Opening the flood gates: interferon-alpha treatment for Sjögren's syndrome.

Interferon (IFN)-alpha is the main IFN produced in response to viral infection. Low levels of IFNalpha can be detected in nasal secretions after exposure to viruses in vivo. Radioimmunoassay has shown that endogenous IFNalpha is low in children, reaches a peak in young adults, and gradually declines with aging. Importantly, this endogenous IFNalpha is significantly decreased in patients with Sjögren's syndrome (SS). IFNalpha has been tested as a therapeutic agent in patients with SS. Intramuscular human leucocyte IFNalpha increases saliva production significantly in patients with SS. Improvements have been noted in lacrimal function and in dryness symptoms. Since IFNalpha infrequently induces autoimmune phenomena and high dose IFNalpha treatment sometimes has a serious adverse event profile, treatment focus has shifted to use of low dose orally-administered IFNalpha. In a single-masked controlled trial, 60 patients with SS randomly received natural human IFNalpha 150IU 3 times a day in an oral lozenge formulation or sucralfate as control for 6 months. At study end, 15 (50%) of the 30 IFNalpha-treated patients had saliva production increases at least 100% above baseline. IFNalpha treatment was well tolerated and no patients withdrew. Labial minor salivary gland biopsies indicated significant decreases in lymphocytic infiltration accompanied by a significant increase in intact salivary gland tissue after 6 months of treatment. In another 12-week double-masked, randomised, placebo-controlled trial, stimulated saliva production in patients with SS receiving IFNalpha lozenges 150IU 3 times daily was significantly increased. This dosage was also suggestive of benefit for 5 of 7 subjective measures of oral and ocular comfort. The tolerability profile of these low dose oral IFNalpha lozenges is excellent; no serious adverse events have been recorded. Adverse effects were generally mild and there were no clinically significant changes in laboratory or clinical safety measures. Low oral doses of natural human IFNalpha thus appear to improve secretory function and relieve dryness in patients with SS without causing significant adverse events. Endogenous or orally administered IFNalpha may activate oropharyngeal lymphoid and epithelial cells and induce production of potent soluble factors which could mediate immunological reactivity. It has been suggested that IFNalpha/beta potentiates clonal expansion and survival of CD8 T cells. Stimulating effects have also been demonstrated on natural killer cell activity, which has been shown to be depressed in patients with SS. It is likely that some combination of these immunological effects results in anti-inflammatory activity and ameliorates signs and symptoms of SS.