SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. ResumenZusammenfassung
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information
Thumbnail image of graphical abstractThumbnail image of graphical abstract

Background

Prednisone doses of up to 8 mg/kg/day have been used to treat feline pemphigus foliaceus (PF). Oral prednisolone has more favourable pharmacokinetics in cats than prednisone; therefore, lower doses of prednisolone may be effective in treating feline PF.

Hypothesis/Objectives

To assess the dose of prednisolone required to induce and maintain remission of PF in cats.

Animals

Thirty-seven client-owned cats with a diagnosis of PF treated with prednisolone monotherapy for induction of remission.

Methods

A retrospective analysis of records of a veterinary dermatology referral practice between the years of 1995 and 2013 was carried out. History, clinical signs, cytological and/or histopathological findings, lack of response to antimicrobials, absence of fungal hyphae on periodic acid Schiff staining and/or negative fungal culture and positive response to immunosuppressive therapy were used to confirm the diagnosis. Cats were included in the study if prednisolone was used as the monotherapy induction protocol.

Results

Complete remission was achieved within 8 weeks in 97% of cats with a median induction dose of 2 mg/kg prednisolone daily. In cats requiring ongoing treatment, 67% were maintained in remission with prednisolone monotherapy. The median maintenance dose was 1.2 mg/kg/week. In 14% of cats, medication was eventually discontinued.

Conclusions and clinical importance

Daily prednisolone at 2 mg/kg is an effective dose for inducing remission of PF in cats. Adverse effects were uncommon with this dose. In a small population, permanent remission may be induced. Secondary bacterial overgrowth and exudate in claw folds resolved in all cases with immunosuppressive therapy; therefore, antimicrobial therapy may be unnecessary.

Résumé

Contexte

Jusqu'à 8 mg/kg/jour de prednisone ont été utilisés pour traiter les pemphigus foliacés félins (PF). La prednisolone orale a une pharmacocinétique plus favorable que la prednisone chez les chats; ainsi, des doses plus faibles de prednisolone pourraient être efficaces pour traiter le PF félin.

Hypothèses/Objectifs

Evaluer la dose de prednisolone nécessaire pour induire et maintenir une rémission des PF chez le chat.

Sujets

Trente-sept chats de clients atteints de PF traités en monothérapie à la prednisolone pour induction de rémission.

Méthodes

Une analyse rétrospective des données d'un service de dermatologie référée entre 1995 et 2013 a été effectuée. Les commémoratifs, les signes cliniques, les examens cytologiques ou histopathologiques, l'absence de réponse aux antimicrobiens, l'absence d'hyphes fongiques à la réaction à l'acide périodique de Schiff et/ou la culture mycologique négative ainsi que la réponse au traitement immunosuppresseur ont confirmé le diagnostic. Les chats ont été inclus dans l'étude si la prednisolone était utilisée seule comme protocole d'induction.

Résultats

Une rémission complète a été obtenue en 8 semaines pour 97% des chats avec une dose moyenne d'induction de 2 mg/kg par jour de prednisolone. Chez les chats ayant besoin d'un traitement d'entretien, 67% étaient maintenus en rémission avec de la prednisolone seule. La dose de maintenance moyenne était de 1,2 mg/kg/semaine. Pour 14% des chats, le traitement pouvait être arrêté.

Conclusions et importance clinique

La dose quotidienne de 2 mg/kg/jour de prednisolone est efficace pour l'induction de rémission des PF de chats. Les effets secondaires étaient rares à cette dose. Dans une petite population, une rémission permanente a pu être induite. Une colonisation bactérienne secondaire et l'exsudat des plis unguéaux se sont résolus dans tous les cas avec le traitement immunosuppresseur; ainsi, un traitement antimicrobien serait inutile.

Resumen

Introducción

dosis de prednisona de hasta 8 mg/kg/día se han utilizado para tratar el pénfigo foliáceo en gatos (PF). La predinisolona oral tiene una farmacocinética más favorable en gatos que la prednisona; por lo tanto dosis menores de prednisolona pueden ser efectivas en el tratamiento de PF en gatos.

