Rituximab therapy for primary Sjögren's syndrome: an open-label clinical trial and mechanistic analysis.

OBJECTIVE: To study the safety and clinical efficacy of rituximab therapy for primary Sjögren's syndrome, as well as to investigate its mechanisms. METHODS: Patients with primary Sjögren's syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression. RESULTS: Twelve female patients with primary Sjögren's syndrome were administered rituximab. They had a median age of 51 years (range 34-69 years) and a median disease duration of 8.0 years (range 2-18 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-type 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature. CONCLUSION: In patients with primary Sjögren's syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells.

Primary immunodeficiencies: 2009 update.

More than 50 years after Ogdeon Bruton's discovery of congenital agammaglobulinemia, human primary immunodeficiencies (PIDs) continue to unravel novel molecular and cellular mechanisms that govern development and function of the human immune system. This report provides the updated classification of PIDs that has been compiled by the International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies after its biannual meeting in Dublin, Ireland, in June 2009. Since the appearance of the last classification in 2007, novel forms of PID have been discovered, and additional pathophysiology mechanisms that account for PID in human beings have been unraveled. Careful analysis and prompt recognition of these disorders is essential to prompt effective forms of treatment and thus to improve survival and quality of life in patients affected with PIDs.

A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis.

BACKGROUND: Interleukin 12 (IL-12), a cytokine that promotes generation of helper T cells subtype 1, is increased in multiple sclerosis. Albuterol sulfate, a ß2-adrenergic agonist, reduces IL-12 expression, so we tested the effect of albuterol as an add-on treatment to glatiramer acetate therapy. OBJECTIVES: To investigate the clinical and immunologic effects of albuterol treatment as an add-on therapy in patients starting glatiramer acetate treatment. DESIGN: Single-center double-masked clinical trial. SETTING: Academic research. Patients Subjects with relapsing-remitting multiple sclerosis. MAIN OUTCOME MEASURES: In this single-center double-masked clinical trial, subjects with relapsing-remitting multiple sclerosis were randomized to receive a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of placebo daily for 2 years or a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of albuterol daily for 2 years. The primary clinical efficacy measurement was the change in Multiple Sclerosis Functional Composite at 2 years, and the primary immunologic end point was the change in expression of IL-13 and interferon γ at each study time point. The classification level of evidence from this trial is C for each question, as this is the first class II clinical trial addressing the efficacy of glatiramer acetate plus albuterol. RESULTS: Forty-four subjects were randomized to receive glatiramer acetate plus albuterol or glatiramer acetate plus placebo, and 39 subjects contributed to the analysis. Improvement in the Multiple Sclerosis Functional Composite was observed in the glatiramer acetate plus albuterol group at the 6-month (P = .005) and 12-month (P = .04) time points but not at the 24-month time point. A delay in the time to first relapse was also observed in the glatiramer acetate plus albuterol group (P = .03). Immunologically, IL-13 and interferon-γ production decreased in both treatment groups, and a treatment effect on IL-13 production was observed at the 12-month time point (P < .05). Adverse events were generally mild, and only 3 moderate or severe events were considered related to the treatment. CONCLUSION: Treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00039988.

Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee.

Primary immunodeficiency diseases (PIDs) are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. More than 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic,immunologic, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international committee of experts has met every 2 years since 1970. In its last meeting in Jackson Hole, Wyo, after 3 days of intense scientific presentations and discussions, the committee has updated the classification of PID, as reported in this article.