Overview

Frustration can arise when treatment for a particular disease fails to lead to clinical improvement. Other cases may initially improve, but then show a decline. Secondary infections, ectoparasites, development of another disease or adverse drug reactions can all lead to presumed treatment failure. In these cases of “treatment failure”, diagnostic steps should be revisited and further diagnostics may be needed.

Objectives of the Presentation

1.  Review common reasons for treatment failure

2.  Review steps to take should treatment fail

Key Diagnostic Steps

When faced with a patient not responding to appropriate therapy, there are multiple steps to take to find out why therapy is not working. First and foremost, client compliance must be checked. The correct dose and frequency of administration must be verified. If the treatment failure involves topical therapy, the owner should be asked how they have been applying or using the topical to make sure application is correct. You can even ask your clients to show you how they have been doing things at home.

Revisit history taking to see if there is additional information you can gather or things that were missed first time around ask additional questions, such as “are other pets affected, are humans in the house affected, any seasonality to the skin disease, has there been a change in clinical signs, what age did the itching start?” To make your time as efficient as possible, consider having a questionnaire owners can fill in ahead of time or have technicians take a history first or read cytology samples while you are talking to clients.

Doses of medications and length of treatment should also be revised when dealing with a case of treatment failure. For example, an animal receiving glucocorticoids for atopic dermatitis presents for non-pruritic hair loss. This hair loss may, in fact, be due to the long-term use of glucocorticoids as opposed to the atopic disease. Attention should be paid to the time of year the pet is presenting to you the treatment failure may coincide with a change of season and be due to a peak in the number of allergens and a “flare-up” of the patient’s allergic dermatitis.

Questions should be asked as to whether there have been any dietary indiscretions that could have triggered a food allergic reaction, e.g., Was there just a Canada Day barbeque with Uncle Fred who we all know likes to sneak food to the dog under the table?

In allergic patients with previously controlled pruritus, who re-present for pruritus ± dermatologic lesions, cytology should always be performed to check for the presence of a secondary infection. Secondary infections (bacterial pyoderma and Malassezia dermatitis) are common reasons for perceived treatment failure as they mask the effects of anti-inflammatory therapy. Treatment may involve systemic or topical therapy, or a combination of the two. If left untreated, infections will continue to lead to treatment failure. Superficial bacterial and yeast infections must be treated for a 4-week period. Deep bacterial pyoderma should be treated for a longer period (8–12 weeks). It is also very important to repeat cytology at the end of the course of antimicrobial to document the infection has resolved and that you are not dealing with a case of antibiotic resistance.

Demodicosis, Sarcoptes or other ectoparasites must also be ruled out via skin scrapings, as they can lead to a worsening of clinical signs in a previously stable patient. An animal receiving high doses of glucocorticoids can develop demodicosis. Flea combing and examination for flea dirt should also be repeated. Individuals on long-term glucocorticoids can begin to show alopecia, erythema, pruritus and papular eruptions that many clinicians will interpret as a “flare up” of the pet’s allergies. Glucocorticoid doses may be increased in these patients. In these cases, it is important to more closely examine and palpate the skin itself. These could be cases of calcinosis cutis developing. Calcinosis cutis can be diagnosed via skin biopsy and treated with topical application of DMSO. Every effort should also be made to wean the pet off of steroids.

Antibiotic resistance has received much attention over the past few years with the incidence of MRSP increasing dramatically¹. Any animal with a bacterial pyoderma not responding to an appropriate dose and selection of antibiotic, should have an aerobic bacterial culture and sensitivity performed and an appropriate antibiotic selected from the list or antibiotics to which the bacteria is susceptible to.

Approach to Treatment Failure

Treatment failure is most often reported when there is a lack of response to glucocorticoids, cyclosporine, oclacitinib or lokivetmab in a presumed atopic dog. If this occurs, there could be an underlying food allergy and, therefore, it is imperative to perform an adequate novel protein or hydrolyzed diet, restricted diet trial.

