The term "Autoimmune disease" is currently making the rounds among dog breeders and exhibitors and in the veterinary community. Diseases caused by a defective immune system are of particular concern among many purebred fanciers. (Some people use the abbreviation AID for (A)uto (I)mmune (D)isease. Due to possible confusion with AIDS, (acquired immune deficiency syndrome), a completely different disease, I have not used this acronym.)
The immune system is a marvelous defense network of white blood cells, antibodies, and other substances used to fight off infections and reject foreign proteins. It is a police force patrolling the body, designed to recognize "self" cells from "non-self" cells by markers found on the surface of every cell in the body. It is this ability that causes the body to reject skin grafts, blood transfusions, and organ transplants. Like anything else, the immune system can fail, either by not doing its job or by doing it too well.
Remember the "boy in the bubble?" Certain children (and Arabian foals) can be born with a severe combined immunodeficiency (SCID). In addition, viruses such as FIV of cats, SIV of monkeys, and HIV of people all cause an acquired immunodeficiency syndrome (AIDS) specific to that species. In all these diseases, the defective immune system fails to protect the body, leaving it vulnerable and open to attack by an opportunistic infection.
Autoimmune disease, on the other hand, is a different kind of immune system failure. In this situation, the ability of the immune system to recognize the "self" marker is lost, and it begins to attack and reject the body's own tissue as foreign. One specific tissue type such as red blood cells may be affected, or a generalized illness such as systemic lupus may result.
What causes the immune system to short circuit and start rejecting normal body tissue? Many theories exist, but the ultimate answer is "We don't know." Jean Dodds, a veterinarian studying immunology, feels that multivalent modified-live vaccines overstimulate the immune system. Others blame environmental pollutants or food preservatives such as ethoxyquin, an antioxidant found in most dog foods. There is strong evidence for a genetic factor in the development of autoimmune disease in many species. And some cases occur spontaneously, causing damage to kidneys, lungs, or thyroid gland.
Anemia 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 hemoglobin, resulting in a decrease in the oxygen-carrying capacity of the blood. Anemia can be caused by blood loss, decreased production of new RBCs, or an increase in the rate of their destruction, known as hemolytic anemia.
In hemolytic anemia, 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 autoantibodies, as in primary AIHA, or can be secondary to drugs, infectious disease, cancer, blood parasites, or heavy metals. Levamisole, certain antibiotics, Dilantin (phenytoin), lead, and zinc have all been implicated as potential causes of hemolytic anemia.
When the spleen and the rest of the immune system is working to rid the body of old, diseased, or damaged RBCs, it is doing its job appropriately. When a large percentage of cells are affected, and they are removed faster then they can be replaced, AIHA results and the animal shows external signs of the disease.
The clinical signs of AIHA are usually gradual and progressive, but occasionally an apparently healthy pet suddenly collapses in an acute hemolytic crisis. The signs are usually related to lack of oxygen: weakness, lethargy, anorexia, and an increase in the heart rate and respirations. Heart murmurs and pale mucous membranes (gums, eyelids, etc.) may also be present. More severe cases also have a fever and "icterus" (jaundice), a yellow discoloration of the gums, eyes, and skin. This is due to a buildup of bilirubin, one of the breakdown products of hemoglobin.
The diagnosis is usually made on these clinical signs as well as a CBC documenting anemia, often with misshapen or abnormally-clumped RBCs. A Coomb's test may be done to confirm the diagnosis. 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 nonresponsive cases. This benefits the dog in two ways: less antibodies are made against the RBCs, and the primary organ responsible for their 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 anemia. In a life-threatening anemia, cross-matched blood may be transfused along with immunosuppressive therapy.
