Survival gains seen with rituximab and mycophenolate in RA lung disease



LIVERPOOL, ENGLAND – Rituximab and mycophenolate mofetil could offer patients with rheumatoid arthritis and concomitant interstitial lung disease a survival advantage over other therapies, according to findings from a large, retrospective, multicenter study.

Data collated by the British Rheumatoid Interstitial Lung (BRILL) network found all-cause mortality in patients with rheumatoid arthritis (RA) and interstitial lung disease (ILD) treated with rituximab was 8% versus 31% for those treated with anti-tumor necrosis factor (TNF) alpha therapies (P = .03). Death from respiratory causes was also significantly lower in the rituximab-treated patients (4% vs. 15%, P = .04).

All-cause mortality was also significantly lower in patients with RA and ILD treated with mycophenolate mofetil (relative risk, 0.65) when compared with azathioprine (RR, 1.42) or other immunosuppressants, which included cyclophosphamide (RR, 1.65) and tacrolimus (RR, 1.74).

However, these data were retrospective, so prospective therapeutic trials are now needed, said Dr. Clive Kelly of Queen Elizabeth Hospital, Gateshead, England. Dr. Kelly, who was the driving force behind the set up of the BRILL network 2 years ago, stated that plans were already afoot to set up these trials with the intention of recruiting 200 patients with RA and ILD across the United Kingdom.

The aim of future studies would be to compare the use of rituximab versus anti-TNF therapies, with or without methotrexate, and mycophenolate mofetil versus azathioprine, with or without oral steroids, to see if the anticipated survival benefit associated with the newer agents is confirmed. Funding for the trials is yet to be secured, but it is hoped that recruitment can begin next year.

When people think of comorbidity in RA, they tend to think about cardiovascular disease first, Dr. Kelly noted at the British Society for Rheumatology annual conference. He observed that ILD has been associated with RA for well over 50 years and that respiratory disease, largely due to ILD and chronic lung damage, is now a "close second" behind heart disease as a cause of death in patients with RA.

Up to 40% of all cases of ILD are discovered in RA patients postmortem, he said, but with the increased use of high-resolution computed tomography (HRCT) in the 1990s, around a quarter of patients with RA were found to have changes on lung scanning.

Today, the prevalence of clinically significant lung disease is estimated to be around 5% in RA, with a lifetime risk thought to be around 7.7%. Patients with RA who develop ILD are around three times more likely to die than are those who do not, with a reported mean survival around 2.6 years from the diagnosis of lung disease until the advent of these recent studies.

The BRILL network consists of 16 centers located throughout the United Kingdom and was set up to establish a national database of all cases of ILD in RA patients that had been reported by these centers over a 25-year period, beginning in 1988. Patients were included in the database if clinical symptoms, such as shortness of breath or chest crackles, or pulmonary function tests had indicated ILD, and abnormal findings had been confirmed via HRCT.

For the current study, Dr. Kelly and coinvestigators from the BRILL Network looked at a subset of 188 patients with RA and ILD who had been diagnosed between 2000 and 2012. A control group of 188 patients with RA without ILD were included for comparison, matched for age, sex, and duration of RA.

Patients with ILD were more likely than those without to use biologics or immunosuppressants. Of the 188 patients with ILD, 57 were treated with either rituximab or anti-TNF drugs and 83 were treated with immunosuppressants.

The median age at which ILD was identified was 64 years, ranging from 42 to 87 years. The median duration of RA at ILD diagnosis was 9 years and the median duration of ILD was 4 years.

Dr. Kelly reported that RA preceded lung disease in the majority (83%) of cases, while 10% of patients developed ILD before the articular features of their disease became apparent. The onset of RA and ILD was "synchronous" in the remaining 7%.

HRCT results showed that the most common subtype of lung disease was interstitial pneumonia in 65% of cases, which carries the worst overall prognosis, he said. Nonspecific interstitial pneumonia, which is more responsive to early therapy, accounted for 24% of cases. The remaining patients had cryptogenic organizing pneumonia (6%) and or mixed subtypes (5%).

Survival over the 25 years improved, with 67% of RA-ILD patients dying from ILD in 1987-1993, compared with 30% in 2006-2012 (P less than .01). Nevertheless, these data are retrospective, Dr. Kelly observed, and trials are warranted to confirm the effects of specific treatments. He encouraged delegates at the meeting to participate in forthcoming BRILL network studies.

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