Rituximab Disappoints in Sjögren Syndrome

Norra MacReady

February 18, 2014

Rituximab does not appear to relieve symptoms of Sjögren syndrome, at least in the short term, according to findings of a new study conducted in France.

The investigators observed no significant differences at 24 weeks between groups receiving rituximab or placebo in any clinical endpoints or symptoms, including pain, fatigue, salivary flow, and tear production. The drug was administered in 2 infusions over the course of 2 weeks.

Some differences in symptoms and disease activity were seen between the groups at 6 weeks, but they were short-lived, largely because of unanticipated improvement in the control group, senior author Alain Saraux, MD, PhD, professor of rheumatology, Centre Hospitalier Universitaire Brest, France, told Medscape Medical News.

All in all, "the size and duration of the benefit argue against treating [primary Sjögren syndrome] with rituximab," Valérie Devauchelle-Pensec, MD, PhD, from the Centre Hospitalier Universitaire de la Cavale Blanche, Université Bretagne Occidentale, Centre Hospitalier Universitaire Morvan, and Institut National de la Santé et de la Recherche Médicale, Centre d’Investigation Clinique 0502, Centre Hospitalier Universitaire Brest, France, and colleagues conclude in an article published in the February 18 issue of the Annals of Internal Medicine.

The authors studied 120 patients with primary Sjögren syndrome between March 2008 and January 2011. To be eligible for inclusion, patients had to fulfil the European-American Consensus Group criteria for primary Sjögren syndrome and to have active disease, defined as a score of at least 50 mm on at least 2 visual analogue scales (VAS) for global disease, pain, fatigue, and dryness. Patients also had to have recent-onset (<10 years) biologically active or systemic primary Sjogren Syndrome. VAS scores range from 0 to 100 mm, with higher scores indicating more severe symptoms. The primary study outcome was an improvement of 30 mm or more on at least 2 of the 4 VAS scores at 24 weeks.

The patients were randomly assigned to receive a placebo or 1-g infusion of rituximab at weeks 0 and 2. Patients and investigators were blinded throughout the study. The researchers conducted follow-up examinations at weeks 6, 16, and 24. Roche provided the rituximab to the investigators free of charge but played no other role in the study design or analysis.

In the final analysis, there were 63 patients receiving rituximab and 57 patients receiving the placebo, including 57 (90.5%) and 55 (96.5%) women, respectively. The patients had a mean age of 52.9 years (standard deviation [SD], 13.3 years) and 55.6 years (SD, 13.6 years), respectively.

At 6 weeks, 22.4% of patients in the rituximab group improved by 30 mm or more on at least 2 of 4 VAS scores compared with 9.1% of patients in the control group, a difference of 13.3 percentage points (95% confidence interval [CI], 0.8 - 25.8; P = .036). The most significant clinical improvement was seen in fatigue, with 34.7% of the rituximab group and 8.2% of the control group recording VAS improvements of 30 mm or more, a difference of 26.6 percentage points (95% CI, 15.7 - 37.5; P < .001). There was also a difference of 19.1 percentage points (95% CI, 4.4 - 33.7; P = .011) in physician-assessed disease activity. Significant improvements also were seen between the groups in levels of immunoglobulin A (IgA; P = .026) and IgM (P = .004), but in no other physiological or immunological measures.

By week 16, rituximab was still associated with a greater improvement in fatigue (27.2 percentage points vs 8.9 points; 95% CI, 4.1 - 32.6; P = .012), but no other significant difference in clinical improvement, and by week 24, even that difference was gone. However, improvements were seen in levels of IgG, IgM, C4 complement, and β2 microglobulin at 16 weeks, and in all of those components plus IgA at 24 weeks, with rituximab, despite the lack of significant clinical differences. "We do not have any proof about the role [of] immunoglobulins [or] the β2 microglobulin in the pathophysiology of the disease," Dr. Saraux explained.

He expressed some surprise about these findings. "We anticipated greater efficacy [of rituximab], particularly on extraglandular signs and pain." The minimal effect on dryness was less surprising, as that is considered a sign of damage already done, he said.

At least one outside expert was less surprised. "The length of this study was short, considering that Sjögren syndrome is a lifelong condition," said Solomon Forouzesh, MD, associate clinical professor of medicine and rheumatology, University of California, Los Angeles, Geffen School of Medicine and Cedars-Sinai Hospital. "And although it is a relatively rare condition, 120 patients is not a lot. The authors needed a larger sample size." Dr. Forouzesh also questioned the study design. "This is not a disease you can control with 2 infusions. The study should have been designed more like a study for rheumatoid arthritis, in which the infusions are ongoing. You must give this drug continuously over time in order to see improvements in lacrimal glands or salivary flow. A chronic disease like Sjögren syndrome requires ongoing suppression."

Serious adverse events occurred in 13 (20.6%) and 8 (14%) patients, including serious infections in 2 (3.2%) and 5 (8.8%) patients, in the rituximab and placebo groups, respectively. Purpura, cytopenia, cutaneous and respiratory allergic reactions, and hyperglycemia each occurred in 1 patient receiving rituximab but none receiving the placebo. Headache occurred in 1 patient receiving the placebo but none of the patients receiving rituximab. Study limitations included a "debatable" choice of outcome measure and uncertainty about the best interval for assessing treatment efficacy. In addition, many patients had low levels of disease activity at baseline, "and we cannot exclude a better effect of the treatment in more active [primary Sjögren syndrome]," the authors said.

Financial support for this study was received from the Programme Hospitalier de Recherche Clinique 2010. Rituximab was provided free of charge by Roche, which played no further role in the design, conduct, or analysis of this study. Dr. Saraux and Dr. Forouzesh have disclosed no relevant financial relationships. Full conflict-of-interest information is available on the journal's Web site.

Ann Intern Med. 2014;160:233-242. Abstract

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