Incidence of relapse of inflammatory protein‐losing enteropathy in dogs and associated risk factors

Abstract Background Dogs with inflammatory protein‐losing enteropathy (iPLE) that attain remission may be at risk of subsequent relapse. Objectives To determine the incidence of relapse of iPLE in dogs that have previously attained complete clinical and biochemical remission and identify associated risk factors. Animals Seventy‐five client‐owned dogs diagnosed with iPLE. Methods Medical records of dogs diagnosed with iPLE based on histopathology of intestinal biopsy specimens between March 2010 and March 2020 were retrospectively reviewed. Variables were recorded from the time of investigation at histopathologic diagnosis and subsequent follow‐up information was obtained from the records of referring veterinarians. Results Twenty‐three dogs (31%) achieved sustained remission without documentation of relapse for at least 2 years. Nineteen dogs (25%) achieved remission, but then subsequently relapsed within 2 years of histopathologic diagnosis, and 33 dogs (44%) never achieved remission with disease‐associated death occurring a median of 19 (range, 3‐114) days after histopathologic diagnosis. Dogs that achieved remission and subsequently relapsed had significantly higher poor dietary compliance, as defined by frequent scavenging or changing from the recommended diet compared to dogs with sustained remission (P = .01). Conclusions Inflammatory PLE is associated with a high rate of relapse in dogs. Ensuring owners adhere to dietary recommendations might help prevent subsequent relapse in dogs with iPLE that attain initial remission.

of cases. 1 Several studies therefore have focused on prognostic indicators of outcome, where outcome is defined as survival versus nonsurvival for a determined follow-up period. [1][2][3][4][5][6][7][8][9] Factors identified as predictors of negative outcome vary among studies and have included vomiting, monocytosis; abnormal blood urea nitrogen concentration, high C-reactive protein (CRP) concentration, low serum albumin concentration; hypovitaminosis D, body weight, and canine chronic enteropathy clinical activity index (CCECAI). [1][2][3][4][5][6][7][8][9] Studies with long-term follow-up to assess outcome, defined as >6 months, in dogs with iPLE are currently lacking. Furthermore, few studies have documented outcome with regard to resolution of both clinical signs and hypoalbuminemia. 2,5,10 One study assessing Yorkshire terriers with iPLE found that long-term follow-up was achieved in 23 dogs. 5 Thirteen of 23 dogs (57%) had complete resolution of clinical signs and normalization of serum albumin concentration and 3 achieved partial resolution of signs, albumin concentration or both with a median survival time of 44 months. 5 Four of the dogs that achieved complete remission however subsequently relapsed with or without hypoalbuminemia 3 to 20 months after diagnosis, resulting in disease-associated death. Factors associated with clinical relapse in these dogs were not investigated.
To our knowledge, no other study has ascertained from the surviving population of dogs with iPLE what proportion of dogs that achieve clinical and biochemical remission remain in remission versus those that relapse. The incidence of and risk factors for relapse in dogs diagnosed with iPLE are therefore currently unknown. Understanding the incidence of relapse and factors associated with relapse in dogs with iPLE could positively affect earlier or ongoing monitoring and treatment strategies and could impact patient outcome.
Our aims were, first, to ascertain what proportion of dogs that achieved remission remained in remission versus those that went on to relapse. Second, we aimed to identify any associated risk factors from the time of histopathologic diagnosis that were predictive of subsequent relapse in dogs that attained remission. We defined remission as resolution of both clinical signs and hypoalbuminemia and relapse as recurrence of both clinical signs and hypoalbuminemia after initial remission.

| Study animals
The medical records at the Queen Mother Hospital for Animals, Royal

| Outcome classification
The medical records were assessed and the following outcomes were defined for each of the 75 dogs included in the study:

| Remission
Dogs were defined as entering remission if they achieved both resolution of clinical signs and documented resolution of hypoalbuminemia (>26.3 g/L).

| Sustained remission
Dogs were categorized as being in sustained remission (SR) if they achieved and remained in clinical and biochemical remission for 2 years after histopathologic diagnosis.

| Remission-relapsing
Dogs were categorized as remission-relapsing (RR) if, having initially achieved clinical and biochemical remission, they had recurrence of both clinical signs and hypoalbuminemia (<26.3 g/L) within 2 years of histopathologic diagnosis.

| No remission
Dogs were categorized as no remission (NR) if they never achieved resolution of clinical signs and hypoalbuminemia and therefore were euthanized or died as a result of their disease.

| Remission-relapsing
For dogs in the RR group, the following information also was recorded: time from histopathologic diagnosis to relapse (days), time from documented clinical and biochemical remission to relapse (days), serum albumin concentration at relapse, achievement of second remission (categorized as yes or no), and time from documented relapse to second remission (days).

