicity improvement. Starting at the lower end of the dosage and possible pancreatitis. A rare azathioprine induced range is generally recommended. Increasing the dosage hepatotoxicity can be seen that usually responds to after subsequent rechecks and lab monitoring can be drug withdrawal.4 Dosage adjustments can be made performed as the case progresses. Complete blood based on the results of lab monitoring and clinical counts with platelet counts are recommended every

94 W. S. Rosenkrantz

2–3 weeks for the first 3 months of therapy. Initially tacrolimus is much more potent and the oral formula- periodic (every 2–3 months) monitoring of chemistry tions appear toxic in the canine. Currently, due to the much profiles is also recommended. Once cases are in remis- greater potency and potential toxicity of tacrolimus and sion monitoring can be reduced to every 6 months. lack of adequate dosing regimes, systemic administration is not recommended in canine clinical cases. Both Chlorambucil drugs become activated by binding to specific intracellu- Chlorambucil (Leukeran, Glaxo Wellcome) is an lar receptors, called immunophilins. Cyclosporine binds alkylating agent that functions by affecting the cross- to cyclophilin and tacrolimus binds to FK506-binding linking of DNA. It is considered less toxic and slower proteins. Both drugs inhibit calcium-dependent path- acting than other alkylating agents. It is dosed at 0.1– ways, particularly affecting the enzymatic actions of 0.2 mg kg−1 every 24–48 h. It is available in a 2 mg non- calcineurin, a calmodulin-dependent protein phosphatase. scored coated tablet, making dosing in small dogs and This results in blocking of regulatory proteins that cats easier. Myelosuppression is a concern and similar up-regulate activation genes of T-helper inducer and monitoring as listed with azathioprine should be per- cytotoxic cells. Of the cytokines affected interleukin-2 formed. Other side effects include vomiting, diarrhoea (IL-2) is most notably affected, although many other and anorexia.27 The author uses chlorambucil in the cytokines are affected.32,33 The initial studies of cyclo- canine as a glucocorticoid-sparing drug, as an alterna- sporin in the treatment of pemphigus and other cuta- tive to azathioprine, in combination with glucocorti- neous autoimmune diseases has not been impressive coids and azathioprine in more refractory cases or as a and only limited responses have been seen.34 How- sole therapy in cases not tolerating other therapies. It is ever, these early studies utilized older formulations of also the author’s drug of choice in feline pemphigus cyclosporin. The author has seen some more recent when glucocorticoids do not work or are not tolerated. responses utilizing the microencapsulated formulation (Atopica and Neoral, Novartis). It is dosed at 5– Tetracycline and niacinamide 10 mg kg−1 every 24 h with ketoconazole 5 mg kg−1 every The combination of tetracycline and niacinamide has 24 h. It is also common to use cyclosporin in conjunc- been used with variable success in dogs and humans tion with oral glucocorticoids. However, it may be used with pemphigus.28,29 The author commonly uses this as a sole agent or as a glucocorticoid-sparing agent therapy but usually finds it an adjunctive therapy at (Figs 5, 6). Cyclosporine is also available as a topical best for the pemphigus complex. It may be more suc- 0.2% ointment (Optimmune, Schering-Plough). The cessful in localized cases such as pemphigus foliaceus author and his associates have seen some adjunctive limited to the face or pemphigus erythematosus. Tetra- effects utilizing this ointment for localized forms of cycline has anti-inflammatory properties affecting pemphigus. Even more impressive are the responses seen complement activation, antibody production, chemo- from the topical administration of 0.1% tacrolimus. taxis, prostaglandin synthesis, lipases and collagenases. In a recent study at the author’s practice 10 cases of Niacinamide inhibits mast-cell degranulation and discoid lupus erythematosus (DLE) and 2 cases of PE phosphodiesterase. Adverse reactions include vomit- were treated. Eight of the 10 dogs of DLE and both PE ing, diarrhoea, anorexia and increased liver enzymes. cases improved with therapy. In 6/8 cases no other When gastrointestinal complications occur, discontin- medications were used except the topical tacrolimus. uing the niacinamide may reduce or eliminate these No adverse reactions were noted in any of the cases.35 problems. In rare cases the tetracycline may still pro- duce beneficial results. The dosage recommendations are 500 mg of each drug every 8 h for dogs weighing > 10 kg and 250 mg every 8 h for dogs weighing < 10 kg. Clinical response may take 1–2 months. If clinical response is seen the frequency can be reduced to twice or even once daily.

