Іmmune-Mediated Polyarthritis

WHAT IS YOUR DIAGNOSIS? A three-year-old, female neutered, cross breed presented to the Internal Medicine Service with a history of lethargy and pyrexia. The dog was up to date with vaccinations as well as both flea and worming treatments. There was no travel history. Over the preceding week there had been a reduction in appetite which had progressed to anorexia. The referring veterinary surgeons had treated with a course of oral potentiated amoxicillin and meloxicam after identifying a rectal temperature of 40.1 oC. There was no improvement in the clinical signs in the following 48 hours, with the rectal temperature increasing to 40.5oC. On examination, the dog was bright, alert and responsive although anxious. Her mucous membranes were pink and moist, with a capillary refill time of less than two seconds. Peripheral lymph nodes were within normal limits. There was no evidence of skin tenting. She had a heart rate of 120 beats per minute, with good quality, synchronous pulses. The respiratory rate was 42 breaths per minute, with no adventitious lung sounds. Rectal examination was unremarkable, although she had remained pyrexic at 40oC. Her body condition score was 4/9. What is your problem list and differential diagnoses for this patient? Elevated rectal temperature: Hyperthermia (Hypothalamatic set point remains normal) Exercise induced Anxiety Environmental temperature high page 1 of 9 Hyperthyrodism Pyrexia Infection - Septic peritonitis - Pyothorax - Pyometra - Pneumonia - Pyelonephritis - Gastroenteritis - Cellulitis/abscessation - Prostatitis - Discospondylitis - Leptospirosis - Parvo virus - Borrelia - Anaplasma - Erlichia Inflammatory - Pancreatitis - Juvenile cellulitis (Puppy strangles) Immune-mediated - Immune-mediated haemolytic anaemia - Immune-mediated thrombocytopenia - Immune-mediated neutropenia - Immune-mediated polyarthritis - Steroid responsive meningoencephalitis arteritis - Systemic lupus erythematosus page 2 of 9 - Nodular panniculitis Neoplasia - Lymphoma - Leukaemia - Multiple myeloma - Histiocytic sarcomas - Solid tumours - Secondarily infected tumours Central lesion affecting the hypothalamus - Neoplasia - Inflammatory – meningoencephalitis of unknown origin (MUO) - Abscess - Trauma - Haemorrhage - Thromboembolic disease Miscillaneous - Vaccine related - Drug related e.g. TMPS - Panosteitis - Metaphyseal osteopathy Anorexia Inability to eat - Neuromuscular disease - Oral disease e.g. periodontal diseases, foreign body, tumour - Orthopaedic disease e.g. fractures, ankylosis Nausea page 3 of 9 Pyrexia Behavioural - Pain - Fear How would you investigate this case? 1. Full neurological examination - To include thoracolumbar palpation for discomfort - Full manipulation of the neck through all motions - Evaluation of cranial nerves and mentation to assess for intracranial lesions 2. Full orthopaedic examination - Evaluating joints through full range of motion - Palpating joints for heat, swelling and effusion - Observing the patient walking 3. Haematology 4. Serum biochemistry 5. C reactive protein levels 6. Evaluation for tick borne diseases 7. Urine analysis 8. Thoracic radiographs 9. Abdominal ultrasound/radiographs Case progression: Full neurological examination was all within normal limits Full orthopaedic evaluation was all within normal limits page 4 of 9 Haematology identified: 0.38 x109/l Ref. 0 x109/l Globulins 47 g/l Ref. 25 – 45 g/l Potassium 3.3 mmol/l Ref. 3.5 – 5.5 mmol/l C-reactive protein 100 mg/L > 0 – 10 mg/L Neutrophils (band) Serum biochemistry: 4DX testing, which tests qualitively for antibodies to Erlichia, Anaplasma and Borrelia as well as Dirofilaria antigen, was all negative. Thoracic radiographs were unremarkable. Abdominal ultrasound was performed and found to be unremarkable. Urine analysis found the urine to be concentrated, with a specific gravity of 1.046 and the remainder within normal limits. Urine culture yielded no growth What is your interpretation of these results? An increased presence of non-segmented neutrophils, or bands, is suggestive of inflammation or infection, as there is increased bone marrow production with resultant release into circulation before maturity is reached. Their presence could suggest that a physiologic cause is less likely. Hyperglobulinaemia can be seen related to inflammation, as the globulins measured include gamma globulins such as antibodies. Marked hyperglobulinaemia can be