Hipótesis/Objetivos

evaluar la dosis de predinisolona requerida para inducir y mantener remisión en gatos con PF.

Animales

treinta y siete gatos de propietarios particulares con diagnostico de PF tratados con monoterapia de prednisolona para inducir remisión.

Métodos

se llevó a cabo un análisis retrospectivo de los historiales de un centro de referencia de dermatología veterinaria entre los años 1995 y 2013. Para confirmar el diagnostico se utilizaron la historia, signos clínicos, hallazgos citológicos y/o histopatológicos, falta de respuesta a antimicrobianos, ausencia de hifas de hongos con tinción de PAS y/o cultivo negativo y respuesta favorable a tratamiento inmunosupresor. Los gatos se incluyeron en el estudio si prednisolona se utilizó como monoterapia de inducción en el tratamiento.

Resultados

se obtuvo remisión completa dentro de un período de ocho semanas en un 97% de los gatos, con una dosis media de inducción de 2 mg/kg de prednisolona diaria. En gatos que necesitaron mas tratamiento, un 67% se mantuvieron en remisión con monoterapia de prednisolona. La dosis media de mantenimiento fue de 1,2 mg/kg/semana. En un 14% de gatos la medicación fue finalmente interrumpida.

Conclusiones e importancia clínica

prednisolona diaria a dosis de 2 mg/kg es efectiva para inducir remisión en gatos con PF. Los efectos adversos fueron inusuales con esta dosis. En un pequeño porcentaje se pueden ver remisión permanente. Sobrecrecimiento bacteriano secundario y exudado alrededor de las uñas desaparecieron en todos los casos con el tratamiento inmunosupresor; por lo tanto el tratamiento antimicrobiano puede no ser necesario.

Zusammenfassung

Hintergrund

Prednison Dosen von bis zu 8 mg/kg/Tag sind verwendet worden um den Pemphigus foliaceus der Katze (PF) zu behandeln. Prednisolon per os zeigt eine bessere Pharmakokinetik bei Katzen als Prednison; daher könnten niedrigere Dosen an Prednisolon für die Behandlung von felinem PF wirksam sein.

Hypothese/Ziele

Eine Beurteilung der Prednisolon Dosis, die nötig ist, um die Remission des PF bei der Katzen zu induzieren und zu erhalten.

Tiere

Siebenunddreißig Katzen in Privatbesitz mit der Diagnose PF wurden mit Prednisolon Monotherapie behandelt, um eine Remission zu induzieren.

Methoden

Eine retrospektive Analyse der Krankengeschichten einer veterinärdermatologischen Überweisungspraxis zwischen den Jahren 1995 und 2013 wurde durchgeführt. Die Anamnese, klinische Symptomatik, die zytologischen und/oder histopathologischen Befunde, die unzureichende Wirkung von Antibiotika, die Abwesenheit von Pilzhyphen auf PAS (Periodic Acid Schiff) Färbung und/oder eine negative Pilzkultur und eine positive Reaktion auf immunsuppressive Behandlung wurden verwendet, um die Diagnose zu bestätigen. Es wurden jene Katzen in die Studie inkludiert, bei denen das Behandlungsprotokoll aus Prednisolon als Monotherapie zur Induktion bestand.

Ergebnisse

Eine gänzliche Remission wurde innerhalb von 8 Wochen bei 97% der Katzen mit einer medianen Induktionsdosis von 2 mg/kg Prednisolon täglich erzielt. Bei Katzen, die einer weiteren Behandlung bedurften, wurden 67% mit Prednisolon als Monotherapie in Remission gehalten. Die mediane Erhaltungsdosis betrug 1,2 mg/kg/Woche. Bei 14% der Katzen wurde die Behandlung mit der Zeit beendet.

