J Vet Intern Med 2010;24:278–284
Canine Steri le N odular Pannic ulitis : A R etr os pec tiv e S tu dy o f 1 4 Cas es A.L. O’Kell, N. Inteeworn, S.F. Diaz, G.K. Saunders, and D.L. Panciera Background: Sterile nodular panniculitis (SNP) is an uncommon inflammatory condition of subcutaneous fat that can be idiopathic, but has also been associated with underlying conditions such as pancreatic disease or systemic lupus erythematosus (SLE). The pathogenesis and clinical course of the condition are not well understood. Objectives: To retrospectively review cases of SNP associated with systemic signs, concurrent disease, or both and characterize the clinical, laboratory, imaging, and histopathologic findings, treatment, and response to treatment. Animals: Fourteen dogs with histologically confirmed SNP diagnosed between 1996 and 2008. Methods: Retrospective study. Results: Skin lesions were ulcerated or draining nodules in 9 dogs and nonulcerative subcutaneous nodules in 5. Most dogs had systemic signs, such as fever, inappetence, lethargy, and multiple lesions. Common clinicopathologic findings included neutrophilia with or without left shift, increased alkaline phosphatase activity, mild hypoglycemia, hypoalbuminemia, and proteinuria. Concurrent diseases included pancreatic disease, SLE, rheumatoid arthritis, polyarthritis, lymphoplasmacytic colitis, and hepatic disease. Dogs responded to immunosuppressive doses of corticosteroids when administered. Prognosis for recovery was related to the underlying disease process. Conclusions and Clinical Importance: SNP is not a single disease. Rather, it is a cutaneous marker of systemic disease in many cases. After thorough evaluation for concurrent disease and infectious causes, immunosuppressive treatment is often effective. Key words: Dog; Pancreas; Steatitis.
anniculitis is an inflammatory condition of subcutaneous fat with a wide variety of causes and clinical presentations. These causes include infection, trauma, foreign body, postinjection site inflammation, vasculitis, nutritional (vitamin E deficiency), drug eruption, insect bite, neoplasia, and sterile nodular panniculitis (SNP).1,2 SNP is an idiopathic disorder1,3–5 that is either primary in origin or associated with a variety of other illnesses, including pancreatic nodular hyperplasia,6 pancreatic neoplasia,7–9 pancreatitis,10 and immunologic diseases such as rheumatoid arthritis11 and systemic lupus erythematosus (SLE).3 Concurrent inflammation of fat in the abdomen,12 epidural space,13 and bone7 can occur in dogs with SNP, as can other inflammatory conditions such as polyarthritis.7 Skin lesions, which may ulcerate, can be solitary or multiple, and multiple lesions are more commonly associated with systemic signs such as pyrexia, lethargy, and anorexia.1,3 Relatively few cases have been reported in dogs, and a clear understanding of the pathogenesis and clinical course is lacking. The objective of this retrospective study is to describe cases of SNP associated with systemic signs, concurrent
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From the Departments of Small Animal Clinical Sciences (O’Kell, Inteeworn, Diaz, Panciera) and Biomedical Sciences and Pathobiology (Saunders), Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA. Dr Inteeworn is presently affiliated with the Section of Radiation Oncology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. Work was done at the Virginia Maryland Regional College of Veterinary Medicine. Corresponding author: D. L. Panciera, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061; e-mail:
[email protected].
Submitted March 11, 2009; Revised September 4, 2009; Accepted November 10, 2009. Copyright r 2009 by the American College of Veterinary Internal Medicine 10.1111/j.1939-1676.2009.0449.x
Abbreviations: ALP ALT SLE SNP UPC
alkaline phosphatase alanine aminotransferase systemic lupus erythematosus sterile nodular panniculitis urine protein : creatinine ratio
disease, or both and to characterize the clinical, laboratory, imaging, and histopathologic findings, treatment, and response to treatment.
