Successful management of feline pemphigus foliaceus with pentoxifylline and topical hydrocortisone aceponate

Abstract The treatment regimen for feline pemphigus foliaceus (PF), an autoimmune disease caused by auto‐antibodies against proteins of the desmosome junction, usually includes high doses of oral or parenteral immunosuppressive drugs, typically glucocorticoids. This case adds to a growing body of evidence that topical hydrocortisone aceponate is effective for the treatment of feline PF, and demonstrates the practical use of a non‐invasive diagnostic method for histopathology when owners refuse a biopsy to support a clinical diagnosis of PF. Finally, this case highlights an international trend of owner‐initiated treatment of feline infectious peritonitis (FIP) using unlicensed, unregistered drugs.

etc.) (Coyner et al., 2018;Peterson & McKay, 2010;Preziosi, 2019). It's important to inform clients about the high relapse risk, either spontaneously or during treatment adjustments. The time until disease control can vary but is on average 3 weeks (Bizikova & Burrows, 2019b;Coyner et al., 2018;Preziosi et al., 2003). In human medicine, drugassociated PF is subdivided into drug-triggered and drug-induced PF (Pile et al., 2021;Wolf et al., 1991). In the latter, there is a good chance of stopping medication without disease relapse after initial treatment and cessation of the offending drug. The former typically needs longterm treatment similar to spontaneous cases of PF (Wolf et al., 1991).
Here we describe a successful therapeutic approach to PF in a cat with severe co-morbid disease, in which the administration of immunosuppressive doses of systemic glucocorticoids was considered contraindicated. A non-invasive technique to support our diagnosis was used, which may be useful when full thickness biopsies are not possible.

CASE DESCRIPTION
A On physical examination at referral, all vital signs were within normal limits. The cat's body weight was 3.45 kg and the body condition score was 3/9, indicating the cat was underweight. Mild, multi-focal erythema and crusting were present on the dorsal nose, concave pinnae and the dorsal, interdigital, haired skin and claw folds of all four paws. Some of the digits were swollen and the cat resented  (Figure 3). On repeating serum biochemistry, the only residual abnormality was a mild persistent hyperglobulinaemia (5.6 g/dl, normal range: 2.8-5.1 g/dl). The total serum protein (8.7 g/dl, normal range: 5.7-8.9 g/dl), albumin (3.1 g/dl, normal range: 2.2-4.0 g/dl) and the albumin/globulin ratio had resolved (0.5, normal range: 0.5-1.2). The two alopecic areas persisted.

