By: Marie Buckley, VMD, Residency Trained
It’s that time of year again! While many factors are believed to contribute to the seasonality of immune-mediated disease, we certainly appreciate an up-tick (pun intended) in these diseases in the warmer months. Here are some of the drugs that have been by our side year after year along with some newer agents that you may see us using more often.
IBD – Inflammatory bowel disease
IMHA – Immune-mediated hemolytic anemia
ITP – Immune-mediated thrombocytopenia
IMPA – Immune-mediated polyarthritis
PLE/PLN – Protein losing enteropathy/Nephropathy
Mechanism of action: Glucocorticoids have a wide array of immunosuppressive and immunomodulatory effects. The primary immunosuppressive pathway involves binding of a cytosolic glucocorticoid receptor that translocates to the nucleus either inhibiting or enhancing transcription of certain genes. Steroids also help to stabilize inflammatory cell membranes and inhibit phospholipase A2, a major enzyme in the arachidonic acid pathway. Lastly, steroids prevent release of pro-inflammatory cytokines and down regulate expression of Fc receptors on macrophages.1
Uses: Steroids continue to be the mainstay of treatment for basically any immune-mediated disease, at least initially. Prednisone and prednisolone are used most commonly with prednisolone usually being reserved for cats, patients with significant liver dysfunction, or patients with otherwise altered absorption (such as with IBD).
Side effects: While inexpensive and widely available, steroids carry a multitude of dose dependent side effects. The most common side effects include increased thirst and urination and an increased appetite (iatrogenic hyperadrenocorticism). Some dogs also experience muscle weakness or a general disinterest in daily activities (something best described to owners as laziness). Especially in larger dogs, loss of muscle mass early on in treatment can be substantial and disconcerting to owners watching their pet’s weight drop at every recheck. It is important to remember that the side effects will improve as the dose is reduced, and muscle mass, other than “pred head,” can return with time. At higher doses, omeprazole is commonly used concurrently as a gastroprotectant. Steroids can increase the risk of thromboembolism, especially in already hypercoagulable patients (such as with IMHA, PLE/PLN).
Other comments: A target long-term maintenance dose for dogs requiring steroids lifelong falls into the range of 0.25-0.5mg/kg of prednisone or prednisolone every other day to once daily. Factors such as the disease being treated, patient side effects, and alternative therapies should be factored into the decision for maintenance therapy. In cats, an acceptable long-term maintenance dose would be 2.5mg-5mg of prednisolone every other day to once daily. Cats tolerate steroids remarkably well though are predisposed to developing diabetes mellitus, especially when using repeated depo injections. Caution is advised when using steroids in a cat with possible heart disease as these patients can be pushed into congestive heart failure.
Cyclosporine (Ciclosporin, cyclosporine A)
Mechanism of action: This drug works primarily to interfere with T-lymphocyte activation and proliferation by preventing the production of IL-2. This cytokine is vital to T-cell proliferation and without it, cytotoxicity is reduced. Cyclosporine also increases the production of TGF-beta which further interferes with proliferation of IL-2 stimulated T-cells and production of antigen specific cytotoxic lymphocytes.2
Uses: It can be used in conjunction with steroids for a variety of immune-mediated diseases including, but not limited to, IMHA, ITP, IBD, or IMPA. 2-4
Side effects: It is quite safe though there is the possibility of hepatotoxicity or nephrotoxicity usually at higher than therapeutic blood levels. There is also the possible increased risk of developing cancer, particularly lymphoma along with infections including toxoplasmosis and fungal disease. It is generally well tolerated with gastrointestinal side effects seen most commonly. These side effects can usually be overcome by starting at a lower dose and then increasing to the desired dose or using anti-nausea medication for the first few days of therapy. There are anecdotal reports that freezing the capsules helps to reduce signs of GI upset. There are no studies regarding clinical efficacy or changes in bioavailability after such practices to the author’s knowledge so freezing is best avoided.5
Drug formulations/monitoring: Cyclosporine should always be administered as a microemulsion (Neoral or generic) as other formulations have reduced bioavailability (Sandimmune). Compounding cyclosporine is not recommended. The liquid Atopica produced for cats makes it easier, not only to administer, but to dose appropriately for cats and smaller patients without having to compound customized patient doses. Even though the FDA requires generic formulations to demonstrate bioequivalence, and therefore would make generics a cheaper alternative, this may not translate to clinical equivalence. There are concerns in human transplant patients regarding the interchangeability between many of these formulations and the brand Neoral . 5
The discussion regarding drug level monitoring is seemingly endless. From the best way to monitor blood levels (trough versus peak), to the best assay to use, to whether drug levels even correlate with clinical response, there is no consensus.5,6 Because blood level monitoring is often used to uncover the differences between generic and brand name products, the results can be difficult to interpret. In other words, is it possible that blood levels are not an adequate way to monitor our patients or predict the immunosuppressive effects of the formulation we are using? The pharmacokinetics of this drug is complicated and there does not appear to be an easy answer to these questions.