Materials and Methods Medical records from 1996 to 2008 at the Virginia-Maryland Regional College of Veterinary Medicine (VMRCVM) were reviewed. Inclusion criteria were as follows: (1) diagnosis of panniculitis confirmed by histopathology, (2) infectious cause not identified by culture or special histopathologic stains, (3) no other identifiable cause such as trauma, foreign body, injection site reaction, drug eruption, insect bite, vasculitis, or local neoplasia, and (4) the presence of signs of systemic illness or concurrent disease, including fever, inappetence, lethargy, and apparent pain distant to skin lesions. Biopsies from the dogs included in the study were reviewed by a board-certified pathologist. Specimens were stained with hematoxylin and eosin, as well as periodic acid-Schiff, Gomori’s methenamine silver, Gram’s stain, Fite-Faraco, and Zielhl-Neelsen to identify bacteria, fungi, and mycobacteria. Panniculitis was diagnosed by finding inflammation of the subcutaneous tissue5 and was classified according to the predominant inflammatory infiltrate (suppurative, pyogranulomatous, granulomatous, lymphoplasmacytic). The presence of necrosis, fibroplasia, or fibrosis were recorded. Samples from 1 case were not available for review, and the original histopathology report was used. Cases without adequate biopsy material to definitively diagnose panniculitis and characterize the inflammation were excluded.
Canine Sterile Nodular Panniculitis Data recorded were signalment, body weight, history, previous treatment, rectal temperature, physical examination, lesion description, lesion number and distribution, clinicopathologic findings, diagnostic imaging, microbiologic culture results, cytology, histopathology, concurrent conditions, treatment, and response to treatment. Follow-up data were obtained by review of medical records from the VMRCVM or records from the referring veterinarian when available. Duration of follow-up was recorded, as well as response to treatment. Response was defined as complete resolution with withdrawal of therapy, complete resolution with ongoing therapy, partial response with therapy, and no response. The occurrence of relapses, as well as treatment and response, also was recorded.
Results Signalment and History Fourteen cases met the inclusion criteria. Of the 14 cases, 13 were examined by a board-certified pathologist (G.K.S.) specifically for this study, whereas the original histopathologic report was used for the remaining case. Three dogs were mixed breed, 2 were dachshunds (1 miniature and 1 standard), 2 were poodles (1 miniature and 1 standard), and the remaining dogs comprised 1 each of 7 different breeds. The median body weight was 9.8 kg (range, 4–47.7 kg). Nine were spayed females and 5 were neutered males. The median age was 9 years (range, 3–15 years). Skin lesions were noted in 13 dogs at the time of initial presentation, and in 1 dog 4 days after admission for treatment of pancreatitis. Other historical complaints were decreased appetite (4), pyrexia (4), lameness (3), generalized pain (2), vomiting (1), exophthalmos (1), tenesmus (1), and Horner’s syndrome secondary to otitis media (1). The median duration of clinical signs was 50 days (range, 0–210 days). Ten dogs had received one or more antibiotic before evaluation with no improvement in clinical signs noted. One dog, treated with antibiotics, IV fluids, and acupuncture was reported to have had a partial response. One dog had undergone surgical removal of a solitary lesion but it recurred. Corticosteroids had been administered to 2 dogs and nonsteroidal anti-inflammatorys to 3 dogs, with undetermined responses.
Physical Examination Skin lesions were solitary in 2 and multiple in 12 dogs. Lesions were described as ulcerated or draining nodules or tracts in 9 and as subcutaneous, nonulcerative nodules in 5 dogs. Lesions ranged in size from 0.5 to 3 cm in diameter, but in 7 dogs the size of the lesions was not reported. Lesion distribution most commonly included the trunk (10), neck and ventral cervical area (4), head (3), and perineum, hindquarters, and tail base (3). Other areas affected were the mammary area (2), axilla (2), inguinal region (2), and foot pads (1). Two dogs presented with generalized lesions. Fever (4102.5 F) was present in 11 dogs with a median temperature of 103.5 F (range, 102.7–105.51F). Other abnormal findings on physical examination included peripheral lymphadenopathy (5) that was generalized in
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3 and regional in 2 dogs, joint effusion, pain on manipulation of the joint or both (4), shifting leg lameness (1), systolic heart murmur (5), spinal hyperpathia (2), generalized weakness (2), generalized muscle atrophy (2), abdominal mass (2), and excessive joint laxity (1). Two dogs had no physical examination abnormalities except for the skin lesions. Overall, 13/14 dogs had historical or physical examination findings of systemic disease.