Schlussfolgerungen und klinische Bedeutung

Eine tägliche Prednisolon Dosis von 2 mg/kg ist eine effektive Dosis, um eine Remission des PF bei Katzen zu erreichen. Nebenwirkungen waren bei dieser Dosierung selten. Bei einem geringen Teil der Katzen kann möglicherweise eine permanente Remission induziert werden. Eine sekundäre bakterielle Überwucherung und das Exsudat im Krallenfalz verschwanden in allen Fällen mit immunsuppressiver Therapie; daher sollte eine antimikrobielle Behandlung unnötig sein.


Introduction

  1. Top of page
  2. ResumenZusammenfassung
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Pemphigus foliaceus (PF) is an autoimmune skin disease characterized by the breakdown of epidermal intercellular connections.[1] Glucocorticoids are thought to be effective in the treatment of this disease due to effects on both humoral and cell-mediated immunity, inhibition of inflammatory mediators and suppression of autoantibody levels.[2, 3] Glucocorticoids, however, have been reported to control only 35–50% of feline PF cases adequately.[4, 5]

In the past, remission of pemphigus foliaceus in cats has been induced with 6.6 mg/kg/day of oral prednisolone.[6] Current recommendations are to use prednisolone at 4–5 mg/kg daily for induction.[7] A 1982 study by Manning et al.[8] supports the effectiveness of this dose; two cats with PF achieved complete remission using prednisolone at 2–3 mg/kg twice a day and were maintained in remission on 2 mg/kg prednisolone every second day.[8] Whilst the above doses were effective, it is possible that lower doses may have achieved the same result. Preziosi et al.[9] published a retrospective study of 57 cats with PF, in which triamcinolone (0.6–2 mg/kg daily) gave complete remission in 15 of 15 cats and prednisone (4–5 mg/kg daily) was less effective, achieving complete remission in eight of 13 cats (62%).[9] There have been other reports of glucocorticoids as therapy for feline PF; however, small numbers of cases, lack of detail of which glucocorticoids were used or use of concurrent immunosuppressive medications make comparisons on relative efficacy of glucocorticoids difficult.[5]

The aim of this retrospective study was to assess the dose of prednisolone required (when used as monotherapy) to induce and maintain remission of PF in cats.

Materials and methods

  1. Top of page
  2. ResumenZusammenfassung
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

A retrospective search of the medical records of a referral practice was conducted for cats with a diagnosis of pemphigus foliaceus between the years of 1995 and 2013. Cats were eligible for inclusion in the study if they fulfilled the following criteria.

  1. Clinical history and physical examination findings were consistent with a diagnosis of PF, and a diagnosis of PF was made by a veterinary dermatologist.
  2. Histopathological samples (when taken) were reviewed by a veterinary dermatologist at the time of sampling and received a diagnosis of PF. Where possible, the original biopsy slides or recuts of the original biopsy were examined by the primary author. In accordance with a previous study, acantholytic cells in these histopathological sections were identified in three high-power fields (×400), the first field being selected for the presence of acantholytic cells and the next two being randomly selected.[9] Histopathological findings were considered diagnostic for PF based on the presence of intact or degenerate intra-epidermal pustules containing granulocytic cells and acantholytic keratinocytes.[9]
  3. If histopathological samples were not taken, the original records must have specified that moderate to numerous acantholytic cells singly or in rafts (three or more acantholytic keratinocytes) were present on cytology.
  4. Dermatophytosis was ruled out by either a negative periodic acid Schiff stain, a negative fungal culture or both.
  5. Bacterial infection was ruled out on the basis of no micro-organisms using cytology and/or histopathological methods. For claw-fold disease, only an incomplete response to antimicrobial therapy and complete resolution with immunosuppressive therapy was adequate for inclusion.
  6. Prednisolone was used as a monotherapy induction protocol for a minimum of 2 weeks.
  7. Follow-up information for at least 4 weeks from the time of diagnosis was available.

Data collected

The following data were recorded: age, breed, sex and clinical signs (including pruritus) present on examination at the time of referral, month of onset of clinical signs, details of potentially stressful life events in the month preceding onset of clinical signs, details of steps taken to rule out fungal and bacterial disease, cytological and histopathological findings where applicable, whether original histopathology slides were available for review, induction dose of prednisolone, time to complete remission, or details of partial remission if complete remission was not achieved, details of any other therapies added, outcome, month of relapse of disease if applicable, dose and frequency of therapeutic drugs at the time of relapse, final or maintenance dose of therapeutic drugs, length of follow-up and details of any adverse effects.

