No Evidence That Therapeutic Systemic Corticosteroid Administration is Associated With Laminitis in Adult Horses Without Underlying Endocrine or Severe Systemic Disease.

a Knowledge Summary by

Catherine McGowan BVSc, MACVSc, DEIM, DipECEIM, PhD, FHEA, MRCVS ¹

Daniel Cooper BVSc, MRCVS ²

Joanne Ireland BVMS, PhD, CertAVP(EM), MRCVS ³

¹University of Liverpool
²Clent Hills Equine LLP
³Animal Health Trust
^*Corresponding Author (c.m.mcgowan@liv.ac.uk)

Question

In reported cases of iatrogenic laminitis in adult horses and ponies, is therapeutic administration of systemic corticosteroid associated with the onset of laminitis?

Clinical scenario

Horses have been reported to develop laminitis following therapeutic systemic corticosteroid administration and the risk of laminitis induced by administration of exogenous glucocorticoids remains a contentious issue in equine medicine. Previously the lack of reported adverse reactions to corticosteroids has been cited as evidence to suggest no association with laminitis. Additionally, many studies investigating the use of corticosteroids in treatment of various conditions (such as recurrent airway obstruction and musculoskeletal disorders) have not observed induction of laminitis.

It has been suspected that the development of laminitis following corticosteroid therapy is more likely in horses with an underlying disease that causes laminitis, specifically, Systemic Inflammatory Response Syndrome (SIRS) or severe systemic disease and endocrine disease. Johnson et al suggest that most widely recognised form of endocrinopathic laminitis occurs in association with steroid administration and that use of corticosteroids must be measured against the well-recognised risk of complicating laminitis (Johnson et al 2004). Johnson et al also state the likelihood of laminitis appears to be greater with the more potent agents such as triamcinolone laminitis (Johnson et al 2004), while an earlier review suggests the association with laminitis has not been reported for use of prednisone or prednisolone (Johnson et al 2002).

Early in vitro research demonstrated corticosteroid potentiation of the vasoconstrictor actions of catecholamines and serotonin, suggesting the resulting venous obstruction on the hoof may cause laminitis (Eyre & Elmes 1980). Skin perfusion was decreased in a study using six days of daily dexamethasone and the authors suggested perfusion to the hoof may also be reduced, increasing the risk of laminitis (Cornelisse et al 2006). Following a standard overnight dexamethasone suppression test, non-obese ponies with a history of prior laminitis showed elevated insulin concentration and exaggerated production of insulin in response to corticosteroids compared to control ponies (Bailey et al 2007). After a single administration of triamcinolone, one study reported a prolonged period (3 – 4 days) of hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia (French et al 2000). Additionally, four of the five horses in this study developed laminar rings without clinical laminitis (French et al 2000). In a small cross-over study, healthy horses demonstrated marked insulin resistance following alternate day dexamethasone administration for three weeks (Tiley et al 2007; Tiley et al 2008). Insulin resistance is associated with a predisposition to laminitis (McGowan 2008); therefore it is possible that glucocorticoid-induced decrease in insulin sensitivity may increase the risk for development of laminitis

Although these studies demonstrate pathophysiological effects of exogenous steroid administration which offer plausible mechanisms by which corticosteroids may induce laminitis, particularly in those animals with existing predisposing factors, they do not provide sufficient evidence to support the hypothesis of increased risk of laminitis associated with the use of steroids in clinical practice. Therefore, this knowledge summary aimed to identify cases of iatrogenic equine laminitis following systemic administration of corticosteroids and to appraise the evidence linking corticosteroid administration and laminitis onset.

The evidence

Thirteen publications, reporting a total of 40 iatrogenic cases of laminitis following systemic corticosteroid administration, were identified in the literature searches (summarised in Table 1). These comprised six single case reports, three case series, one non-randomised clinical trial of dexamethasone for the treatment of chronic respiratory disorders, a database of adverse drug events, a journalistic style anecdotal case report and a court case transcript. Included publications were of level 4 (case series) or level 5 (mechanism-based reasoning) (OCEBM Levels of Evidence Working Group). Only one observational study aimed to evaluate the prevalence of laminitis amongst horses treated with triamcinolone (McCluskey & Kavenagh 2004). No experimental studies investigating the frequency of laminitis following therapeutic corticosteroid administration were identified.