Laboratory Testing A CBC was performed in all cases. Nine dogs had a leukocytosis (median, 26.2 103/mL; range, 16.2–48.1 103/mL) characterized by a mature neutrophilia in 5 (median segmented neutrophils, 17.4 103/mL; range, 15.4– 24.4 103/mL) or neutrophilia (median segmented neutrophils, 21.6 103/mL; range, 17.9–44.3 103/mL) with a left shift in 4 (median band neutrophils, 1.5 103/ mL; range, 0.19–3.5 103/mL). One had neutrophilia (segmented neutrophils, 10.8 103/mL) with a left shift (band neutrophils, 0.24 103/mL) in the absence of an absolute leukocytosis, and 2 demonstrated only a left shift (band neutrophils, 0.35 103/mL and 2.6 103/mL, respectively) with toxic change. Nine dogs had nonregenerative anemia (median hematocrit, 34.7%; range, 28.6– 39.4%). Six dogs had lymphopenia, 1 had a lymphocytosis, 5 had a monocytosis, and 1 had an eosinophilia. Serum biochemistry was performed in all cases. Common abnormalities included an increase in alkaline phosphatase (ALP) activity in 12 dogs (median, 283 U/L; range, 136–3013 U/L), mild hypoglycemia in 10 (median, 76 mg/dL; range, 58–83 mg/dL), and hypocalcemia in 6 (median, 9.1 mg/dL; range, 8.0–9.2 mg/dL), all of which had concurrent hypoalbuminemia. Hypoalbuminemia was present in 10 (median, 2.15 g/dL; range, 1.5–2.4 g/dL) of which 5 had hypoalbuminemia alone and 5 had hypoalbuminemia and hyperglobulinemia (median globulins, 4.8 g/dL; range, 4.1–7.2 g/dL). Other abnormalities noted less commonly included hyperbilirubinemia (4), low total carbon dioxide concentration (4), low blood urea nitrogen concentration (4), low serum creatinine concentration (3), hyperphosphatemia (3), hypercalcemia (3), increased blood urea nitrogen concentration (2), increased serum creatinine concentration (2), hyperglobulinemia without hypoalbuminemia (2), increased alanine aminotransferase (ALT) activity (2), hypercholesterolemia (2), hyponatremia (2), and hyperkalemia (2). The following were noted in only 1 dog each: hypocholesterolemia, hypokalemia, hyperchloremia, hypernatremia, and hypochloremia. One dog with subacute cholangiohepatitis had marked increases in both ALP and ALT that developed while receiving doxycycline; this dog had waxing and waning subcutaneous nodules for 8 months before development of liver disease. Amylase and lipase activity, measured in 3 dogs, both were increased in 1 dog that was diagnosed with pancreatitis, whereas lipase alone was markedly increased (28,382 U/L) in a dog with pancreatic adenocarcinoma. Bromosulfophthalein retention was increased in the 2 dogs tested. A variety of other tests was performed less consistently. Urine protein : creatinine (UPC) ratio was
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abnormal (40.5) in all 5 dogs tested, with a range of 0.9– 3.61 (median, 2.5). Coagulation tests were evaluated in 7 dogs, with prolongation of both prothrombin time and partial thromboplastin time in 1 dog, and partial thromboplastin time alone in 5. D-dimers were detected in the only dog evaluated. Antinuclear antibody testing was positive in 1 of the 5 dogs tested. Rheumatoid factor was negative in the only dog tested. Testing for infectious diseases was performed sporadically. Bartonella serology was performed in 2 (both negative) and PCR in 1 (negative). Toxoplasma serology in 1 dog showed possible exposure (IgM, 1 : 128, IgG, 0). Borellia serology in 2 dogs was interpreted as possible exposure or vaccination in 1 and possible exposure or cross reaction with spirochetes in 1. Rocky Mountain spotted fever serology was negative in 2. Neospora serology was negative in 1. Ehrlichia canis serology was performed in 2 with 1 positive and 1 negative result. Cytology of skin lesions was performed in 9 cases by either impression smears or fine needle aspirates. Results were reported as suppurative inflammation with necrosis in 2 cases, and 1 each of suppurative inflammation, pyogranulomatous inflammation, pyogranulomatous and suppurative inflammation, suppurative inflammation with fibroplasia and granulomatous inflammation, and nondiagnostic. Two samples were considered possibly neoplastic (1 inflamed spindle cell tumor and the other a neoplasm of epithelial origin). These samples subsequently were found to be non-neoplastic based on histopathology. Aerobic bacterial culture of skin biopsy specimens was performed in 13 cases and anaerobic bacterial culture in 11. Of 2 cases with positive results, 1 grew a single colony of Bacillus subtilis and 1 grew 1 1 Macrococcus bovicus and 1 1 Staphylococcus epidermidis. All others were negative. Cultures for fungi (9), Mycobacterium (3), and Mycoplasma (1) were negative.
