Immunosuppressive drugs in canine primary IMHA: what's the evidence?

Background

In the treatment of immune-mediated haemolytic anaemia (IMHA), both primary (idiopathic) and secondary, immunosuppressive therapy is essential. Exogenous glucocorticoids are considered the mainstay of treatment and the therapy that is most crucial for establishing early control of the disease process and remission. Additional immunosuppressive agents are often added. This may be in an attempt to reduce the dose of glucocorticoid needed and thereby reduce associated steroid side-effects. In some cases these agents are turned to in patients in whom the early response to glucocorticoids is inadequate in the hope of being able to achieve initial disease control.

Azathioprine is an agent that has been used off-licence quite extensively as an additional immunosuppressive agent in dogs; it should not be used in cats based on current understanding. In its favour it has going that it is a cheap drug. However it is essential to realise – and clinicians often are not clear about this – that azathioprine is reported to have a lag in onset of effect; exactly how long seems unclear based on current information but the minimum period is said to be 7-10 days, more likely the delay is longer. So it is not helpful in establishing early remission but potentially useful going forward.

Cyclosporine has also been used although clinical experience is less. It is licensed in dogs for dermatological purposes and is thought to have a relatively fast onset of efficacy; however high cost has previously limited widespread uptake for IMHA. Mycophenolate mofetil (MMF) is another agent that has been evaluated more recently, again off-licence, as an agent that may have a quicker onset than azathioprine but be less expensive than cyclosporine. And other agents (e.g. cyclophosphamide) have also been explored with more or less clinical experience.

So with that in mind, is there any evidence on immunosuppressive therapy in canine IMHA? How to use glucocorticoids? One immunosuppressive agent versus another?

Paper

The following systematic review was published in 2013. I am going to just report my selected highlights from the paper but won’t make any comments on the methodology; the paper is not just about immunosuppression but this will be my focus here. In general terms, systematic reviews can be critiqued with respect to their methodology and moreover, very importantly, their findings are clearly very dependent on the evidence available to review at the time – as is accepted in the paper here. That said in terms of veterinary evidence this type of paper certainly would be considered higher quality than the myriad individual retrospective case series that are often cited as evidence.

Swann JW, Skelly BJ. Systematic Review of Evidence Relating to the Treatment of Immune-Mediated Hemolytic Anemia in Dogs. J Vet Int Med 2013. 27:1-9.

“…clinical choices are still largely guided by experience, anecdote, and personal preference rather than by objective evidence.”

Aim: systematic evaluation of current evidence regarding immunosuppressive and antithrombotic drugs in the management of canine primary IMHA.

Trials included were required to present at least 1 outcome measure that related to the survival of individual treatment groups rather than just assessing changes in clinical or biochemical parameters during management of the disease.

19 articles met their inclusion criteria for the review; these collectively reported data from 843 cases.
Corticosteroids were used in every case; product, formulation and dose varied quite widely between reports.
In terms of other immunosuppressive drugs , azathioprine, cyclosporine and cyclophosphamide were the three most common.
All cases were reported from referral centres.
Publication dates for the studies considered spanned a 30-year period.

“The review shows that there are few pieces of high-quality evidence available to inform clinicians managing cases of IMHA in dogs.” The authors go on to expand on and dissect the various ways in which the evidence available for review had shortcomings.

Their “Practical Conclusions” with respect to immunosuppressive drugs:

“Use of glucocorticoids alone will result in a successful outcome in a high proportion of cases.” But they are unable to provide any guidance about the effect of dosage on outcome given the nature of the evidence available to review.

No consensus over duration of treatment, tapering strategy, or appropriate response to relapse.

“There is…no published clinical evidence available to guide a choice between azathioprine, cyclosporine, or no ‘second line’ drug”. But they acknowledge that their major benefit may be a glucocorticoid dose-sparing effect. However this is an area that has received very little attention so far.

Based on the evidence they reviewed “the authors do not consider the use of cyclophosphamide to be justified when alternative products are available”.

Authors’ conclusion:

“The quality of evidence available to guide clinical decisions in the treatment of IMHA is generally poor and further research of a higher quality will be required to investigate existing and novel therapeutic regimens for the disease.”

(SJ) Of interest, a Brief Communication paper in the current issue of Journal of Veterinary Emergency and Critical Care reports the use of mycophenolate mofetil (MMF) in five dogs with primary (idiopathic) IMHA. Although a prospective study, with such a small sample size personally I am not sure we can take much from this study at this time other than to await such time as it can contribute to a systematic review or meta-analysis going forward.

Also see:

Azathioprine in dogs with IMHA (BestBETs for Vets)

Cyclophosphamide in dogs with IMHA (BestBETs for Vets)