Serum MPA concentrations after oral MMF administration in dogs are highly variable and call into question its suitability
as a post-transplant immunosuppressant.37 In addition, the dose predicted for immunosuppression by pharmacokinetic studies and extrapolation from experience in people
results in severe, intractable diarrhea and weight loss in laboratory dogs.38 Nevertheless, the few published reports in dogs with naturally occurring immune-mediated diseases have suggested that, in
some patients, MMF is effective at lower doses, with limited side effects.
Leflunomide is an inactive prodrug hydrolyzed in the intestine and plasma to the active metabolite teriflunomide (formerly
known as A77 1726).39,40 Teriflunomide's mechanism of immunosuppression is similar to that of MPA, but rather than interfering with purine biosynthesis,
inhibition of the enzyme dihydroorotate dehydrogenase selectively prevents lymphocyte de novo pyrimidine production. Teriflunomide
may further interfere with lymphocyte proliferation and function by inhibiting tyrosine kinases associated with several cytokine
and growth factor receptors, although whether this occurs at clinically relevant drug concentrations is unclear.41 Finally, although not directly related to its use as an immunosuppressive agent, teriflunomide also inhibits replication
of a number of herpesviruses, including feline herpesvirus-1.42
Leflunomide is primarily used in people to treat immune-mediated arthritides, including rheumatoid arthritis and psoriatic
arthritis.39,40 Use in other autoimmune diseases or for immunosuppression of transplant recipients has also been reported, including Crohn
disease, systemic lupus erythematosus, immune-mediated vasculitides, and some nephropathies.39 However, leflunomide is still limited to use as a rescue agent in people for most diseases in which efficacy has been demonstrated
because of the high prevalence of side effects, many of which are quite severe (see Above).
Use of leflunomide has been reported for monotherapy treatment of 14 dogs with immune-mediated polyarthritis and in conjunction
with methotrexate in 12 cats with rheumatoid arthritis (Table 1).43,44 Two of the dogs and all of the cats had been previously treated with prednisone with minimal to no improvement noted, or
intolerable side effects of prednisone had led to alternative therapy. Complete resolution of clinical signs in both groups
of animals occurred in about two-thirds of animals; however, disease remission in both groups was primarily determined by
the presence of clinical signs (i.e. lameness and semiobjective pain scoring systems) rather than repeat arthrocentesis, joint radiography, and rheumatoid factor
titer measurement. In addition, most dogs with immune-mediated polyarthritis required concurrent administration of a nonsteroidal
anti-inflammatory drug (NSAID) for pain relief during the initial leflunomide treatment period.
Additional diseases in dogs and cats that have been treated with leflunomide after failure of conventional therapy include
IMHA, ITP, Evans' syndrome, nonsuppurative meningoencephalomyelitis, systemic histiocytosis, immune-mediated polyarthritis,
and pemphigus foliaceus; most reported cases have resulted in disease remission.45,46 However, studies comparing the efficacy of leflunomide with traditional immunosuppressive drug regimens are still lacking,
and whether this drug should be incorporated into first-line therapy protocols or used as a rescue agent is still unknown.
Leflunomide may occasionally be associated with vomiting or diarrhea, particularly at the upper end of recommended dose ranges.
When these clinical signs do occur, temporary drug dose reductions usually lead to rapid resolution of gastrointestinal upset;
following one to two weeks of this decreased dose, patients will oftentimes tolerate a return to the initial higher dose without
recurrence of side effects. In people, in addition to gastrointestinal upset and skin rashes, leflunomide has also been associated
with several life-threatening idiosyncratic reactions, including acute and chronic hepatotoxicosis, severe myelosuppression
with secondary infections, interstitial lung disease, and toxic epidermal necrolysis.39,40 Thus far, none of these severe side effects have been reported in dogs or cats, so leflunomide holds promise for more widespread
use in the future.