CURRENT ALTERNATIVE THERAPEUTICS

Cyclosporine and tacrolimus Cyclosporine (Atopica and Neoral, Novartis) and tacrolimus (Prograf oral formulation and 0.03 and 0.1% Protopic topical preparation, Fujisawa USA, Inc.) are immunosuppressant agents that have been used extens- ively in human medicine, primarily to prevent organ transplant rejection.30,31 However, these drugs have also been evaluated for the treatment of autoimmune Figure 5. Pre-cyclosporin therapy in a case of pemphigus diseases. Both of these drugs work similarly, however, erythematosus.

Pemphigus: current therapy 95

Side effects seen with cyclosporin most commonly to inhibit the proliferation of lymphocytes and the pro- include anorexia, vomiting or diarrhoea. More serious duction of antibodies relatively selectively with mini- side effects are rarely seen. Other side effects reported in mal effects on other tissues. In humans it has been used limited cases include weight loss, nephrotoxicity, gingival in a variety of autoimmune skin diseases. The main hyperplasia, papillomatosis, hirsutism and involuntary side effects include bone marrow suppression, nausea, shaking.34,36 Drugs which inhibit the hepatic micro- vomiting, diarrhoea and an increased incidence of somal isoenzyme P450 system, increase blood infections. It does not have significant renal or hepatic cyclosporin levels thus ketoconazole is commonly used toxicity. Canine studies show success rates of ≈ 50% concurrently with cyclosporin. It allows for a lower with some dogs weaned off prednisone completely, cyclosporin dosage and thus cost, making cyclosporin whereas others have relapsed when the glucocorticoids more cost effective. Severe side effects have been seen in were dropped too low. Dosages ranged from 22 to dogs with oral tacrolimus as a sole or combined therapy. 39 mg kg−1 every 24 h divided every 8 h. Side effects These side effects include anorexia, vomiting, diarrhoea, were minimal but the most common included pyo- weight loss, impaired glucose metabolism, marked hepato- derma and malassezia, diarrhoea and leukocytosis. toxicity and infections.37,38 Other side effects seen in Expense is a limiting factor as a 23 kg dog will require humans include nephrotoxicity, neurotoxicity and hyper- therapy costing US$10 per day.39,40 tension.37 The topical preparation appears very safe in the cases treated the author’s practice and no side effects have been seen.35 Monitoring serum levels of ADDITIONAL ALTERNATIVE THERAPY both cyclosporin and tacrolimus have been evaluated. In the author’s experience the serum levels of cyclosporin Cyclophosphamide generally do not correlate with clinical responses. Cyclophosphamide (Cytoxan, Bristol Myers) is another However, there may be some limited value to monitor alkylating agent. It is considered very potent and can these levels when clinical responses are not seen. If lev- be used individually or in conjunction with glucocorti- els are still in the low therapeutic range dosages could coids and chlorambucil. It is available in 25 or 50 mg be increased in an attempt to obtain a response. When tablets. The dosage is 1.5 mg kg−1 every 48 h. The author topical tacrolimus therapy was utilized in the author’s does not routinely use this drug due to the potential for practice, there was no correlation with serum or whole haemorrhagic cystitis and because of the effectiveness blood tacrolimus levels and clinical improvement or of other therapies. adverse clinical effects or laboratory abnormalities.35 Chrysotherapy Mycophenolate mofetil Chrysotherapy is the use of gold as a sole or adjunc- Mycophenolate mofetil (CellCept, Roche Pharmaceu- tive therapy. It has immune-modulating and anti- ticals) is a new drug that inhibits de novo purine (gua- inflammatory effects but its exact mechanism of action nine) synthesis. B and T lymphocytes are dependent is not known.4,27 Gold is available in two forms, an oral upon guanosine synthesis because they are unable to formulation auranofin (Ridaura, SmithKline Beecham) use the salvage guanosine synthesis pathway. This unique and an injectable form. Only one of the injectable aspect of lymphocytes allows mycophenolate mofetil forms is still commercially available sodium aurothiomalate (Myochrysine, Merck). The older form of injectable gold, aurothioglucose (Solganal, Schering) is no longer available. It is this form that most specialists had experience with. The author found aurothioglucose to be quite effective in feline pemphigus as a sole or combination therapy with glucocorticoids. The author considered success in canine pemphigus poor. When utilized it was dosed at 1 mg kg−1 intramuscu- larly once a week. It had a long lag phase and some cases would not respond for 10–16 weeks. Once remission was obtained the dosage could be reduced to monthly or in some cases of feline pemphigus, discontinued completely with remission maintained. The author has not used the alternative injectable gold, sodium aurothiomalate and no published reports exist on its effectiveness in canine or feline pemphigus. The author has limited experience using the oral formulation, auranofin, however, others have reported some success using 0.05–0.2 mg kg−1 every 12 h.41 The toxic effects in humans are a concern with one-third of the Figure 6. Twelve weeks post cyclosporin therapy in a case of patients having some type of reaction, although the pemphigus erythematosus. majority are minor. The most common include skin

