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Clinical decision making
Are low doses of oral glucocorticoids as effective as high doses as the sole treatment for canine pemphigus foliaceus?
  1. Nicola Swales,
  2. Emma Place,
  3. Natalie Barnard and
  4. Aiden Foster
  1. Bristol Veterinary School, University of Bristol, Langford, UK
  2. Highcroft Veterinary Referrals, Whitchurch, Bristol, UK

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Bottom Line

  • The management of canine pemphigus foliaceus is challenging because the skin condition does not always respond to therapy, and this may lead to euthanasia. Furthermore, dogs will often show signs of adverse reactions to medication. Therapy usually relies on oral steroids, often in combination with adjunct therapies, although the effectiveness of the latter remains difficult to ascertain.

  • The use of oral glucocorticoids at an initial dose of 2 mg/kg/day may prove effective in some cases. In the long term, some cases may require higher doses, and some may be satisfactorily managed with lower doses. There is no clear indication from these studies that dogs must be given higher doses of steroids.

  • There is a need to monitor clinical cases and use ancillary therapies (eg, bathing and antibiotics) and adjunct therapies to balance the therapeutic response to steroids against their adverse effects.

Clinical scenario

A middle-aged cocker spaniel presented one month ago with a history of crusting skin lesions and pruritus. Cytology of the lesions revealed acantholytic keratinocytes and a marked neutrophilic infiltration, with no microorganisms evident. Histopathology of lesional skin showed large subcorneal pustules, acantholytic keratinocytes and neutrophils, hence a diagnosis of pemphigus foliaceus was made.

The dog was treated with prednisolone at 2 mg/kg.1 Following two weeks of once-daily dosing, the dog became lethargic, polyphagic, polydipsic and polyuric, with inappropriate toileting in the house, behavioural changes and weight gain. The owners found these side effects to be unacceptable and requested a reduction in the dose of prednisolone to hopefully reduce them.

The question

In [dogs with pemphigus foliaceus] is oral [low-dose prednisolone/prednisone] as effective as [high-dose prednisolone/prednisone] for the [management of the disease]?

Search parameters

The search terms (dogs/ OR dog* OR canine* OR canid*) AND (exp prednisolone/ OR prednisolone OR exp prednisone/ OR prednisone) AND (pemphigus/ OR pemphigus) were used in CAB and Medline searches, using Ovid.

Medline: (Dogs/ or dog*.mp. or canine*.mp. or canid*.mp.) and (exp Prednisolone/ or prednisolone.mp or Prednisone/ or prednisone.mp.) and (Pemphigus/ or pemphigus.mp.)

CAB Abstracts: (exp dogs/ or dog*.mp. or canine*.mp. or canid*.mp.) and (prednisolone/ or prednisolone.mp. or prednisone/ or prednisone.mp.) and pemphigus.mp.

Search outcome

  • Twenty-one papers were found in the Medline search.

  • Fifteen were excluded because they did not answer the question.

  • In total, six relevant papers were obtained.

  • Forty papers were found in the CAB search.

  • Four were excluded because they were duplicates.

  • Twenty-nine were excluded because they did not answer the question.

  • Five papers were unavailable, and only abstracts were available for two.

  • In total, two total relevant papers were obtained.

  • In addition, three relevant papers were found via Google Scholar.

  • Overall, a total of 11 relevant papers were identified.

Search last performed: 30 October 2019

Ten publications in other languages were also found, including five for which the full article was not available. Of these 10 papers, there was one with no English abstract2 and five in which there was insufficient information in the abstract to include their content.3-7

In one paper, there was an association between pemphigus foliaceus and nematode infection, and the skin condition resolved when the dog was wormed.8 In another, a dog with pemphigus foliaceus did not respond to various oral therapies and the lesions were surgically excised.9 Two other case studies showed a good response to intravenous immunoglobulins, after a poor response to oral prednisone and azathioprine, with the dogs eventually going into remission with no additional therapy.10,11

Five single case reports were excluded where comorbidities were present that may have been causative in the development of pemphigus foliaceus. These included:

  • A dog that developed pemphigus foliaceus after splenectomy for haemangiosarcoma tumour, where the causes may have been a drug reaction or paraneoplastic.12 The dog recovered completely after a short course of oral prednisolone and mycophenolate mofetil;

  • A dog with Leishmaniosis that did not respond to treatment with prednisolone and azathioprine for pemphigus foliaceus;13