associated with certain infections, such as Erlichiosis or Leishmaniasis. Another possible cause could be as a paraneoplastic syndrome, particularly with multiple myeloma or lymphoma. The marginally low potassium was attributed to decreased intake, secondary to the anorexia and supplemented appropriately with intravenous fluid therapy over 24 hours. page 5 of 9 C-reactive protein was markedly elevated. This is a biomarker for inflammation. Whilst it is sensitive for identifying inflammation, it is not specific for the underlying cause and adds little identifying the underlying cause, other than it being associated with inflammation. The main value of performing this is that it can provide a baseline from which to trend and draw comparisons. At this point, with no obvious changes on clinical examination or investigations. The patient was discharged at this point with maropitant and mirtazapine to stimulate the appetite. Four days later the patient represented following the development of vocalisation when the collar was placed or removed. A repeat neurological examination was performed, this time eliciting neck pain on both maximal flexion and extension of the neck. Joint manipulation was not resented, with no effusion or discomfort appreciated. What are the differential diagnoses for neck pain? Meningitis - Steroid responsive meningitis arteritis - Infectious – Toxoplasma, Neospora - Iatrogenic Intervertebral disc disease/protrusion/extrusion Osteoarthritis Osteomyelitis Multiple myeloma Osteosarcoma Atlantoaxial subluxation page 6 of 9 Immune-mediated polyarthritis Muscle pain - Neospora - Toxoplasma - Polyradiculoneuritis - Trauma How would you progress with this case? The patient was anaesthetised. A CT scan was performed to evaluate for lytic lesions or instabilities of the axial skeleton, it also allowed for the assessment of the brain position to ensure there was no evidence of raised intracranial pressure or brainstem herniation, which would be contraindications for certain procedures. Cerebrospinal fluid was sampled from the cisterna magnum. When analysed, the CSF fluid was grossly clear and cytologically unremarkable, with no evidence of inflammation. The protein content was also within normal limits. Arthrocentesis was performed from both carpi, stifles and tarsi. Subjectively, there was an increase in the volume of the fluid for the patient’s size, and the fluid was less viscous than expected. page 7 of 9 Cytology from the joints, identifying an abundance of non-degenerate neutrophils Cytologically, the cell count was elevated with the proportion of neutrophils ranging from 38 – 68% neutrophils, which the normal being less than 10%. Culture of the joint fluid yielded no growth. What is your diagnosis, how would you treat and monitor this case? This patient was diagnosed with immune-mediated polyarthritis (IMPA) on the basis of multiple joints having marked inflammation and negative fluid cultures. Joint fluid cultures can often yield false negatives when cultures and must be interpreted with caution. To ensure that the IMPA is primary, and not secondary to an underlying condition, a diagnosis of exclusion must be reached. This would consist of the investigation above to exclude other potential disease processes, which had already been page 8 of 9 performed in pursuing the cause of the pyrexia of unknown origin. This patient was treated with immunosuppressive doses of prednisolone (2 mg/kg per day) to good effect. Additional immunosuppressive medications which could be used as secondary agents would include; mycophenolate mofitil, azathioprine, cyclosporine and leflunomide. Ideally, clinical remission would be confirmed by repeating arthrocentesis to ensure that the neutrophil presence had resolved. An alternative would be reassessing the previously measured C-reactive protein, which can provide a surrogate marker for inflammation. We would aim for clinical resolution of signs (normothermia and absence of neck pain) alongside normalisation of the C-reactive protein. The Creactive protein measurement is not infallible and there can be normalisation with the disease process found to still be ongoing when the joints are re-sampled. Once a clinical and clinicopathological resolution has been achieved, the aim would be to reduce the immunosuppressive medications by 20 – 25% every 3 – 4 weeks, re-evaluating the patient and CRP levels, if presumed reliable, prior to each dose reduction. page 9 of 9