Canine sterile neutrophilic dermatosis (resembling Sweet’s syndrome) with severe extracutaneous manifestations

Sterile neutrophilic dermatosis is a rare disease in dogs, similar to Sweet’s syndrome in humans. This case report describes the treatment of a 2-year old Bearded Collie that was presented with a 3-week history of fever, hindlimb weakness, peripheral lymphadenomegaly and leucocytosis. Blood tests revealed severe leukocytosis, renal azotaemia, elevated liver enzymes and bilirubinaemia. Skin lesions started to appear in week four. Histology revealed a sterile neutrophilic dermatitis resembling Sweet’s syndrome. The dog displayed extracutaneous manifestations, including fever, polyarthritis, a severe leukemoid reaction, anaemia, hepatopathy and nephropathy. Issues regarding the use of criteria for the diagnosis of Sweet’s syndrome in humans that are used for dogs with sterile neutrophilic dermatosis, are discussed in this case report. The condition resolved with dexamethasone and mycophenolate mofetil as a novel steroid-sparing therapy. Three months later the dog relapsed, which rapidly responded to short-term dexamethasone treatment and temporarily increased mycophenolate mofetil dosage.


Introduction
Sterile neutrophilic dermatosis (SND) in dogs is similar to acute febrile neutrophilic dermatosis in humans, otherwise known as Sweet's syndrome (SS). 1,2 haracteristics of SND and SS include neutrophilic leukocytosis, mature neutrophils in the upper dermis, pyrexia and improvement of symptoms with corticosteroid treatment. 1,3 3][4][5][6][7][8] General illness and extracutaneous signs may appear much earlier than the dermatological signs of this disease complex. 1,2 ystemic corticosteroids are the therapy of choice for SND in humans and dogs, rapidly improving clinical signs, supporting the idea that the multifactorial pathogenesis involves immune complexes, circulating antibodies and pro-inflammatory cytokines. 1This report describes severe SND with extracutaneous manifestations in a Bearded Collie that was treated successfully with dexamethasone and mycophenolate mofetil (MMF, Cellcept ® , Roche Pharma AG).To our knowledge, this is the first case of SND in dogs treated with MMF as steroid-sparing agent.

