Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Open trial of Bruton's tyrosine kinase inhibitor (PRN1008) in the treatment of canine pemphigus foliaceus.

BACKGROUND: Bruton's tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is one of the most common canine autoimmune skin diseases. OBJECTIVES: To determine the safety and efficacy of the BTKi PRN1008 in the treatment of cPF. ANIMALS: Four privately owned dogs. METHODS AND MATERIALS: Four dogs diagnosed with PF were administered BTKi PRN1008. Initial dosages approximated to 15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for 20 weeks, attempting to decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels and urinalyses, and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Serum anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin (Ig)G titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells (PBMC). RESULTS: All four dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. Three dogs continued to improve and sustained near complete remission by 20 weeks, at which point three responses were considered "good" and one "fair". Final daily dosages were in the range 17-33 mg/kg. Anti-DSC-1 IgG titre decreased dramatically in one dog, was undetectable in two and was uninterpretable in one dog. No dogs had detectable IgG to DSG1. A possible adverse event occurred in one dog. CONCLUSIONS AND CLINICAL IMPORTANCE: BTKi PRN1008 monotherapy may have some beneficial effects in some cases of cPF.

Efficacy of a Bruton's Tyrosine Kinase Inhibitor (PRN-473) in the treatment of canine pemphigus foliaceus.

BACKGROUND: Bruton's tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is the most common canine autoimmune skin disease. OBJECTIVES: To determine the safety and efficacy of a BTKi in cPF treatment. ANIMALS: Nine privately owned dogs. METHODS AND MATERIALS: Nine dogs diagnosed with PF were administered BTKi PRN473. Initial dosages were ≈15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for a maximum of 20 weeks, attempting decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels, urinalyses and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin G (IgG) titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells. RESULTS: All nine dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. At the end of the study, four responses were considered "good", two "fair", two "poor" and one dog withdrawn due to recurrence of a previously excised mast cell tumour. Four dogs continued to improve by Week 4; three sustained near complete remission by study's end. The anti-DSC-1 IgG titre decreased in three dogs, increased in two, was undetected in three and was not performed in the withdrawn dog. No dogs had detectable IgG to DSG1. Possible adverse effects occurred in three dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Bruton's tyrosine kinase inhibitor monotherapy may have beneficial effects in some cases of cPF.

Clinicopathological findings and clinical outcomes in 49 cases of feline pemphigus foliaceus examined in Northern California, USA (1987-2017).

BACKGROUND: Few studies have described the pathophysiology, clinical course, treatment outcomes and quality of life (QoL) of cats with pemphigus foliaceus (PF). OBJECTIVE: Describe clinicopathological features, treatment outcomes and impacts on QoL in feline PF. ANIMALS: Forty-nine client-owned cats with PF that presented to a veterinary teaching hospital between 1987 and 2017. METHODS AND MATERIALS: Medical records and histopathological reports were reviewed to obtain clinicopathological data and treatment outcomes. Owners were contacted and requested to complete a questionnaire to obtain long-term follow-up and evaluate the impacts of PF on QoL of cats and owners. RESULTS: Domestic short/medium/long hair breeds were most commonly affected, with pinnae, head, haired face, nasal planum and ungual folds most frequently involved. Associated pruritus and systemic signs of illness were common. Vasculopathological changes were noted in a small proportion of cats. Corticosteroid monotherapy was sufficient to induce complete remission in the majority of cats. Pemphigus foliaceus and its management had a negative impact on QoL of both cats and owners. Receiving/administering medications, attending veterinary appointments, and financial and time commitments were cited sources of stress for affected cats and/or owners. CONCLUSIONS AND CLINICAL IMPORTANCE: Results illustrate that affected cats generally respond favourably to treatment but do require long-term therapy. The exact aetiology of the vasculopathological changes was unclear; it may reflect the stage or severity of disease or suggest the presence of a cutaneous adverse drug reaction. Clinicians managing cats with PF should be aware of the potential negative impact on QoL of owners and cats and adjust management accordingly.