  • A dog that developed pemphigus foliaceus after ingesting Echinacea purpurea plants. After treatment with prednisone and mycophenolate mofetil, the dog went into remission and all therapies were stopped;14

  • A dog that was treated for pemphigus foliaceus and concurrent generalised demodicosis, with complete resolution seen in a matter of several months. The dog received oral prednisolone at an initial dose of 2 mg/kg, which was then tapered, as well as amitraz and antimicrobial agents;15

  • A dog that was treated for pemphigus foliaceus after the administration of afoxolaner, which was considered to be the likely trigger for the condition. Oral steroids and ciclosporin therapy were associated with a good response. In the long term, the skin condition was managed with low doses of medication.16

Summary of evidence

Paper 1: Pemphigus foliaceus in dogs: a review of 37 cases17

Patient group: A total of 37 dogs, with a mean age of 4.2 years, diagnosed with pemphigus foliaceus according to histopathology (with or without direct immunofluorescence).

Study type: Case series

Outcomes: Details of how the efficacy of treatment was measured, and the assessment periods and criteria were not recorded.

Key results: Twenty-three dogs were treated with prednisone at doses ranging from 4.4 to 6.6 mg/kg daily. The doses were tapered to 1.1 mg/kg, which nine dogs were solely maintained on. Side effects included polyuria, polydipsia, weight gain, lethargy, weakness and pyoderma in dogs treated long term. Five dogs had recurrent bacterial urinary tract infections. Four dogs were given prednisone and cyclophosphamide concurrently, and two were given concurrent azathioprine due to inefficacy of prednisone alone. Side effects seen in these cases were iatrogenic Cushing’s disease, demodicosis, urinary tract infections and pyoderma.

Eleven dogs were given prednisone with concurrent aurothioglucose (gold salts). Three of these dogs were maintained solely on gold salts after cessation of prednisone, and three were maintained with gold salts and alternate-day administration of low-dose (1.1 mg/kg) prednisone, though the lesions recurred after stopping the prednisone in these cases. Two dogs presented with oral ulceration, possibly due to the gold salts, and therapy was unsuccessful in the remaining cases. All three dogs maintained on gold salts with prednisone had recurrent bacterial urinary tract infections.

Only nine of the 37 dogs had no side effects reported. Eighteen of 34 dogs were managed successfully for one year or more, representing a 53 per cent survival rate.

Study weaknesses: Though the study was relatively large-scale compared to others, it is difficult to assess efficacy because of the multiple treatment groups. A 53 per cent survival rate is mentioned, but it is unclear whether the dogs that did not survive died from the disease or were euthanased due to inefficacy of the treatment, occurrence of side effects or other reasons. A vague timescale of one to seven years survival was given, but it was unknown how many dogs survived this long at such high doses of corticosteroids, given that it was not reported when the dose of prednisone was tapered to 1.1 mg/kg.

Spaniel dog with periocular alopecia and crusting associated with pemphigus foliaceus

Paper 2: Pemphigus foliaceus of the footpads of three dogs18

Patient group: Three middle-aged dogs – a German shepherd, a Newfoundland and a cocker spaniel – with pemphigus foliaceus localised to the footpads, diagnosed using histopathology and direct immunofluorescence. Each dog was treated with high doses of prednisone (2 to 3.3 mg/kg) that were then tapered to lower alternate-day doses.

Study type: Case series

Outcomes: Details of assessment periods and criteria were not recorded.

Key results: Dog 1 was treated for over two years with an alternate-day dose of 0.6 mg/kg, but it is not known whether this dog went into remission. Dog 2 was lost to follow-up due to side effects. Dog 3 was treated with an alternate-day dose of 0.7 mg/kg for five months but relapsed three months after ceasing therapy. The lesions went back into remission once 0.7 mg/kg prednisone was given daily.

Study weaknesses: This is a small study, and the dogs were not assessed at predefined points, nor were any lesional scores used to assess treatment efficacy. It is unknown whether the disease was treated to remission. One dog was lost to follow-up due to the side effects of steroids.

Paper 3: Observations on the immunopathology and therapy of canine pemphigus and pemphigoid19

Patient group: Twenty-seven dogs with pemphigus or pemphigoid disorders (including seven dogs with pemphigus foliaceus), treated with up to four chemotherapeutic regimens depending on efficacy.

Study type: Uncontrolled clinical trial.

