Idiopathic, nonerosive, noninfectious arthritis was firstreported in the mid 1970s as a disease of canine joints

without obvious etiology.1 The condition is now referredto as canine idiopathic immune-mediated poly-arthritis (IMPA) and may be differentiated into 4 sub-groups according to an absence of defined associations(type I), associations with infection (type II), associationswith gastrointestinal tract disease (type III), and associa-tions with neoplasia (type IV).2 Idiopathic immune-medi-ated polyarthritis is now recognized as the most commonimmune-mediated arthritic condition in dogs3,4 and themost common cause of pyrexia of unknown origin indogs in a referral hospital population.5,6 Only 1 published

report2 documents the success of treatment and long-termprognosis for dogs with IMPA.

Vaccination as a trigger for immune-mediated dis-ease in dogs and humans has frequently been suggest-ed.7 A temporal association between canine immune-mediated hemolytic anemia with vaccination has beendocumented.7 Recent vaccination with live feline cali-civirus has been associated with feline polyarthritis.8

Type I canine IMPA associated with vaccination hasbeen reported in 4 dogs.9 The purpose of this retro-spective study was to determine the signalment, clini-cal signs, laboratory findings, relationship to vaccina-tion, and response to treatment in dogs with type IIMPA. Other types of IMPA (II, III, and IV) were notincluded in this study because the success of theirtreatment depends on the initiating cause.2,4 Wehypothesized that the onset of canine type 1 IMPAcould be associated with recent vaccination (within 1month) and that the prognosis for recovery with treat-ment could not be related to historical or laboratoryfindings at the time of referral.

Criteria for Selection of CasesMedical records of dogs evaluated at the Glasgow

University Veterinary School, Edinburgh UniversityVeterinary School, and the University of CambridgeVeterinary School from January 1997 to July 2002 withtype I immune-mediated polyarthritis were reviewed.Only dogs for which full clinical records, radiographicevaluations, details of treatment, and follow-up data (asdefined by reexamination, telephone conversationswith owners, or both) were available were included inthe study. The diagnostic criteria for inclusion weredogs with nonerosive polyarthritis confirmed by radi-ographic assessment of affected joints; cytologic analy-sis of samples from multiple arthrocenteses; andabsence of rheumatoid arthritis,10 systemic lupus ery-thematosus,11 polyarthritis-polymyositis,12 or poly-arthritis-meningitis syndrome.4 In addition, dogs ofChinese Shar Pei and Akita breeds were excludedbecause of the breed-associated immune-mediated poly-arthritis recognized in those dogs.4 Results of arthrocen-tesis were considered diagnostic if cytologic analysis offluid from at least 2 joints in each dog revealed abnor-malities (automated WBC concentration > 3 X109cells/L or appearance of highly cellular synovial fluidwith cell population > 10% neutrophils and no intra- orextracellular bacteria13). Also, dogs must not have hadevidence of an infective disease process, gastrointestinaldisease, or neoplasia, as determined on initial or subse-quent investigations. Dogs were considered to havenegative results for rheumatoid arthritis if no erosivechanges were identified on examination of the radi-

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Type I immune-mediated polyarthritis in dogs: 39 cases (1997–2002)

Dylan N. Clements, BVSc; Robyn N. A. Gear, BVSc; James Tattersall, BVSc; Stuart Carmichael, BVMS, MVM; David Bennett, BvetMed, PhD

Objective—To determine clinical signs, laboratoryfindings, relationship to vaccination, and response totreatment for type I immune-mediated polyarthritis(IMPA) in dogs. Design—Retrospective study.Animals—39 dogs.Procedure—Clinical records and radiographic reportsfrom 3 university referral hospitals were reviewed.Clinical signs, laboratory and investigative findings,relationship to vaccination, and response to treatmentwere evaluated.Results—Clinical signs and initial laboratory and clini-cal investigative findings were frequently abnormalbut were nonspecific and not associated with likeli-hood of recovery. Time of vaccination was not associ-ated with onset of disease. Chemotherapeuticimmunosuppression resulted in complete cure in56% of dogs. Continuous medication was required in18% (7/39) of dogs, relapses were treated success-fully in 13% (5/39) of dogs, and 15% (6/39) of dogsdied or were euthanatized as a result of disease.Conclusions and Clinical Relevance—The possibleinvolvement of vaccination in type I IMPA was not madeclear from this study because of the small populationsize. Signalment, clinical signs, and results of diagnostictests other than multiple synovial fluid analyses weregenerally nonspecific. Most dogs with type I IMPAresponded to initial immunosuppressive treatment, but31% (12/39) of dogs relapsed, required further treatment,or both. (J Am Vet Med Assoc 2004;224:1323–1327)

