Canine Sarcoidosis Treated Successfully With Oclacitinib: A Case Report

ABSTRACT

A male Finnish Lapphund presented with widespread papular skin lesions, which were diagnosed as cutaneous sarcoidosis based on histopathological results. Multiple diagnostic techniques, including bacterial and fungal culture, special staining, electron microscopy and in situ hybridisation, failed to identify a specific causative agent. Remission was achieved with oral oclacitinib.

A male Finnish Lapphund presented with widespread papular skin lesions, which were diagnosed as cutaneous sarcoidosis based on histopathological results. Multiple diagnostic techniques, including bacterial and fungal culture, special staining, electron microscopy and in situ hybridisation, failed to identify a specific causative agent. Remission was achieved with oral oclacitinib.

1. Introduction

Sarcoidosis is a granulomatous disease reported in dogs, horses, cattle and humans [1, 2, 3, 4, 5, 6, 7]. The aetiology is unknown [7]. Canine sarcoidosis remains a rare disease, with two published case reports [1, 2]. Lesions include erythematous papules, plaques and nodules on the trunk, lateral thighs, neck, face and ears, often with bilateral symmetry [1, 2, 8]. Differential diagnoses include sterile or infectious granulomatous and pyogranulomatous diseases, and neoplasia [8].

Diagnosis is based on clinical evaluation, exclusion of infectious diseases and the presence of granulomas on histopathological evaluation. These granulomas lack a prominent surrounding rim of lymphocytes (so‐called naked granulomas) in the superficial‐to‐deep dermis, consisting of epithelioid macrophages [1, 2, 8].

Reported successful treatments include corticosteroids and ciclosporin [1, 2, 8]. The present report describes a case of sarcoidosis in a dog, including the diagnostic investigation and successful management with oclacitinib.

2. Case Report

A 7‐year‐old, 25.9 kg, intact male, Finnish Lapphund was presented with numerous nonpruritic papular skin lesions that were first noted 8 months before examination. There was no recent history of vaccination, medication or known infections. The dog had never travelled outside northern Europe.

On physical examination, hundreds of small, firm, alopecic papules up to 3 mm in diameter were observed on the trunk, lateral thighs and behind the left ear. The papules were bilaterally symmetrically distributed and most numerous along the dorsal midline of the trunk. Apart from the skin lesions and mild discomfort on palpation of these, the dog appeared clinically normal. Cytological results obtained by impression smear and skin scrapings from the dorsal trunk failed to show micro‐organisms or parasites.

Four 8 mm punch biopsies were collected under general anaesthesia with intramuscularly administered dexmedetomidine 0.006 mg/kg (Cepedex 0.5 mg/mL; CP Pharma Handelsgesellschaft mbH) and butorphanol 0.12 mg/kg (Butorgesic vet 10 mg/mL; CP Pharma Handelsgesellschaft mbH), intravenous propofol 0.77 mg/kg (Proposure 10 mg/mL; Corden Pharma S.p.A.) and local anaesthesia with lidocaine 0.77 mg/kg (Lidor Vet 10 mg/mL; VetViva Richter GmbH). Fluralaner (Bravecto 1000 mg; Intervet International B.V.) was administered perorally (38.6 mg/kg) to rule out ectoparasites. Complete blood count (CBC) and serum biochemistry results were within reference ranges.

On histopathological examination, all skin biopsies showed granuloma formation in the dermis (Figure 2a,b). The granulomas consisted of tight, well‐formed aggregates of epithelioid macrophages without peripheral lymphocytic cuffing. Coalescent granulomas formed discrete dermal nodules. The epidermis ranged from uninvolved to mildly acanthotic and hyperkeratotic. Special stains, including Ziehl–Neelsen (ZN), modified ZN, periodic acid Schiff, Gram and Grocott's methenamine silver (GMS), were negative for pathogens. Immunohistochemical evaluation (IHC) (Figure 2c) showed that the epithelioid cells forming the granulomas exhibited weak, reticular Iba‐1 positivity and MAC‐1 negativity. A low number of CD3‐positive T‐lymphocytes were observed at the periphery of some granulomas, along with sparse CD79‐positive B cells.

FIGURE 2.