Outcomes: Details of assessment periods and criteria were not recorded.

Key results: Seven dogs were initially administered with 1.1 mg/kg prednisolone twice daily. All seven cases were unsuccessfully managed, and side effects (polyuria, polydipsia, depression and muscle wastage) were reported. Five dogs then received 3.3 mg/kg prednisolone twice daily, which was then tapered down to 1.1 mg/kg once lesions were resolving. One of the five was managed successfully on this regimen, but the remaining four were unable to be managed on a high enough dose of prednisolone to keep the disease in remission without side effects occurring. Two dogs were successfully managed on 3.3 mg/kg prednisolone combined with cyclophosphamide but were euthanised four months later for unstated reasons. Three dogs were started on aurothioglucose treatment due to the side-effects of prednisolone, which led to successful management.

Study weaknesses: This is a large-scale study, but it included many different pemphigus disorders, not just pemphigus foliaceus. It is difficult to determine the efficacy of each regimen as we do not know which of the seven dogs that started with prednisolone treatment subsequently went into each regimen. The method of determining treatment efficacy was not recorded.

Paper 4: Pemphigus foliaceus in 91 dogs20

Patient group: Ninety-one dogs of varying ages and breeds, all diagnosed with pemphigus foliaceus based on histopathology or suggestive cytology, clinical signs and response to therapy.

Study type: Retrospective.

Outcomes: Times until initial improvement and complete remission were recorded. Improvement was defined as one or more small areas of scaling, crusting or erythema without the need for changes in therapy. The follow-up period was recorded for each dog.

Key results: Thirty-eight dogs were maintained on prednisone or prednisolone alone, with doses ranging from 1.5 mg/kg to 5 mg/kg. Sixteen dogs were managed on prednisone or prednisolone long term, with 15 going into remission. Thirteen dogs received other therapies – triamcinolone, dexamethasone, azathioprine, doxycycline and niacinamide, tetracycline and niacinamide and topical pimecrolimus, either alone or in combination – concurrently with prednisone or prednisolone.

Side effects, including iatrogenic Cushing’s disease, lethargy, polyuria, polydipsia and anorexia, were more common with combination therapies than with just prednisone or prednisolone alone. Of the 15 dogs that went into remission with prednisone or prednisolone alone, five were euthanased for reasons unrelated to the pemphigus foliaceus or the side effects of the medication.

Study weaknesses: The exact doses used for each dog in this study are unknown, so it is impossible to compare higher to lower doses in terms of efficacy or incidence of side effects. The retrospective nature of the study did not allow analysis of lesion scores to aid in determining improvement and remission.

Paper 5: Diabetes mellitus induced in a dog after administration of corticosteroids and methylprednisolone pulse therapy21

Patient group: An eight-year-old female, neutered chow chow with a two-month history of facial and footpad erythema and crusting, with secondary pruritus. The diagnosis of pemphigus foliaceus was based on cutaneous histological findings and immunofluorescence.

Study type: Case report.

Outcomes: Complete blood count and serum biochemistry were measured, and the presence of lesions was monitored.

Key results: The dog was treated with 2.2 mg/kg of prednisone and alternate-day azathioprine. Clinical remission was reached in two weeks but the dog was re-examined due to anorexia, depression, collapse and hepatomegaly. Steroid hepatopathy was suspected. Prednisone was replaced with low-dose dexamethasone followed by methylprednisolone pulse therapy, which led to the dog being diagnosed with diabetes mellitus.

Study weaknesses: It is difficult to attribute each of the side effects to a particular steroid due to the multiple steroids used in this case.

Paper 6: Pemphigus foliaceus: a report of two cases in the dog22

Patient group: A four-year-old female, neutered Labrador retriever with a four-week history of non-pruritic, generalised crusting skin lesions and a 13-year-old entire female Jack Russell terrier with a six-week history of non-pruritic generalised crusting. The diagnosis of pemphigus foliaceus was made on the basis of compatible clinical signs, negative fungal culture and the results of dermatohistopathology and immunofluorescence.

Study type: Case series.

Outcomes: Dog 1 was assessed at seven days, 17 days, two months and six months. Dog 2 was assessed at 10 days, six weeks and six months.

