Sjogren’s Still an Orphan Disease?


Sjogren’s fails a clinical trial with rituximab and a cost analysis. Even with a significant discount, it’s still not cost effective.

Researchers writing in the June 5 online issue of Arthritis and Rheumatology say that rituximab, an anti–B cell therapy, failed to improve symptoms of fatigue and oral dryness in patients with primary Sjogren’s syndrome (SS). The study also included a cost analysis. Even with a significant discount, rituximab still was not cost effective.

“The results of this study indicate that rituximab is neither clinically effective nor cost effective in this patient population,” wrote researchers who were led by Simon J. Bowman Ph.D., FRCP, of University Hospitals Birmingham, England.

Few effective treatments for Sjogren’s syndrome

Sjogren’s syndrome is a systemic complex autoimmune disease most commonly associated oral and ocular dryness, fatigue, and pain. Approximately 5% of patients go on to develop fibromyalgia and systemic lupus erythematosus. And, 5-10% of patients will experience cutaneous involvement, peripheral neuropathy, nonerosive arthritis, interstitial cystitis, and lung and renal disease. The disease is associated with B cell hyperreactivity.

Most treatments focus on relieving symptoms. Low-dose prednisolone and hydroxychloroquine are used in mild disease, but hydroxychloroquine is generally ineffective. Intravenous methylprednisolone, cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil or chlorambucil are used to treat severe disease, but with limited effectiveness. Biologics, such as rituximab, were hoped to actually reverse the course of disease - not just treat symptoms.

Sjogren's affects approximately one in 1,644 people and by UK standards, it is not an orphan disease in which the cut-off is less than one per 2,000 people. But others point to population-based studies that show that the disease affects one in 2,304 people which suggests that it is indeed an orphan disease.

The study

Rituximab is a monoclonal antibody that targets CD20. It is recommended in combination with methotrexate for the treatment of rheumatoid arthritis. Smaller, uncontrolled studies show that it may be effective in Sjogren’s as well.

With 133 patients, “TRACTISS” was the fourth and largest double-blind, placebo-controlled, parallel-group trial of patients with primary Sjogren’s syndrome. Sixty-six patients were randomized to a placebo and 67 received rituximab.

Patients who exhibited symptoms of fatigue and oral dryness were recruited from 25 rheumatology clinics in the United Kingdom between August 2011 to January 2014. They were randomized to receive either an intravenous placebo (250 ml saline) or intravenous rituximab (1,000 mg in 250 ml saline) in two courses at weeks zero, two, 24 and 26, with pre- and post- infusion corticosteroids.

Of patients in the treatment group, 24 achieved the primary endpoint of a 30% reduction in fatigue or oral dryness at 48 weeks as measured by visual analog scale. Similarly, 21 of 56 placebo patients reached the same endpoint. The response rates were 39.8% for the treatment group and 36.8 for the placebo group (adjusted odds ratio 1.13 [95% confidence interval 0.50, 2.55]). The only significant improvements that were recorded were for unstimulated salivary flow.

Patients received two courses of treatment, each comprising of two doses of 1,000 mg of rituximab. “Patients were not significantly more likely to report a response to treatment at the 48-week time point (in terms of a reduction of 30% of baseline measurement in either oral dryness or fatigue on a VAS questionnaire) than those randomized to receive placebo,” researchers wrote. “Although there did not appear to be any excess risk due to rituximab, the results of the TRACTISS trial do not support the general use of rituximab in treating primary SS, particularly in patients with recent disease onset and/or low disease activity.”

This study also included a cost analysis finding a mean cost for patients of about $13,934 in U.S. dollars. A small, but not significant difference in costs was observed between treatment and placebo. The main driver of costs was the rituximab infusion. Researchers found no significant difference in costs when rituximab was excluded. Even with a large discount, rituximab was still not cost-effective.


Correction: October 24, 2017

An earlier version of this article incorrectly stated that the NIH considers Sjogren syndrome an orphan disease in the United States. The NIH does NOT consider Sjögren a rare disease.



This study was funded by Arthritis Research UK


Simon J. Bowman, Colin C. Everett, John L. O'Dwyer, Paul Emery, et al. "Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjögren's Syndrome,"

Arthritis and Rheumatology

. First published June 5, 2017. DOI:  10.1002/art.40093  Baodong Qin, Jiaqi Wang, Zaixing Yang, Yan Liang, Renqiang Zhong. "Response to: ‘Is primary Sjögren's syndrome an orphan disease? A critical appraisal of prevalence studies in Europe’ by Cornec and Chiche,"

Annals of the Rheumatic Diseases

. Published Online First: 11 November 2014. DOI: 10.1136/annrheumdis-2014-206885 

National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center. 


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