11/27/2017. Re-thinking PPID Advances in Diagnostics and Disease Recognition. Overview. Disclosures. Employed by Boehringer Ingelheim Animal Health

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Shoemaker DVM, MS Professional Service Boehringer-Ingelheim

2 Disclosures Overview Overview of PPID Clinical signs Employed

4 Terminology Cushing s Disease in Dogs/Man PPID is the most

1 Re-thinking PPID Advances in Diagnostics and Disease Recognition Craig F. Shoemaker DVM, MS Professional Service Boehringer-Ingelheim Vetmedica Inc. 2 Disclosures Overview Overview of PPID Clinical signs Employed by Boehringer Ingelheim Animal Health Diagnostic EEG Updates I.D. PPID Treatment/Management Additional considerations Take homes 3 4 Terminology Cushing s Disease in Dogs/Man PPID is the most common endocrine disorder in horses Equine Cushing's Disease should now be identified as: Pituitary Pars Intermedia Dysfunction (PPID) 5 PU/PD Polyphagia Abdominal enlargement Lethargy Alopecia, pruritis Thin skin, pyoderma Panting Infertility 1

Anatomy of the Equine Pituitary Gland Three regions: Pars distalis Pars intermedia Pars nervosa Pathophysiology of PPID

with aging Accelerated process in some horses As dopaminergic neurons are lost, melanotrophs are less inhibited Hyperplasia

consequence of oxidative damage Accumulation of misfolded α- synuclein in dopaminergic nerve terminals, similar to patients

(Courtesy of Dianne McFarlane) (McFarlane D, et al.

intermedia dysfunction. J Neuroendocrinol 17:73-80, 2005.) Risk Factors: Who Gets PPID?

TWH What about horses younger than 15yr?

2 Anatomy of the Equine Pituitary Gland Three regions: Pars distalis Pars intermedia Pars nervosa Pathophysiology of PPID Dopamine interacts with D2 receptors in PI melanotrophs and inhibits activity Dopaminergic neurons undergo oxidative damage with aging Accelerated process in some horses As dopaminergic neurons are lost, melanotrophs are less inhibited Hyperplasia develops and melanotrophs secrete more hormones Permissive environment for neoplasia; functional pituitary adenomas develop Dopamine (McFarlane et al., J Neuroendocrinol 2005) 7 Pathophysiology of PPID PPID and Parkinson's: Loss of Dopaminergic Neurons In part, a consequence of oxidative damage Accumulation of misfolded α- synuclein in dopaminergic nerve terminals, similar to patients with Parkinson s disease Both diseases are slowly progressive But why don t PPID horses shake? (Courtesy of Dianne McFarlane) (McFarlane D, et al. Nitration and increased alpha-synuclein expression associated with dopaminergic neurodegeneration in equine pituitary pars intermedia dysfunction. J Neuroendocrinol 17:73-80, 2005.) Risk Factors: Who Gets PPID? Risk Factors: Age, Breed Ponies are more susceptible Morgan horses Paso Fino Arabian Quarter horses Saddlebreds Warmbloods TWH What about horses younger than 15yr? 15-30% horses/ponies > 15 years of age Risk Factors Equine Metabolic Syndrome (EMS) Genetic predisposition to obesity Accompanied by insulin dysregulation (ID) Increased laminitis risk Accelerated degeneration of dopaminergic neurons Transitional period between diseases PPID developing in younger horses PPID exacerbates ID Rohrbach, Andrews F. Sommerdahl C. et al. J Vet Intern Med Frank N, Geor R. Bailey S. Durham A. and Johnson P, J Vet Intern Med

Delayed haircoat shedding Skeletal muscle atrophy Typically beginning along the topline Regional

Skeletal muscle atrophy Rounded abdomen Abnormal sweating (increased or decreased)

Laminitis Seizure like activity/blindness Parasitism Tendon laxity/desmitis Clinical Signs: Change

supraorbital fat Regional Adiposity Too THIN in others Loss of topline muscle mass Swayed back Ribs

Shedding Change in attitude: Little more lethargic Is he really that old?