Remission

Cats were considered to have achieved complete remission when no clinical signs of active disease were present. Specifically, this was defined as no adherent crusts, erosions, signs of inflammation or caseous claw-fold exudate. Focal small areas of lifted crusts with underlying healed skin, alopecia, claw staining or dried exudate were not considered as signs of active disease. Cats were considered to have achieved partial remission when disease was improved by at least 50% (based on subjective interpretation of records if a percentage of improvement was not specifically noted).

Maintenance and final drug doses

Cats in complete remission from disease on the same drug protocol for 6 months or longer were considered to have achieved a maintenance drug protocol. If the length of time was <6 months or the dose of medication had varied within the last 6 months, the dose of medications they were receiving as of their last visit was termed the final dose.[5]

Response to therapy

Response to therapy was graded as poor, fair or good according to the following definition based on a study by Irwin et al.[5]

Poor: disease flares at 50% or more of examinations, necessitating increases and/or changes in the medications used, with the cat still having active signs of disease or in remission for only short periods of time.

Fair: PF generally responsive to therapy, but more frequent flares (2–3/year), significant enough to require short increases in drug dose or change in type of drug used and/or had persistent focal areas of active disease that were moderate in severity.

Good: in 75% of examinations, the cat was reported to be in complete remission or to have only fewer than three areas of mild disease, which did not require changes in systemic treatments, with no more than one flare per year of mild severity and/or short duration.[5]

Data analysis

The induction dose of prednisolone in each case was recorded, and results were analysed to provide the mean and median dose and interquartile range. The time to complete remission was recorded in 36 of 37 cats, and this information was analysed to provide a mean and median time to complete remission, as well as to provide a percentage of cats achieving complete remission in 2 weeks or less and 4 weeks or less. Data were analysed to provide a percentage of cats treated with prednisolone as monotherapy and to evaluate how many of these cats achieved maintenance drug protocols or final drug protocols or were able to discontinue medication completely. The total weekly prednisolone dose was calculated for cats that had been stable on the same dose for 6 months or longer. Information relating to the time of relapse and the drug doses at the time of relapse was also evaluated.

Results

  1. Top of page
  2. ResumenZusammenfassung
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

The search of clinic records identified 65 cats with a diagnosis of pemphigus foliaceus; 37 cats satisfied the inclusion criteria and were used for data analysis (see Table S1 in Supplementary material). In 23 of 37 cats, the diagnosis was confirmed by histopathology. In 13 of 23 cases, the original biopsies were available for review by the primary author. All cases that were available for review had at least one section that was clearly diagnostic for PF according to the inclusion criteria. In 14 of 37 cats, the diagnosis was based upon cytological findings together with a consistent history, clinical signs and response to treatment (no histopathology was performed on these cases).

In this case series, 36 of 37 cats achieved complete remission with prednisolone monotherapy within 8 weeks of starting treatment. One cat was initially treated with prednisolone monotherapy (2.5 mg/kg twice daily) but had not achieved complete remission at the 2 week revisit. Due to clinician preference, chlorambucil was added to the protocol and the dose of prednisolone was increased to 4 mg/kg twice daily. This cat achieved complete remission 2 weeks later.

The mean total daily induction dose was 2.3 mg/kg and the median induction dose was 2 mg/kg. The interquartile range was 1.25–3 mg/kg/day. The mean and median time to complete remission was 2 weeks. Twenty-three of 37 cats (62%) achieved complete remission in 2 weeks or less, and 33 of 37 cats (89%) achieved complete remission in 4 weeks or less (Figure 1).

image

Figure 1. Induction dose of prednisolone versus time to complete remission.

