Autoimmune Diseases

Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to certain organs or involve a particular tissue in different places. The treatment of autoimmune diseases is typically with immunosuppression—medication which decreases the immune response.

There are several types of autoimmune disease found in dogs and these together with symptoms and possible treatments are listed below.

What causes the immune system to malfunction?

Many theories exist amongst veterinary professionals, but the ultimate answer is "We don't really know." Jean Dodds, a vet studying immunology, feels that multivalent modified-live vaccines over stimulate the immune system. Other vets blame environmental pollutants or food preservatives such as ethoxyquin, an antioxidant found in many dog foods. There is also strong evidence for a genetic factor in the development of autoimmune disease and some cases occur spontaneously, causing damage to kidneys, lungs, or thyroid gland.

Haemolytic anaemia

Anaemia is a clinical sign, not a disease, and is defined as a decrease in the number of red blood cells (RBCs) or the amount of haemoglobin, resulting in a decrease in the oxygen-carrying capacity of the blood. Anaemia can be caused by many things including blood loss (haemorrhage), iron deficiency, lack of certain vitamins, such as folic acid and vitamin B12, bone marrow problems, leukaemia, kidney failure, decreased production of new RBCs, or an increase in the rate of their destruction - (haemolytic anaemia).

In haemolytic anaemia, the RBCs become "defective" in the eyes of the immune system by acquiring markers on the cell surface that are recognized as "non-self." These markers can be true auto antibodies, as in primary AIHA, or can be secondary to drugs, infectious disease, cancer, blood parasites, or heavy metals. Levamisole (used as an anti-cancer agent and as a wormer), certain antibiotics, Phenytoin (anti-epileptic), lead, and zinc have all been implicated as potential causes of haemolytic anaemia.

Red Blood Cells

All of the cells in the blood, red blood cells, all types of white blood cells, and platelets are made in the bone marrow from stem cells. RBCs contain the iron-rich protein haemoglobin, they carry oxygen from the lungs to all cells in the body and carry carbon dioxide from the cells back to the lungs.

Red blood cells are constantly being manufactured and have an estimated life-span of approx. 120 days. Damaged & old RBC's are broken down by the spleen. When the spleen & the rest of the immune system is working to rid the body of old, diseased, or damaged RBCs, it is doing its job correctly. However, when a large percentage of red blood cells are damaged they are removed from the circulation faster than they are replaced, as a result AIHA occurs.

Symptoms of HA

The clinical signs of HA are usually gradual & progressive, but occasionally an apparently healthy dog suddenly collapses in an acute haemolytic crisis. The symptoms are the same for all types of severe anaemia (i.e. regardless of cause) and include:

• Pale mucous membranes (gums, eyelids, etc.)
• Weakness
• Lethargy
• Anorexia
• Increased heart rate & respiration
• Heart murmurs

More severe cases also have a fever and "icterus" (jaundice), a yellow discoloration of the gums, eyes, and skin. This is due to a build-up of bilirubin, one of the breakdown products of haemoglobin.

Diagnosis

The diagnosis is usually made on these clinical signs as well as a complete blood count documenting anaemia, often with misshapen or abnormally-clumped RBCs. A Coomb's test (antiglobulin test) may also be done to confirm the diagnosis.

Treatment

Corticosteroids are the primary drugs used to treat any autoimmune disease. Very high immunosuppressive doses are used initially to induce a remission, and then the dose is very slowly tapered over many weeks or months to a low maintenance dose. Most affected dogs must be kept on steroids the rest of their lives and are susceptible to relapses.

If steroids alone are insufficient, more potent immunosuppressive drugs such as Cytoxan (cyclophosphamide) or Imuran (azathioprine) may be added. These chemotherapeutics are very effective, but the dog must be monitored closely for side effects, including a decreased white blood count.

Splenectomy, the surgical removal of the spleen, has also been recommended for none responsive cases. This benefits the dog in two ways: less antibodies are made against the RBCs, and the primary organ responsible for red blood cell destruction is removed. An animal can live quite normally without a spleen.

Blood transfusions are rarely used. Adding foreign protein can actually intensify the crisis state, increase the amount of bilirubin and other breakdown products the liver must process, and suppress the bone marrow's natural response to anaemia. In a life-threatening anaemia, cross-matched blood may be transfused along with immunosuppressive therapy.

Haemolytic Anaemia is more prevalent in Cocker Spaniels than some other breeds, however research so far does not indicate that the problem is inherited. It seems that environment, age and sex play an important role in an animal developing an auto-immune condition.

Immune-mediated thrombocytopenia

ITP is the destruction of "thrombocytes" (clotting cells) by the immune system in much the same manner as RBCs are destroyed in AIHA.

Symptoms of ITP

Signs & symptoms are those of a clotting disorder (regardless of cause) and include:

• Bruising
• Bleeding gums
• Excessive bleeding during oestrus
• Blood in the urine or stool
• Excessive bleeding following trauma

Diagnosis

Before ITP can be diagnosed, many more common diseases must be ruled out. These include, but are not limited to, warfarin poisoning, various clotting disorders (haemophilia, Von Willebrand disease), Malabsorption, bladder or prostate infection, cancer, and intestinal parasites.