Diagnostic Imaging Thoracic radiographs were performed in 9 cases, and were interpreted as normal in 3. One dog each had the following findings: interstitial pattern, bronchointerstitial pattern, mild cardiomegaly, hepatomegaly, multiple thoracic wall masses (subcutaneous nodules of SNP), and prominent main pulmonary artery. Abdominal ultrasonography was performed in 11 cases. Six dogs had lymphadenopathy, and 2 dogs each had hepatomegaly, pancreatic mass, unilateral adrenal mass, and splenic mass. Abnormal kidneys were identified in 5 dogs including 1 each of hyperechoic kidneys, hyperechoic renal foci, renal cysts, irregular kidneys, and hydronephrosis. Other abnormalities, each noted in a single dog, included unilateral adrenomegaly, enlarged and hypoechoic pancreas (consistent with pancreatitis), hyperechoic liver with hypoechoic nodules, and ureteroliths. Multiple hyperechoic nodules not associated with organs throughout the abdomen were found in 1 dog, and were interpreted as possible fat necrosis. Based on other imaging studies, 4 dogs had degenerative valvular heart disease, 1 had erosive polyarthropathy, 1 had osteomyelitis, and 3 had joint swelling.
Histopathology Necrotizing panniculitis was observed in 6 cases. Two cases had suppurative inflammation, 2 had granulomatous inflammation, and 2 had suppurative and granulomatous inflammation associated with the areas of necrosis. In 6 cases, pyogranulomatous panniculitis was present. Concurrent suppurative dermatitis, pyogranulomatous dermatitis and furunculosis, pyogranulomatous myositis and dermatitis, and lymphadenitis were observed in 1 case each. Lymphoplasmacytic inflammation occurred along with the pyogranulomatous infiltrate in 1 case. Suppurative panniculitis was described in 2 cases, with inflammatory infiltrate extending into the dermis with fibrin accumulation in 1 case. Two of 3 dogs with pancreatic pathology had saponification of subcutaneous fat characterized by necrosis of fat with deposition of an amorphous basophilic material within the necrotic adipocytes. One other dog had a similar but less severe lesion but no evidence of pancreatic disease. Fibrosis was present in 9 of the above cases. No organisms were visualized in any sample with special stains. The only biopsy not reviewed by an author of this study was originally evaluated by a board-certified pathologist. Cultures for aerobic and anaerobic bacteria, fungi, and mycobacteria were negative in this dog.
Concurrent Disease A variety of concurrent diseases was diagnosed in 12 dogs, with some having multiple conditions. Pancreatic diseases, including pancreatitis, pancreatic adenocarcinoma, and a pancreatic mass of unknown origin, were present in 3 dogs with clinical signs typical of pancreatic disease, including vomiting and anorexia, as well as abnormalities on laboratory tests and imaging consistent with the diagnosis. Liver disease was found in 4 dogs. In 2 dogs, there was biochemical evidence of hepatic failure, but liver biopsies were not obtained. In the other 2 dogs, histopathology showed subacute cholangiohepatitis (possible drug reaction) in 1 and vacuolar hepatopathy with suppurative hepatitis in the other. Chronic valvular degeneration without heart failure was present in 5 dogs. Three dogs had ultrasonographic evidence of adrenal disease, with a unilateral adrenal mass in 2 and unilateral adrenomegaly in 1, although abnormal adrenal function was not suspected or evaluated in these dogs. Proteinlosing nephropathy without azotemia was present in 5 dogs, with UPC ratio 4 1.0 in 3, 1 of which was diagnosed with SLE and 1 with rheumatoid arthritis. Other renal diseases were found in 3 cases, including chronic renal failure, hydronephrosis, and renal cysts. The dog with renal cysts was also 1 of the 5 dogs with proteinuria. Four dogs had arthropathies; 2 had suppurative polyarthritis, 1 had suppurative monoarthritis, and 1 had rheumatoid arthritis. Keratoconjunctivitis sicca was present in 2 dogs, both of which were historical diagnoses. Other problems, each found in 1 dog included SLE, probable pulmonary thromboembolism, lymphoplasmacytic colitis consistent with inflammatory bowel disease (IBD), suppurative splenitis, ureterolithiasis, possible tibial osteomyelitis based on radiographic
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appearance, urinary tract infection, Horner’s syndrome secondary to otitis externa and media, and cranial cruciate ligament rupture.