Download figure to PowerPoint

Twenty-four of 37 cats (65%) were treated with prednisolone monotherapy for induction of remission and ongoing control of pemphigus. Of these 24 cats, four cats were able to discontinue medication completely without relapse of disease. Of the remaining 20 cats that were maintained on prednisolone only, 12 had been receiving the final recorded dose for <6 months (medication requirements were still stabilizing). Eight cats were on ‘maintenance’ doses (i.e. they were stable on the same dose for longer than 6 months) and had a median weekly dose of prednisolone of 1.2 mg/kg with a range of 0.5–3.5 mg/kg.

Thirteen of 37 cats had other drugs added to their treatment protocol either before or after complete remission due to clinician preference, as a prednisolone-sparing treatment or to treat relapses of disease (see Table S2 in Supplementary material). In three cats, all medications were able to be discontinued without relapse; the remaining ten cats were maintained with other drug protocols.

For seven cats, their medication could be discontinued completely; five of these cats were lesion free for over 12 months. Follow-up times during which these cats were lesion free were 12, 14, 16 and 17 months and 6 years. Of these five cats, two were <1 year old, one was 8 years old and two were >10 years old. Thus, five of 37 cats (14%) diagnosed with PF were able to discontinue all medications and remain in remission for longer than 12 months.

Twenty-five of 37 cats (68%) experienced a disease relapse after achieving complete remission. The most common time for relapse was 6 months or less after diagnosis (16 of 25 cats) during the medication taper. The median dose of prednisolone at the time of relapse was 1.8 mg/kg/week.

The outcome (as defined above) was good or fair in 31 of 37 cats (84%) and poor in six of 37 cats. Of the 23 of 37 cats with a good outcome, 18 of 23 (78%) were treated with prednisolone only.

Follow-up times for cats in the study ranged from 4 weeks to 8 years, with a median follow-up period of 14 months. Thirty-three of 37 (89%) were followed for over 3 months and 24 of 37 (65%) were followed for over 12 months.

Recorded adverse effects in the 24 cats treated solely with prednisolone were minimal. In 18 of 24 cats, there were no reported adverse effects. Two cats had an increase in appetite and one of these had weight gain as a consequence; one cat had a transient decrease in appetite and bloody faeces, one cat had diarrhoea and two cats developed upper respiratory tract infections. Some adverse effects that may have been due to prednisolone were seen in the cats which were also treated with other drugs; however, owing to the combination therapy it was not possible to attribute the adverse effects definitively to glucocorticoid use. Two of these cases involved serious adverse effects. One cat treated with chlorambucil, aurothioglucose and fluctuating doses of prednisolone (never <1 mg/kg once daily) over the course of 32 months developed diabetes mellitus and renal failure. Another cat treated with 4 mg/kg prednisolone twice daily for 4 weeks as well as chlorambucil developed two large skin tears.

Tables S1–S3 in Supplementary material summarize the clinical presentation, diagnostic tests, treatments and outcomes. Data S1 in Supplementary material details data collected regarding breed predisposition, season of onset, presence or absence of stress, cytological findings in claw-fold exudate and response to immunosuppressive versus antimicrobial treatment of claw folds. Figure S1 in Supplementary material shows the age of the cats at presentation.

Discussion

  1. Top of page
  2. ResumenZusammenfassung
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

In this retrospective study, prednisolone at 2 mg/kg/day or less was effective in inducing remission in the 23 of 37 cats (62%) that received this dose as an induction protocol. Higher doses of prednisolone were used due to clinician preference in the other cats; it is possible that these cats may also have responded to a lower dose. Prednisolone as a monotherapy induction protocol for feline PF resulted in remission of disease in 36 of 37 cats (97%), and 33 of 37 cats (89%) achieved complete remission in 4 weeks or less.