Three publications (including eight cases) did not report information regarding the type of corticosteroid administered (Cripps & Eustace 1999; Lose 1980; Slater et al 1995). Of the 32 cases of iatrogenic laminitis reported in the other included publications, 53% (n=17) were reported to occur following administration of triamcinolone (Cohen & Carter 1992; McCluskey & Kavenagh 2004; Ryu et al 2004; U.S. FDA), 34% (n=11) were reported to occur following administration of dexamethasone (Fredrick & Kehl 2000; Humber et al 1991; Muyelle & Oyaert 1973; Vandenabeele et al 2004; U.S. FDA), 3% (n=1) occurred following administration of methylprednisolone (U.S. FDA) and 3% (n=1) occurred following administration of betamethasone (U.S. FDA). Two further cases were reported to develop laminitis following the administration of more than one corticosteroid (Anon 2005; Winfield et al 2013).

Ten publications (including 14 cases) reported some information regarding duration of treatment or number of corticosteroid treatments, of which 79% of cases (n=11/14) developed laminitis following multiple doses of corticosteroid (Cohen & Carter 1992; Fredrick & Kehl 2000; Humber et al 1991; Muyelle & Oyaert 1973; Ryu et al 2004; Vandenabeele et al 2004; Winfield et al 2013). The remaining 21% of cases (n=3/14) developed laminitis following administration of corticosteroid on a single occasion; however two of these cases received multiple intra-articular doses of unknown corticosteroid (Lose 1980) or triamcinolone (McCluskey & Kavenagh 2004) and the other case received multiple doses of dexamethasone and possibly multiple intra-articular doses of triamcinolone (Anon 2005).

Summary of the evidence

Appraisal, application and reflection

• The aim of this knowledge summary was to critically appraise published evidence of iatrogenic equine laminitis following systemic administration of corticosteroids. It was beyond the scope of this review to evaluate the extensive published literature reporting on the therapeutic use of systemic corticosteroids where laminitis has not been observed or reported as an adverse event following treatment.
  
  
• The 13 included publications were predominantly descriptive studies and provided low level evidence pertaining to the potential association between therapeutic administration of systemic corticosteroid and the onset of laminitis (OCEBM Levels of Evidence Working Group). No studies of an appropriate design to determine the incidence of laminitis following corticosteroid treatment or evaluate temporal relationships between corticosteroid administration and the onset of laminitis (i.e. longitudinal analytical studies) were identified.
  
  
• The only observational study investigating iatrogenic laminitis following treatment with triamcinolone reported a prevalence of 0.8% (n=1/132; 95% confidence interval 0 – 2.2%) (McCluskey & Kavenagh 2004). In the same study, three other cases of laminitis were reported, of which two were diagnosed with laminitis prior to triamcinolone but did not develop laminitis subsequent to its use. Therefore, laminitis following triamcinolone administration was observed in 33% of horses with a previous history of laminitis (n=1/3). The third horse developed laminitis 18 months after triamcinolone therapy as a result of post foaling toxaemic metritis (McCluskey & Kavenagh 2004). Of 106 equine laminitis cases reported as adverse drug events over a 26 year period, 18% (n=19) were attributed to corticosteroid treatment, whereas 35% of cases (n=37) were attributed to administration of anthelmintics and 32% (n=34) were reported following treatment with antibiotics or antiprotozoals (U.S. FDA).
  