ITP is the destruction of "thrombocytes" (clotting cells) by the immune system in much the same manner as RBCs are destroyed in AIHA. Clinical signs of this disease include bruising; excessive bleeding following trauma, at surgery, or during estrus; or blood in the urine or stool. These patients do not usually present in the crisis state that AIHA patients can exhibit, and they relapse less frequently. 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 (hemophilia, Von Willebrand's disease), bladder or prostate infection or cancer, and intestinal parasites. A CBC, platelet count, and clotting profile are needed. A bone marrow biopsy is helpful as well, and a Coomb's test may be run if other autoimmune diseases are suspected.
Treatment is the same as for AIHA -- large doses of corticosteroids and the addition of cyclophosphamide or vincristine 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.
Prognosis in AIHA is guarded. Those cases presenting in a fulminating crisis state often die before aggressive therapy can be instituted, while others may not achieve or maintain remission. In ITP, the prognosis is usually favorable, although ovariohysterectomy is recommended once platelet counts are normal. This decreases the risk of uterine hemorrhage should a relapse occur. As discussed last month, affected dogs and bitches should not be used for breeding stock, due to the effects of the steroids and the risk of genetic transmission of the susceptible state.
As a group, autoimmune diseases of the skin are uncommon to rare in frequency. Diagnosis is often difficult, especially for the general practitioner who may see one or two cases during a career. Skin biopsy and immunofluorescent staining are generally required to diagnose one of these diseases, and the prognosis for recovery may vary. Our old friends the corticosteroids are the primary mode of therapy.
"Pemphigus complex" is a group of four autoimmune skin disorders characterized by "vesicles" and "bullae" (blisters), erosions, and ulcers. In "pemphigus vulgaris", common pemphigus, the lesions are usually found in the mouth and at mucocutaneous junctions, those borders of haired skin and mucosal tissues. Such areas include the eyelids, lips, nostrils, anus, and prepuce or vulva. There may also be skin lesions in the groin or axillae (armpits). The blisters are thin, fragile, and rupture easily. The skin lesions are described as red, weeping, ulcerated placques.
In contrast, the lesions of "pemphigus vegetans" are thick and irregular and proliferate into vegetative lesions marked by oozing and pustules. It is thought to be a more benign form of pemphigus vulgaris.
"Pemphigus foliaceous" is rarely found in the mouth or at mucocutaneous junctions. The blisters are only temporary; redness, crusting, scales, and hair loss are more common presenting signs. Pemphigus foliaceous usually begins on the face and ears and often spreads to the feet, footpads, and groin. Secondary skin infections are common, and fever, depression, and anorexia may occur in severe cases.
"Pemphigus erythematosis" looks clinically like foliaceous and is frequently found on the nose. Ultraviolet light aggravates this form of pemphigus and can lead to a misdiagnosis of nasal solar dermatitis (Collie nose). It is considered a benign form of pemphigus foliaceous. The term "bullous pemphigoid" sounds a lot like "pemphigus," and clinically this disease resembles that group of diseases. The same type of vesicles and ulcers may be found in the mouth, at mucocutaneous junctions, and in the axillae and groin. Differentiation is possible only through biopsy. Evaluation of the vesicles is critical to the diagnosis, and because they rupture so soon after formation, a dog must often be hospitalized and examined every two hours until the biopsies can be taken.
"Discoid lupus erythematosis" is thought to be a benign form of systemic lupus (to be discussed next month) and is an autoimmune dermatitis of the face. It is most common in Collies and Shelties; more than 60 percent of affected dogs are female. The lesion is often described as a "butterfly pattern" over the bridge of the nose and must be differentiated from nasal solar dermatitis and pemphigus erythematosis.
Finally, Vogt-Koyanagi-Harada-like syndrome (VKH) is an extremely rare syndrome, possibly of autoimmune origin, leading to depigmentation and a concurrent eye disease. The black pigments of the nose, lips, eyelids, footpads, and anus fade to pink or white, and there is an acute uveitis (inflammation of the eyes) Early treatment may prevent blindness, but the pigment loss is usually permanent. As you can see by the above descriptions, many autoimmune diseases are similar in appearance. Except for discoid lupus, there is no breed, sex, or age predilection for these problems.
