Ulcerative Dermatitis

Ulcerative dermatitis is a type of behavioral abnormality that specifically leads to a skin disorder. The disorder occurs due to excessive scratching.

Ulcerative dermatitis is an abnormal behavior wherein a mouse is excessively scratching itself resulting in serious skin lesions and deformations.

Ulcerative dermatitis affects a lot of rodents used in research. Affected rodents may have skin lesions caused anywhere on the body, but occurs frequently on the shoulders and also on the neck. Lesions can be single or multiple in number.

It is common to euthanize mice that are afflicted with ulcerative dermatitis.

Ulcerative dermatitis is described as a necrotic ulceration with high levels of inflammation and a surrounding serocellular crust, similar to human skin conditions that have traces of inflammatory ulceration.

In animal research, if mice develop ulcerative dermatitis and respond poorly to treatment, it is important to assess what the cause of the lesions was, in case the cause of the lesions was something else like infestation with Myobia musculi (fur mites), neoplasia, or systemic disease.

Ulcerative Dermatitis vs. Aggression

Ulcerative dermatitis and aggressive interactions are the two most common reasons why mice appear with skin lesions. However, these two causes vary in nature. While ulcerative dermatitis is self-inflicting, aggressive behaviors occur in a social encounter between two mice.

In order to identify whether an observed lesion is self-inflicted or due to an aggressive interaction, scientists are trying to find a way to distinguish external skin wounds by scoring them. Although this classification approach is still developing with regards to sensitivity and specificity, it is safe to say that skin lesions are likely to be different in nature depending on their cause. For example, it is likely that aggression-caused wounds appear to be more punctate, discrete in shape, and with concomitant enlargement of the lymph nodes. Such wound characteristics are not frequently observed with regard to ulcerative dermatitis.

The Difficulties of Ulcerative Dermatitis in a Research Setting

Treatment and prevention are also very difficult, thus ulcerative dermatitis is a problem that is bound to occur at the lab at one point or another.

The challenges presented by ulcerative dermatitis to researchers are serious. First of all, ulcerative dermatitis is very common in C57BL/6 mice and mice with that background. This is problematic since C57BL/6 are extensively used in behavioral neuroscience for research purposes.

Furthermore, the clinical nature of ulcerative dermatitis can introduce confounds into an experiment since it oftentimes with systemic pathologic changes, including splenomegaly and lymphadenopathy, which could ultimately influence results. Also, at the site of ulceration, high inflammation is coupled with an increased presence of lymphocytes, neutrophils, mast cells, and macrophages.

Since this is a self-destructive, abnormal behavior, there is no known or clear view of what the function of dermatitis could be.

The following factors have been known to trigger ulcerative dermatitis in mice:

• Age: Ulcerative dermatitis has been associated with young and old age in mice. Thus, a mice’s age can be a trigger for this skin disorder.
• High-fat diet: Mice that are fed with a high-fat diet (like 60% or 33% fat content) have a higher risk of developing ulcerative dermatitis than control mice that eat a 10% fat diet.
• Gender: Ulcerative dermatitis is significantly more common in females than males, suggesting an effect of gender in the manifestation of the disease.
• Genetic mutation: Due to the high frequency of this disease in C57BL/6 mice and related strains, it is believed that a genetic mutation may be responsible for this. Furthermore, recent findings have pointed to the Adh4 gene as being a potential source of this skin picking disease.
• Seasonality: It is believed that there is a seasonality effect of ulcerative dermatitis with the highest peak incidence occurring around midsummer.
• Humidity: Humidity plays another role in the development of ulcerative dermatitis. A large majority of cases will occur in an environment with 35 to 45% humidity levels.

In order to study ulcerative dermatitis, research techniques must be employed based on the experimental question or variable of interest. These techniques and methods are used for studying ulcerative dermatitis:

• Behavioral studies: Behavioral studies are very useful for studying abnormal behaviors like ulcerative dermatitis because they enable the researcher to profile, describe, and quantitatively assess ulcerative dermatitis across mouse strains and interventions like diet.
• Pharmaceutical studies: Pharmaceutical studies are used when studying the effect of certain drugs or supplements on ulcerative dermatitis. This is done in order to determine how a drug will affect the manifestation of ulcerative dermatitis across mouse strains. This type of study is also useful when studying ulcerative dermatitis treatments in the context of disease models like skin picking disorder.
• Genetic studies: Genetic studies are useful for identifying potential genes involved in the etiology of ulcerative dermatitis. Through genetic studies, a better understanding can be gained of the reasons that ulcerative dermatitis varies across mouse strains.