Case report
A two-year old male intact Bearded Collie was presented to the primary care veterinarian with apathy, hindlimb weakness and possible polyuria/polydipsia for three days.The dog was limping after playing a few days earlier.The owner administered robenacoxib (Onsior ® Elanco Tiergesundheit AG) once off, however this did not improve the condition.The dog was properly vaccinated and healthy up to that stage.It had never been out of the country.The dog was febrile and the right tarsal joint was swollen.The subscapular and popliteal lymph nodes were enlarged.Initial blood tests showed slight hyperbilirubinaemia.The antinuclear antibody titre was positive.The dog was treated with metamizol (Vetalgin ® , MSD Animal Health GmbH) once off, doxycycline (Doxycyclin ® , Spirig Healthcare AG) for eight days and prednisolone (Spiricort ® , Spirig Healthcare AG).The prednisolone dosage was tapered over 11 days from 20 mg/kg to 5 mg/kg (Table 2).The treatment reduced the swelling of the tarsal joints and the dog's hind-limb weakness improved.One week later the dog showed renewed apathy and anorexia and was admitted to our clinic.The dog lost 3 kg bodyweight in three weeks (body-scoring index 3/9), had mild-icteric mucous membranes and warm, swollen tarsal joints.Cytological examination of synovia from the right tarsal joint, revealed a cell count of 17'090/µl, several erythrocytes, abundant non-degenerated neutrophils (92%), monocytes, some lymphocytes, and no bacteria.These results are compatible with an immune-mediated arthritis.
Follow-up haematology revealed a mild leukocytosis with neutrophilia (Figure 1), while the chemistry profile showed mild renal azotaemia (UREA 23.2 mmol/l, CREA 226 µmol/l), elevated liver enzymes (ALT 39 U/l, AP >120 U/l, GGT 5 U/l) and hyperbilirubinemia (78 µmol/l).The coagulation profile was normal.The packed cell volume (PCV) was normal initially, but nine days later the PCV started to fall, resulting in a normocytic, normochromic, regenerative anaemia.(Figure 1).The leukocytes increased massively (92.7 × 10 9 /L three weeks after initial presentation, Figure 1), coinciding with the appearance and worsening of the skin lesions and the lowest level of PCV.Serological tests for Dirofilaria immitis, Babesia canis, Ehrlichia canis, Anaplasma phagozytophilum, Leishmania infantum, and Leptospirosis spp were negative.Chest radiographs were unremarkable.Abdominal ultrasonographic examination suggested presence of an acute, diffuse hepatic inflammatory process, reactive lymphadenopathy and mild bilateral chronic nephropathy.
Three weeks after the first symptoms, macroscopic erosive skin lesions and erythema started to appear around the dog's lips.Soon more lesions appeared on the nose, hind legs, ventral abdomen and the whole thorax (Figure 2A).Macroscopically, the lesions on the hind legs showed large ulcerations, erythema and multifocal crusts.The abdomen and thorax displayed smaller erosions, maculae and crusts.In-house cytology on impression smears of some affected skin areas showed neutrophils, macrophages and signs of secondary pyoderma with intracellular bacteria and Malassezia.Prescapular and popliteal lymph nodes showed a heterogenic population of lymphatic cells with numerous small lymphocytes, few plasma cells and macrophages, corresponding to reactive hyperplasia.Analysis of fine needle aspirate (FNA) samples of the spleen revealed a heterogenic population of leukocytes with numerous non-degenerative neutrophils, small and large lymphocytes, monocytes and macrophages.The FNA of the liver revealed normal hepatocytes and pronounced intracanalicular bile plugs.These findings are unspecific for many hepatopathies.Histological analysis of various skin biopsies revealed a moderate to severe, interstitial neutrophilic infiltration extending from the superficial to the deeper dermis (interstitial neutrophilic dermatitis, Figure 3A and B).Additionally, a moderate to severe, periadnexal lymphoplasmacytic infiltration was present (Figure 3B).
Multifocal haemorrhages and a moderate oedema were observed in the superficial dermis.The skin biopsy from the right knee displayed a multifocal necrotic epidermis associated with a severe compact parakeratotic hyperkeratosis, multifocal intraepidermal neutrophilic pustule formation and occasional swollen keratinocytes (Figure 3B).In some biopsies occasional furunculosis was present, characterized by foamy macrophages surrounding keratin scales and free hair shafts.
Prednisolone treatment (0.25 mg/kg) was continued for three days but was discontinued because the dog panted heavily.Before treatment was resumed with dexamethasone seven days later, skin biopsies were taken for histological analysis as discussed above.Dexamethasone was started on 0.28 mg/kg once daily (Dexadreson ® , MSD Animal Health GmbH), and the skin lesions started to improve (Figure 2B, 2C).MMF was added as steroid-sparing agent to reduce the steroid dosage, and tapered over time (from 10 mg/kg once daily to 10 mg/kg every four days).Auxiliary systemic and local skin treatments were also applied (Table 2).
The dog was pretreated with doxycycline.Due to the critical condition of the dog on presentation in our clinic, and while Leptospirosis and Leishmaniosis had not been excluded as differential diagnoses, the decision

Fluid therapy
Ringer was made to add different antibiotics to the treatment plan to cover the four quadrants.While the dog's condition did not improve initially, amoxicillin was replaced with clindamycin to better cover anaerobic bacteria.At this stage, antibiotic culture and sensitivity testing was not performed while it was suspected that bacterial growth would be unlikely under triple antibiosis.
The skin lesions improved over time, and two and a half months after initial presentation the syndrome went into remission.A secondary mild pyoderma with pus-  tules covering the abdomen and upper hind legs remained for weeks.The pyoderma resolved after the glucocorticoid therapy was discontinued.The dog was symptom-free for just over five months, when a new skin lesion was noticed on the inguinal region.Cytology confirmed the presence of numerous non-degenerative neutrophils.This lesion disappeared after five days of dexamethasone treatment (0.28 mg/kg), which was then tapered off.The MMF treatment was temporarily increased to a daily dose.Eight months after initial presentation, the syndrome went into remission with MMF 250 mg every third day.