DISCUSSION
The diagnosis of non-effusive FIP can be challenging, since the most The diagnosis of PF in this cat with presumptive concurrent noneffusive FIP prompted a treatment approach without the use of traditional immunosuppressive drugs that could result in an adverse outcome. We elected to use topical administration of a hydrocortisone aceponate spray, which has been described previously in two cases of feline PF (de Bellis, 2008;Neuber & Shaw, 2011). This drug formulation is licenced for the treatment of inflammatory and pruritic dermatoses as well as atopic dermatitis in dogs. Use in cats is off-label, although, previous studies support its safety and efficacy (de Bellis, 2008;Neuber & Shaw, 2011;Sauvé, 2019;Schmidt et al., 2012).
In addition, in order to avoid significant suppression of the Th1 immunity by conventional therapy and because of its efficacy in treatment of human pemphigus vulgaris, pentoxifylline was added (Kummari et al., 2020;Marsella & Nicklin, 2000;Takehana et al., 2002).
Although not efficacious against FIP, it is known to be well tolerated in cats with FIP (Fischer et al., 2011).
In human medicine, pentoxifylline has been used as an adjuvant medication for the treatment of pemphigus vulgaris since it has been shown to inhibit TNF-alpha, playing a partial role in the pathogenesis of the disease (Didona et al., 2019;El-Darouti et al., 2009;Frew et al., 2011;Tham et al., 2020;Zhao & Murrell, 2015). Further studies are needed to evaluate the role of this cytokine in the pathogenesis of feline and canine PF as well as the potential role of pentoxifylline as an effective treatment alternative for this disease. Did the adverse event appear after the suspected drug was administered?
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? Interpretation all results: doubtful, the reaction was likely related to factors other than a drug.
Both itraconazole and lime sulphur are suspected initiators of PF in cats (Bizikova & Burrows, 2019a, Preziosi et al., 2003. However, as the skin lesions developed before both of these medications were administered and before the first injection of the antiviral drug, it is unlikely these drugs played a role. This was also supported by the calculated Naranjo score (Table 1), based on a questionnaire designed for the determination of a drug to be involved in an adverse event (Naranjo et al., 1981). Provocation, re-administration of the offending drug, was however not considered due to the possibility of an even more serious reaction. An association with vaccination or a deworming product was considered less likely given the long-time interval of several months in between the application of these products and the development of PF.
Viral infections such as COVID-19, Epstein-Barr virus, human endogenous retroviruses, herpesvirus (human and equine) and canine parvovirus are reported to trigger autoimmune diseases (Ehrenfeld et al., 2020;Favrot et al., 2000;Herder et al., 2012;Nelson et al., 2014;Ruocco et al., 1996;Wang et al., 2005). In addition, FCoV has been directly implicated to cause cutaneous papular to nodular lesions in cats with FIP, characterised histologically by granulomatous inflammation and necrosis. FCoV can be detected in the cytoplasm of macrophages within the dermis in affected skin, using immunohistochemistry (Cannon et al., 2005;Declercq et al., 2008;Redford & Al-Dissi, 2019). The gross appearance, distribution of skin lesions and histopathological findings in our case were not consistent with FIP-associated dermatitis. There is increased evidence of a potential association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans and the rapid development of autoimmune and/or autoimmune dysregulation. Several reaction patterns such as cutaneous rashes, vasculitis, autoimmune cytopenia, antiphospholipid syndrome, central and peripheral neuropathy, myositis, myocarditis, Guillain-Barré syndrome, Miller Fisher Syndrome and Kawasaki like disease haven been described (Ehrenfeld et al., 2020;Saad et al., 2021;Talotta & Robertson, 2020). However, since FIP is common and concurrent PF has not previously been reported, such a mechanism is unlikely, yet still possible.
Overall, a spontaneous form of PF is highly unlikely and the final causative trigger is unclear in this case.
The focal temporarily crusted and alopecic lesions which were persistent and non-responsive to therapy were considered a sequela of the owner-administered injections since they correlated with the injection sites and this is a well-known phenomenon in veterinary dermatology (Berrocal, 2004;Gross TL, 2005). Severe irritation and focal areas of necrosis have been reported subsequent to subcutaneous injections of nucleoside analogues such as remdesivir and GS441524 in cats (Izes et al., 2020;Pedersen et al., 2018;Pedersen et al., 2019). In addition, the owner had not administered any topical spot-on products.
This case also highlights the challenges veterinarians currently face due to a growing widespread practice in Hong Kong and other regions of the use of unregistered, unlicensed drugs that claim to be nucleoside analogues, by owners desperate for a cure of an otherwise fatal disease of their pet (Jones et al., 2021).
Finally, this report also demonstrates that performing histopathology on crusts obtained from representative skin lesions can support a diagnosis of PF when collection of full-thickness skin biopsies is not possible. Nevertheless, further studies are needed to evaluate the diagnostic utility of this described technique. Other non-invasive techniques to support a diagnosis include cytological examination of fineneedle aspirate contents of intact pustules. However, such lesions may be absent when pruritus is present or the pustules rupture due to their thin and fragile nature. Care needs to be taken in interpreting cytological results, since Staphylococcus spp. and dermatophytes can cause PFlike lesions as described in humans and dogs and anecdotally in cats (Olivry & Linder, 2009;Scott, 1980).
In summary, this report describes the first case of feline PF in China and an effective alternative treatment approach consisting of pentoxifylline and topical hydrocortisone aceponate in a patient with a history of a severe systemic infectious disease.

ACKNOWLEDGEMENTS
The author would like to thank Queenie Yuen Ting Cheong, Jeffrey Yip, Daniela Hernandez Muguiro and Michael Wat for assistance and support in this case and Sonya Bettenay for her appreciated contribution.

ETHICS STATEMENT
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required due to the nature of this case report.

CONFLICT OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are available in the supplementary material of this article.