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NATURE MEDICINE VOLUME 9 | NUMBER 11 | NOVEMBER 2003 1337

Imagine a disease with no cure, no knowncause and an elusive diagnosis. Dubbed the‘great imitator’ because it mimics so manyother diseases, systemic lupus erythematosus(SLE) has remained an enigma—until now.With new genetic technologies and the com-plete sequence of the human genome, scientistsare poised to take a quantum leap in unravelingits mysteries.

SLE is an autoimmune disease where thebody attacks its own cells and tissues, causinginflammation in various parts of the body,including the skin, kidneys, heart and nervoussystem. It affects 1.4 million people in the USalone. In its worst form, lupus can be fatal: 15%of patients die from kidney disease, cardiovas-cular disease or infections.

The discovery of potential biomarkers willsoon allow doctors to predict the severity of thedisease, says Timothy W. Behrens, professor ofrheumatology and autoimmune diseases at theUniversity of Minnesota. “We are very close tothe identification of several of the genes thatincrease a person’s chances for developinglupus,” Behrens says. Behrens and others pre-sented their research at a meeting in Septemberin Washington, D.C.

Using gene expression microarrays, Behrensand his colleagues have identified a ‘signature’of genes activated by interferon in patients withlupus. Although the precise biochemistry isunknown, evidence suggests that the disease issomehow activating the interferon pathway,says Behrens. The researchers analyzed thou-sands of genes in the peripheral blood cells of48 lupus patients and 42 healthy controls.

Nearly 80% of the SLE patients have higherexpression of 14 genes, referred to collectivelyas the interferon gene expression signature, theresearchers found (Proc. Natl. Acad. Sci. USA100, 2610–2615; 2003). The signature seems tobe a marker for patients with the more severetype of lupus, which can involve the brain, kid-neys and blood cells, Behrens says.

“We believe that there is potential for thedevelopment of new diagnostic tests based onthe signature,” says Behrens. Many patientsnow go up to four years before a definite diag-nosis is made. “In the near future,” Behrensadds, “these types of data—the genes a personcarries and the pattern of gene expression intheir blood cells—will be used by doctors toindividualize therapy in a way that has neverbeen possible.”

The results have also spurred interest in initi-ating clinical trials with drugs that block theinterferon pathway. Several trials are under wayto explore manipulation of chemical pathways

in lupus patients. A phase 1 clinical trial spon-sored by the US National Institutes of Health isinvestigating the safety and effects of the mono-clonal antibody MRA, which blocks the actionof interleukin-6, thought to lead to organ dam-age in SLE patients.

The US National Institute of Allergy andInfectious Diseases is conducting a phase 1study that explores the possibility of B-celldepletion as a potential treatment for lupus.

Because they produce autoantibodies, B cellshave an essential role in lupus pathogenesis.Rituxan, an antibody to CD20, can block pro-duction of B cells in patients with non-Hodgkin lymphoma. Researchers hope that byinterrupting autoantibody production by the Blymphocyte, Rituxan might be an effectivetherapy for lupus as well.

Lupus is more common in women ofHispanic, Asian and Native American descent.Children and adolescents represent 15% of SLEpatients. As more afflicted children survive intoadulthood, atherosclerotic cardiovascular dis-ease has emerged as a major concern.

Laura Schanberg, associate professor at DukeUniversity Medical Center, is planning to testwhether the statin Lipitor can reduce choles-terol levels in children with lupus. “This is thefirst ever drug intervention trial in pediatricSLE,” says Schanberg. The researchers havestarted enrolling patients into the trial at a fewsites, with the rest of the sites expected to startenrolling later this year.

Amy K. Erickson, Washington, D.C.

Scientists closing in on true identity of the ‘great imitator’

The Japanese government has approved a five-year grant, with ¥56 million slated for the firstyear, to create a single recombinant vaccine forfour common childhood diseases. Researchersat Osaka University and Toyama Medical andPharmaceutical University plan to insertgenes encoding the antigens for measles,mumps and rubella into the varicella(chickenpox) virus. There are currently norecombinant vaccines against multiplediseases licensed for human use.

Improving vaccine coverage, particularlyfor measles, is a priority for Japanese healthofficials, says Keiko Taya, chief of theimmunization program at Japan’s InfectiousDisease Surveillance Center. The governmentis currently assessing its vaccine policies—statistics indicate that measles coverage in2001 was only 50% for one-year-olds, and thatadult cases are on the rise.

According to project leader KoichiYamanishi, the researchers decided to usevaricella as the vector because it has arelatively large amount of dispensable DNA,which makes it a good candidate for acceptingforeign genes. The team—which includesMichiaki Takahashi, who developed the Okavaricella vaccine now used worldwide—hasalready successfully expressed hepatitis B and

Japanese scientists plan MMR alternativeC

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Skin deep: The characteristic butterfly rash inlupus can be indicative of a severe disease affect-ing internal organs.

HIV antigens in varicella.Another advantage of varicella is that

compared with other vaccines, such asmeasles, its side effects are relatively mild.“The varicella backbone is very safe,” saysAnne Gershon, director of the pediatricinfectious disease division at ColumbiaUniversity. But Gershon cautions that thesafety and efficacy testing process could take along time—the researchers aim to have avaccine ready for clinical trials within fiveyears. Gershon also notes that currentvaccines are safe and effective.

Yamanishi says Japan’s problem may not berelated to the effectiveness of the vaccines, butto the time it takes to receive them. Japanesechildren now receive four separatevaccinations for measles, mumps, rubella andvaricella, a process prone to delays. Japandiscontinued use of the MMR vaccine in 1993over concerns that the Urabe mumps strainused in Japanese MMR vaccines was associatedwith adverse side effects such as meningitis.Anew MMR vaccine isn’t likely to be availablefor several more years.“If [a child] catches evena common cold during [that] year, the nextinjection gets delayed,”says Yamanishi.“Oneinjection could be much more convenient.”

I-han Chou, Tokyo

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