Histopathological, immunohistochemical and transmission electron microscopy (TEM) findings for a dog with sarcoidosis. (a) Histopathological confirmation of canine sarcoidosis. Haired skin: Coalescing, granulomatous dermatitis with well‐formed epithelioid granulomas that preserve adnexal structures. The granulomas comprise tight, well‐organised aggregates of epithelioid macrophages without peripheral lymphocytic cuffing. Haematoxylin & eosin. (b) Higher magnification of (a) highlighting the well‐formed granulomas composed predominantly of epithelioid macrophages. The granulomas appear compact and lack a surrounding lymphocytic infiltrate, characteristic of sarcoid‐type inflammation. H&E. (c) Immunohistochemically, the epithelioid cells forming the granulomas exhibit weak, reticular anti‐Iba‐1 positivity. Immunohistochemical evaluation with Iba‐1 antibody. (d) Epithelioid macrophages appear in TEM as large, irregularly shaped cells closely apposed to neighbouring cells. They exhibit abundant cytoplasm, sparse phagolysosomes (asterisk), oval nuclei with dispersed chromatin and well‐developed mitochondria and rough endoplasmic reticulum. Scalebars = 2 μm.

Following the initial histopathological diagnosis, five additional skin biopsies were collected (Figure 1a,b) using the same protocol and fixed in glutaraldehyde for transmission electron microscopy (TEM). One biopsy sample was aseptically divided, and the bottom portion of the tissue sample was submitted for aerobic and anaerobic bacterial culture. An impression smear for cytological evaluation obtained from the deep margin of one biopsy sample did not show micro‐organisms. Wood's lamp examination was negative. Hairs and scales were obtained for dermatophyte culture. Bacterial and fungal cultures yielded negative results.

FIGURE 1.

Cutaneous lesions located on the dorsolateral trunk of a dog with sarcoidosis. (a) The haircoat has been clipped on the right flank for inspection and taking samples. The stitches at the biopsy collection sites are seen. (b) A close‐up of the clipped area before biopsy collection shows several mildly erythematous and exfoliative papules up to 3 mm in diameter. (c) The same area 2 months later shows fewer and smaller papules compared to (a). Biopsy sites are hyperpigmented.

For ultrastructural analysis, small tissue samples were fixed in glutaraldehyde, post‐fixed in osmium tetroxide, dehydrated and embedded in epoxy resin. Ultrathin sections were stained with uranyl acetate and lead citrate and examined using TEM. In addition to evaluating cellular and subcellular morphology, TEM was specifically used to search for a potential antigenic agent underlying the observed inflammatory reaction; however, in TEM (Figure 2d), a potential agent, such as microbes or foreign particles, responsible for the excessive granulomatous inflammation could not be identified.

In situ hybridisation (ISH) with a probe targeting bacterial 16S rRNA (Bio‐Techne; Advanced Cell Diagnostics) to formalin‐fixed samples was performed consistent with the manufacturer's protocol. A positive signal was detected only in a small portion of granulomas.

Therapy with oclacitinib (0.63 mg/kg once every 12 h; Apoquel, Zoetis) was started because the owner was reluctant to use other medications, previously reported as effective, owing to the dog's history of gastrointestinal upset. The owner was informed of the off‐label use of oclacitinib. Computed tomography to assess potential multisystemic involvement was declined.

On Day (D)18, after initiating treatment, the previous discomfort had subsided. The number and size of the papules were decreased. Two weeks later (D32), the overall number of papules had significantly decreased from the original presentation. The biochemistry profile and CBC remained within reference ranges.

During subsequent follow‐up visits on D46 and D67 (Figure 1c) the number and size of the papules gradually decreased. A few scaly crusts remained on D119. The oclacitinib dose was decreased to 0.63 mg/kg once daily. Two months later, it was decreased to 0.32 mg/kg once daily. There was a recurrence of discomfort on palpation, which prompted a return to 0.63 mg/kg once daily. Further tapering attempts yielded the same results.

One year and 4 months after initiating the therapy, no papules could be detected. The dog appeared in good general condition. The CBC showed a mild decrease in white blood cells (WBC 5.59 × 10³/μL, reference: 6–17 × 10³/μL) and lymphocytes (0.65 × 10³/μL, reference 1.0–4.8 × 10³/μL). The oclacitinib dose was gradually reduced, yet the dog exhibited a recurrence of signs, and the once‐daily 0.63 mg/kg dose was resumed.

Two years and 1.5 months after initiating oclacitinib therapy, a CBC was repeated. The WBC, lymphocyte count and globulin levels were slightly below the reference ranges (4.69 × 10³/L, 0.71 × 10³/L and 19 g/L [23–52 g/L], respectively). Two truncal papules under 2 mm in diameter were observed. Oclacitinib was continued at a dose of 0.63 mg/kg once daily.

3. Discussion

The clinical presentation with numerous symmetrically distributed papules mainly on the trunk, and histopathological findings of ‘naked granuloma’ formation in the dermis seen in our case were consistent with those previously reported in canine sarcoidosis [1, 2, 8].