Treatment, Follow-Up, and Response Ten dogs were treated with prednisone or prednisolone (1–3 mg/kg/d). Seven of these dogs were treated concurrently with antimicrobial drugs. Cyclosporine (5 mg/kg/d) and azathioprine (2.5 mg/kg/d) were used concurrently with prednisone in 1 dog each, and vitamin E was used in combination with immunosuppressive agents in 2 dogs. One dog was treated for concurrent disease (pancreatitis) only, and 1 dog was euthanized shortly after diagnosis. Two dogs were treated with antimicrobials only. Follow-up information was available in 12 cases. The duration of follow-up ranged from 2 months to 4 years. Of the 8 dogs treated with corticosteroids for which follow-up was available, the response to treatment was complete in 4 cases, complete with ongoing therapy in 3, and partial in 1. None of the dogs that responded completely but were still receiving therapy had attempts to discontinue treatment before they were either euthanized or lost to follow-up. The dog with pancreatitis was not treated specifically for panniculitis and the lesions resolved after treatment for the pancreatitis. The 2 dogs placed on antibiotics as a sole therapy showed no response. One of these dogs was diagnosed with pemphigus foliaceous 5 months later and was treated with prednisone and azathioprine; response was complete with ongoing therapy. The dog with pancreatic adenocarcinoma was euthanized shortly after diagnosis and no treatment was attempted. In 1 dog, complete resolution of lesions was followed by relapse after cessation of treatment on 2 occasions. The recurrent lesions resolved completely both times with reinstitution of prednisone therapy and the addition of vitamin E. Five dogs were euthanized months to years after diagnosis because of a variety of causes unrelated to panniculitis.
Discussion SNP must be differentiated from other forms of panniculitis and diseases with similar clinical findings including infectious diseases such as bacterial, fungal, or mycobacterial infection, sterile granuloma and pyogranuloma syndrome, foreign bodies, injection site reaction, insect bite, drug eruption, and neoplasia.1 Many of these diseases cause panniculitis, which is defined simply as inflammation of the subcutaneous fat. Most cases of panniculitis are limited to solitary lesions without clinical signs of systemic illness.2 In the largest description of panniculitis because of all causes to date, 46/57 dogs had solitary lesions, and only 3/57 had systemic clinical signs.2 In the present study, in which only cases with SNP were evaluated, all but 1 dog had evidence of systemic illness, including fever, inappetence, lymphadenopathy, and lameness or hyperpathia, because signs of systemic illness or concurrent disease were inclusion criteria. The dog without systemic clinical signs was later diagnosed with pemphigus foliaceous. The prevalence of
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SNP in dogs with all causes of panniculitis was not determined in the present study. SNP was differentiated from other causes of panniculitis by characteristic findings on histopathology and failure to identify infectious agents based on special stains of biopsies, bacterial, mycobacterial, and fungal cultures, and, in some cases, serologic testing. Although testing for all infectious agents was not performed in all cases, the negative cultures obtained in most cases, lack of organisms on histopathology, lack of other clinical abnormalities consistent with these infections, and response to corticosteroids in most cases were considered sufficient to rule out these diseases. However, because of the retrospective nature of the study and the identification of newly described infectious agents as well as development of new testing techniques over the span of the study, testing for infectious agents was not consistent and is a weakness of this report. Although histopathology and failure to identify infectious agents are necessary to confirm the diagnosis of SNP, a number of factors was identified in this study that could be used to increase the diagnostic consideration of SNP over other causes of panniculitis. Consistent with the breed predispositions previously reported, 2 dachshunds and 2 poodles were identified in our study.4,6,11,13,14 Unlike most other reports of SNP in dachshunds,4,11,13 the 2 dogs of this breed in the present report had concurrent diseases (rheumatoid arthritis, lymphoplasmacytic colitis) that have documented associations with panniculitis in humans.15,16 Although dachshunds have been suggested to have a genetic predisposition for panniculitis, our findings stress the importance of a thorough evaluation of each patient to search for important concurrent conditions. Evidence of systemic inflammation was present in most of the dogs with SNP based on the presence of fever and neutrophilia with