From the Department of Veterinary Clinical Studies, University ofGlasgow Veterinary School, Bearsden, Glasgow, Scotland, G61 1QH,UK (Clements, Carmichael, Bennett); the Department of VeterinaryMedicine, University of Cambridge, Cambridge, England, CB3 0ES,UK (Gear); and the Department of Veterinary Clinical Studies,University of Edinburgh, Edinburgh, Scotland, EH25 9RG, UK(Tattersall).

Address correspondence to Mr. Clements.

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ographs of affected joints14 and negative results for sys-temic lupus erythematosus if there was no evidence ofother body system involvement based on clinical or lab-oratory examinations; dogs were seronegative for anti-nuclear antibody when tested.15

ProceduresDetails of age, breed, sex, neuter status, vaccination

history, clinical signs at time of referral, clinically affect-ed joints, duration of clinical signs prior to referral,hematologic and biochemical evaluations at referral,urinalysis, radiographic and ultrasound evaluations,arthrocentesis, immunosuppressive treatment regi-mens, and response to treatment were obtained fromthe medical records. Antinuclear antibody tests wereperformed on all dogs with abnormalities detected viahematologic, serum biochemical, or urinalysis tests.The relationship to vaccination was evaluated via thedate of vaccination relative to the date of onset of clini-cal signs. Mean age, time to referral, number of jointsaffected, highest WBC concentration, and duration ofimmunosuppression were calculated. Remission at fol-low-up examination was defined as an absence of clini-cal signs and synovial fluid analysis that detected WBCconcentration < 3 X 109 cells/L, with a cell populationthat included < 10% neutrophils.

Statistical analyses—The frequency of diagnosisof type 1 IMPA at the Glasgow University VeterinarySchool was compared with the frequency of evaluationof each breed in the general hospital population overthe same time period by use of the χ2 test statistic.Breeds were considered to be at increased risk for type1 IMPA if the odds ratio and lower bound of its 95%confidence interval were > 1. Only breeds for whichmore than 2 cases of type 1 IMPA were included in thisanalysis.

The study population was divided into 4 assess-ment groups on the basis of treatment success (definedas complete remission with immunosuppressive thera-py) versus nonsuccess (defined as recurrence, continu-ous treatment required, euthanasia, or death) or treat-ment success (defined as complete remission withimmunosuppressive therapy or recurrence also treatedsuccessfully) versus nonsuccess (defined as continuoustreatment required, euthanasia, or death). Variableswere assessed for normality by use of the Kolmogorov-Smirnov test. Parametric data (age and number of jointsinvolved) were compared among groups by use of sin-gle 2-tailed t tests, and nonparametric data (time toreferral, time from routine vaccination, and highestWBC concentration) were compared by use of a MannWhitney U test. Success of treatment was compared byuse of Fisher exact tests for dichotomized data, includ-ing sex, neuter status, the presence of pyrexia, inap-petance, lymphadenopathy, signs of back pain at refer-ral, hematologic abnormalities, leucocytosis, leucope-nia, anemia, thrombocytopenia, serum biochemicalabnormalities, high serum activity of alkaline phos-phatase, high serum activity of liver enzymes or bileacid concentration, hypoalbuminemia, hyperglobuline-mia, or hypocalcemia. A value of P < 0.05 was consid-ered significant for all comparisons.