96 W. S. Rosenkrantz rashes, oral ulceration, proteinuria and bone marrow IVIg is a sterile, high purified IgG preparation made depression. In dogs and cats reactions are limited but from pooled human plasma and typically contains can include bone marrow depression, oral ulcers, more than 95% unmodified IgG. It has a functionally glomerulonephropathy and one report of fatal toxic intact Fc-dependent effector function and only con- epidermal necrolysis when two dogs were immedia- tains trace amounts of IgA and IgM. There are numer- tely switched from azathioprine to aurothioglucose.42 ous immunomodulatory properties, most are mediated Eosinophilia may precede the development of the by the Fc portion of the IgG. Some of the postulated cutaneous drug reactions. Monitoring should include mechanisms include: functional blockade of Fc recep- complete blood counts with platelet counts every 2– tors, elimination of circulating immune complexes, 3 weeks for the first 4 months of therapy and then anti-idiotypic suppression of autoantibodies, inhibi- quarterly to semi-annually thereafter. Periodic chemis- tion of complement mediated damage, modulation try profiles and urinalysis should also be performed of cytokines, regulatory effects on cellular immune initially every 4–6 weeks during the first 4 months of response and blockade of cell surface death receptor therapy and then every 6 months thereafter. Fas and its specific ligand.45 IVIg should be given at 1 g/kg intravenously during Dapsone and sulfasalazine a 6–12 hour period once or can be given two days Dapsone (Dapsone, Jacobus) and sulfasalazine (Azulfidine, consecutively. It is possible that this therapy could be Pharmacia) have been used either as sole therapies or repeated monthly as it is used in humans but this has in combination with glucocorticoids in cases of canine not been fully evaluated in the canine. Since there is no pemphigus.27,43 Dapsone decreases complement acti- commercial canine immunoglobulin available human vation, antibody production, lysosomal enzyme synthesis products are used. There are many products commer- and neutrophil chemotaxis. It is dosed at 1 mg kg−1 cially available but the author is only familiar with every 8 h and should only be used in dogs. Cats have Sandoglobulin ® (Sandoz, East Hanover, NJ, USA) a increase sensitivity to dapsone with higher incidence of 6% solution. The safety of this form of therapy is not haemolytic anaemia and neurotoxicity. Side effects completely evaluated in the canine but it appears to be include anaemia, neutropenia, thrombocytopenia, hepato- safe in the limited number of cases treated and is very toxicity, gastrointestinal signs, neuropathies and cuta- safe in humans. Mild side effects reported in humans neous drug eruptions. It has a lag phase of 4–8 weeks. include: headache, myalgia, flushing, nausea, blood Monitoring complete blood and platelet counts, chem- pressure changes and tachycardia usually in the first istry profiles and urinalyses every 2–3 weeks for the hour of administration. Severe anaphylactic reactions first 4 months is recommended. After 4 months may occur in patients with IgA deficiency. Sugar addit- monitoring can be reduced to every 3–4 months. ives such as sucrose, maltose and glucose are often Sulfasalazine is converted in the colon to sulfapyridine added to stabilize the immunoglobulin preparations 5-aminosalicylate which has anti-inflammatory proper- and there are rare reports of acute renal failure related ties. It is dosed at 10–40 mg kg−1 every 8 h. It may be to these sugars.45,46 more effective in cases of pemphigus that are more neu- trophilic. A severe side effect is the development of Relapsing or Refractory Cases keratoconjunctivitis sicca. Tear production should be A small number of cases will present as a therapeutic monitored every 2–4 weeks. Blood counts and chemistry challenge. Often these have been on traditional modes profiles should be checked initially every 2 weeks for of therapy, and have either failed to respond or have the first 6 weeks and then tapered to every 2–4 months. had adverse reactions to these forms of therapy. When dealing with such cases, switching the type of glucocor- Human Intravenous Immunoglobulin (IVIG) Therapy ticoid therapy, may obtain a response. If this fails, High dose intravenous immunoglobulins (IVIgs) have trying aggressive glucocorticoid shock intravenous been used in human immune-mediated and autoimmune therapy can also be of value. This is often combined diseases as an alternative or adjuvant therapy. They have with a different immunosuppressive or alternative also been used in canine primary immune-mediated therapy as listed above. If these treatment options fail haemolytic anaemia (IMHA). In a study of 10 dogs with trying some of the additional alternative therapies primary IMHA that had failed to respond to conventional should be discussed with the owner. Unfortunately immunosuppressive therapy, 5 of the 10 dogs had clinically there will be a number of cases that will be euthanized significant responses. 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Résumé Les pemphigus sont des dermatoses auto-immunes qui peuvent se présenter sous des formes cliniques multiples et représenter un challenge diagnostique et thérapeutique. Cet article présente une revue des différentes formes de pemphigus, notamment le pemphigus foliaceus (PF), le pemphigus erythematosus (PE), le pemphigus panépidermique pustuleux (PPP), le pemphigus vulgaris (PV) et le pemphigus paranéoplasique (PNP). Le traite- ment est décrit en détail en insistant sur les thérapeutiques les plus souvent utilisées (glucocorticoides, azathioprine, chlorambucil et tétracycline et niacinamide); les alternatives actuelles (cyclosporine et tacrolimus et mycophenolate mofetil) et d’autres alternatives comme la cyclophosphamide, la cryothérapie, la dapsone et la sulfasalazine.