These tests are key in the scientific process of observing and quantifying the frequency and severity of the behavioral scratching and subsequent skin lesions.

To do this, researchers use rating scales or scoring systems. Below we will take a closer look at an ulcerative dermatitis scoring system and the information that it can provide.

A scoring system described by Hampton et al. is a modification of a dermatitis scale used in humans. The scale ranges from 0 to 100 where the highest and most severe score is 100.

The system scores the following four categories and then calculates a severity score:

A) Scratching Number: The number of scratches in a two-minute period.

• Score 0: No scratching observed during the observational period.
• Score 1: Less than 5 scratches during the observational period.
• Score 2: 5-10 scratches observed within the 2-minute observation period.
• Score 3: More than 10 scratches observed.

B) Character of Lesion: Describes the nature of the lesion.

• Score 0: No lesion present.
• Score 1: Excoriations only or a small crust of ≤2mm.
• Score 2: Multiple small crusts or a coalescing crust of ≥2mm.
• Score 3: Erosion or ulceration.

C) Length of Lesion: Diameter of the largest lesion identified.

• Score 0: Lesion diameter is 0 cm.
• Score 1: Lesion diameter is <1 cm.
• Score 2: Lesion diameter is 1-2 cm.
• Score 3: Lesion diameter is >2 cm.

D) Regions Affected: The regions of the body affected by the lesion.

• Score 0:
• Score 1: One region is affected, either region 2 (the middle region of the body, starting from behind the ears all the way down to the ribcage) or region 3 (the region spanning from under the ribcage down to the tail).
• Score 3: Both regions 2 and 3 affected.
• Score 4: Region 1 (the head) and/or one of the other affected regions.

E) Severity Score: The final score is calculated through a formula that considers the scores from categories A-D.

Severity Score = [ (A + B + C + D) ÷ 12 ] x 100

Since ulcerative dermatitis is known to be resistant to treatment, any pharmaceutical findings are noteworthy. In this section, we cover major findings regarding the effect of pharmaceuticals or supplements on ulcerative dermatitis. Treatments can be either topical or systemic.

Lithium Supplementation

Ulcerative dermatitis has an unknown etiology. But, it may be somehow caused or influenced by the insulin signaling pathway. Lithium acts as an insulin-mimetic. A lithium enriched-diet in healthy wild-type mice has been shown to increase their susceptibility to developing ulcerative dermatitis. This indicates that insulin, which lithium mimics, is somehow implicated in the manifestation of ulcerative dermatitis in mice.

Maropitant Citrate

Maropitant citrate is a tachykinin neurokinin 1 (NK1) receptor antagonist and prevents binding to occur on the NK1 receptor. Substance P (SP) is a neuropeptide that has been linked to the itch-scratch behavior. Administration of maropitant citrate prevents SP from binding to NK1 receptors. Mice that are with 1 mg/kg maropitant citrate will have at least a 10% improvement in their lesion size when compared with controls given only water or with mice given 5 mg/kg of the same substance. A significant difference in lesion size is observable after 15 days of treatment. Although the exact mechanism of ulcerative dermatitis remains unknown, it is possible that inhibiting SP binding led to a decrease in the itch sensation which, in turn, reduces scratching behaviors and, ultimately, the skin trauma associated with ulcerative dermatitis.

Vitamin E

A study by Lawson et al. showed that adding 3000 IU of vitamin E to mice’s ad libitum diet for 8 weeks is associated with positive treatment results of ulcerative dermatitis. In this study, 45% of mice with ulcerative dermatitis with vitamin E in their diet had complete lesion recovery and hair regrowth. It took about 2 to 5 weeks for mice to completely repair from their lesions.

Therefore, vitamin E is a partial solution for treating ulcerative dermatitis, especially given that the complete response rate is less than 50% success. However, it is still a valuable and promising option, especially for researchers that breed genetically engineered mice. Since genetically engineered mice are costly and time-consuming to create, it may be a good idea to consider feeding them (or any breeding strain) with a vitamin E-fortified diet. For researchers whose studies revolve around oxidative injury, vitamin E may not be such a promising solution for addressing ulcerative dermatitis since vitamin E’s anti-oxidative properties could affect experimental results.

However, more research is necessary on this topic since there are some mixed results out there. For example, another study showed that vitamin E does not prevent ulcerative dermatitis and may, in fact, accelerate its incidence. Thus, more research may be necessary on this topic in order to reach a consensus.