ResultsA diagnosis of type I IMPA was reported in 46 dogs

examined at the 3 veterinary teaching hospitals duringthe study period. Seven cases were excluded because ofinsufficient follow-up information. Labrador Retrievers(n = 7), German Shepherd Dogs (4) and cross-breeds(3) were most commonly seen, and 20 breeds were rep-resented overall. None of these breeds had increasedrisk relative to the general population at the GlasgowUniversity Veterinary School. Twenty dogs were classi-fied as large-breed dogs (> 22 kg [48.4 lb]). Mean ± SDage at referral was 4.9 ± 2.5 years (range, 3 months to11 years). The sex distribution was 14 sexually intactmales, 3 neutered males, 9 sexually intact females, and13 neutered females. Clinical signs commenced from 4days to 2 years prior to referral (mean, 64 ± 112 days).

Twenty-seven dogs were vaccinated; the time ofvaccination was known for 21 dogs, 3 dogs were notvaccinated, and the vaccination history was not knownfor 9 dogs. For dogs that were vaccinated, the mostrecent vaccination had been administered 6.1 months(mean) before the onset of clinical signs (median, 8 ±15 months; range, 2 weeks to 6 years). Two dogs devel-oped clinical signs of disease within 1 month of vacci-nation. Prior to referral, all dogs were treated withantimicrobials (n = 22), corticosteroids (8), or non-steroidal anti-inflammatory drugs (15).

Stiffness was the most common clinical sign atreferral and affected all dogs. Nearly half of the dogshad pyrexia (n = 22), lymphadenopathy (20), or inap-petance (18), and 9 dogs had signs of lumbar spinalpain. Less common signs at referral included polydip-sia (n = 3), signs of depression (3), exercise intolerance(2), and lethargy (2).

At referral, clinical signs of joint involvement(swelling, pain, or heat) were observed in all limbs in28 dogs, only hind limbs in 10 dogs, and only fore-limbs in 1 dog. Carpal joints were most commonlyaffected (n = 31 dogs), followed by hock joints (28),stifle joints (28), and elbow joints (17).

Thoracic radiography was performed in 20 dogs. Noabnormalities were detected in 12 dogs. Cardiomegalywas observed in 3 dogs and an interstitial lung patternwas identified in 2 dogs, a bronchointerstitial pattern in2 dogs, pleural effusion in 1 dog, and peritoneopericar-dial diaphragmatic hernia in 1 dog. Abdominal radiogra-phy was performed in 9 dogs, with no abnormalitiesdetected in 6 dogs. Lumbar spondylosis was identified in2 dogs and hepatomegaly in 1 dog.

Radiographs of clinically affected joints revealedsoft tissue swelling, joint effusion, or both in all dogs.Abdominal ultrasonography was performed in 11 dogsand revealed sublumbar lymphadenopathy in 6 dogs,splenomegaly in 1 dog, hepatomegaly in 1 dog, renalcysts in 1 dog, prostatomegaly in 1 dog, and no abnor-malities in 1 dog.

Routine hematologic and serum biochemical testswere performed on blood samples taken from 36 dogs.Most commonly, neutrophilic leucocytosis was observed(n = 18), followed by anemia (6), thrombocytopenia (3),and leucopenia (3). No hematologic abnormalities wereidentified in 11 dogs. Serum biochemical abnormalitieswere identified in 26 dogs, with high activity of alkaline

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phosphatase in 15 dogs, high activity of alanine amino-transferase or aspartate aminotransferase in 7 dogs,hypoalbuminemia in 8 dogs, hyperglobulinemia in 4dogs, azotemia in 3 dogs, and hypercalcemia in 2 dogs.

Rheumatoid factor measurements16 were performedin 17 dogs; the results were negative in 15 dogs, 1 doghad a low titer (optical density, 2/10), and 1 dog had ahigh titer (optical density, 7/10). Antinuclear antibodytests17 were performed in 25 dogs; 23 dogs had negativeresults, and 2 dogs had a low titer (1:8). Urinalysis wasperformed in 13 dogs, and the results were within ref-erence ranges in 5 dogs. Four dogs had hematuria, and4 dogs had proteinuria.

Arthrocentesis was performed on 2 to 8 joints(mean, 4 joints/dog) of each dog. In 9 dogs, the jointfluid samples were assessed by smear examination onlyand subjectively assessed to have high neutrophil con-centrations in all instances. In 30 dogs, synovial fluidwas sent for WBC analysis; the highest WBC concen-tration from each dog ranged from 3.7 X 109 to 130 X109 cells/L (mean, 41.9 X 109 cells/L; reference range, <3.0 X 109 cells/L). In most dogs, neutrophils were pre-dominant (range, 20% to 98%; reference range, <10%), although mononuclear cells were also high in 20dogs (mean, 6.1 X 109 cells/L; range, 0.8 to 17.5 X 109

cells/L).

