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Do I Need an ANA? Some Thoughts About Man’s Best Friend and the Transmissibility of Lupus

We cared for an elderly female who had enjoyed reasonable health. She was taking enteric coated aspirin for osteoarthritis when she developed profound weakness, lethargy, and black tarry stools. Laboratory studies showed hematocrit 9 vol%, hemoglobin 3.3 g%, and white blood cell count 17,500/mm³. She responded nicely to cessation of aspirin, transfusion, sucralfate, and famotidine with hemoglobin 10.3 g% and hematocrit 31 vol%. Additional studies found blood urea nitrogen 24 mg%, creatinine 0.3 mg/ml, urinalysis with microscopic hematuria, platelet count 35,000/mm³, lymphopenia (5%) on differential count, T4 0.4 µg/ml (normal 1–3.6), Coombs’ antibodies positive 1:4, reticulocyte count 5.8%, and antinuclear antibodies (ANA) 1:50 (significant positive). She subsequently developed cutaneous lesions, alopecia, and lymphadenopathy, and expired. Her life partner had ocular Sjögren’s syndrome and ANA 1:25.

The patient, Goldie, is shown in Figure 1A and together with her significant other, Tevye, in Figure 1B. Goldie was known to many in rheumatology, as Figure 1A was featured in discourses about "complementary" and "alternative" medicine to illustrate certain issues of credibility⁹. That story merits brief mention. Goldie was a certified nutritional consultant. In Figure 1A she is shown proudly sitting next to her diploma in her consultative nutritional practice. She acquired her diploma from the American Association of Nutritional Consultants, which is "a professional association dedicated to maintaining ethical standards in nutritional and dietary consulting." The diploma indicates that Goldie was a professional member in good standing several years ago. How did she acquire this certification? Goldie wrote (with assistance) to this organization at their Las Vegas address and obtained an application. The form requested the applicant’s name, address, age, and the number of years that the applicant had been interested in nutrition. All these questions could be answered readily. There was an optional question on the application form asking about the candidate’s educational background. Not wanting to be misleading, we indicated that Goldie was enrolled in the local community college, which was true. We neglected to mention that it was for a course in obedience training or that she had flunked. With her membership Goldie received a Hertz car-rental discount card, malpractice insurance, and a gold MasterCard with a $7500.00 limit. Because of her exemplary credit rating she was subsequently offered a platinum card with a $20,000 limit and was able to obtain one for Tevye as well (Figure 1B). Goldie had seriously contemplated running for public office.

Figure 1A. Goldie, certified nutritional consultant, in her consultative nutrition practice, with permission⁹.

Figure 1B. Goldie, who had lupus, and her consort, Tevye, who had Sjögren’s syndrome.

Did Goldie have lupus? Yes. Canine lupus (and Sjögren’s syndrome) are quite similar to their human counterparts^10-19. While diagnostic/classification criteria have not been formally adopted, authorities generally accept those descriptors of human disease as valid^10-19. Goldie had Coombs’ positivity, skin disease, thrombocytopenia, hematuria, lymphopenia, and ANA positivity, as well as adenopathy and hypothyroidism.

What are the salient features of canine SLE? It was first described in dogs in 1965¹⁰. SLE has also been reported in reptiles, hamsters, guinea pigs, mice, rats, pigs, mink, rabbits, horses, and cats^10-19. Other canine autoimmune disorders are discoid lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, poly/dermatomyositis, glomerulonephritis, myasthenia gravis, skin diseases, and uveitis. The prevalence of lupus in dogs is 0.02–0.03% (1/5000)^16-19. There has been no clear sex or breed predilection. The clinical features are similar to human SLE: arthritis, fever, skin disease, alopecia, nephritis, Evans’ syndrome, myopathy, ulcers, serositis, adenopathy, and neurologic symptoms. Management has included nonsteroidal antiinflammatory drugs, steroids, gold, dapsone, antimalarials, tetracyclines, levamisole, azathioprine, cyclophosphamide, methotrexate, chorambucil, vincristine, splenectomy, plasmapheresis, and immunoadsorbtion. There is limited information about prognosis; remissions and longterm survivals have been reported^16-19.