Discussion
Sweet's syndrome in humans is divided into four etiological categories: 1) classical, 2) malignancy-associated, 3) drug-induced and 4) localised acute febrile neutrophilic dermatosis. 1,9 ajor criteria include, 1) acute onset of erythematous cutaneous lesions including papules, plaques and nodules, and, 2) histopathological findings corresponding to a neutrophilic dermatitis with no infectious agents present.Minor criteria include 1) fever, 2) associated underlying disease/vaccination or pregnancy, 3) leukocytosis with neutrophilia and, 4) rapid response to glucocorticoid therapy. 1 Other laboratory abnormalities may be present, depending on which organs are also affected.They are however not part of the formal criteria for this disease complex.Both major criteria, and two of four minor criteria are required for the diagnosis SND.A summary of the published cases is given in Table 1.Classical SND was reported in a Dachshund with no extracutaneous manifestations.The skin lesions resolved within a week of treatment with glucocorticoids and doxycycline. 3Two cases of SND in dogs with gastroenteritis and arthritis, respectively, were also reported.One case resolved after glucocorticoid treatment, while the other was treated with meloxicam and fentanyl. 7Other cases include localised subcutaneous acute febrile ND that responded to glucocorticoid treatment 2 and three dogs with drug-induced SND that died despite treatment. 4,5 o malignancy-associated SND has been reported for dogs.
The six criteria can be generally applied to diagnose SND in dogs, however, no formal criteria have been published 3 .Schoellhorn et al. 2 argued that up to 2012, of the five published cases of SND in dogs only three out of six dogs survived the disease with glucocorticoid treatment.It was unclear if the criterion of response to glucocorticoid treatment can be used in dogs.Three new cases have been published since, where all dogs survived the disease.Two were treated with glucocorticoids and one with analgesia and a non-steroidal anti-inflammatory drug. 7,8  criteria for classical SS were fulfilled in our case and SND diagnosed.The relapse in symptoms during dose
La dermatosi neutrofila sterile è una malattia rara nei cani ed è simile alla sindrome di Sweet negli esseri umani.Questo studio descrive il trattamento di un bearded collie di 2 anni che è stato presentato con una storia di febbre di 3 settimane, debolezza degli arti posteriori, linfoadenomegalia periferica e leucocitosi.Gli esami del sangue hanno rivelato grave leucocitosi, azotemia renale, enzimi epatici elevati e bilirubinemia.Le lesioni cutanee sono apparse alla quarta settimana.L'istologia ha rivelato una dermatosi neutrofila sterile simile alla sindrome di Sweet.Il cane mostrava delle manifestazioni extracutanee, compresa febbre, poliartrite, una reazione leucemoide severa, anemia, epatopatia e nefropatia.reduction and without any know trigger indicates it was autoimmune induced, i.e. idiopathic.Extracutaneous manifestations are also associated with the SND disease complex, but do not always occur. 9In dogs, joints and the digestive tract seem to be the most afflicted locations apart from cutaneous lesions. 2,7,10 Te dog reported here also presented initially with polyarthritis, fever, diarrhoea, hepatopathy and nephropathy.Cutaneous lesions can precede or occur simultaneously with or later than extracutaneous signs.In this case the skin lesions appeared three weeks after the initial presentation with fever and polyarthritis.
In this case report, the dog initially displayed a not yet regenerative anaemia three weeks after initial presentation at the primary care veterinarian (Figure 1).This is presumably linked to the primary disease of SND.In one case, a dog had immune-mediated haemolytic anaemia associated with SND. 6 Another dog displayed a mild non-regenerative anaemia. 10A leukemoid reaction with severe neutrophilia like in our case occurs rarely, and coincided with appearance and worsening of the skin lesions.In most other case reports on dogs, the neutrophilic leukocytosis was mild (15.7 -31.8 × 10 9 /L), 2,5,7,8 and in one case a massive neutrophilia was measured (54.0 × 10 9 /L). 6e treatment of choice for SND is glucocorticoids initially applied at an immunosuppressive dosage. 1 In most cases, it improved the skin lesions. 3,5,7,8 Hee MMF was used as a steroid-sparing agent.This is to our knowledge the first report of MMF being used together with a glucocorticoid against SND.Other steroid-sparing agents used in the treatment of SS include immunoglobulin, chlorambucil, clofazimine, azathioprine and cyclosporine. 1,11 n a case of exophthalmos related to SND, cyclosporine was successfully used in combination with dexamethasone and prednisolone. 82][13] Adverse reactions in dogs with pemphigus treated with MMF include pyoderma and Malassezia, diarrhoea and leucocytosis. 11n our case, a mild secondary pyoderma was noted after the MMF treatment started, due a temporary side effect to the immunosuppressive action of the glucocorticoid and MMF therapy.
Two-and-a-half months after initial presentation and treatment with glucocorticoids and MMF, the syndrome went into remission.A minor relapse after five months was brought under control with dexamethasone treatment for nine days.Eight months after initial presentation, the syndrome was kept under control with MFF 250 mg every third day.While the disease complex is very rare, practitioners should include it in their list of differential diagnoses when faced with a patient with skin lesions of this kind and typical haematological changes.Extracutaneous signs are not always present, but can be severe.présentait des manifestations extracutanées telles que fièvre, polyarthrite, réaction leucémoïde sévère, anémie, hépatopathie et néphropathie.Les questions relatives à l'utilisation des critères de diagnostic du syndrome de Sweet chez l'homme chez les chiens atteints de dermatose neutrophilique stérile sont abordées dans le présent rapport de cas.La maladie a été traitée avec la dexaméthasone et le mycophénolate mofétil en tant que thérapie innovante permettant d'économiser des stéroïdes.Trois mois plus tard, le chien a rechuté mais a rapidement répondu à un traitement de courte durée à la dexaméthasone et à une augmentation temporairement la dose de mycophénolate mofétil.

