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Safety and Efficacy of Leflunomide in Dogs | VETgirl Veterinary Continuing Education Podcasts

In today’s VETgirl online veterinary continuing education podcast, we review the safety and efficacy of leflunomide in dogs. It seems as if leflunomide is a medication that some clinicians use quite routinely, whereas others have limited or even no experience using. Regardless of which category you fall into, don’t fret! Today we will review some basic information about this medication, as well as a recent retrospective study evaluating its use. Leflunomide is an immunosuppressive medication that is used to treat a variety of immune-mediated conditions in dogs, including but not limited to immune-mediated hemolytic anemia (IMHA), immune-mediated polyarthritis (IMPA), immune-mediated conditions of the central nervous system (CNS), and inflammatory bowel disease (IBD). It works by inhibiting the synthesis of pyrimidine and thereby inhibiting lymphocyte proliferation (Plumb). Past studies have evaluated this medication at starting doses of 3-4 mg/kg/day, which showed positive response rates at this dosing (Gregory, Colopy, Fukushima).

In this study entitled “A Retrospective Study on the Safety and Efficacy of Leflunomide in Dogs,” Sato et al looked at 92 dogs that were treated with leflunomide over a 20-year period at Colorado State University’s Veterinary Teaching Hospital. The authors performed a medical record search for dogs that were prescribed leflunomide during that time period, and they excluded dogs that had inadequate follow-up available. The records were evaluated for signalment, body weight and surface area, the indication for prescribing leflunomide, as well as the starting and tapering dosages prescribed, duration of treatment, other prescribed medications, response to therapy, and adverse events. The authors defined adverse events as clinical changes (e.g., lethargy, anorexia, vomiting, diarrhea, coughing, bleeding, other), hematologic changes if pre and post-therapy CBCs were available for non-hematologic disorders, and hepatotoxicity. Patients with new or escalated doses of glucocorticoids were excluded from analysis for hepatotoxicity. The definition of having a positive response to therapy varied based on the underlying disorder.

So who was being prescribed this medication? Of the 92 dogs that fit the investigators’ inclusion criteria, the median age was 7 years old with a median body weight of 23.7 kg. A total of 32 breed classifications were represented, and the most common underlying diseases in descending order were IMPA, IMTP, IMHA, IBD, IMHA and IMTP (e.g., Evans Syndrome), pancytopenia, vasculitis, immune-mediated neutropenia, uveitis, and cutaneous histiocytosis. Recall that past studies have evaluated this medication with starting doses of 3-4 mg/kg/day, which has also previously been the recommended dosage in common formularies (Plumb). However in this study, the investigators found that median starting dose was 1.7 mg/kg/day, with a range of 0.8 to 4.3 mg/kg/day. It was being used as an adjunctive therapy in the majority of dogs, most commonly being added to prednisolone therapy.

Knowing that the median dose prescribed was lower than in previous studies, you may be wondering how well leflunomide performed. In 51% of the dogs, leflunomide was discontinued during the observation period. Approximately half of these were due to remission of the underlying disease, which is great! Another 25% were due to euthanasia or death because of the severity of their underlying disease. That leaves 13% of cases in which the medication was discontinued due to adverse effects and another 11% due to lack of response. In other words, this population showed just under a quarter of dogs that either had adverse effects or a lack of response to this therapy. A total of 8.7% of the entire population had clinical changes that were considered potentially secondary to leflunomide.

So what were the adverse events? What should we be warning owners about when using this medication? Of the 8 dogs that developed side effects, acute diarrhea was observed in 3 dogs within a week of starting therapy. Discontinuation or dose reduction led to resolution of diarrhea in all 3, and all patients were also receiving other therapies at the time. Another 2 dogs were reported to be lethargic within a week of treatment, which again was reported to resolve after stopping therapy. Interestingly, 3 dogs developed unexplained hemorrhage within 6-20 weeks of starting therapy. All three developed hematochezia, with one having concurrent hematuria and one having concurrent ecchymosis. Only one of the dogs was receiving concurrent clopidogrel, and another cause of the bleeding could not be identified on diagnostic work-ups in any of these 3 dogs. The dog receiving clopidogrel had both leflunomide and clopidogrel discontinued at the time of bleeding, and the signs resolved. Signs did not recur after the clopidogrel was restarted 3 weeks later.