What does it mean that 2 unrelated dogs belonging to a rheumatologist were ANA positive with rheumatic diseases? The following series of questions will attempt to address and clarify this.

Are pets associated with autoimmune or rheumatic disease in their owners? Yes. Multiple sclerosis was more frequent than expected among individuals exposed to (healthy) cats or dogs (p < 0.001), with exposure particularly striking during the 10 years prior to illness (p < 0.01)²⁰. Scleroderma patients were more likely to have owned a dog, more than one dog, or cats than controls²¹. And among Paget’s disease patients dog ownership (not cat) was more common than controls²².

Is canine lupus transmissible? Maybe. A compelling series of experiments was reported suggesting transmission²³. A colony of dogs was bred from parents with SLE. Cell-free filtrates prepared from spleen were injected into newborn puppies, mice, and rats. The rats had no abnormalities, dogs developed ANA, and mice developed ANA and anti-dsDNA. Several passages of spleen cells or cell-free filtrates in syngeneic mice shortened the time of appearance of ANA from 9 to 4 months. Some mice developed lymphomas with the presence of murine lymphoma viruses detected. Puppies inoculated with this lymphoma developed ANA within 4 months. These data were interpreted as suggesting the presence in canine SLE of an agent (? virus) that induced serologic abnormalities of SLE in mice and dogs, activated latent murine leukemia viruses, and spread by horizontal and vertical routes²³. We are not aware that these observations have been consistently repeated or confirmed.

Is human lupus transmissible among patient contacts? While lupus has not been, autoantibodies have. Lupus patients (80–82%), consanguinous (27–73%) and nonconsanguinous (0–39%) relatives, and close household contacts (27–73%) had increased lymphocytotoxic and anti-RNA antibodies in several studies^24-28.

Is human lupus transmissible from handling serum? Not demonstratively, but autoantibodies seem to be. Carr, et al reported 18/56 (32%) of personnel in SLE laboratories bound > 30% of 0.1 µg 125 I denatured calf thymus ANA (ammonium sulfate precipitated) versus 2/58 (13%) of healthy controls and 4/40 (10%) of non-SLE laboratory workers (p < 0.001). Fluorescent ANA were all negative²⁹. Several other rheumatologists have related similar observations⁹ (RJ DeHoratius, B Hahn, G Bole, R Persellin, R Carr, R Lahita: personal communication). DeHoratius, et al have noted lymphocytotoxic antibodies in laboratory personnel exposed to lupus sera³⁰, and Zarmbinski, et al found anti-dsDNA and antibodies to synthetic polynucleotides³¹. Carr recently communicated, however, that "I don’t know of a single case of lupus developing (among rheumatologists, scientists, or lab workers) that hadn’t been evident earlier" (R Carr, personal communication).

Is lupus transmissible between pets and owners? Maybe. A recent interesting example may have been Millie, the spaniel of US President and Mrs. Bush, who had lupus while her owners had Graves’ disease; indeed Charles L. Christian, MD, was invited to review those records³². Beaucher, et al described 2 families with many members having immunologic abnormalities and/or disorders, each family having a pet dog with clinical symptoms and anti-dsDNA³³; however, dogs have non-Ig dsDNA binding proteins³⁴, which probably explained those examples³⁵. Other groups of investigators reported that neither lupus nor autoantibodies were observed in families having pet dogs with lupus^13,36,37; however, in one of these studies 3 instances of positive ANA were noted in family members with lupus dogs³⁷. Two small studies found no clinical lupus or autoantibodies in dogs belonging to lupus patients^38,39; another found elevated anti-dsDNA among such dogs⁴⁰.