  
• Only eight publications (each reporting a single case of iatrogenic laminitis) provided information regarding the time of onset of laminitis relative to corticosteroid administration (Anon 2005; Cohen & Carter 1992; Fredrick & Kehl 2000; Humber et al 1991; Lose 1980; McCluskey & Kavenagh 2004; Ryu et al 2004; Winfield et al 2013). One of the eight cases occurred during corticosteroid treatment (onset of laminitis reported on day 4 of a 5 day course) (Fredrick & Kehl 2000). Onset or diagnosis of laminitis was reported to occur 7 days (McCluskey & Kavenagh 2004), 8 days (Lose 1980), 10 days (Humber et al 1991), 11 days (Anon 2005), 20 days (Cohen & Carter 1992) and 23 days (Ryu et al 2004) after cessation of corticosteroid treatment. Two of these cases, one with severe systemic disease (Ryu et al 2004) and one with hepatopathy and hyperadrenocorticism (Cohen & Carter 1992), occurred three weeks after the last dose of corticosteroid. The longer the period of time between drug administration and disease onset, the less likely the drug was a contributing factor in the aetiology due to its reduced efficacy in the body as time passes (Harkins et al 1993). The time frame for both these two cases appears to be too long to suggest a direct causal association, especially as in both cases laminitis occurred over a week after the onset of clinical signs of systemic disease. In the remaining case, laminitis was reported to have occurred within 4 months of commencing corticosteroid treatment (Winfield et al 2013).
  
  
• Seven publications provided diagnostic information, of which five (representing eight cases) reported confirmation of diagnosis via radiography (Cohen & Carter 1992; Cripps & Eustace 1999; Fredrick & Kehl 2000; Lose 1980; Ryu et al 2004) and two (representing two cases) reported confirmation via gross pathology at post mortem examination (Humber et al 1991; Winfield et al 2013). Few included studies provided detailed clinical information regarding the presentation and severity of laminitis. Two epidemiological studies of laminitis (Cripps & Eustace 1999; Slater et al 1995) did not include any clinical information pertaining to iatrogenic laminitis cases, and reported only that animals had received corticosteroids prior to the onset of laminitis, while the Center for Veterinary Medicine Cumulative Adverse Drug Event (ADE) Summaries Report (U.S. FDA) provided no details other than the type of corticosteroid administered prior to laminitis. Where reported, laminitis most frequently affected all four feet (67%, n=4/6) (Fredrick & Kehl 2000; Humber et al 1991; Lose 1980; Winfield et al 2013), and a further two cases (33%, n=2/6) (Cohen & Carter 1992; Ryu et al 2004) developed bilateral forelimb laminitis. Outcome was reported for 18 cases, of which 50% (n=9) were reported to have survived/recovered, although two cases were reported to have been retired from their previous athletic use due to laminitis (McCluskey & Kavenagh 2004; Ryu et al 2004). One non-surviving case was euthanased due to progression of pemphigus vulgaris rather than laminitis (Winfield et al 2013) and the reason for euthanasia was unclear in one further non-surviving case (Humber et al 1991).
  
  
• Diagnostic evaluation of underlying disease(s) was infrequently reported. Of the five laminitis cases occurring during treatment or within two weeks of corticosteroid administration, one horse was obese with marked regional adiposity, suggestive of equine metabolic syndrome (Fredrick & Kehl 2000); one horse had a previous history of laminitis (McCluskey & Kavenagh 2004) and one had severe systemic disease (Humber et al 1991). A further three cases had evidence of severe systemic disease (Cohen & Carter 1992; Ryu et al 2004; Winfield et al 2013). Of four iatrogenic laminitis cases reported amongst horses treated with dexamethasone for pemphigus foliaceus, two non-surviving cases for which serum albumin was measured were hypoalbuminaemic (Vandenabeele et al 2004).
  
  
• In conclusion, no studies that sought to investigate a potential causal association between therapeutic corticosteroid administration and laminitis were identified and there is currently insufficient evidence to support such an association in healthy adult horses. There is weak evidence of an association between administration of multiple doses of systemic corticosteroid and the onset of laminitis in adult horses with underlying endocrine disorders or severe systemic disease.   Therefore, underlying diseases predisposing to laminitis should be considered prior to administration of corticosteroids, particularly where multiple or large doses are indicated. However, this knowledge summary has highlighted a paucity of information on iatrogenic laminitis and a well-designed cohort study is required to quantify the apparently small risk of iatrogenic laminitis following therapeutic administration of systemic corticosteroid.