Resumen El pénfigo es una enfermedad cutánea autoinmune que puede presentarse con una variedad de formas y puede presentar dificultades de tratamiento. Se discuten los diferentes tipos y el diagnóstico de pénfigo foliáceo (PF), pénfigo eritematoso (PE), pénfigo panepidérmico pustular (PPP), pénfigo vulgar (PV) y pénfigo paraneoplásico (PNP). Se hace un especial hincapié en la terapia. Se incluyen las terapias más frecuentemente empleadas en la actualidad (glucocorticoides, azatioprina, clorambucil y tetraciclina y niacinamida); terapias alternativas actuales (ciclosporina y tacrolimus y mofetil micofenolato) y terapias adicionales alternativas (ciclofosfamida, crisoterapia, dapsona y sulfasalazina).

Zusammenfassung Pemphigus ist eine autoimmune Hauterkrankung, die in einer Vielzahl von Formen vorhanden sein kann und schwierig zu handhaben und behandeln ist. Es wird ein Überblick über die ver- schiedenen Formen von Pemphigus, wie Pemphigus foliaceus (PF), Pemphigus erythematodes (PE), panepider- maler pustulärer Pemphigus (PPP) Pemphigus vulgaris (PV) und paraneoplastischer Pemphigus (PNP) und deren Diagnose gegeben. Dabei wurde ein besonderer Schwerpunkt auf die Therapie gesetzt. Miteinbezogen wurden die gebräuchlichsten Therapeutika (Glukokortikoide, Azathioprine, Chlorambucil, und Tetrazyklin und Niacinamid), gängige alternative Therapeutika (Cyclosporin, Tacrolimus and Mycophenolat mofetil) und andere alternative Therapeutika (Cyclophosphamid, Chrysotherapy, Dapson und Sulfasalazin).