or without a left shift. Other findings present in 4 50% of the cases in this study that might be useful in considering SNP as a diagnosis in dogs with compatible skin lesions include increased ALP, mild hypoglycemia, and hypoalbuminemia. Inclusion of a control group with panniculitis because of other causes would be necessary to ensure that these abnormalities were the result of panniculitis rather than coincidental concurrent disease. Because many cases in this study were associated with systemic disease, and because an infectious cause must be ruled out, the aforementioned abnormalities concurrent with nodular cutaneous lesions should lead to a thorough evaluation to rule out infectious disease and search for underlying or concurrent systemic disease. Cytology of impression smears or fine needle aspirates of the skin lesions indicated the presence of suppurative, pyogranulomatous, or granulomatous inflammation with variable necrosis as has been reported by others.2,7,8,14 However, these findings are not specific for SNP, and 2 cases in the present report were interpreted as possibly neoplastic, indicating that cytology alone is inadequate for diagnosis and can be misleading. In addition, infectious causes of panniculitis cannot be excluded based on cytology. Concurrent disease processes were detected in 12 dogs at the time of diagnosis. Based on reports in dogs as well
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as in humans, we postulate that in at least 5 of these cases SNP may have had a direct association with a concurrent disease process (pancreatic disease, rheumatoid arthritis, SLE, and possibly lymphoplasmacytic colitis). Pancreatic disease, including pancreatitis, pancreatic neoplasia, and pancreatic nodular hyperplasia, has been reported in association with panniculitis in dogs.6–10 The mechanism by which pancreatic disease induces panniculitis currently is unclear. It has been speculated in humans that pancreatic enzymatic activity may cause fat necrosis leading to panniculitis, but evidence for this is inconclusive.15,17 Two of the 3 dogs with pancreatic disease had histopathological changes similar to those previously described as being unique to SNP secondary to pancreatitis,5 specifically necrosis and saponification of fat combined with suppurative to pyogranulomatous inflammation. The occurrence of a dog without evidence of pancreatic disease that had similar, but less severe, histopathological changes indicates that the lesion may not be pathognomonic for pancreatic disease. Although this dog could have had subclinical pancreatitis, it had no clinical, ultrasonographic, or biochemical changes suggestive of pancreatitis. Although some reports of panniculitis associated with pancreatitis note saponification, it is not consistently described in dogs.7,8,10 Similar to panniculitis secondary to pancreatitis in humans,15,17,18 no specific treatment was required for resolution of the panniculitis in the dog with pancreatitis in this study. In humans, the triad of pancreatic disease, panniculitis, and arthritis has been reported.17–19 Arthritis in these cases is thought to be secondary to periarticular fat necrosis or local extension of subcutaneous lesions.18 Dogs in the present report, similar to those reported previously,7 had arthritis in joints without adjacent SNP lesions. In addition, only one of the dogs with arthritis had pancreatic disease. It seems likely that the polyarthritis associated with SNP is immunologically mediated, possibly as a result of antigenantibody complex deposition in the synovium. The complete response to immunosuppressive therapy in the 2 dogs with arthritis also supports this hypothesis. One dog in this study had polyarthritis and probable osteomyelitis along with a pancreatic adenocarcinoma. Osteomyelitis in dogs with panniculitis appears to be caused by intramedullary fat necrosis.7 Although histopathology of the affected bone was not available in the dog with radiographically diagnosed osteomyelitis from our study, this seems a likely possibility. Rheumatoid arthritis has a known association with several types of panniculitis in humans15,16 and has rarely been reported in the dog.11 The most common type in humans involves nonulcerated nodules in the vicinity of the joints with suspected extension of inflammation from overlying lesions into the synovium.16 A rare type involves development of pannicultis distant to affected joints, similar to the dog in our report.15 Panniculitis is an infrequent manifestation of SLE in humans15 and has rarely been reported in dogs with SLE.20 There are no reports of panniculitis in dogs with IBD, but in humans both ulcerative colitis and Crohn’s disease are associated with panniculitis.15,16 The complete re-