N-Acetylcysteine and Glutathione

In humans, N-acetylcysteine is used to treat trichotillomania and skin picking disorder. N-Acetylcysteine acts as a precursor to glutathione, an endogenous antioxidant that is found in the brain. Due to the similarities between skin picking disorder, trichotillomania,  and ulcerative dermatitis, it is possible that N-Acetylcysteine is effective in treating excessive skin lesions in mice. A study by Whitaker et al. showed just that. The majority of mice improve gradually throughout chronic treatment with N-Acetylcysteine.

The same study showed that even when glutathione is administered intranasally, mice with ulcerative dermatitis will improve and their lesions will significantly reduce in size and severity. Glutathione is able to reduce the severity of dermatitis lesions by about 50% and some of the treated mice improve completely by 2-4 weeks of treatment while the other mice do not respond to treatment.

Some patients with trichotillomania or skin picking disorder respond poorly to N-Acetylcysteine, thus glutathione may be a promising alternative.

In addition to the pharmaceutical interventions described above, there are some environmental treatments that have been found to help in managing and/or preventing the disease.

Caloric Restriction

Caloric restriction, the limiting of calories in diet, has been established to affect many aspects of physiology, including: gene expression, immune responses, enzyme activities, and the rate of protein synthesis. Mice that are given 60% of the average food intake are less likely to develop lesions and are likely to survive twice as long as mice fed on an ad libitum diet. However, there may be a genetic component to the effectiveness of this intervention. Nevertheless, caloric restriction is an intervention with promising results in addressing ulcerative dermatitis.

Clipping of Toenails

Another intervention has shown promising results in reducing the severity of ulcerative dermatitis by clipping toenails. By trimming a mouse’s nails and interfering with their need to scratch, a mouse is more likely to recover from ulcerative dermatitis. In fact, a study by Adams et al. showed that toenail clipping was associated with healing in 93.3% of mice within a 14-day period.

C57BL/6 Mice Display Ulcerative Dermatitis Spontaneously

C57BL/6 mice are one of the go-to mouse strains for behavioral research. In C57BL/6 mice, ulcerative dermatitis can develop spontaneously. Thus, since one of the most commonly used mouse strains in research can abruptly develop ulcerative dermatitis, this is a condition that researchers are bound to encounter at some point during their careers. Furthermore, ulcerative dermatitis is also likely to develop in mice on a C57BL/6 background.

When ulcerative dermatitis manifests in this mouse strain, it has a sudden onset and a rapid time course. Also, the lesions which develop are highly variable. Furthermore, it has been established that C57BL/6 female mice are more prone to developing ulcerative dermatitis, but the findings on this are mixed.

IRs1 Mice

Mice that are deficient for the insulin receptor substrate 1 (IRs1) gene have been found to be completely resistant to the development of ulcerative dermatitis. IRs1 is a key component of the insulin-like growth factor-1 (IGF) signaling pathway. Thus, if mice that lack this receptor do not develop ulcerative dermatitis, it indicates that IRs1 may somehow be implicated in the etiology of this inflammatory skin disorder.

iNOS mice

Mice that lack the gene of inducible nitric oxide synthase (iNOS) will develop significantly more ulcerative dermatitis when compared to other strains. iNOS-deficient mice have about 50% incidence of ulcerative dermatitis, much higher than the 5% incidence in C57BL/6 strain. Ulcerative dermatitis appears in iNOS-deficient mice around 16 to 20 months of age.  iNOS is involved in skin repair. It’s absence and the subsequent high prevalence in ulcerative dermatitis in mice suggests that it may be involved in the etiology of the disease.

High-fat Induced Obesity

Obesity is induced in mice through a high-fat diet. This also translates to human cases of obesity, since a large proportion is caused due to following a high-fat diet chronically. Some mice that are induced with obesity with a high-fat diet will demonstrate ulcerative dermatitis. Since ulcerative dermatitis can also be caused through a high-fat diet, as mentioned previously, some mice that are used to model obesity are likely to develop this skin inflammation disorder. In such experiments, mice that have ulcerative dermatitis are very likely to be euthanized.

Skin Picking Disorder

Ulcerative dermatitis, as a spontaneously developing skin inflammation condition, is used as a model of skin picking disorder. In humans, skin picking disorder affects about 4% of the general population. Ulcerative dermatitis shares some overlap with skin picking disorder in the following domains: epidemiology, behaviors, and similarity to hair pulling with regards to mechanisms and comorbidity. The relationship between skin picking disorder and ulcerative dermatitis was recently suggested, thus it is a model that is still under scientific scrutiny and in the process of developing.

Yes. Ulcerative dermatitis affects behavioral assessment significantly. In fact, if a mouse develops ulcerative dermatitis during the course of an experiment, it must be noted and reported. Ulcerative dermatitis can affect experimental results and can confound the observations acquired during the experiment. For example, the higher levels of inflammation and macrophages which occur in parallel with the ulcerative lesions can cloud research findings.