Thus serologic abnormalities have been reported to have been transmitted from dogs to dogs, dogs to mice, and mice to dogs²³. Humans handling lupus sera have greater than normal prevalence of anti-ssDNA, anti-dsDNA, anti-RNA, and lymphocytotoxic antibodies^24-28. In small studies, household members with ANA positive or lupus dogs did not have serologic abnormalities or lupus in 2 studies^13,36 and may have in 2 studies^33,37 (not including President and Mrs. Bush) (Table 1). Dogs of lupus patients were normal in 2 small studies^38,39 and had anti-dsDNA in another⁴⁰.

So, should the author (RSP) who owned the ANA positive dogs be tested for antinuclear antibodies? These data indicated a possible risk of autoantibodies but no documented risk of overt lupus. However, in the interest of science, sera from virtually the entire family, including the dogs, were sent to the laboratory of another of the authors (MR) for serologic examination. The results are presented in Figure 2. Both dogs indeed had positive ANA; Goldie also had elevated titers of anti-RNP by ELISA and had 2 precipitin lines that could not be identified. Three family members had positive ANA, and 2 others had immunologic disorders with negative ANA. The children’s maternal grandmother had been known to have SLE since 1965, asymptomatic for many years, but was still ANA positive 1:1080 (nucleolar and homogeneous); one of her daughters, living in another household (and who disliked dogs), had Hashimoto’s thyroiditis and was found to have an ANA 1:120. The other daughter had vitiligo, was ANA negative, and had one son ANA 1:120 and one son ANA negative with mild psoriasis; it was in this household that the dogs resided.

Table 1. Published findings on lupus transmission between pets and owners. Certain rheumatologic/immunologic disorders (multiple sclerosis20, scleroderma21, and Paget’s disease22) were more frequent among dog owners. Serologic abnormalities have been transmitted from dogs to dogs, dogs to mice, and mice to dogs23. Humans handling lupus sera had greater than normal prevalence of anti-ss-DNA, anti-ds-DNA, anti-RNA, and lymphocytotoxic antibodies24–28. Household members with ANA-positive or lupus dogs did not have serologic abnormalities or lupus in 2 studies13,36 and may have in 2 studies33,37 (not including US President and Mrs. Bush). Dogs belonging to lupus patients were normal in 2 small studies38,39 and had increased anti-ds-DNA in another40.

Figure 2. The family, the dogs, their autoantibodies (black boxes), and their immunologic disorders. ANA, antinuclear antibodies; Nc, nucleolar pattern; H, homogeneous pattern; sp, speckled pattern; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; wnl, no evident rheumatologic/immunologic disease.

Is this all mere coincidence? That is certainly possible. But it seems unlikely to expect to find 2 ANA positive, unrelated animals and in the household of a family with ANA positivity and/or immunologic diseases in 3 generations. It is intriguing to speculate that this family has heritable tendencies to autoantibodies and/or immunologic diatheses, that this susceptibility might have been transmitted to the pets, and/or pets and family members experienced common, provocative exposure — an interpretation consistent with certain of the published observations reviewed^19-33,37,40. This brief discussion has focused on aspects of canine lupus; data about lupus in other species are beyond the scope of the commentary but are not incompatible with this perspective^1-8. Unfortunately, in the absence of specific antibodies, and with the demise of Goldie, additional serologic studies in this family are not possible.

Should this family get another dog?

RICHARD S. PANUSH, MD;
Chair, Department of Medicine,
Saint Barnabas Medical Center,
Saint Barnabas Health Care System,
Livingston, NJ 07039;

MARC L. LEVINE, DVM,
South Orange Animal Hospital,
South Orange, NJ 07039;

MORRIS REICHLIN, MD,
Professor and Chief,
Division of Rheumatology,
University of Oklahoma Medical Center,
and Director, Arthritis and Immunology Laboratory,
Oklahoma Medical Research Foundation,
Oklahoma City, OK 73104, USA.

Supported in part by NIH grant RO1AR43975-05 (to Dr. Reichlin).

Address reprint requests to Dr. Panush.

The authors appreciate the assistance of Tommysena Smith-Fields in preparing the manuscript.

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