Rituximab for Scleroderma-Associated Pulmonary Arterial Hypertension

Rituximab, developed by Roche, is a biologic medicine that is currently being investigated to treat people with systemic scleroderma.

Marketed under the brand name Rituxan in the U.S. and MabThera in Europe, rituximab is approved to treat blood cancers including non-Hodgkin’s lymphoma and certain adults with rheumatoid arthritis.

How rituximab works

In scleroderma, an autoimmune disease, the immune system goes awry and starts to attack healthy connective tissue. These attacks trigger damaging responses, particularly inflammation and an overproduction of collagen. Collagen is a major component of scar tissue, and its excess results in the patches of tight and hard skin that characterize this disease. 

In systemic scleroderma, a severe form, disease processes can affect and damage such internal organs as the lungs.  Damage that thickens tissue of the arteries supplying blood to the lungs narrows those vessels and restricts the flow, raising blood pressure — leading to a condition called pulmonary arterial hypertension. An estimated 10 percent of systemic scleroderma patients develop PAH, as the condition is also known.

Rituximab is an immune-modulating therapy, one that works to suppress the immune system. It is a type of antibody, a protein designed to recognize and interact with a particular target. Specifically, rituximab binds to CD20, a protein found on the outside of immune cells called B-cells and triggers their destruction.

B-cells are overactive in systemic scleroderma and can stimulate collagen production. By reducing the numbers of B-cells available, rituximab may be able to reduce the symptoms of systemic scleroderma. In particular, rituximab is thought to be beneficial in earlier stages of the disease, or in scleroderma patients with lung involvement.

Rituximab in clinical trials

Rituximab has been used extensively off-label to treat systemic scleroderma and patients with lung damage, such as scleroderma with associated pulmonary arterial hypertension or pulmonary fibrosis.

A retrospective analysis of 10 systemic scleroderma patients treated with off-label rituximab in a Brazilian clinic is discussed in an article published in the journal Revista Brasileira de Reumatologia. Five patients with early but rapidly progressing scleroderma saw an improvement in skin symptoms, and all 10 patients experienced improvement or stabilization in lung symptoms. Similar results were seen in another group of 10 patients in Italy also treated off-label rituximab, detailed in an article published in the journal Autoimmunity Reviews.

There are also several completed and ongoing trials investigating rituximab in scleroderma, and more specifically in treating lung involvement in systemic scleroderma patients.

For example, a randomized, double-blind, and placebo-controlled Phase 2 clinical trial (EudraCT 2008-07180-16), examining the effects of rituximab in 16 systemic scleroderma patients is ongoing in the Netherlands. Initial results, published in the journal Rheumatic & Musculoskeletal Diseases showed that rituximab treatment led to an improvement in patients with lung involvement. But the authors reported that the study was too small to produce statistically significant results due, and recommended the trial should be repeated with a larger group of scleroderma patients with lung involvement.

An open-label Phase 2 study (NCT00379431), carried out in Belgium, assessed the effect and safety of rituximab in patients with early systemic scleroderma. Results, published in the journal Clinical and Experimental Rheumatology, demonstrated significant improvements in skin symptoms and lung function in 14 patients with diffuse systemic scleroderma.

A recently completed Phase 2/3 clinical trial (NCT01748084), carried out in France, investigated the efficacy and safety of rituximab in 22 systemic scleroderma patients with arthritis symptoms. Its primary aim was to assess rituximab’s efficacy with articular symptoms, and secondary goals measured skin and lung involvement. The trial was completed in April 2016 but the results have not yet been released.

Other information

Rituximab is administered as an infusion into a vein.

Rituximab is associated with several side effects, including nausea, rash, itchiness, hot flushes, loss of appetite, diarrhea or constipation, and changes in blood pressure. As rituximab affects the immune system, patients are at greater risk of infection while taking the medication.


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