Key results: Dog 1 was started on 0.6 mg/kg prednisolone twice daily due to hepatic dysfunction identified by serum biochemistry. After seven days of no improvement, this was increased to 1 mg/kg twice daily, which led to all lesions healing after 10 days. The prednisolone dose was then tapered to 0.6 mg/kg on alternate days. New lesions appeared after two months, so the dose was changed to 1 mg/kg on alternate days. Despite improvement, the dog was euthanased six days later due to perceived poor prognosis.

Dog 2 was started on 1.5 mg/kg prednisolone twice daily. Marked improvement was seen after 10 days, so the dose was then tapered. All lesions had healed after six weeks, so prednisolone therapy was stopped, and the dog was still in remission around four months later.

Study weaknesses: This small case series used different doses of prednisolone between cases, making an assessment of effective doses difficult.

Paper 7: Canine pemphigus foliaceus: a retrospective study of 43 clinical cases and therapy (2000–2005)23

Patient group: Forty-three dogs diagnosed with pemphigus foliaceus based on clinical history, clinical examination, cytology of lesions and histopathology.

Study type: Retrospective.

Outcomes: Cases were re-examined every three to four weeks, and complete blood count, serum biochemistry and urinalysis were performed. If azathioprine was added to the treatment regimen, dogs were examined every two weeks. Owner-assessed improvement was measured in percentages.

Key results: The dogs were started on 1 to 2 mg/kg prednisone once daily for three to four weeks, then the dose was tapered if improvement was seen. If no improvement was seen, azathioprine was added to the treatment regimen. Twenty-three dogs responded to prednisone alone, and 20 required the introduction of azathioprine. Thirty-seven dogs had satisfactory control of lesions, evaluated by owners as between 70 and 100 per cent improvement. Five dogs were lost to follow up, and one was deemed to have unsatisfactory improvement (40 per cent) on combination therapy. No adverse effects were reported.

Study weaknesses: Owner assessment of improvement was used in this large-scale study, rather than veterinary surgeon assessments, which could make measuring less reliable due to inter-rater variation and lack of veterinary knowledge.

Paper 8: Oral glucocorticoid pulse therapy for induction of treatment of canine pemphigus foliaceus – a comparative study1

Patient group: Thirty-eight dogs with pemphigus foliaceus based on clinical criteria (including facial involvement) and cutaneous histological changes. One group received high-dose pulse therapy with three days of 10 mg/kg prednisone/prednisolone once daily, followed by a target dose of 2 mg/kg/day. Pulses could be repeated at weekly intervals if deemed necessary. The other group received a dose equal to or greater than 2 mg/kg/day of prednisone/prednisolone until lesion remission. Ancillary therapies were allowed in both groups for the first 12 weeks. If lesions were present after four weeks of therapy then adjuvant therapies, including azathioprine and ciclosporin, were allowed in both groups.

Study type: Retrospective

Outcomes: Complete remission (CR) was recorded when no lesions were present. Incidence and time to CR were recorded for the first 12 weeks, as well as the number of dogs receiving ancillary therapy, the number of dogs requiring adjuvant therapies and the incidence of severe adverse events.

Key results: The continuous therapy group comprised of 20 cases. By week 12, three dogs were in clinical remission, 12 needed adjuvant therapies and two had severe adverse events – one dog died suddenly, and one developed myelosuppression due to azathioprine therapy. Side effects of polyuria, polydipsia, polyphagia and weight gain were seen.

The pulse therapy group comprised of 18 cases. By week 12, 11 dogs were in clinical remission, two received adjuvant therapies and two had severe adverse events – one was euthanased due to iatrogenic Cushing’s disease, and one suffered from gastrointestinal bleeding). Similar side effects were also seen in this group, along with aggression (n=2) and diarrhoea (n=2). There was no statistically significant difference in the time to reach CR, the number of dogs receiving adjunct therapy or the number showing adverse effects between the two treatment groups.

Study weaknesses: The limitations of this study are its retrospective nature and the small number of cases involved. Given that prednisone needs to be converted to prednisolone, it was suggested that the former might not be the optimal steroid for oral dosing. It would have been potentially useful to see individual case records, especially in the continuous therapy group, to see what dose of steroids was used when cases were in CR.

Paper 9: Outcome and complications associated with treatment of pemphigus foliaceus in dogs: 43 cases (1994–2000)24

Patient group: Forty-three dogs diagnosed with pemphigus foliaceus based on suggestive clinical signs, cytology and histopathological examination.

Study type: Retrospective.

Outcomes: Case records were analysed to record treatment, duration of treatment and adverse events.