• Ulcerative dermatitis is a type of skin disorder that is associated with bacterial flora.
• Ulcerative dermatitis occurs due to excessive scratching.
• Research rodents are affected by this disease, potentially influencing test results.
• It is common to euthanize mice that are afflicted with ulcerative dermatitis.
• It is important to determine the cause of the lesions, whether it’s ulcerative dermatitis or something else like systemic disease or aggression.
• The following factors have been known to trigger ulcerative dermatitis in mice: age, high-fat diet, gender, genetic mutations, seasonality, and humidity.
• To study ulcerative dermatitis, the following research techniques can be used: behavioral studies, pharmaceutical studies, and genetic studies.
• A scoring or rating system can be used to quantify the severity of ulcerative dermatitis.
• Pharmaceutical studies on ulcerative dermatitis have shown that:
  • Lithium supplementation is an insulin-mimetic and its supplementation increases the risk of developing ulcerative dermatitis. Thus, insulin may somehow be implicated in the development of ulcerative dermatitis.
  • Maropitant citrate treatment improves mice’s lesion severity.
  • Vitamin E, when given to mice with ulcerative dermatitis, is associated with a 50% success rate.
  • N-acetylcysteine and glutathione have shown promising results in treating ulcerative dermatitis.
• Caloric restriction is an environmental intervention that reduces mice’s risk of developing ulcerative dermatitis.
• Toenail clipping is another environmental intervention that increases improvement of ulcerative dermatitis.
• In C57BL/6 mice, ulcerative dermatitis can develop spontaneously.
• Mice that are deficient for the insulin receptor substrate 1 (IRs1) gene have been found to be completely resistant to the development of ulcerative dermatitis.
• Mice that lack the gene of inducible nitric oxide synthase (iNOS) will develop significantly more ulcerative dermatitis when compared to other strains.
• A high-fat Western-style diet (HFWD) potentiates the development of ulcerative dermatitis.
• A mutation in the alcohol dehydrogenase 4 (Adh4) gene may be related to the manifestation of ulcerative dermatitis.
• The following disease models feature ulcerative dermatitis: high-fat induced obesity and skin picking disorder.

1. Lawson, Gregory W., et al. “Vitamin E as a treatment for ulcerative dermatitis in C57BL/6 mice and strains with a C57BL/6 background.” Journal of the American Association for Laboratory Animal Science 44.3 (2005): 18-21.
2. Neuhaus, Brit, et al. “Experimental analysis of risk factors for ulcerative dermatitis in mice.” Experimental dermatology 21.9 (2012): 712-713.
3. Kastenmayer, Robin J., Michele A. Fain, and Kathy A. Perdue. “A retrospective study of idiopathic ulcerative dermatitis in mice with a C57BL/6 background.” Journal of the American Association for Laboratory Animal Science 45.6 (2006): 8-12.
4. Hampton, Anna L., et al. “Progression of ulcerative dermatitis lesions in C57BL/6Crl mice and the development of a scoring system for dermatitis lesions.” Journal of the American Association for Laboratory Animal Science 51.5 (2012): 586-593.
5. Williams-Fritze, Misty J., et al. “Maropitant citrate for treatment of ulcerative dermatitis in mice with a C57BL/6 background.” Journal of the American Association for Laboratory Animal Science 50.2 (2011): 221-226.
6. George, Nneka M., et al. “Antioxidant therapies for ulcerative dermatitis: a potential model for skin picking disorder.” PloS one 10.7 (2015): e0132092.
7. Perkins, Susan N., et al. “Calorie restriction reduces ulcerative dermatitis and infection-related mortality in p53-deficient and wild-type mice.” Journal of investigative dermatology 111.2 (1998): 292-296.
8. Adams, Sean C., et al. “A “pedi” cures all: toenail trimming and the treatment of ulcerative dermatitis in mice.” PloS one 11.1 (2016): e0144871.
9. Sundberg, John P., et al. “Primary follicular dystrophy with scarring dermatitis in C57BL/6 mouse substrains resembles central centrifugal cicatricial alopecia in humans.” Veterinary pathology 48.2 (2011): 513-524.
10. Liu, Lumei, et al. “The effects of Dietary Fat and iron interaction on Brain regional iron contents and stereotypical Behaviors in Male c57Bl/6J Mice.” Frontiers in nutrition 3 (2016): 20.
11. George, Nneka M., et al. “Antioxidant therapies for ulcerative dermatitis: a potential model for skin picking disorder.” PloS one 10.7 (2015): e0132092.