Rituximab Defeats IgG4-Related Disease in Open-Label Study

Rituximab has proven uniformly and resoundingly effective against the baffling syndrome known as IgG4-related disease (IgG4-RD), in a small prospective uncontrolled study funded by Genentech and carried out at Massachusetts General Hospital and the Mayo Clinic. The drug quickly resolved symptoms, reduced IgG4 levels dramatically, and allowed patients to discontinue steroids (the only medications currently effective against the syndrome's wide range of fibro-inflammatory symptoms), reported John Stone MD at the 2013 annual meeting of the American College of Rheumatology in San Diego.

Stone's team also reported that the syndrome is associated with "striking elevations" in peripheral plasmablasts, not seen in any other disorder. This should prove as an important biomarker, he said, because about 30% of patients confirmed by biopsy to have IgG4-RD do not have elevations of serum IgG4.

IgG4-RD was first described only 10 years ago, and is often mistaken for a range of other rheumatic conditions including Sjogrens syndrome, lupus, and sarcoidosis. It is the primary cause of retroperitoneal fibrosis, but also causes lymphadenopathy and painful, disfiguring fibrosis of the salivary and lacrimal glands and the orbits.

To date, the only effective treatment has been steroids which patients can rarely taper or discontinue. There has been no good evidence that any steroid-sparing regimen is effective, Stone said.

Dramatic results with rituximab in a few cases prompted Stone and his team to launch the 30-patient open-label pilot trial, which involved tapering steroids over the course of two months and giving patients two 1000-mg IV doses of rituximab plus methotrexate. Typical for IgG4-RD, most patients in the trial (87%) were men and the mean age was 63.

Of the 28 patients who completed six months of the rituximab regimen, 92% achieved the primary outcome goals: at least a 2-point decline in the IgG4-RD Responder Index and continued avoidance of steroids. The overall decline in the IgG4-RD Responder Index was from a pretreatment mean of 12 to a mean of 2.1. For 73% of patients, the Global Physician Assessment had fallen to zero after six months.

Three patients did require addition of steroids during the trial to achieve disease control, but two of them later reached complete remission.

There were seven adverse events, Stone said, none of them related to the rituximab. These included cold-agglutinin hemolytic anemia, Amaurosis fugax traceable to the IgG4 abnoormality rather than to the treatment, and a case of Legionnaire's disease that had been undetected at intake.

"This [strategy] makes sense, but we've been down that road before in rheumatology," commented rheumatologist Arthur Kavanaugh MD, professor of medicine at the University of California San Diego. "We're really in an absence of information" about IgG4-RD, he added, "and this is some evidence, althought it's not controlled. It is support for the kind of things we like to do, and I look forward to more data."

Something that particularly intrigues Stone is the "enormous peripheral plasmablast expansion" noted in all MGH patients at baseline. Even outside the trial, he said, all patients with IgG4 RD show an increase in plasmablasts, even those who have normal serum IgG4 concentrations.

Genetic sequencing studies show that these plasmablasts share portions of the immunoglobulin molecule that are common to patients with dramatically different clinical presentations of IgG4-RD, Stone said, raising the possibility of common underlying antigens. Rituximab quickly reduces the prevalence of these plasmablasts. Although the patients' B cells reconstitute quickly after treatment, Stone said, the plasmablasts continue to decline.

"We think that the cells that are making the IgG4 are short-lived plasmablasts and plasma cells," Stone said in response to a question, "so that when the pool that normally creates them is depleted [by rituximab], it cannot be repleted. We think this has an important effect on a T cell that we have identified. But I can't tell you any more about that right now."