Figure 1 :
Figure 1: Development of haematology results (packed cell volume, PVC; white blood cells, WBC) in a two-year old Bearded Collie with sterile neutrophilic dermatosis over time.Day 1 denotes the first day of presentation at the primary veterinarian.Day 12 denotes the first day of presentation in the referral clinic.Glucocorticoid therapy (prednisolone and dexamethasone) as well as steroid-sparing therapy (Mycophenolate mofetil, MMF) is portrayed in relation to the appearance of skin lesions.*At this stage (day 64) the skin was somewhat more inflamed but there were signs of a secondary pyoderma, including pustules, possibly because of the immune suppressant effect of the glucocorticoid therapy.

Figure 2 :
Figure 2: Macroscopic skin changes on the hind legs of a two-year old Bearded Collie with sterile neutrophilic dermatosis over time, including large ulcerations, erythema and multifocal crusts.The abdomen and thorax displayed smaller erosions, maculae and crusts.A. Two weeks after initial skin lesions started, nine days after initial dexamethasone treatment.B. Four weeks after initial skin lesions started, three weeks after initial dexamethasone treatment.C. Eighteen weeks after initial skin lesions started, three weeks after dexamethasone treatment was ceased.

Figure 3 :
Figure 3: Histological changes from skin biopsies taken 7 days after onset of skin lesions of a two-year old Bearded Collie with sterile neutrophilic dermatosis over time.A. Skin biopsy from the right elbow: a large number of neutrophils (thin arrows) can be observed both in the superficial and deep dermis.Haematoxylin and eosin stain, 100× magnification.Inset: Detail of the above-mentioned neutrophilic infiltrate.Haematoxylin and eosin stain, 200× magnification.B. Skin biopsy from the right knee of a two-year old Bearded Collie with sterile neutrophilic dermatosis over time: a large number of neutrophils (thin arrows) can be observed both in the superficial and deep dermis and intravascularly.Multifocal to coalescing, severe periadnexal lymphoplasmacytic infiltrates are present (arrowheads).The overlying epidermis displays a severe parakeratotic hyperkeratosis (arrow) and an intraepidermal pustule filled with neutrophils (star).Haematoxylin and eosin stain, 100× magnification.Inset: Detail of the above mentioned neutrophilic and lymphoplasmacytic infiltrates.Haematoxylin and eosin stain, 200× magnification.

Table 1 :
Overview of reported cases of canine sterile neutrophilic dermatosis

Table 2 :
Drugs administered during the treatment of the dog since admission in our clinic (s = stationary, a = ambulatory)