Treatment—Twenty-six dogs were treated withprednisolone alone, initially at an immunosuppressiveand anti-inflammatory dosage (1 to 2 mg/kg [0.45 to0.9 mg/lb], PO, q 24 h, or divided equally q 12 h) forapproximately 2 weeks, at which time gradual dosagereduction was initiated until an anti-inflammatorydosage (< 0.5 mg/kg [< 0.23 mg/lb], PO, q 24 to 48 h)was reached, generally after 4 to 6 weeks. The pred-nisolone dosage was further tapered for varyinglengths of time thereafter, depending on the responseto treatment.

Thirteen dogs responded to a single course ofprednisolone of 4 to 16 weeks’ duration (mean ± SD, 8± 4.5 weeks) without recurrence. One dog was initial-ly treated for 3 months with prednisolone, followed byeuthanasia as a result of recurrent clinical signs 1 yearlater. Two dogs required continuous low-dosage pred-nisolone (0.2 mg/kg [0.09 mg/lb], PO, q 24 h and 0.05mg/kg [0.023 mg/lb], PO, q 24 h, respectively) to ame-liorate clinical signs. One dog required prednisoloneadministration for 2 years, after which clinical remis-sion was maintained via oral administration of aloevera. One dog was treated with prednisolone for 4months, followed by crystal therapy (homeopathiccrystal placed in the dog’s water bowl), which coincid-ed with remission of clinical signs. Four dogs respond-ed to administration of prednisolone and antimicrobialagents for 8 weeks; 1 dog was euthanatized 6 monthslater because of recurrence of disease.

Four dogs responded to prednisolone administra-tion initially but subsequently relapsed between 3 and 12months after treatment (mean, 7.8 ± 4.5 months). Onedog responded to a further course of prednisolone of 8weeks’ duration; 2 dogs responded to courses of pred-nisolone (anti-inflammatory dosage) and levamisolea (5mg/kg [2.3 mg/lb], PO, q 48 h) of 8 and 12 weeks’ dura-

tion, respectively; and 1 dog responded to a course ofprednisolone (anti-inflammatory dose) and azathioprineb

(2 mg/kg, PO, q 24 h for 7 days, then 2 mg/kg, PO, q 48h) of 8 weeks’ duration, followed by continuous pred-nisolone administration at an anti-inflammatory dose.

Six dogs did not respond to the initial prednisoloneadministration of 4 to 8 weeks’ duration. Two dogs weretreated with levamisole and prednisolone (anti-inflam-matory dose) for 4 weeks. Both dogs relapsed butresponded to either prednisolone alone (immunosup-pressive dose, 8 weeks) or prednisolone (anti-inflam-matory dose) and cyclophosphamidec (50 mg/m2, PO, q24 h for 7 days, then q 48 h) for 8 weeks. The seconddog was euthanatized 8 months after diagnosis becauseof recurrence of clinical signs. One dog was treated suc-cessfully via administration of prednisolone (anti-inflammatory dose) and azathioprine for 8 weeks.Another dog was treated with prednisolone (anti-inflammatory dose), levamisole, and azathioprine for 4weeks, followed by azathioprine and cyclosporine Ad (5mg/kg, PO, q 24 h) continuously. One dog was treatedwith prednisolone (anti-inflammatory dose) andcyclophosphamide for 4 weeks. One dog was treatedwith prednisolone (anti-inflammatory dose) in combi-nation with azathioprine and levamisole for 4 weeksand then with cyclosporine A for 3 months beforeeuthanasia because of unremitting disease 6 monthsafter diagnosis.