Other comments: Cost or intolerance of the drug are the biggest downsides to using this medication. It was shown in one study that food decreased absorption by 22% and a reason to give the medication on an empty stomach.7A later study found that administration with food did not influence clinical outcomes in atopic dogs. Giving with food did not appear to reduce adverse GI effects in that same study though the author feels like it is better tolerated with food.8
Mechanism of action: This is a purine analog which, once incorporated into DNA, interferes with transcription and reduces proliferation of cells.2 While there is a concern that this drug takes at least 2 weeks to start working, one study showed in vitro inhibition of lymphocyte blastogenesis within the first week.9 Both cell-mediated and humoral immunity appears to be affected by azathioprine and is often used in conjunction with steroids.10
Uses: Azathioprine is most often used in the treatment of IMHA, ITP, IBD and systemic lupus erythematosus.2 There are conflicting studies regarding its benefit in treating IMHA with some studies supporting its use and others finding no benefit.11,12
Side effects: Most common adverse effects are liver toxicity, bone marrow suppression, and acute pancreatitis though it is generally well tolerated and relatively inexpensive.1 This medication is not safe enough for routine use in cats.10
Other comments: Owners should be instructed to wear gloves with this medication, especially if splitting tablets.
Mechanism of action: This drug inhibits inosine monophosphate dehydrogenase which is an enzyme necessary for de novo purine synthesis. The end result is a reduction in B and T cell proliferation.2
Uses: Now that this drug is generic, it is relatively cheap and can be a useful alternative when cyclosporine can’t be used due to financial constraints. It also has a faster onset of action compared to azathioprine.1It is best used in conjunction with steroids but can be used as a third agent with steroids and cyclosporine.2 It is becoming more common as part of treatment for IMHA. 13 In one study using 6 dogs with ITP, it was used successfully as a single agent.14 Mycophenolate is also the second agent after steroids to be recommended in the treatment of confirmed immune-mediated glomerulonephritis by the ACVIM renal consensus group based on positive responses in human trials.15 The information regarding the use of this drug in cats is limited to a case report of two cats with steroid-refractory IMHA.16
Side effects: It is generally well tolerated with GI upset, including diarrhea and decreased appetite, being the most common side effect. These side effects can be self-limiting during the first few days of therapy but can also be troublesome as long as the drug is being used.10
Other notes: Because the drug can cause birth defects, owners should be instructed to wear gloves when administering mycophenolate, especially if splitting tablets, or the drug should be compounded into an appropriately sized capsule.
Mechanism of action: The metabolite of this drug reversibly inhibits dihydro-orotate dehydrogenase, the rate limiting step in de novo pyrimidine synthesis thus inhibiting B and T cell proliferation.1 By the same mechanism, leflunomide can inhibit smooth muscle cell proliferation and the production of proinflammatory cytokines by fibroblasts. At higher doses, leflunomide also inhibits growth factor-associated tyrosine kinases.2
Uses: It has been used as a single agent to treat immune-mediated polyarthropathy in dogs and had also been used to treat IMHA, ITP, and canine reactive histiocytosis.1,2,17
Side effects: Trimethylfluoroanaline (TMFA) is a toxic metabolite that adversely affects the gastrointestinal tract leading to the most common side effect, inappetence.2 Fortunately, canine lymphocytes are much more sensitive to the active agent compared to human lymphocytes, allowing veterinarians to use much lower doses, translating into improved tolerance of the drug. Hepatotoxicity and myelotoxicity are also possible though not commonly seen.1 This medication can be used in cats, though there are few studies in this species. 2
Other comments: The introduction of a generic product made it a more practical treatment option in recent years; however, intermittent shortages have been frustrating, and, once again, have limited its use. It is recommended by some to monitor trough drug levels during therapy.2,10
Mechanism of action: Chlorambucil is an alkylating agent and, as for all drugs in this class, causes cross-linking of DNA and breaks in the DNA molecule thus interfering with DNA replication and RNA transcription.10
Uses: Historically used in cats with small cell GI lymphoma, this agent has proven useful in treating cats with steroid refractory IBD.10 Whether this subset of cats instead has small cell lymphoma that is missed on biopsy or misclassified by a pathologist is another discussion. Other than using it to treat cancer, chlorambucil has been used to treat pemphigus foliaceus in dogs and cats and other immune-mediated diseases in cats (such as IMHA, ITP).10A recent retrospective study suggested that chlorambucil is a more effective drug than azathioprine when used concurrently with prednisolone to treat IBD/PLE (dandrieux) in dogs.18
Side effects: Myelosuppression is a dose dependent concern, necessitating regular hematologic panel evaluation. Other side effects involve the GI tract and include inappetence, vomiting, and diarrhea. 10
Other comments: The commercially available product can be cost prohibitive though compounding can be a viable alternative. For larger patients, even compounding may not be cost effective. It is not advisable to compound this into a liquid due to the concern for increased exposure to this chemotherapeutic agent not only to the patient (if he or she does not swallow it) but also to the owner.