Methodology Section

Search Strategy
Databases searched and dates covered:	PubMed accessed via the NCBI website (1950 – Present) Thomson Reuters Web of Science (1898 – Present) CAB Abstracts on the CAB Direct interface (1910 – Present) SciVerse Scopus (1823 – Present) International Veterinary Information Service (IVIS) database (1997 – Present) Further relevant records were identified by the authors via the bibliographies and reference lists of retrieved publications and published conference proceedings.
Search terms:	(equine or horse* or pony or ponies ) AND (laminitis or laminitic) AND (corticosteroid* or glucocorticoid* or dexamethasone or dex or prednisolone or methylprednisolone or triamcinolone or TMC or betamethasone)
Dates searches performed:	26/05/2015 and 27/05/2015

Exclusion / Inclusion Criteria
No limitations regarding study design, setting, sample size or study population were imposed.
Exclusion:	Non-English language, narrative or non-systematic review articles (or non-systematic reviews published in conference proceedings or as letters/correspondence), unpublished data, pharmacokinetic, in vitro or in vivo experimental studies.
Inclusion:	Any reported case of laminitis occurring in an adult horse or pony following the systemic administration of corticosteroid(s).

Search Outcome
Database	Number of results	Excluded – non- English language publication	Excluded – non-systematic review article, conference proceeding or letter	Excluded – pharmacokinetic / in vitro / in vivo e xperimental study	Excluded – did not answer PICO question/no iatrogenic laminitis case(s) reported	Total relevant papers
NCBI PubMed	34	1	10	6	13	4
Thomson Reuters Web of Science	84	1	31	12	34	6
CAB Abstracts	86	1	44	13	24	4
SciVerse Scopus	66	5	30	7	19	5
International Veterinary Information Service (IVIS) database	70	0	69	0	1	0
Other sources	7	0	1	0	1	5
Total relevant papers when duplicates removed						13