sponse to immunosuppressive therapy in the dog with lymphoplasmacytic colitis in our study supports an immune-mediated mechanism for both conditions. It is unclear if a true association between the 2 conditions exists, however, because IBD is very common, and panniculitis has not been described in conjunction with IBD to the authors’ knowledge. Several conditions detected in dogs in our study (eg liver disease, splenic disease, protein-losing nephropathy) have unclear association with panniculitis. Hepatic disease has not been reported previously in dogs in association with panniculitis, and although there are several case reports in humans,21–24 the evidence for a cause and effect relationship is unclear. Of the 2 cases in our study with a histopathologic diagnosis of liver disease, 1 had waxing and waning skin lesions present for 8 months before developing cholangiohepatitis, whereas the dog with suppurative hepatitis and vacuolar hepatopathy also had SLE. The 2 other dogs with liver disease in the present study did not have liver biopsy performed, so it is not possible to comment on any association between the presumed hepatic abnormalities and SNP. These dogs did not receive specific treatment for liver disease, but were treated with an antimicrobial and prednisone. One had a complete response and 1 had a partial response. Although it is possible that the treatment administered to these 2 dogs resulted in improvement of the liver disease with secondary resolution of the panniculitis, it seems more probable that corticosteroid administration was directly responsible for the response. Similar to 1 dog described in the current report with suppurative splenitis, sterile splenic abscess has been reported as a complication of panniculitis in humans.25 The mechanism is unknown, but it has been speculated to be either a systemic response to chronic inflammation or because of embolization of lipid to the spleen.25 The high prevalence of dogs with protein losing nephropathy in this report might suggest a relationship between the disorders. However, protein losing nephropathy often is associated with a variety of chronic inflammatory disorders because of antigen-antibody deposition.26 Glomerulopathy has been reported as an uncommon complication of SNP in humans rather than a cause.27–30 Proposed mechanisms include leakage of oxidized lipids inciting granulomatous inflammation and fibrosis27 and immune complex glomerulonephritis.28,30 Renal biopsies were not done in any of the dogs in this report, and a cause and effect relationship cannot be established. In humans, panniculitis is rarely associated with inherited a-1-antiproteinase deficiency.31 A single case report in the veterinary literature describes a case of panniculitis, polyarthritis, and meningitis in a dog associated with low a-1-antiproteinase activity as well as Bartonella infection.32 However, 2 other studies4,11 failed to find an association between genetic polymorphisms or low a-1antiproteinase concentrations in canine panniculitis. Dogs in the present study were not evaluated for a-1-antiproteinase deficiency. One of the weaknesses of this retrospective study was the inconsistency in testing for infectious agents. Al-
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though 2 cases had positive aerobic bacterial cultures, these organisms were interpreted as being contaminants in both cases. Organisms associated with granulomatous or pyogranulomatous inflammation of the skin or subcutis include Actinomyces, Nocardia, Blastomyces, Histoplasma, Coccidioides, Cryptococcus, Sporothrix, other opportunistic fungi (eg, Aspergillus), Prototheca, Pythium,5 various Mycobacteria,5,33,34 Leishmania,5,35,36 and Bartonella.32,37 Dogs with cutaneous mycobacterial infections usually have no systemic signs, and histopathology with acid-fast stains or culture are often sufficient for diagnosis.33,34 Many dogs with symptomatic leishmaniasis have cutaneous lesions that may mimic SNP, but many have systemic signs including weight loss, generalized lymphadenopathy, and other abnormalities including ocular disease, vomiting, diarrhea, or epistaxis.36 In addition, Leishmania frequently are visualized on histopathology of affected tissues, and also can be detected with polymerase chain reaction (PCR) and immunohistochemical testing.35,36 Bartonella species recently have been associated with meningoradiculoneuritis and dermatitis or panniculitis in 3 dogs37 and with panniculitis, polyarthritis, meningitis, and a-1-antiproteinase deficiency in 1 dog.32 Bartonella serology and PCR should be considered in cases of panniculitis, especially when associated with signs of meningitis or polyarthritis. SNP usually is treated with immunosuppressive agents unless contraindicated by concurrent conditions. Oral prednisone or prednisolone are most commonly used.1,3 Prednisone was the most commonly used agent in the cases reviewed here, either alone or in conjunction with