As in other autoimmune diseases previously discussed, the primary goal of therapy is to suppress the body's immune response with large doses of systemic glucorticoids. More potent drugs like Cytoxan or Imuran are used if steroids fail. Gold therapy has been advocated for the pemphigus group or pemphigoid. In cases where nasal depigmentation has occurred, tattooing the affected area helps prevent the sunburn and squamous cell carcinoma that may follow.
The prognosis for discoid lupus is usually good, but it is variable in the other diseases. Many dogs with VKH are euthanized due to blindness. Breeding affected dogs is not recommended. Currently, little information exists on the heritability of autoimmune skin diseases.
The classic example of a multi-systemic autoimmune disease is systemic lupus erythematosis (SLE), also known as lupus. Often called the "great imitator, lupus can mimic nearly any other disease state. The signs of SLE may be acute (sudden onset) or chronic and are usually cyclic. A fluctuating fever that does not respond to antibiotics is one of the hallmark signs, as is a stiff gait or shifting lameness (polyarthritis, see below). Other signs may include a hemolytic anemia or thrombocytopenia, leukopenia (a low white blood count), or a symmetrical dermatitis, especially over the bridge of the nose ("butterfly lesion,").
Two other organ systems may be affected by SLE. Polymyositis, an inflammation of multiple muscle groups, causes gait abnormalities, muscle wasting, fever, and pain as well as the attitude changes one expects from a dog that hurts. A similar inflammation of the glomerulus, the functional unit of the kidney, produces a condition termed glomerulonephritis. This leads to protein loss in the urine and eventual renal (kidney) failure.
As when diagnosing similar diseases, a CBC (complete blood count), serum chemistry analysis, and urinalysis are starting points. The antinuclear antibody test (ANA) has become the definitive test for diagnosing SLE. It more consistently diagnoses positive cases than older tests and is less affected by time and steroid therapy. This test requires only a few milliliters of serum, which is sent to a veterinary laboratory specializing in animal assays.
Therapy is based on the anti-inflammatory and immunosuppressive effects of corticosteroids or the more potent Cytoxan and Imuran, discussed in the January issue. However, because of the wide-ranging effects of lupus, other supportive therapy tailored for the individual case may be required. Antibiotic therapy is important for those dogs with infections due to low white cell counts and immunosuppressive therapy. Support for the dog with renal dysfunction may include fluid therapy and a low protein diet.
The prognosis for patients with SLE is guarded, especially when complicated by kidney disorder. Severe, generalized infections of the kidney (pyelonephritis), joints (septic arthritis), or bloodstream (septicemia) are usually non-treatable signs of advanced disease.
Immune-mediated polyarthritis can be seen in SLE as above or as an independent finding. Several different specific diseases are included in this classification, but the major signs are all similar. A high fever, joint pain and swelling, and a lameness that seems to shift from leg to leg are typical findings. In some cases enlarged lymph nodes are found. In deforming (erosive) arthritis, like rheumatoid arthritis (RA) X-rays of the joints are helpful, but they are normal in the nondeforming (nonerosive) types. Blood values may be normal, elevated, or low.
In uncomplicated immune-mediated polyarthropathies, clinical remission can be achieved with corticosteroids in about half the cases. In the rest, Cytoxan or Imuran is used to induce remission, which can then be maintained with steroids. With the exception of rheumatoid arthritis, the prognosis is generally good. Fortunately for Akita people, RA is more common in toy breeds.
Researchers have recently begun exploring the possibility that many well-known diseases have an immune component. Endocrine diseases like hypothyroidism or diabetes mellitus may be caused by immune rejection of hormone-producing cells. Kerratoconjunctivitis sicca (KCS or "dry eye") due to the shut-down of tear production responds to the antirejection drug cyclosporine. Chronic active hepatitis (liver disease) may also have an immune basis. These and many other areas of medicine are being explored for possible connection to the complicated world of autoimmune disease.
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