1. Anon (2005) Philip John Glyn (t/a Priors Farm Equine Veterinary Surgery) v Jane McGarel-Groves, Erik Grandiere, Clinique Veterinaire Equine De Chantilly. Case Number: HQ O3X 01706.[vLex: United Kingdom] [online] Available from: http://high-court-justice.vlex.co.uk/vid/hq-o3x-01706-52923646  [Accessed 29/07/2015]
2. Bailey, S.R. et al., (2007) Effect of dietary fructans and dexamethasone administration on the insulin response of ponies predisposed to laminitis. Journal of the American Veterinary Medical Association, 231 (9), pp.1365-1373. http://dx.doi.org/10.2460/javma.231.9.1365
3. Center for Veterinary Medicine Cumulative Adverse Drug Event (ADE) Summaries Report 01/01/1987 – 30/04/2013. [U.S. Food and Drug Administration] [online] Available from: http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055369.htm  [Accessed 29/07/2015]
4. Cohen, N.D. and Carter, G.K. (1992) Steroid hepatopathy in a horse with glucocorticoid-induced hyperadrenocorticism. Journal of the American Veterinary Medical Association, 200 (11), pp. 1682-1684.
5. Cornelisse, C.J. et al., (2006) Thermographic study of in vivo modulation of vascular responses to phenylephrine and endothelin-1 by dexamethasone in the horse. Equine Veterinary Journal, 38 (2), pp. 119-126.  http://dx.doi.org/10.2746/042516406776563251
6. Cripps, P.J. and Eustace, R.A. (1999) Factors involved in the prognosis of equine laminitis in the UK. Equine Veterinary Journal, 31 (5), pp. 433-442.
   http://dx.doi.org/10.1111/j.2042-3306.1999.tb03845.x
7. Eyre, P and Elmes, P.J. (1980) Corticosteroid-induced laminitis? Further observations on the isolated, perfused hoof. Veterinary Research Communications, 4 (1), pp. 139-143. http://dx.doi.org/10.1007/BF02278492
8. Frederick, D.M. and Kehl, M. (2000) Case report: Back from the brink. Equus, 272, pp. 34-41.
9. French, K., Pollitt, C.C. and Pass, M.A. (2000) Pharmacokinetics and metabolic effects of triamcinolone acetonide and their possible relationships to glucocorticoid-induced laminitis in horses. Journal of Veterinary Pharmacology and Therapeutics, 23 (5), pp. 287-292. http://dx.doi.org/10.1111/j.1365-2885.2000.00288.x
10. Harkins, J.D., Carney, J.M. and Tobin, T. (1993) Clinical use and characteristics of the corticosteroids. Veterinary Clinics of North America: Equine Practice, 9 (3), pp.543-562.
11. Humber, K.A. et al., (1991) Azathioprine for treatment of immune-mediated thrombocytopenia in two horses. Journal of the American Veterinary Medical Association, 199 (5), pp. 591-594.
12. Johnson, P.J. et al., (2002) Glucocorticoids and laminitis in the horse. Veterinary Clinics of North America: Equine Practice, 18 (2), pp. 219-236. http://dx.doi.org/10.1016/s0749-0739(02)00015-9
13. Johnson, P.J. et al., (2004) Endocrinopathic laminitis in the horse. Clinical Techniques in Equine Practice, 3 (1), pp.45-56. http://dx.doi.org/10.1053/j.ctep.2004.07.004
14. Lose, M.P. (1980) Drug-induced laminitis in a colt. Modern Veterinary Practice, 61 (7), pp. 608-610.
15. McCluskey, M.J. and Kavenagh, P.B. (2004) Clinical use of triamcinolone acetonide in the horse (205 cases) and the incidence of glucocorticoid-induced laminitis associated with its use. Equine Veterinary Education, 16 (2), pp. 86-89. http://dx.doi.org/10.1111/j.2042-3292.2004.tb00272.x
16. McGowan, C.M. (2008) The role of insulin in endocrinopathic laminitis. Journal of Equine Veterinary Science, 28 (10), pp. 603-607. http://dx.doi.org/10.1016/j.jevs.2008.08.004
17. Muylle, E. and Oyaert, W. (1973) Lung function tests in obstructive pulmonary disease in horses. Equine Veterinary Journal, 5 (1), pp. 37-44.  http://dx.doi.org/10.1111/j.2042-3306.1973.tb03191.x
18. Oxford Levels of Evidence 2 [Oxford Centre for Evidence-Based Medicine – OCEBM Levels of Evidence Working Group] [online] Available from: http://www.cebm.net/index.aspx?o=5653 [Accessed 11/08/2015].
19. Ryu, S. et al., (2004) Glucocorticoid-induced laminitis with hepatopathy in a Thoroughbred filly. Journal of Veterinary Science, 5 (3), pp. 271-274.
20. Slater, M.R., Hood, D.M. and Carter, G.K. (1995) Descriptive epidemiological study of equine laminitis. Equine Veterinary Journal, 27 (5), pp. 364-367. 
    http://dx.doi.org/10.1111/j.2042-3306.1995.tb04071.x
21. Tiley, H.A., Geor, R.J. and McCutcheon, L.J. (2007) Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses. American Journal of Veterinary Research, 68 (7), pp.753-759. http://dx.doi.org/10.2460/ajvr.68.7.753
22. Tiley, H.A., Geor, R.J. and McCutcheon, L.J. (2008) Effects of dexamethasone administration on insulin resistance and components of insulin signaling and glucose metabolism in equine skeletal muscle. American Journal of Veterinary Research, 69 (1), pp. 51-58. http://dx.doi.org/10.2460/ajvr.69.1.51
23. Vandenabeele, S.I.J. et al., (2004) Pemphigus foliaceus in the horse: A retrospective study of 20 cases. Veterinary Dermatology, 15 (6), pp. 381-388.  http://dx.doi.org/10.1111/j.1365-3164.2004.00423.x
24. Winfield, L.D. et al., (2013) Pemphigus vulgaris in a Welsh pony stallion: Case report and demonstration of antidesmoglein autoantibodies. Veterinary Dermatology, 24 (2), pp. 269-e60 http://dx.doi.org/10.1111/vde.12002