WASHINGTON - "The wolf is in no danger of going extinct," David Isenberg told a group of listeners at the American College of Rheumatology 2006 Annual Meeting. "But over the next 10 or 15 years, we're going to make things much harder for him."

That's "wolf" as in lupus, or technically speaking, systemic lupus erythematosus. Though most people think of rheumatoid arthritis first when they hear "rheumatology," the ACR meeting also is a place to hear about new research on other inflammatory diseases, and noninflammatory diseases that affect the joints or connective tissue, as well: lupus, ankylosing spondylitis and even osteoporosis, with Thousand Oaks, Calif.-based Amgen Inc. presenting clinical trial data on denosumab.

Isenberg, a professor of rheumatology at University College London who gave a "Meet the Professor" overview talk of current and upcoming lupus treatments at the meeting, struck an optimistic tone: "In 15 years definitely . . . and five years quite possible, the standard treatment for patients with lupus will have radically changed," he predicted. "We're going from serendipity to sense."

Isenberg spent much of his session talking about B-cell depletion, both with erstwhile oncology agents such as Genentech Inc. and Biogen Idec Inc.'s rituximab (Rituxan) and therapeutics in advanced-stage clinical trials (among them La Jolla Pharmaceuticals' abetimus sodium [Riquent], now in Phase III trials to test whether the compound delays the onset of renal flares). But new lupus findings at the meeting ran the gamut from such late-stage advances all the way back to improved animal models.

Lupus strikes up to 90 percent women, and researchers from St. Louis University and the University of Texas Southwestern Medical Center reported on a mouse model that is gender-specific, with females showing far worse symptoms by the age of 4 months, though to date, the researchers do not know the mechanism behind the differential effect. The mice were double knockouts for the proapoptotic proteins Fas and Bim. Knockouts for either protein alone "develop severe and prolonged experimental arthritis," Jack Hutcheson, of the University of St. Louis, told the audience at a symposium on new animal models for lupus. But it is the double knockouts only that show marked gender specificity.

Another presentation at the same session reported on Baff knockouts. Baff activates B cells and seems to play a role in the development of lupus. The Baff knockouts, though, pose something of an interesting conundrum: Do they have lupus or don't they? Chaim Jacob, from the University of California at Los Angeles, told the audience that Baff knockout mice, despite having almost no B cells, still develop the sort of autoantibodies that are typical of lupus. But importantly, their kidneys look like they have lupus.

But he added that "they don't develop proteinuria" - protein in the urine, which usually is a sure sign of kidney damage. "And they don't die, either." "Pathologically, they have disease. Histologically, they have disease. But clinically, they are protected." His conclusion? "We have to be careful about which parameters we are monitoring in clinical trials of Baff antibodies."

Session moderator Chaim Puttermann, a professor at the Albert Einstein College of Medicine in New York City, reported on the protein Tweak (or TNF-like weak inducer of apoptosis), a potential therapeutic target for lupus.

Tweak is a member of the TNF superfamily, which is the target of Amgen's etanercept (Enbrel), Centocor's infliximab (Remicade) and Abbott Laboratories' adalimumab (Humira). But Tweak, and its receptor Fn14, are both monogamous, meaning that blocking the interaction would have fairly specific effects.

Puttermann, who collaborated with Cambridge, Mass.-based Biogen Idec on the research, was a co-author on several posters reporting that lupus patients have high levels of Tweak, that those high levels in turn lead to the release of cytokines, and that in mice, blocking the interaction between Tweak and Fn14 prevented cytokine release and kidney damage.

Clinical trials, too, brought potentially encouraging news: ZymoGenetics Inc. and Serono SA presented results from a Phase Ib study in lupus patients treated with atacicept. The results showed that atacicept was well tolerated across all dose levels and schedules in the study. In addition, atacicept therapy was associated with clear biologic activity, as shown by dose-dependent reductions in several biologic markers.

And Human Genome Sciences Inc. announced that the 76-week results of a Phase II trial demonstrated that its LymphoStat-B (belimumab) reduced disease activity in patients with serologically active lupus, exhibited durable biological activity, and appeared safe and well tolerated. In the LymphoStat-B treatment groups, the percentage of serologically active SLE patients who achieved the primary efficacy endpoint for Phase III trials of LymphoStat-B increased from 46 percent at Week 52 to 56 percent at Week 76, with no increase in infections.