Three dogs were initially treated with cyclosporine A(5 mg/kg, PO, q 24 h), of which none responded, and allrequired further immunosuppressive treatment from 2 to12 weeks after initiation (mean, 6 weeks). One dog wassubsequently treated successfully with the continuationof administration of cyclosporine and the addition of animmunosuppressive dose of prednisolone, and a seconddog was successfully treated with the addition of contin-uously administered azathioprine. The final dog wasunsuccessfully treated with combinations of pred-nisolone (anti-inflammatory dose) and cyclophos-phamide (50 mg/m2, PO, q 24 h for 7 days, then q 48 hfor 3 weeks) and then with prednisolone and azathio-prine (2 mg/kg, PO, q 24 h for 7 days, then q 48 h for 2weeks) before euthanasia because of unremitting disease.One dog died the day after diagnosis, before treatmentwas initiated.

Three dogs were treated with prednisolone (anti-inflammatory dose) in combination with levamisole (1dog, 4 weeks of treatment), azathioprine (1 dog, 10weeks of treatment), and cyclophosphamide (1 dog,continuous treatment).

No significant differences between groups werefound for signalment, time of vaccination, clinical signs attime of referral, hematologic or serum biochemical abnor-malities, number of joints affected, joint fluid WBC con-centration, or results of immunosuppressive treatment.When dogs that relapsed but were subsequently success-fully treated were included in the successfully treatedgroup, a significantly (P = 0.015) larger number of dogs inthe unsuccessfully treated group had inappetance.

DiscussionThe signalment of dogs in this series was similar to

that described previously,2 in which German Shepherd

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Dogs and Labrador Retrievers were found to be over-represented. For dogs evaluated at the GlasgowUniversity Veterinary School, this reflected the overallfrequency of these breeds within the general hospitalpopulation and was not a true over-representation. Itwould appear that all dog breeds may be affected bytype I IMPA and that obvious sex, neutering, and agepredispositions do not exist. Results of a recent study18

indicate an association between certain immunogenet-ic markers (major histocompatability antigens) andcanine IMPA. Dogs with these antigens are more likelyto develop IMPA when exposed to certain, as yet unde-fined, environmental factors.

Bilaterally symmetrical joint involvement is typicalof IMPA.2 Joints are generally swollen and painful onpalpation and manipulation, but not in all dogs.Although hematologic and serum biochemical abnor-malities were detected in most dogs reported here,these were often nonspecific and in some instancesmay have been the result of previous glucocorticoidadministration.

Dichotomization of dogs into treatment responsecategories (successful vs unsuccessful) was carried outbecause the ultimate goal of any treatment is resolutionof disease without recurrence. Because no significantdifferences were observed between groups for any of thevariables we assessed, a second dichotomization wasperformed that allocated dogs that relapsed but weresubsequently treated successfully into the successfullytreated group. No significant differences were evidentbetween groups other than for inappetance, which wasmore common in the unsuccessfully treated group. Webelieve that no reliable associations with treatment out-come could be made with the variables assessedbecause type I IMPA is a complex disease that is fre-quently cyclical in nature with multiple possible etiolo-gies, making statistical comparisons difficult. Similarnonspecific changes have been reported by Bennett2 andJacques et al.19 The absence of rheumatoid factor andantinuclear antibody in nearly all the dogs tested in ourstudy has also been reported by those authors. An anti-nuclear antibody test was not performed in dogs unlessthere was evidence of involvement of other body sys-tems as judged on the basis of clinical examination,laboratory investigation, and diagnostic imaging.15

The results of thoracic, abdominal, and joint radi-ography (other than soft tissue changes) and abdomi-nal ultrasonography were unremarkable in most dogs.The absence of erosive changes and presence of jointeffusions were expected in cases of type I IMPA. Thethoracic and abdominal changes were nonspecific, andall abnormal findings appeared incidental, with theexception of lymph node enlargement that wasthought to be related to the immune-mediated natureof the disease.

