AUGUST 2010 • WWW.RHEUMATOLOGYNEWS.COM /CT DISEASES 43 May Be First Biologic Okayed for SLE

BY BRUCE JANCIN cause our instruments are blunt. The true effect is prob- Dr. van Vollenhoven offered the following updates on ably much better than we think.” the status of other major classes of biologic agents in FROM THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY Atacicept, another anti– cytokine agent, is now terms of their prospects as SLE therapies: R OME — What a difference a year makes. in a phase III randomized clinical trial for SLE, he said. Ǡ Anti–interferon-alpha. High serum levels of inter- At last year’s rain-drenched EULAR gathering in There is further encouraging news. At the Rome con- feron-alpha are present in SLE. It is produced by plas- Copenhagen, earlier optimism regarding the prospects gress, Dr. Daniel J. Wallace presented positive results macytoid dendritic cells in response to stimulation by for biologic therapies for systemic lupus erythemato- from the phase IIB EMBLEM trial of epratuzumab, a immune complexes. Several companies currently have sus gave way to a pervasive pessimism. Highly en- humanized anti-CD22 . Unlike anti–interferon-alpha agents in clinical trials for SLE. couraging studies had been followed by a rash of neg- rituximab, an anti-CD20 monoclonal antibody that The key issue will be safety: Interferon-alpha plays key ative major clinical trials, which dashed many observers’ completely obliterates B cells, epratuzumab reduced roles in viral immunity and tumor defenses, Dr. van hopes that biologics would have a clinically meaning- them by about half in the study. Vollenhoven noted. ful impact in SLE. But that was then. The EMBLEM trial was a 12-week, multicenter, dou- Ǡ Anti–-6. (RoActemra) “It’s a year later now. The sun has been shining every ble-blind, randomized study involving 227 patients achieved improvements in SLEDAI and arthritis in a re- day in Rome, and I can tell you that there are now a lot with moderate to severe SLE who were already on stan- cent National Institutes of Health phase I study in 16 of reasons to think biologics are going to make a real dard therapy. The key finding was that patients who re- SLE patients (Arthritis Rheum. 2010;62:542-52). Neu- difference in the treatment of lupus,” Dr. Ronald van ceived a cumulative intravenous dose of 2,400 mg of tropenia was a frequent limiting side effect. Additional Vollenhoven said. Clearly, the epratuzumab—either as 600 mg interleukin-6 and interleukin-6 receptor antagonists are most exciting recent development Early data from weekly (37 people) or 1,200 mg in early clinical trials. is that the anti–B cell cytokine the EMBLEM trial every other week (37 people)— Ǡ Rituximab. Early, uncontrolled studies were “excit- agent belimumab (Benlysta) show that had a responder rate twice that of ing and encouraging,” recalled Dr. van Vollenhoven, achieved its primary end points in epratuzumab controls on placebo (38 people). who led several of them. Then came the failed phase two separate, exceptionally large halved, rather EMBLEM’s responder rate in- III, randomized, double-blind, controlled EXPLORER phase III clinical trials. than eliminated, dex end point was a novel com- and LUNAR trials, which contributed prominently to “Safety was excellent in those B cell numbers. posite outcome measure that was the glum global prospects for biologic therapy of a year trials; that’s really a great com- aimed at overcoming the sort of ago. EXPLORER established that rituximab (Rituxan) ponent of the story. So I think be- DR. WALLACE limitations Dr. van Vollenhoven is unlikely to be of benefit in nonrenal lupus. Many limumab is very likely to become cited. It’s defined as a reduction of rheumatologists have concluded that LUNAR showed the first registered biologic for SLE,” predicted Dr. van all baseline BILAG grade A disease to grade B-D, and BI- the same for lupus nephritis, but Dr. van Vollenhoven, Vollenhoven, senior physician in the department of LAG grade B to grade C or D, in all body systems; no who was on the trial’s steering committee, remains un- rheumatology and chief of the clinical trials unit of the BILAG worsening in other organ systems; no deterio- convinced. In as-yet-unpublished data, he has shown Karolinska Institute, Stockholm. ration in SLEDAI or physicians’ global disease activity as- that rituximab works quite slowly in lupus nephritis, If so, belimumab would also be the first new thera- sessments; and no increase in corticosteroids and/or im- with about one-half of treated patients showing a par- py of any sort approved for SLE in more than 40 years. munosuppressive agents over baseline levels. Overall, the tial response after 1 year, and complete responses be- Dr. van Vollenhoven, who was on the steering com- responder rate index was 43.2 for the 74 patients on a to- ing seen only after about 2 years. LUNAR, he noted, mittees of both the BLISS-76 (Belimumab in Subjects tal of 2,400 mg of epratuzumab vs. 21.1 for those on was a 1-year trial, so it didn’t capture the late respons- With Systemic Lupus Erythematosus–76) and BLISS-52 placebo. Especially impressive were the epratuzumab-in- es. “It could be that rituximab