Glucocorticoids have been reported to control only 35–50% of feline PF cases adequately.[4, 5] Previous studies suggest two possible reasons for this. First, cats may require higher doses of some glucocorticoids than dogs.[10] One study found that cats have fewer cellular dexamethasone receptors in the liver and skin and that the binding affinity of these receptors was less than that in dogs.[11] Second, the prodrug prednisone is not well absorbed by the feline gastrointestinal tract and/or converted by the feline liver into biologically active prednisolone; in one study, only 21% of orally administered prednisone appeared in the blood as prednisolone.[12] A recent study found that a single 2 mg/kg oral dose of prednisolone produced significantly higher plasma prednisolone concentrations (fourfold higher area under the curve) than prednisone.[13] The study also found that cats with a high body condition score had higher plasma prednisolone concentrations (twofold) than cats with a normal body condition.[13] The authors concluded that oral prednisone had a low comparative bioavailability compared with prednisolone in cats and that lean body mass or ideal body weight should be taken into account for dosing.[13]

In the present study, 30 cats required maintenance therapy (seven cats were free of medication at the conclusion of the study). Of the cats still requiring medication, 67% were controlled with prednisolone monotherapy. Eight cats had been maintained on a median total weekly dose of 1.2 mg/kg prednisolone for >6 months with no need to change the dose of their medication. In the other cats, the dose required was still fluctuating (had changed in the previous 6 months), so was not used for data analysis.

Twenty-five of 37 cats relapsed with disease after achieving complete remission. The most common period for relapse was 6 months or less after diagnosis, while medication was being tapered. These figures were not used for data analysis. The rate of tapering was different in each case, and factors that may impact relapse include both the percentage reduction in medication and the time in between each dose reduction, none of which was standardized in this study owing to its retrospective nature.

Reported adverse effects were uncommon. Fewer adverse effects reported in cats treated with prednisolone monotherapy may reflect the fact that refractory cases were treated more aggressively with both glucocorticoids and other drugs. Other studies have also shown that cats tolerate prednisolone therapy well. In one study, seven of 14 cats were treated with 4.4 mg/kg/day of prednisolone for 56 days with no adverse clinical effects other than mild polyuria and polydipsia.[14] In another study, no adverse effects were reported for four cats treated with 5 mg/kg of methylprednisolone acetate weekly for 4 weeks.[15]

One possible reason for resistance to treatment is emotional stress; this has been associated with pemphigus lesions in humans but has not been investigated in animals.[16-18] In humans, anxiolytic medications have been suggested as useful adjunctive treatments in the management of PF.[17]

Findings regarding clinical presentation in this study were mostly consistent with previous studies. The exception was the total percentage of cats with claw-fold involvement, which, at 81%, was higher than previously reported. Many cats with claw-fold disease had bacterial overgrowth in the claw-fold exudate, which responded to immunosuppressive therapy rather than antimicrobial therapy, indicating that the bacteria were not the primary pathogen but were colonizing opportunistically. No cats were excluded from the study due to a failure of claw-fold exudate to respond to immunosuppressive therapy.

A limitation of this retrospective study is that not all cases had a histological diagnosis of pemphigus foliaceus. While desirable, in clinical practice it may not always be possible to obtain a histopathological diagnosis of pemphigus in cats due to client constraints or where claw folds are the only affected site. In the latter situation, a diagnostic biopsy specimen may require amputation of the third phalanx and may provide little additional data over cytology alone.

Acknowledgements

  1. Top of page
  2. ResumenZusammenfassung
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

The authors would like to thank Ralf Mueller, Sonya Bettenay and Michael Shipstone for permission to use cases presented to their referral service from 1995 to 1999, as well as David Robson for assistance with the manuscript.

References

  1. Top of page
  2. ResumenZusammenfassung
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Supporting Information

  1. Top of page
  2. ResumenZusammenfassung
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
vde12081-sup-0001-FigS1.xlsxapplication/msexcel12KFigure S1. Age of cats at presentation.
vde12081-sup-0002-FigS1.tifimage/tif3178K 
vde12081-sup-0003-TableS1.docxWord document31KTable S1. Diagnostic criteria.
vde12081-sup-0004-TableS2.docxWord document35KTable S2. Treatment summary.
vde12081-sup-0005-TableS3.docxWord document18KTable S3. Breeds and odds ratio.
vde12081-sup-0006-Suppinfo.docxWord document21KData S1. Epidemiological information, claw-fold cytology and response to treatment of claw-fold exudate.

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.