3 PPID Clinical Signs: Early vs.late Early Decreased athletic performance Change in attitude/lethargy Regional hypertrichosis Delayed haircoat shedding Skeletal muscle atrophy Typically beginning along the topline Regional Adiposity Laminitis Advanced Lethargy Generalized hypertrichosis Loss of seasonal haircoat shedding Skeletal muscle atrophy Rounded abdomen Abnormal sweating (increased or decreased) Polyuria/polydipsia Recurrent infections Regional adiposity Absent reproductive cycle / infertility Laminitis Seizure like activity/blindness Parasitism Tendon laxity/desmitis Clinical Signs: Change in Body Conformation/Condition Too FAT in some places Cresty neck Fat pads at tail head Bulging supraorbital fat Regional Adiposity Too THIN in others Loss of topline muscle mass Swayed back Ribs visible Advanced: Rounded abdomen (pot-bellied) 13 "He's just getting old" 14 Early Signs Abnormal Shedding Change in attitude: Little more lethargic Is he really that old? Delayed shedding of winter hairs Compare to other horses in the barn Discolored hairs Slow gradual loss of muscle mass Over the topline Unexplained Laminitis (unconfirmed cause) Abnormal Shedding Abnormal Shedding

Laminitis Clinical Signs: Laminitis and PPID 19 Chronic

Insidious episodes that escape owner detection.

(Schott, 2011) Insulin status Main cause of euthanasia

filling of water buckets Stall wetter than

intake; provide additional water sources Increased

Immunosuppression Solar abscesses; systemic (liver,

Sinusitis/tooth root abscesses Respiratory Skin

21 22 Other symptoms Infertility/inappropriate

Delayed wound healing Osteoporosis Recurrent

4 Laminitis Clinical Signs: Laminitis and PPID 19 Chronic laminitis: ~60-65% of PPID horses suffer from laminitis Insidious episodes that escape owner detection. Radiographic prevalence (43%) > clinical evidence (12%) (Schott, 2011) Insulin status Main cause of euthanasia Polyuria/Polydipsia May go unrecognized Freq. filling of water buckets Stall wetter than before/smells bad Hovering over water source Measure intake; provide additional water sources Increased Susceptibility to Infection Decreased WBC function Immunosuppression Solar abscesses; systemic (liver, tongue) White line disease Dental disease Sinusitis/tooth root abscesses Respiratory Skin Parasitism Higher FEC s Other infectious diseases? Other symptoms Infertility/inappropriate lactation Abnormal sweating or inability to sweat Delayed wound healing Osteoporosis Recurrent tendon/ligament injury Clinical Signs Associated with PPID In The Equine Athlete Kirchherr KF, Baus MR, Kremburg JR, Grubbs ST, Neal DL, and Keefe TR 23 4

Introduction PPID Diagnostic challenges in the sport horse Many of the same clinical signs identified in early or advanced PPID may be recognized in the sport horse Including tendon or suspensory

5 Introduction PPID Diagnostic challenges in the sport horse Many of the same clinical signs identified in early or advanced PPID may be recognized in the sport horse Including tendon or suspensory ligament degeneration Suspensory ligament injuries Considered a common cause of lameness in the equine athlete A recent histopathological study concluded that an association exists between PPID and suspensory ligament (SL) degeneration Study Objective The objective of this study was to identify the most common clinical signs associated with PPID in the sport horse Material and Methods (Study Design) Sport horses >10 years of age, any breed, and sex were eligible for study enrollment Must be exhibiting one or more of the early or advanced clinical signs of PPID Including suspensory ligament desmitis Forty-nine horses were enrolled Demographic data, signalment, and a physical examination was conducted Each horse was tested for PPID using the TRH stimulation test Measuring ACTH at 0 (T0ACTH) and 10 (T10ACTH) minutes Insulin and glucose levels were also determined Normal horses were excluded from the study Blood samples were shipped overnight to: The Animal Health Diagnostic Center, Cornell University, Ithaca, NY for analysis Results Percent PPID + Horses 39% Positive Results Percent HI + Stratified By PPID Status Results The most common clinical signs observed in the PPID + horses were: Delayed regional shedding Loss of epaxial muscle mass Regional adiposity Skeletal muscle atrophy Suspensory desmitis PPID + was significantly (P= 0.023) associated with lameness (suspensory desmitis, tendon laxity, superficial digital flexor tendonitis) *32% PPID+ were HI+ 7% PPID- were HI+ *(p = 0.022) Of the horses that were lame, 70% were PPID + 5