vitamin E, azathioprine, or cyclosporine. A good response to treatment with resolution of SNP lesions was noted in 7 of 8 dogs treated with immunosuppressive drugs. These results are similar to those of another retrospective study4 in which 495% were successfully treated with immunosuppressive drugs; 28% went into remission and 66% required prolonged immunosuppressive therapy. In our study, only 1 dog relapsed twice after drug withdrawal, and was treated successfully by reinstitution of prednisone therapy as well as vitamin E. In 3 dogs that responded completely but were still being treated, no attempt was made to discontinue treatment before euthanasia or loss to follow-up. Medications may have been discontinued successfully in these 3 dogs. Lack of consistent follow-up is a major limitation of this study. Because SNP typically responds to corticosteroid administration, it is not possible to determine if the resolution of panniculitis is the result of control of primary diseases such as rheumatoid arthritis, SLE, and lymphoplasmacytic colitis, or a direct effect on inflammation of the panniculus. Therefore, we cannot use response to treatment as a certain indication of a cause and effect relationship. In addition to a variety of immunosuppressive treatments, oral vitamin E and potassium iodide1,3 have been recommended, but their efficacy is unknown. Prospective, controlled and randomized clinical trials are needed to determine the most efficacious treatment. Although the response to treatment in this report is largely attributed to immunosuppressive drugs, short-
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term antimicrobial therapy was instituted in the majority of dogs. Because most of these dogs had been previously treated with and did not respond to antimicrobials, we speculate that the antimicrobial therapy was not the cause for improvement. This conclusion is supported by failure to find an infectious cause in any case. However, the resolution of skin lesions in the dog with pancreatitis simply with supportive therapy of the pancreatitis suggests that nonimmunologic mechanisms may be responsible for panniculitis in some cases. This highlights the fact that SNP is not a distinct disease, but a heterogenous disorder with many possible causes. The condition is not well understood in dogs, and more studies are needed to further characterize the disease. SNP can be, as reported here, a cutaneous marker of a concurrent disease process. Although at least 5 dogs in this study had diseases that have a strong association with SNP in humans, it is difficult to determine if the other diseases diagnosed in many of the remaining dogs have a relationship to SNP or if they were merely coincidental. By limiting our inclusion criteria to cases that had clinical signs of systemic illness or a disease that has been associated with panniculitis in other species, we ensured that cases with panniculitis caused by disease other than SNP were not included. Inclusion of a control group of dogs with panniculitis due to causes other than SNP would have allowed stronger conclusions regarding the association of the concurrent illnesses and diagnostic test results with SNP. Additional studies will be necessary to determine if there truly is an association between SNP and diseases other than those associated with the pancreas or primary immune-mediated disorders. Until then, dogs with cutaneous lesions compatible with SNP should have a thorough diagnostic evaluation performed for underlying or concurrent disease and for infectious agents that could result in panniculitis.
References 1. Scott DW, Miller WH Jr, Griffin DE. Muller and Kirk’s Small Animal Dermatology, 6th ed. Philadelphia, PA: Elsevier Health; 2001:1156–1162. 2. Scott DW, Anderson WI. Panniculitis in dogs and cats: A retrospective analysis of 78 cases. J Am Anim Hosp Assoc 1988;24:551–559. 3. Torres SMF. Sterile nodular dermatitis in dogs. Vet Clin North Am Small Anim Pract 1999;29:1311–1314. 4. Yamagishi C, Momoi Y, Kobayashi T, et al. A retrospective study and gene analysis of canine sterile panniculitis. J Vet Med Sci 2007;69:915–924. 5. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin Diseases of the Dog and Cat. Clinical and Histopathologic Diagnosis, 2nd ed. Ames, IA: Blackwell Science Ltd; 2005. 6. Moreau PM, Fiske RA, Lees GE, et al. Disseminated necrotizing panniculitis and pancreatic nodular hyperplasia in a dog. J Am Vet Med Assoc 1982;180:422–425. 7. Gear RNA, Bacon NJ, Langley-Hobbs S, et al. Panniculitis, polyarthritis, and osteomyelitis associated with pancreatic neoplasia in two dogs. J Small Anim Pract 2006;47:400–404. 8. Brown PJ, Mason KV, Merrett DJ, et al. Multifocal necrotising steatitis associated with pancreatic carcinoma in three dogs. J Small Anim Pract 1994;35:129–132.
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