| Statistical analysis
To evaluate risk factors, data collection, checking, and cleaning were performed in Microsoft Excel (2021). Categorical data were summarized by count and percentage. Median and range were calculated for continuous variables. The data were imported into IBM SPSS (Statistical Product and Service Solutions) version 28 statistical software for analysis. Statistical analyses were carried out to identify variables that were significantly different among the NR, SR, and RR groups. For continuous data, a Shapiro-Wilks test was used to assess normality. For normally-distributed data, 1-way analysis of variance (ANOVA) was used to compare data among NR, SR, and RR groups and an independent t-test was used to compare data between SR and RR groups only. For nonnormally distributed data, a Kruskal-Wallis test was used to compare data among NR, SR and RR groups and Mann-Whitney U test was used to compare data between the SR and RR groups. A chi-squared test was used to compare categorical data among the NR, SR, and RR groups. Significance was defined as P < .05 for all analyses and Tukey's post hoc analysis was used for all significant findings.

Sustained remission
Twenty-three dogs (31%) achieved SR for 2 years after diagnosis.
Three-year follow-up data was available for 16 of the 23 dogs and 4 year follow-up data was available for 14 of the 23 dogs with no evidence of clinical or biochemical relapse. Note: Statistical analyses were used to identify variables that were significantly different between dogs that never achieved clinical and biochemical remission, dogs that achieved sustained remission and dogs that achieved remission and relapsed.

| SR and RR
No significant difference was found when comparing the following risk factors between the SR and RR groups: Days from diagnosis to documented remission (P = .2), serum albumin concentration at remission (P = .73) and days until prednisolone dose of 0.5 mg/kg (P = .87).
A significant difference was found when comparing dietary compliance between the SR and RR groups (P = .01).

| DISCUSSION
Long-term studies to assess the incidence of relapse of iPLE in dogs that achieve initial clinical and biochemical remission are currently lacking. [1][2][3][4][5][6][7][8][9][10] Our study aimed to determine the incidence of relapse of  In our study, relapse of iPLE was associated with a poor prognosis, with 50% of dogs dying or being euthanized as a result of their disease process. Previous studies have reported even lower survival rates. 5 Many dogs that survived their first relapse also went on to suffer additional episodes of relapse in the future, a pattern more characteristic of IBD in humans. 12 The poor prognosis associated with relapse is likely the result of a number of factors including disease progression, unresponsiveness to treatment, and financial constraints.
However, a limitation of our study was that relapse was defined as recurrence of clinical signs and hypoalbuminemia, but repeat confirmation of histopathologic diagnosis was not required. Only 1 dog in the RR group had repeat endoscopic biopsies and repeat histopathologic diagnosis of lymphoplasmacytic enteritis. Clinical relapse in some dogs therefore could have been the result of a concurrent condition or neoplasia, which may have negatively skewed prognosis. Furthermore, because ileal biopsies were not performed in all cases, intestinal neoplasia, lymphangiectasia or lacteal dilatation could have been missed in some cases. 3 In humans with IBD, shorter times between remission and relapse are associated with poorer prognosis and more frequent relapses. 12 This association was not seen in our study, which could have been a result of small sample size.
Other limitations of our study also occurred as a result of the retrospective study design, including involvement of several clinicians in the cases resulting in variable dosages of prednisolone, as well as diet choice associated with clinician preference, because there currently is no definitive consensus for the treatment of these cases. Not all dogs had repeat serum biochemistry performed if episodes of diarrhea occurred after remission, which could have led to an underestimation of the number of relapse cases. However, dogs reported to have had episodes of diarrhea without repeat biochemistry after remission only were included in our study (and defined as SR) if the episodes of diarrhea resolved without additional medication or changes to medication they were receiving at the time.
In conclusion, our study emphasizes the substantial proportion of dogs that achieve clinical remission of iPLE and suffer relapses of their condition. Dogs that relapsed were found to have worse dietary compliance than those that remained in remission. Therefore, ensuring owners adhere to dietary recommendations might help prevent subsequent relapse in dogs with iPLE that attain initial remission. Prospective studies are required to investigate the relationship between dietary compliance and relapse in dogs with iPLE and to identify additional risk factors. Identification of risk factors will help improve monitoring and treatment strategies to try to decrease the incidence of relapse of iPLE and improve patient outcome.

ACKNOWLEDGMENT
No funding was received for this study.

CONFLICT OF INTEREST DECLARATION
Authors declare no conflict of interest.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
The Royal Veterinary College granted ethical approval for the study (URN SR2020-0255).