Key results: Of the 43 dogs, 16 were treated with prednisone alone, with the mean dosage being 2 mg/kg daily. The other 27 dogs were treated with prednisone in combination with other therapies or with other therapies entirely. Adverse events recorded were polyuria, polydipsia, weight gain, lethargy, muscle wastage, recurrent infections, pancreatitis, increased serum liver values, liver failure, disseminated intravascular coagulation, diabetes mellitus, demodicosis and death.

Twenty-six dogs died – 18 were euthanased due to complications of the disease (with two owners stating concurrent financial issues), four died unexpectedly due to causes unrelated to pemphigus foliaceus, and four were euthanased for unrelated reasons.

Study weaknesses: The dogs received various treatment modalities and doses. Therefore, it cannot be determined which adverse events correlated with which treatment method and how many of the cases treated solely with prednisone died and for what reasons.

Paper 10: Prolonged remission after immunosuppressive therapy in six dogs with pemphigus foliaceus25

Patient group: All cases were diagnosed with pemphigus foliaceus based on clinical signs and dermatopathological findings. Cases were treated with steroids and additional cytotoxic drugs, and they were recorded as having no skin lesions for one year after therapeutic interventions were stopped.

Study type: Case series, retrospective.

Outcomes: Remission was based on no skin lesions being observed.

Key results: Five of the six dogs initially received between 1.4 and 2.4 mg/kg of prednisolone daily and, given the lack of response to treatment, they were then treated with azathioprine before going into remission.

One dog was only given prednisone at a dose of 2 mg/kg twice daily. Marked improvement was seen after two weeks, so the prednisone dose was decreased to 1.5 mg/kg twice daily for two weeks and then to 1 mg/kg twice daily for two weeks. Once clinical remission was achieved, the dose was again decreased to 1 mg/kg once daily for two months and then every other day for six months. No relapse was seen.

This study shows the importance of dose reduction when cases are in remission, and that in some dogs it may be feasible to stop all therapies.

Study weaknesses: This study was a small case series. It is unusual for cases to go into remission, so the findings may be unrepresentative of most dogs with pemphigus foliaceus.

Paper 11: CTLA4 overexpressing adipose tissue-derived mesenchymal stem cell therapy in a dog with steroid-refractory pemphigus foliaceus26

Patient group: A dog with pemphigus foliaceus diagnosed on the basis of clinical signs and histopathological findings.

Study type: Case report.

Outcomes: Clinical improvement was not clearly delineated.

Key Results: The dog did not respond to 4.4 mg/kg per day of oral prednisolone over a one-month period. Additional therapies, including ciclosporin and azathioprine, were used for several months and then stopped. The skin condition seemed to improve with concurrent, repeated injections of adipose tissue mesenchymal stem cells, including a formulation expressing cytotoxic T-lymphocyte antigen-4. After the stem cell injections, the dog was managed with 0.25 mg/kg of prednisolone daily, and it was suggested that the stem cell therapy had helped to manage the skin disease.

Study weakness: This study included a single case and there was only partial improvement with combined therapies.

Comments

There were mixed reports of dogs with pemphigus foliaceus being successfully treated with variable doses of glucocorticoids, with or without additional therapies. However, there was no compelling evidence that oral steroids – at the doses of around 2 mg/kg per day – were effective in managing the disease, even when combined with other therapies. There was a suggestion that treatment with intravenous immunoglobulins might be associated with clinical remission, although two single case reports is a limited evidence base.

Higher doses of steroid seem more likely to be associated with clinical remission or improvement, although they also seem to be associated with increased incidences of side effects and higher mortality. There are currently no validated guidelines on how to assess response to treatment of canine pemphigus, although clinical remission with no lesions present has been clearly shown to be feasible within a 12-week period. It may be feasible to manage some cases with minor residual lesions, and this may help to manage the side effects of medication, especially when using oral steroids.

Consequently, it is unclear if doses of glucocorticoids less than 2 mg/kg – alone or with adjunctive therapy –will prove effective in some cases of canine pemphigus.

Critically Appraised Topics (CATs) are a standardised, succinct summary of research evidence organised around a clinical question, and a form of evidence synthesis used in the practice of evidence-based medicine (EBM) and evidence-based veterinary medicine (EBVM). Access to CATs enables clinicians to incorporate evidence from the scientific literature into clinical practice.

References

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