6 Diagnostics Nicholas Frank, DVM, PhD, DACVIM Frank Andrews, DVM, MS, DACVIM Ben Buchanan, DVM, DACVIM, DACVECC Andy Durham, BSc, BVSc, CertEP, DECEIM, MRCVS Janice Kritchevsky, VMD, MS, DACVIM Dianne McFarlane, DVM, PhD, DACVIM Hal Schott, DVM, PhD, DACVIM /equineendogroup/ 31 TRH Stimulation 34 TRH Stimulation Interpretation of Results Thyrotropin Releasing Hormone (TRH) Sources: Reagent grade from Sigma; expensive Protirelin- Compounded from Wedgewood Validated by EEG 1mg/ml 1ml vial $ ml vial $60.00 Can be frozen

Resting ACTH Seasonal Rise in ACTH (Copas, Durham, 2012) 37 38 Sensitivity and Specificity Resting ACTH ACTH Stability Post Collection Advanced Cases (November through June) Sensitivity: 70 80%

Specificity 95% Durham et. al. PPID diagnosis. Equine vet. Educ. (2014) 26 (4) 216-223 Beech et al. 2007; 2011; McGowan et al.

7 Resting ACTH Seasonal Rise in ACTH (Copas, Durham, 2012) Sensitivity and Specificity Resting ACTH ACTH Stability Post Collection Advanced Cases (November through June) Sensitivity: 70 80% Specificity: 80% Early Cases (November through June) Sensitivity: at best shown to be 50% Specificity: unsure, less than 80% During Fall Time-period (August through October) Sensitivity 100% Specificity 95% Durham et. al. PPID diagnosis. Equine vet. Educ. (2014) 26 (4) Beech et al. 2007; 2011; McGowan et al ACTH Stability Whole blood and plasma evaluated at 4, and - 80 C for 30 days. Time affected ACTH levels with storage beyond 4 and 21 Freezing good for 30 days Allows practitioners to reasonably store samples without centrifugation for up to 24hrs. Insulin Assessment Must know insulin status to manage PPID appropriately

# of Horses # of Horses 11/27/2017 Fasting Insulin 44 Insulin Assessment Oral Sugar Test ID PPID Purpose: To gather

results obtained at diagnosis from horses within the US that have at least one clinical sign associated with PPID.

41% Positive 217 Age Groups of Horses Enrolled n=526 180 160 158 140 137 120 103 100 80 69 60 40 33 26 20 0 Under 10

8 # of Horses # of Horses 11/27/2017 Fasting Insulin 44 Insulin Assessment Oral Sugar Test ID PPID Purpose: To gather clinical information that includes signalment, clinical signs, resting ACTH, fasting insulin, and fasting glucose results obtained at diagnosis from horses within the US that have at least one clinical sign associated with PPID ACTH TESTING OVERALL RESULTS Samples Submitted PPID Positive 0 Percent PPID+ Horses % Positive 217 Age Groups of Horses Enrolled n= Under 10 and older PPID Master_537 n= *2 horses with unknown age PPID by age table n=

# of Horses # of Horses 11/27/2017 PPID+ Horses Clinical Signs Present At Initial Diagnosis PPID+ Horses By Age 350 PPID positive Total 180 160 140 120 100 20% 103 33% 158 51% 137 300 250 200 150 294

behavior Laminitis Loss of muscle mass Weight loss Pot Excessive belly/weight urination gain Excessive Abnormal Recurrent thirst sweating infections Other PPID by age table n= 526 49 *Categories are

breeds/cross-breeds represented 222 (43%) were PPID + 203 (39.