doesn’t work in lupus trials, characterized the demonstrated treatment effect duced reductions in neuropsychiatric and cardiorespira- nephritis. But I’ll reserve my judgment because I’ve seen of the anti–B cell cytokine agent as “modest.” But he tory symptoms of SLE, which are often particularly re- such good responses that it still seems to me to be a noted that there is a caveat. sistant to conventional therapies, observed Dr. Wallace pretty good option,” he said. ■ “If the effect size isn’t so big, how relevant is the treat- of the University of California, Los Angeles. ment clinically? It’s a reasonable question. I think the “This is a very encouraging result from a relatively Disclosures: Dr. van Vollenhoven serves as a consultant to modest effect size is a function of the primitive out- small first trial that needs to be confirmed,” Dr. van Vol- GlaxoSmithKline and Human Genome Sciences, which are come measures we have for SLE. The [problem with lenhoven said. “The size of the treatment effect is pret- developing belimumab, and he has received research grants the lupus trials has been]—and still is—that our in- ty impressive. There was a strong positive effect for a from most of the other companies which make biologics for struments aren’t very good,” the rheumatologist said. total dose of 2,400 mg, but 3,600 mg was not effective. rheumatologic diseases. Dr. Wallace is a consultant to “I think we’re picking up a signal and the signal is weak, That’s a little bit strange. I can’t quite put my head UCB, which is developing epratuzumab and funded the but it’s not because the true effect is weak. It’s just be- around that.” EMBLEM trial.

Continued from previous page Interferon, a mainstay of MS treat- time immunosuppressive treatment was Cerebrospinal fluid profiles in gray ment, “causes flares and can lead to cat- initiated, there had likely already been matter myelitis were indistinguishable romyelitis optica, Dr. Birnbaum said at astrophic worsening of SLE and SLE irreversible injury,” according to the from CSF profiles in bacterial meningi- the meeting. CNS disease,” Dr. Birnbaum said. study report. tis, although none of the patients had High-dose IV methylprednisolone is The findings are based on a record re- Patients with gray matter myelitis, meningeal signs or positive bacterial, used to treat both forms of myelitis. view of 22 SLE patients who pre- viral, or fungal cultures. Following that, patients at Hopkins are sented with myelitis to the lupus If gray matter myelitis—and how If obtaining an MRI is not feasible, Dr. placed on steroid-sparing immunosup- center or transverse myelitis cen- Birnbaum said, “the spinal tap can sup- pressive regimens, which may include ter at Hopkins in 1994-2007. to treat it—was more widely port evidence of gray matter myelitis.” azathioprine, mycophenolate mofetil, or Dr. Birnbaum and his col- recognized, ‘hundreds of young He added that in cases in which the rituximab. leagues recognized the syn- differential includes both meningitis Both forms of SLE myelitis are unlike dromes through an analysis of women would be saved from and myelitis, concomitant administra- myelitis that is seen in multiple sclerosis histories, physical exams, lab val- permanent paralysis.’ tion of corticosteroids and antibiotics is (MS) patients, which tends to be trans- ues, follow-up care, and MRIs. appropriate. Both are commonly ad- verse and does not cause the rapid dev- The team discovered that 11 ministered for worsening TB meningi- astation that is seen in gray matter patients had gray matter myelitis, and 11 compared with those with white mat- tis in order to simultaneously eliminate myelitis. had white matter myelitis. There were ter myelitis, had higher median white the infection and quiet the cytokine Currently, however, myelitis in SLE no statistically significant differences be- blood cell counts (385.5 cells/mL vs. 10 storm it produces. and MS patients is often lumped togeth- tween the two groups with regard to cells/mL; P less than .01); higher me- In all, 12 MRIs were available for pa- er under the rubric of “lupoid sclerosis,” age, gender, or ethnicity. Most were dian neutrophilic pleocytosis (71% tients with gray matter myelitis, and 23 Dr. Birnbaum said. women. neutrophilia vs. 15% neutrophilia; P for patients with white matter myelitis. That’s a mistake, he said. Of the 11 patients with gray matter less than .08); higher median total pro- Cord swelling was seen in 91.7% (11) “Under no circumstances should any myelitis, 10 presented for urinary re- tein levels (254 mg/dL vs. 57 mg/dL; P of the gray matter MRIs and in 21.7% (5) of these patients be exposed to the ar- tention. Because of the presence of less than .01); and lower central spinal of the white matter images; post- mamentarium used to treat MS. Lupoid fevers, “all of these patients were un- fluid glucose levels (33 mg/dL vs. 54 gadolinium enhancement was seen in sclerosis does not exist for these SLE pa- fortunately and erroneously diagnosed mg/dL; P less than .02), according to 25% (3) of the gray matter MRIs and in tients,” he said. as having urinary tract infections. By the the study report. 42.9% (10) of white matter images. ■