If a novel protein diet is selected, I prefer diets with exotic proteins due to potential cross reaction of other more common proteins; for example, beef and venison. The owner must be informed that no treats, table scraps, pilling vehicles or flavoured medications can be used during the diet trial (that means you Uncle Fred). The diet trial should involve a diet with a novel protein that the animal has not been exposed to previously and should last for 8 weeks to determine whether an improvement is noted. Cutaneous adverse drug eruptions can lead to a worsening of clinical signs. For example, a dog with a secondary bacterial pyoderma due to allergic skin disease, receives a cephalosporin antibiotic and then develops further dermatologic lesions consisting of erythema, alopecia etc. This animal could be exhibiting signs of a cutaneous adverse drug reaction as opposed to a flareup of allergies. If pruritus occurs primarily in one location where topical products are applied, contact dermatitis should be considered.

In an animal previously responsive to glucocorticoids but now the beneficial effect is waning, consider steroid tachyphylaxis (“steroid fatigue”). The steroid can be switched to another glucocorticoid e.g. oral dexamethasone². If there is a lack of response to a correct dose of cyclosporine, cyclosporine levels can be checked. However, in atopic dogs there does not appear to be a correlation between blood concentrations and clinical response³. If the lack of response to glucocorticoids, cyclosporine and oclacitinib, in a patient with atopic dermatitis, is definitively proved and cytology, skin scrapings, etc., are all negative, one must consider either a case of pruritus refractory to conventional therapy or an incorrect diagnosis. At this point, diagnostic steps should be retraced and revised if necessary. Skin biopsies sent for histopathology can also be a great way to help eliminate and identify a diagnosis.

Immune-mediated disease can usually be diagnosed via histopathology. Other dermatological diseases, such as cutaneous epitheliotropic T cell lymphoma, can present with clinical signs similar to atopic dermatitis but are non-responsive to conventional anti-inflammatory therapy. If histopathology is consistent with atopic dermatitis then more aggressive immunosuppressive therapy may be needed in these refractory cases.

Prior to beginning systemic immunosuppressive therapy, all patients should have full bloodwork performed (complete blood count and serum biochemistry) as well as a urinalysis. Azathioprine has been used in certain cases to treat refractory canine atopic dermatitis at a dose of 2–2.5 mg/kg once daily⁴. Further bloodwork is also recommended every 2–4 weeks after starting therapy due to the potential adverse effects such as myelosuppression and hepatic toxicity (increase in ALT, ALP).

Pruritus can originate from regions other than the skin. Pruritus maybe associated with pain or can also be neuropathic. Studies are lacking to document efficacy of the following medications for treatment of pruritus but could be considered in specific cases. Gabapentin is used in humans to treat neuropathic and uremic pruritus⁵. Side effects include sedation and ataxia. Maropitant is a neurokinin-1 receptor antagonist that inhibits substance P⁶. This medication can have an anti-pruritic effect. Maropitant is licensed to prevent and treat vomiting in dogs as a dose of 2 mg/kg once daily. This dose has also been suggested to decrease pruritus.

5 Key “Take Home” Points

1.  In any case where treatment is not efficacious, cytology and skin scrapings should be performed and client compliance should be verified.

2.  Consider potential antibiotic resistance in a patient with bacterial pyoderma, confirmed on cytology, which is unresponsive to antibiotics.

3.  Taking skin biopsies and sending for dermatohistopathology can provide more information in cases of treatment failure.

4.  In certain pruritic cases consider non-conventional therapy or changing the type of glucocorticoid prescribed.

5.  In a pruritic patient non responsive to therapy for atopic dermatitis, consider food allergies or cutaneous epitheliotropic T cell lymphoma as an underlying etiology.

References

1.  Weese JS, van Duijkeren E. Methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius in veterinary medicine. Vet Microbiol. 2010; 140: 418–429.

2.  Miller WH, Griffin CE, Campbell KL. Dermatologic therapy. In: Miller WH, Griffin CE, Campbell KL. Muller and Kirk’s Small Animal Dermatology 7th ed. St Louis, MO: Elsevier Mosby; 2013: 108–183.

3.  Cotes MES & Swerlick RA. Practical guidelines for the use of steroid-sparing agents in the treatment of chronic pruritus. Dermatol Ther. 2013; 26: 120–134.

4.  Favrot C, Reichmuth P, Olivry T. Treatment of canine atopic dermatitis with azathioprine: a pilot study. Vet Rec. 2007; 160: 520–521.

5.  Yosipovitch G, Bernhard J. Chronic pruritus. N Eng J Med. 2013; 368: 1625–1634.

6.  Grubb T. Chronic neuropathic pain. Topics Comp An Med. 2010; 25: 45–52.