In humans, sarcoidosis is a multisystemic disease, where any organ, including the skin, can be affected. Intrathoracic involvement occurs in 90% of the cases [7]. In horses, the typical presentation is exfoliative and granulomatous dermatitis; however, in the generalised form, multiple organ systems can be affected [5, 9]. Only a few cases of canine sarcoidosis have been reported [1]. In this case, clinical findings did not suggest multisystemic involvement, although no further diagnostic investigations for internal organ involvement were performed.

In horses and cattle, hairy vetch ( Vicia villosa ) can trigger sarcoidosis/systemic granulomatous disease [6, 10], and mycobacteria have been reported in some equine sarcoidosis lesions [9]; however, these have not been documented in dogs.

Sparse bacterial ribosomal 16S ISH signals were detected in some of the granulomas. However, culture studies and extensive multimodal investigations, including histochemical stains and TEM, failed to identify any underlying aetiological agent. We conclude that the detected ISH signals did not support a definitive microbial role in disease pathogenesis. Furthermore, the condition was effectively managed with immunosuppressive therapy alone, without the need for antimicrobial agents. Although no microbes were demonstrable in the lesions, the findings do not entirely rule out the hypothesis of an antecedent microbial trigger that had already resolved by the time of tissue examination.

Histopathological differential diagnoses for canine sarcoidosis include other granulomatous or pyogranulomatous diseases, both sterile and infectious, as well as neoplasia. These include sterile granuloma/pyogranuloma syndrome, characterised by periadnexal‐to‐nodular lesions in the dermis and panniculus, with peripheral macrophages and central neutrophils; reactive histiocytosis, in which a nodular‐to‐diffuse infiltrate extending from the mid‐dermis to the superficial subcutis consists predominantly of dermal dendritic cells, lymphocytes and neutrophils; and cutaneous xanthoma, characterised by lipid deposition [8].

Granulomatous inflammation occurs when microbes or parasites, such as Mycobacterium species, certain fungi or Leishmania species, resist killing and persist within macrophages, thereby triggering a chronic T‐helper cell (Th)1‐mediated immune response that results in their sequestration. Definitive diagnosis is based on identification of the causative agent.

Sarcoidosis with ‘naked granulomas’ can be challenging to distinguish from and may even overlap with certain forms of sterile granulomas. In human medicine, multiple sarcoidosis‐like syndromes and distinct sarcoidosis phenotypes have been described, implying that sarcoidosis may represent a spectrum of related syndromes rather than a single disease [7]. A similar development may occur in veterinary medicine, where the triggers of sterile granulomatous and pyogranulomatous inflammatory reactions remain to be elucidated.

Human cutaneous sarcoidosis is commonly treated with glucocorticoids; however, Janus kinase (JAK) inhibitors have also been found effective [11]. CD4⁺ T cell‐derived interferon (IFN)‐γ is a central pro‐inflammatory cytokine in sarcoidosis. It activates macrophages via the JAK‐STAT (signal transducers and activators of transcription) pathway [11], and therefore oclacitinib, a JAK inhibitor, could be a potentially effective medication in dogs.

Cutaneous sarcoidosis in a Beagle was treated with immunosuppressive doses of oral prednisolone and doxycycline for 2 weeks without effect. Almost complete remission was achieved with a high dose of oral ciclosporin (9 mg/kg/day) after 3.5 months. The dose was tapered to twice weekly 4 months after remission. The follow‐up period was 9 months [2].

Oclacitinib is registered for the treatment of canine atopic dermatitis (cAD), yet it is used with higher extra‐label doses for the treatment of immune‐mediated diseases because of its immune‐modulating effects [12]. In our case, however, oral oclacitinib was initiated with the starting dose for cAD longer than the recommended 14 days: after remission in 4 months the dose was tapered to a maintenance dose used in cAD. Several relapses were seen at further tapering attempts and remission was achieved again when the previous dose was resumed. The decision to continue oclacitinib despite slight haematological abnormalities was based on tolerability, efficacy and owner preference. The follow‐up duration in our case exceeded 2 years.

Despite extensive use of various laboratory methods, the aetiology of sarcoidosis in dogs remains elusive. Moreover, given that granulomatous skin lesions are relatively common in this species, it raises the question of why a sarcoidosis‐like clinical and histological presentation is so rare in dogs. We also conclude that oclacitinib may be an effective therapeutic option for canine sarcoidosis.

Author Contributions

Lotta Pänkälä: writing – original draft; writing – review and editing; investigation, conceptualisation. Kirsti Schildt: conceptualisation; writing – review and editing; methodology; supervision; investigation. Anna Huupponen: methodology; investigation; writing – review and editing. Antti Sukura: methodology; writing – review and editing; investigation. Seppo Saari: conceptualisation; writing – review and editing; supervision; methodology; investigation; visualisation.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.