9 # of Horses # of Horses 11/27/2017 PPID+ Horses Clinical Signs Present At Initial Diagnosis PPID+ Horses By Age 350 PPID positive Total % % % % % % under and older 0 Delayed Cresty neck Decreased shedding athletic behavior Laminitis Loss of muscle mass Weight loss Pot Excessive belly/weight urination gain Excessive Abnormal Recurrent thirst sweating infections Other PPID by age table n= *Categories are NOT Mutually Exclusive and are Independent of ACTH test results Clinical Signs Table n= horses had missing ACTH value 50 Results Five-hundred fifteen horses in final data 66 breeds/cross-breeds represented 222 (43%) were PPID (39.4%) were HI +* Further stratified into1 of 4 groups (PPID + /HI - ) (PPID + /HI + ) (PPID - /HI + ) (PPID - /HI - ) Results Of the 515 horses: 115 (22.3%) were PPID + /HI - 97 (18.8%) were PPID + /HI (20.6%) were PPID - /HI (38.3%) were (PPID - /HI - ) 318 (61.7%) horses diagnosed with endocrine disease *IR = Insulin resistant Treatment Prascend gold standard of care Only FDA licensed product Dopamine agonist Safety and efficacy studies Product support 1mg 60 and 160 tablet blister packs Easily administered Demonstrated STABILITY! Improves quality of life Pergolide Cloud/Veil Horses occasionally appear depressed when treatment initiated; may show inappetance Practical approach: Stop treatment for 2 days Start treatment at.5mg/day Gradually return to full treatment dose

Treatment and monitoring Perform baseline diagnostics (ACTH or TRH

0mg 500kg) Retest with same test in 30 days May take 2 months to

activity, improved attitude, PU/PD, hyperglycemia Long term

mass, fewer infections and episodes of laminitis Uncle Sam- 6 mo.

treatment 57 58 Other Considerations Switching from compounded

10 Treatment and monitoring Perform baseline diagnostics (ACTH or TRH stim.) (Initiate Prascend tx. (.5mg 250 kg pony/1.0mg 500kg) Retest with same test in 30 days May take 2 months to assess clinical signs Initial response (first 30 days) Incr. activity, improved attitude, PU/PD, hyperglycemia Long term response (1-12 months) Imprv. hair coat, incr. skeletal mm. mass, fewer infections and episodes of laminitis Uncle Sam- 6 mo. treatment Brown- 6 mo. treatment Phantom- 6 mo. treatment Other Considerations Switching from compounded pergolide Current status of horse If well controlled consider lower Prascend dose (50% reduction) Retest after 30 days

Other Considerations Removing horses from pergolide Missing doses due to exhibition/competition ACTH may begin to rise in 48 hours 3/6 50% rise by day 2 6/6 by day 10 Risk of

normal diet and pasture Obese (>7/9) lower energy diet/exercise Insulin dysregulation; lower NSC and limit pasture Dietary supplements?

insulin dysregulation Summary Treatment of PPID is truly individualized medicine Test any time of year using resting ACTH Dynamic test with seasonal reference ranges TRH

11 Other Considerations Removing horses from pergolide Missing doses due to exhibition/competition ACTH may begin to rise in 48 hours 3/6 50% rise by day 2 6/6 by day 10 Risk of worsening clinical signs is low USEF considering exemption rule Other Considerations Diet and Exercise Feed selection based on body score and oral sugar test Normal insulin; normal diet and pasture Obese (>7/9) lower energy diet/exercise Insulin dysregulation; lower NSC and limit pasture Dietary supplements? Other Considerations Wellness care Should include dentistry and parasite control Foot care Inadequate control predisposes to infections Attention to body condition Diet; insulin dysregulation Summary Treatment of PPID is truly individualized medicine Test any time of year using resting ACTH Dynamic test with seasonal reference ranges TRH stimulation mid Nov. to mid July Early cases or where lab work does not fit No seasonally adjusted reference ranges Insulin/glucose status must be known Manage the whole horse not just endocrine test results Questions? 65 11

Diagnosis and Treatment

Diagnosis and Treatment of Pituitary Pars Intermedia Dysfunction (PPID) Prepared by the PPID Working Group: Nicholas Frank, DVM, PhD, DACVIM (Group Coordinator) Frank Andrews, DVM, MS, DACVIM Ben Buchanan,