Results of multiple arthrocenteses for detectinginvolvement of several joints in a bilaterally symmetri-cal pattern were diagnostic in all dogs (high synovialfluid WBC concentration with predominantly neu-trophils). Mononuclear cell concentrations were alsohigh in 20 dogs, although the magnitude of theirincrease, compared with the reference value, was lessthan that observed for neutrophils. It is of interest that

a much wider range of synovial fluid WBC concentra-tions was observed (from 3.7 to 130 X 109 cells/L) thanthat reported by MacWilliams and Friedrichs13 and thatthese initial concentrations were not useful as predic-tors of outcome. Although results of examination ofsynovial fluid smears were diagnostic, we advocate theuse of accurate WBC concentrations because smearexaminations have poor specificity for differentiationof degenerative joint disease from inflammatoryarthropathies.20

Among the 21 dogs for which the time of vacci-nation was recorded, 2 developed disease within 1month of vaccination, which is less than the 4 of 13dogs reported by Kohn et al.9 Kohn et al9 also reportedthose cases to be vaccine-associated IMPA, whichresolved quickly without treatment. Disease recurredin 1 dog that was revaccinated. Both dogs in our study,in which vaccination preceded development of the dis-ease, recovered after a single course of prednisolonetherapy. Clearly, vaccination is not a prerequisite fordisease because it was seen in 3 dogs that were not vac-cinated; however, the possible role of vaccination inthe development of immune-mediated disease in cer-tain dogs still requires clarification.

It is interesting to note that polyarthritis, polyarthropathies, and polyarthrosis are reported as sus-pected adverse drug reactions in only 1 dose/1.6 X 106

doses of canine vaccine administered in the UnitedKingdom.21 Canine distemper virus (CDV) has beenimplicated in inflammatory synovitis with increasedconcentrations of anti-CDV antibodies and complexedCDV antigens within the synovial fluid.22,23 AlthoughCDV has not been definitively proven to cause IMPA,it is the authors’ policy to determine antibody titers toCDV prior to booster vaccination in all dogs that haveIMPA. If protective titers are detected, the distempercomponent of the vaccine is not given.

Although the guidelines for treatment of type IIMPA are frequently given in textbooks,3,4 they arederived from clinical experience. To the authors’knowledge, no prospective trials regarding theimmunosuppressive regimen of choice or duration oftreatment for type I IMPA have been performed. Only1 publication indicates treatment outcomes forimmunosuppressive regimens2; prednisolone alone wasused in 68% of dogs and in combination withcyclophosphamide in 32% of dogs.

Newer immunosuppressive drugs, such as aza-thioprine (n = 6 dogs) and cyclosporine A (4), wereused in a small number of dogs in our study.Levamisole, which has an immunomodulatoryaction, was used in only 5 dogs. Comparing the finaloutcome results of our study with those of Bennett,2

dogs in our study had slightly higher rates of recov-ery (56% vs 44%) and requirement for continuousmedication (18% vs 11%) and slightly lower rates ofrelapse treated successfully (13% vs 21%) andeuthanasia or death (15% vs 24%). Most dogsresponded to immunosuppression with prednisolone(81%), although 31% of these dogs subsequently hadrelapsed or required continuous anti-inflammatorytreatment or were euthanatized because of persistentdisease.

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In 1 study,2 no single treatment regimen was com-pletely successful. Hence, it is not surprising that awide variety of treatment regimens were observed inour study. Similar observations have been reported inthe treatment of immune-mediated hemolytic anemia,in which there were no significant differences in mor-tality rate when using multiple immunosuppressivedrug treatments, compared with single immunosup-pressive drugs.24 The small number of dogs in ourstudy made meaningful comparisons of treatment reg-imens impossible. Cyclosporine A, when used alone,did not have any efficacy in treating type I IMPA.

The possible involvement of vaccination in type IIMPA was not made clear from this study because ofthe small population size, but no association was madewith onset of disease and timing of vaccination.Signalment, clinical signs, and results of diagnostictests other than multiple synovial fluid analyses weregenerally nonspecific. Most dogs with type I IMPAresponded to initial immunosuppressive therapy, but28% of dogs did relapse and required further treatment.

aLevacide, Norbrook Laboratories (GB) Ltd, The Green, Great Corby,Carlisle, Cumbria, England.

bImuran, GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex,England.

cEndoxana, Baxter Healthcare Ltd, Wallingford Rd, Compton, Newbury,Berkshire, England.

dNeoral, Novartis Pharmaceuticals UK Ltd, Frimley Business Park,Frimley, Camberley, Surrey, England.

References 1. Pederson NC, Weisner K, Castles JJ, et al. Noninfectious

canine arthritis: the inflammatory, nonerosive arthritides. J Am VetMed Assoc 1976;169:304–310.