A retrospective review of hyperaesthetic leucotrichia in horses in the USA.

BACKGROUND: Hyperaesthetic leucotrichia (HL) rarely affects horses and causes painful lesions on the dorsum that result in leucotrichia. This may be a variant of erythema multiforme (EM), but there are no studies investigating this condition. OBJECTIVES: Describe the clinical and histological features of HL and compare them to the histological features of EM. METHODS: A retrospective review of medical records from 1985 to 2015 identified 15 horses with HL. Thirteen biopsies of HL and five of EM were evaluated and compared. RESULTS: Arabian horses and their crosses (χ(2) (1)  = 8.56, P < 0.01) and American paint horses (χ(2) (1)  = 6.64, P < 0.05) were over represented. The onset of clinical signs was between April and September (14 of 15). The most common clinical signs were pain (15 of 15), leucotrichia (11 of 15), crusting (10 of 15) and alopecia (8 of 15) limited to darkly pigmented skin. The lesions recurred seasonally in 6 of 12 horses and unpredictably in 1 of 12 horse. The most common histological features were the presence of large stellate cells (13 of 13) and oedema (12 of 13) in the superficial dermis, perivascular to diffuse lymphocytic inflammation (13 of 13), pigmentary incontinence (12 of 13), apoptotic keratinocytes (9 of 13) and vesicle formation (8 of 13). Horses with EM (n = 5) had significantly more acanthosis (z = -2.40, P < 0.02) and lymphocytic exocytosis (z = -3.1, P < 0.004), satellitosis (Fisher's exact P = 0.02) and inflammation (z = -2.91, P < 0.004). Horses with HL had significantly more pigmentary incontinence (z = 2.13, P < 0.04) and superficial dermal oedema (z = 2.56, P < 0.002). CONCLUSIONS: HL affects primarily Arabian horses and American paint horses. It occurs mainly in summer and may recur. Histologically HL shares features with EM, but there are significant differences between them.

Aspergillus otitis in small animals--a retrospective study of 17 cases.

BACKGROUND: Aspergillus spp. are saprophytic opportunistic fungal organisms and are a common cause of otomycosis in humans. Although there have been case reports of Aspergillus otitis externa in dogs, to the best of the authors' knowledge, this is the first retrospective case series describing Aspergillus otitis in dogs and cats. OBJECTIVE: To characterize signalment, putative risk factors, treatments and outcomes of a case series of dogs and cats with Aspergillus otitis. ANIMALS: Eight dogs and nine cats diagnosed with Aspergillus otitis. METHODS: A retrospective review of medical records from 1989 to 2014 identified animals diagnosed with Aspergillus otitis based on culture. RESULTS: All dogs weighed greater than 23 kg. The most common putative risk factors identified in this study were concurrent diseases, therapy causing immunosuppression or a history of an otic foreign body. Aspergillus otitis was unilateral in all study dogs and most cats. Concurrent otitis media was confirmed in three dogs and one cat, and suspected in two additional cats. Aspergillus fumigatus was the most common isolate overall and was the dominant isolate in cats. Aspergillus niger and A. terreus were more commonly isolated from dogs. Animals received various topical and systemic antifungal medications; however, otic lavage under anaesthesia and/or surgical intervention increased the likelihood of resolution of the fungal infection. CONCLUSION: Aspergillus otitis is uncommon, typically seen as unilateral otitis externa in cats and larger breed dogs with possible risk factors that include immunosuppression and otic foreign bodies; previous antibiotic usage was common.

Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies.