These are just a few of the immunosuppressive options we have available. Unfortunately, prospective, randomized, double-blinded clinical trials are lacking, leaving large gaps in our overall knowledge. If there are ever any questions regarding the use of immunosuppressive therapies, we would be happy to discuss!
- Whitley NT, Day MJ. Immunomodulatory drugs and the application to the management of canine immune-mediated disease. J Small Anim Pract 2011;52:70-85.
- Gregory C. Immunosuppressive agents. In: Bonagura JD, Twedt DC, eds. Kirk’s current veterinary therapy. 15th Saunders Elsevier, St. Louis, MO, 2014: 268-274.
- Allenspach K, Ruefenacht S, Sauter S, et al. Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroid-refractory inflammatory bowel disease. J Vet Intern Med 2006;20:239-244.
- Rhoades AC, Vernau W, Kass PH, Herrera MA, Sykes JE. Comparison of the efficacy of prednisone and cyclosporine for treatment of dogs with primary immune-mediated polyarthritis. J Am Vet Med Assoc 2016;248:395-404.
- Archer TM, Booth DM, Langston VC, et al. Oral Cyclosporine treatment in dogs: A review of the literature. J Vet Intern Med 2014;28:1-20.
- Archer TM, Fellman CL, Stokes JV, et al. Pharmacodynamic monitoring of canine T-cell cytokine responses to oral cyclosporine. J Vet Intern Med 2011;25:1391-1397.
- Steffan J, Strehlau G, Maurer M, Rohlfs A. Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs. J Vet Pharmacol Ther 2004;4:231-238.
- Thelen A,Mueller RS, Linek M, et al. Influence of food intake on the clinical response to cyclosporin A in canine atopic dermatitis.Vet Rec 2006;159:854–856.
- Ogilvie GK, Felsburg PJ, Harris CW. Short-term effect of cyclophosphamide and azathioprine on selected aspects of the canine blastogenic response. Vet Immunol Immunopathol 1988;18: 119-127.
- Garden OA. Immune-mediated diseases and therapies. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 7th Saunders Elsevier, St. Louis, MO, 2010: 737-742.
- Piek CJ, van Spil WE, Junius G, Dekker A. Lack of evidence of a beneficial effect of azathioprine in dogs treated with prednisolone for idiopathic immune-mediated hemolytic anemia: a retrospective cohort study. BMC Vet Res 2011;7:15.
- Reimer ME, Troy GC, Warnick LD. Immune-mediated hemolytic anemia: 70 cases (1988-1996). J Am Anim Hosp Assoc 1999;35:384-391.
- Wang A, Smith JR, Creevy KE. Treatment of canine idiopathic immune-mediated haemolytic anaemia with mycophenolate mofetil and glucocorticoids: 30 cases (2007 to 2011). J Small Anim Pract 2013;54:399-404.
- Yau VK, Bianco D. Treatment of five haemodynamically stable dogs with immune-mediated thrombocytopenia using mycophenolate mofetil as a single agent. J Small Anim Pract 2014;55: 330-333.
- Segev G, Cowgill LD, Heiene R, Labato MA, Polzin DJ. Consensus recommendations for immunosuppressive treatment of dogs with glomerular disease based on established pathology. J Vet Intern Med 2013;27:S44-S45.
- Bacek LM, Macintire DK. Treatment of primary immune-mediated hemolytic anemia with mycophenolate mofetil in two cats. J Vet Emerg Crit Care 2011;21:45-49.
- 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.
- Dandrieux JR, Noble PJ, Scase TJ, Cripps PJ, German AJ. Comparison of a chlorambucil-prednisolone combination with an azathioprine-prednisolone combination for treatment of chronic enteropathy with concurrent protein losing enteropathy in dogs: 27 cases (2007-2010). J Am Vet Med Assoc 2013;242:1705-1714.