2. Bennett D. Immune-based non-erosive inflammatory jointdisease of the dog. 3. Canine idiopathic polyarthritis. J Small AnimPract 1987;28:909–928.

3. Bennett D, May C. Joint diseases in dogs and cats. In: EttingerS, ed. Textbook of veterinary internal medicine. 4th ed. Philadelphia: WBSaunders Co, 1995;2032–2077.

4. Bennett D, Day MJ. Immune-mediated musculoskeletal andneurological disease. In: Day MJ, ed. Clinical immunology of the dogand cat. London: Manson Publishing, 1999;126–145.

5. Bennett D. Pyrexia of unknown origin. In Pract 1995;17:470–481.

6. Dunn KJ, Dunn JK. Diagnostic investigations in 101 dogswith pyrexia of unknown origin. J Small Anim Pract 1998;39:574–580.

7. Duval D, Giger U. Vaccine-associated immune-mediatedhemolytic anemia in the dog. J Vet Intern Med 1996;10:290–296.

8. Dawson S, McArdle F, Bennett D, et al. Investigations of vac-cine reactions and breakdowns after feline calicivirus vaccination.Vet Rec 1993;132:346–350.

9. Kohn B, Garner M, Lubke S, et al. Polyarthritis followingvaccination in four dogs. Vet Comp Orthop Traumatol 2003;16:6–10.

10. Bennett D. Immune-based erosive inflammatory joint dis-ease of the dog. 1. Clinical, radiological and laboratory investiga-tions. J Small Anim Pract 1987;28:779–797.

11. Bennett D. Immune-based erosive inflammatory joint dis-ease of the dog. 1. Pathological investigations. J Small Anim Pract1987;28:799–819.

12. Bennett D, Kelly DF. Immune-based non-erosive inflamma-tory joint disease in the dog. 2. Polyarthritis/polymyositis syndrome.J Small Anim Pract 1987;28:891–908.

13. MacWilliams PS, Friedrichs KR. Laboratory evaluation andinterpretation of synovial fluid. Vet Clin North Am Small Anim Pract2003;33:153–178.

14. Bennett D. Immune-based erosive inflammatory joint dis-ease of the dog: canine rheumatoid arthritis. 1. Clinical, radiologicaland laboratory investigations. J Small Anim Pract 1987;28:779–797.

15. Bennett D. Immune-based non-erosive inflammatory jointdisease of the dog. 1. Canine systemic lupus erythematosus. J SmallAnim Pract 1987;28:871–889.

16. Bell SC, Carter SD, May C, et al. IgA and IgM rheumatoidfactors in canine rheumatoid arthritis. J Small Anim Pract 1993;34:259–264.

17. Bennett D, Kirkham D. The laboratory identification ofserum antinuclear antibody in the dog. J Comp Pathol 1987;97:523–539.

18. Ollier WE, Kennedy LJ, Thompson W, et al. Dog MHCalleles containing the human RA shared epitope confer susceptibil-ity to canine rheumatoid arthritis. Immunogenetics 2001;53:669–673.

19. Jacques D, Cauzinille L, Bouvy B, et al. A retrospectivestudy of 40 dogs with polyarthritis. Vet Surg 2002;31:428–434.

20. Gibson NR, Carmichael S, Li A, et al. Value of direct smearsof synovial fluid in the diagnosis of canine joint disease. Vet Rec1999;144:463–465.

21. Gaskell RM, Gettinby G, Graham SJ, et al. Veterinary ProductsCommittee working group report on feline and canine vaccination.Vet Rec 2002;150:126–134.

22. Bell SC, Carter SD, Bennett D. Canine distemper viral anti-gens and antibodies in dogs with rheumatoid arthritis. Res Vet Sci1991;50:64–68.

23. May C, Carter SD, Bell SC, et al. Immune responses tocanine distemper virus in joint diseases of dogs. Br J Rheumatol 1994;33:27–31.

24. Grundy SA, Barton C. Influence of drug treatment on sur-vival of dogs with immune-mediated hemolytic anemia: 88 cases(1989–1999). J Am Vet Med Assoc 2001;218:513–546.

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