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

[...]

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.

[…]