OBJECTIVE: The goal of this work was to compare the efficacy of the norepinephrine and dopamine reuptake inhibitor bupropion with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder with high levels of anxiety (anxious depression). METHOD: Ten double-blind, randomized studies from 1991 through 2006 were combined (N = 2122). Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score >or= 7. RESULTS: Among patients with anxious depression (N = 1275), response rates were greater following SSRI than bupropion treatment according to the HAM-D-17 (65.4% vs. 59.4%, p = .03) and the Hamilton Rating Scale for Anxiety (61.5% vs. 54.5%, p = .03). There was also a greater reduction in HAM-D-17 mean +/- SD scores (-14.1 +/- 7.6 vs. -13.2 +/- 7.9, p = .03) and a trend toward statistical significance for a greater reduction in HAM-A mean +/- SD scores (-10.5 +/- 7.4 vs. -9.6 +/- 7.6, p = .05) in favor of SSRI treatment among patients with anxious depression. There was no statistically significant difference in efficacy between bupropion and the SSRIs among patients with moderate/low levels of anxiety. CONCLUSIONS: There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Using the number-needed-to-treat (NNT) statistic as 1 indicator of clinical significance, nearly 17 patients would need to be treated with an SSRI than with bupropion in order to obtain 1 additional responder. This difference falls well above the limit of NNT = 10, which was suggested by the United Kingdom's National Institute of Clinical Excellence. Nevertheless, the present work is of theoretical interest because it provides preliminary evidence suggesting a central role for serotonin in the regulation of symptoms of negative affect such as anxiety.

Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of anxiety symptoms in major depressive disorder: a meta-analysis of individual patient data from 10 double-blind, randomized clinical trials.

The goal of this work was to compare the efficacy of the norepinephrine-dopamine reuptake inhibitor bupropion with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of anxiety symptoms in major depressive disorder (MDD). Ten double-blind, randomized studies, involving a total of 2890 bupropion-, SSRI- or placebo- treated patients were pooled. Anxiety symptoms of depression were defined using the Hamilton depression rating scale (HDRS) Anxiety-Somatization factor (HDRS-AS) score, as well as the Hamilton anxiety scale (HAM-A) score. Both bupropion and the SSRIs led to a comparable degree of improvement in anxiety symptoms, defined using the HDRS-AS score (-3.8+/-2.8 vs. -3.9+/-2.8, p=0.130) or HAM-A score (-8.8+/-7.2 vs. -9.1+/-7.0, p=0.177). There was no consistent difference in the time to anxiolysis between the two treatment groups. In addition, there was no difference in the proportion of bupropion- and SSRI- remitters who continued to experience residual anxiety, defined as a HDRS-AS score >0 at endpoint (69.2% vs. 74.7%, p=0.081) or a HAM-A score >7 at endpoint (9.5% vs. 8.4%, p=0.284). Finally, there was no statistically significant difference in the severity of residual anxiety symptoms between bupropion- or SSRI- treated patients with remitted depression, defined using the HDRS-AS (1.15+/-1.14 vs. 1.25+/-1.09, p=0.569), or HAM-A scores at endpoint (3.30+/-2.89 vs. 3.31+/-2.89, p=0.552). Contrary to clinician impression, there does not appear to be any difference in the anxiolytic efficacy of bupropion and the SSRIs when used to treat MDD.

Selective serotonin reuptake inhibitors treatment effects on auditory measures in depressed female subjects.

The purpose of this study was to evaluate the auditory effects of selective serotonin reuptake inhibitors (SSRI), known to enhance serotonin (5-HT) transmission in the brain. The experimental group consisted of 14 clinically depressed female subjects, and the control group consisted of 11 non-depressed females. A battery of tests was administered to the experimental group while on and off of SSRI medication. The control group was also administered the test battery twice. Results indicated no significant differences in the control group between sessions. The experimental group showed significantly smaller transient evoked emissions, higher SCAN-A (auditory processing test) composite scores, and smaller amplitude growth functions for Auditory brainstem response peak V and Auditory late response peak N(1)P(2) while on SSRI medication. The increased 5-HT levels in the presence of SSRI (due to reduced reuptake of 5-HT) may be contributing to the significant changes seen in auditory measures with the experimental group.