The authors also investigated potential hematologic abnormalities as a result of leflunomide use. A total of 31 dogs had non-hematologic diseases with baseline and post-treatment CBCs performed, and these dogs could therefore be included for analysis of hematologic side effects. Two of the 31 dogs developed mild thrombocytopenia when CBCs were performed 2 weeks after starting treatment, and both dogs had their platelets normalize following a 50% dose reduction. For dogs with a second post-treatment CBC performed, none had evidence of hematologic disturbances. Furthermore, anemia or neutropenia was not noted in any dogs.

Lastly, of the 16 dogs that met the inclusion criteria to assess for hepatotoxicity, only 1 developed increases in ALT and ALP 2 weeks after starting therapy. The authors defined hepatotoxicity as a new increase in ALT or ALP above reference range or a 2-fold increase compared to baseline if values were already elevated. In the one dog with elevations, the ALT normalized and the ALP decreased after a 50% dose reduction in leflunomide. You may be wondering if there were any differences between those dogs that developed adverse effects and those that did not. In other words, were any identifiable patient risk factors found that may impact our decisions to prescribe this therapy? In short, the answer is no! Age, sex, breed, body weight, and body surface area showed no significant differences between groups. However, the authors did find that the median dose prescribed was significantly higher in the group that had adverse effects than in those without, with a difference of 2.9 mg/kg/day compared to 1.6 mg/kg/day. But what about treatment efficacy? Did leflunomide even work, and if so, did the dosing matter? In those dogs in which the authors were able to assess treatment response, they found an overall total of 70.5% of dogs had an apparent positive response to leflunomide! Interestingly, there was not a significant difference in the dosages of leflunomide used in those dogs that did respond versus those that did not.

The authors discuss a few important limitations of their study. One is that given its retrospective design, defining the true onset of toxicity was difficult due to variability in recheck examinations and laboratory testing. Other limitations the authors address include the small number of dogs included, particularly the small number assessed for hepatotoxicity and for response to treatment, the concurrent use of other medications in many dogs, and the lack of monitoring of teriflunomide (an active metabolite of leflunomide that is monitored in people).

So what can we take away from this VETgirl podcast? Leflunomide appears to be another effective option as treatment for a variety of immune-mediated conditions in dogs, with an overall positive response rate of over 70% in this study. However a lower starting dose of 2 mg/kg/day of leflunomide may be safer and of similar efficacy compared to previously published higher doses of 3-4 mg/kg/day. However the authors of this study do emphasize that given the small number of dogs and the retrospective nature of their investigation, a larger prospective study is warranted to more clearly characterize the safety and efficacy of this medication and the best dosing recommendations. An interesting side effect noted in this study population was unexplained bleeding, which would be a VETgirl indication to consider discontinuation of this drug.

References:
1. Sato M, Veir JK, Legare M, et al. A retrospective study on the safety and efficacy of leflunomide in dogs. J Vet Intern Med 2017;31:1502-1507.
2. Plumb D. Veterinary Drug Handbook. 6th ed. Ames, IA: Iowa State University Press, 2008.
3. Gregory CR, Stewart A, Sturges B, et al. Leflunomide effectively treats naturally occurring immune-mediated and inflammatory diseases of dogs that are unresponsive to conventional therapy. Transplant Proc 1998;30:4143–4148.
4. Colopy SA, Baker TA, Muir P. Efficacy of leflunomide for treatment of immune-mediated polyarthritis in dogs: 14 cases (2006–2008). J Am Vet Med Assoc 2010;236:312–318.
5. Fukushima K, Eguchi N, Ohno K, et al. Efficacy of leflunomide for treatment of refractory inflammatory colorectal polyps in 15 miniature dachshunds. J Vet Med Sci 2016;78:265–269.

Abbreviations:
ALT – Alanine aminotransferases
CBC – Complete blood count
CNS – Central nervous system
IBD – Inflammatory bowel disease
IMHA – Immune-mediated hemolytic anemia
IMPA – Immune-mediated polyarthritis
ITP – Immune-mediated thrombocytopenia

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