A complete blood count including a platelet count and Partial thromboplastin time test (clotting profile) should be undertaken. A bone marrow biopsy may be helpful too, and a Coomb's test may be run if other autoimmune diseases are suspected.

Treatment

Treatment is the same as for AIHA i.e. large doses of corticosteroids and the addition of cyclophosphamide or vincristine (chemotherapy drugs) if steroids alone fail. Splenectomy can be performed; however, the surgical risk is greater in a patient with ITP due to the poor clotting ability. Transfusion of fresh whole blood or of platelet-rich plasma can be helpful in ITP.

Cushing's Disease/Addison's disease (Hyperadrenocorticism)

Addison's disease AND Cushing's disease are both correctly known as hyperadrenocorticism. With Cushing's disease too much cortisol is produced, with Addison's disease too little cortisol is produced.

Causes

Hyperadrenocorticism occurs for two reasons, a tumour of the adrenal gland that produces adrenal hormones or stimulation of the normal adrenal glands from the hormones that control it. The primary reason for this to occur is a pituitary gland tumour that produces excessive ACTH, which stimulates the adrenal gland to produce corticosteroids (cortisol). Adrenal gland tumours account for 15% of the cases of spontaneous hyperadrenocorticism. Pituitary tumours account for 85%.

Symptoms

Cushing's disease (syndrome) causes:

• Increased drinking
• Increased urination
• Increased appetite
• Panting
• High blood pressure
• Hair loss - usually evenly distributed on both sides of the body
• Pendulous abdomen
• Thinning of the skin
• Susceptibility to skin infections & diabetes
• Weakening of the heart & skeletal muscles

Addison's disease causes:

• Muscle weakness
• Lethargy
• Vomiting
• Diarrhoea
• Hyperpgimentation (small patches of darkened skin)
• Joint pain
• Poor appetite
• Muscle tremors/shivering

Diagnosis

The diagnosis of Cushing's can be done with several blood tests. A general hint of Cushing's can be obtained by a blood panel. To confirm it, a test known as a low dose dexamethasone test is done. A baseline blood sample is drawn in the morning, an injection of dexamethasone given and a follow-up blood test done 8 hours later. In a normal dog, the dexamethasone should suppress cortisol levels in the blood stream. In Cushing's disease this effect does not occur. Once the disease is diagnosed, it is possible to differentiate between the adrenal tumors and pituitary gland tumors using a second test, a high dose dexamethasone suppression test. Most dogs with pituitary tumors will have cortisol suppression on this test. There are other tests used, including ACTH response tests (assess the functioning of the adrenal glands) and urine cortisol/creatinine ratios to diagnose this disease. X-rays and ultrasound can help determine if an adrenal gland tumour is present.

Diagnosis of Addison's disease is usually determined by a blood test called the ACTH (cosyntropin) stimulation test (also known as a synacthen test) which measures how well the adrenal glands respond to the hormone ACTH. ACTH is a hormone produced in the pituitary gland that stimulates the adrenal glands to release cortisol.

In this test, blood cortisol, urine cortisol, or both are measured before and after a synthetic form of ACTH is given by injection. The normal response after an ACTH injection is a rise in blood and urine cortisol levels. Dogs with Addison’s disease or long-standing secondary adrenal insufficiency have little or no increase in cortisol levels.

Treatment

If it can be determined that there is an adrenal gland tumour which is causing Cushing's syndrome, it can be removed. Many vets prefer to have a specialist attempt this since the surgical risks can be high. Pituitary gland tumors are not usually removed in veterinary medicine. This situation is treated using Lysodren  or ketaconazole.  By administering drugs in proper amounts it is possible to destroy a portion of the gland to keep the production of corticosteroids to normal levels. Obviously, close regulation of this using blood testing is necessary since overdoing it can cause severe problems with Addison's disease - hypoadrenocorticism. Treatment of Cushing's disease caused by pituitary tumors is symptomatic therapy i.e. it does not cure the pituitary tumour.

Medical management of Addison's involves administration of glucocorticoids and mineralocorticoids to replace the adrenal insufficiency.

Addison's Crisis

Crisis occurs when the physiological demand for glucocorticoid cortisol exceeds the ability of adrenal glands to produce sufficient quantities. Crisis is likely to occur at times of stress as these hormones are routinely associated with the natural 'fight or flight' mechanisms. Typical stresses to the body are:

• Fear/fright - fireworks/thunderstorms/separation anxiety (any event that an individual dog is fearful of)
• Major or minor infections
• Injury
• Surgery
• Pregnancy
• General anaesthesia

An Addison's crisis can be life threatening and it is important to seek immediate veterinary treatment. Signs of a crisis are a sudden increase in severity of the common symptoms (listed above), dehydration, vomiting/diarrhoea collapse and bracycardia (a slow heart rate). Treatment involves supporting the dog:

• IV saline solution to help replace lost electrolyte and other minerals. IV saline can also dilute the high levels of potassium in the blood
• IV dextrose
• IV prednisolone sodium succinate or dexamethasone sodium phosphate to replace glucocorticoids
• IV Calcium gluconate to treat life-threatening heart arrythmias
• Administration of oxygen
• Drug therapy to replace glucocorticoids