Another Rituximab Discussion

Let's talk rituximab today, shall we?

The results of a study done in France on rituximab therapy in the treatment of Sjogren's syndrome were recently released; the abstract and study authors are published online in the Annals of Internal Medicine and can be found here. The study was titled Treatment of Primary Sjögren Syndrome With Rituximab: A Randomized Trial. The conclusion of the study:

"Rituximab did not alleviate symptoms or disease activity in patients with pSS at week 24, although it alleviated some symptoms at earlier time points....In conclusion, our data do not support the use of rituximab therapy in many patients with recent-onset or systemic [primary Sjogren's syndrome]," they stated."

Here's how the study was conducted:

The authors studied 120 patients with primary Sjögren syndrome between March 2008 and January 2011. To be eligible for inclusion, patients had to fulfil the European-American Consensus Group criteria for primary Sjögren syndrome and to have active disease, defined as a score of at least 50 mm on at least 2 visual analogue scales (VAS) for global disease, pain, fatigue, and dryness..... 

The primary study outcome was an improvement of 30 mm or more on at least 2 of the 4 VAS scores at 24 weeks.The patients were randomly assigned to receive a placebo or 1-g infusion of rituximab at weeks 0 and 2. Patients and investigators were blinded throughout the study. The researchers conducted follow-up examinations at weeks 6, 16, and 24....... 

At 6 weeks, 22.4% of patients in the rituximab group improved by 30 mm or more on at least 2 of 4 VAS scores compared with 9.1% of patients in the control group, a difference of 13.3 percentage points (95% confidence interval [CI], 0.8 - 25.8; P = .036). The most significant clinical improvement was seen in fatigue, with 34.7% of the rituximab group and 8.2% of the control group recording VAS improvements of 30 mm or more, a difference of 26.6 percentage points (95% CI, 15.7 - 37.5; P < .001). There was also a difference of 19.1 percentage points (95% CI, 4.4 - 33.7; P = .011) in physician-assessed disease activity. Significant improvements also were seen between the groups in levels of immunoglobulin A (IgA; P = .026) and IgM ( P = .004), but in no other physiological or immunological measures. By week 16, rituximab was still associated with a greater improvement in fatigue (27.2 percentage points vs 8.9 points; 95% CI, 4.1 - 32.6; P = .012), but no other significant difference in clinical improvement, and by week 24, even that difference was gone. However, improvements were seen in levels of IgG, IgM, C4 complement, and β2 microglobulin at 16 weeks, and in all of those components plus IgA at 24 weeks, with rituximab, despite the lack of significant clinical differences. [Bolding mine]

Immediately after the study release, several stories interpreting the results appeared, and the tone of these discussions were quite pessimistic, like this one: Rituxan Offers Little Help for Sjogren's, found on Medpage today. And this from Medscape Nurses: Rituximab Disappoints in Sjögren Syndrome.

Having only read the headlines, my initial reaction was one of disbelief. You may remember that two years ago, I began rituximab infusion cycles separated by six months, and until I had an unusual response (neutropenia) I was very happy with the results. I received one gram of rituximab IV along with some pre-meds; and two weeks later another gram IV. Initially after my infusions, I was pretty tired but within a month could see a distinct increase in my energy levels and I had a modest improvement in my saliva production. The positive effects lasted for about a total of four to five months; and at six months the cycle of treatment was repeated, and my increase in energy was repeated as well.

So in an attempt to understand this all a bit better, I went back to read the study reports and the articles discussing the study, and realized that my experience with the drug was exactly the same as the study participants.

Um. Wait a minute here....My experience with this drug was very similar to those described in the study. I consider my experience one that assisted me enormously in the day to day struggles with Sjogren's related fatigue. The researchers didn't see it that way: "our data do not support the use of rituximab therapy in many patients with recent-onset or systemic [primary Sjogren's syndrome]." We're both looking at the same data but drawing opposite conclusions.

Is it possible that once again, fatigue is not considered a debilitating element of our disease and was discounted as a significant symptom in this study?

Sigh. Let's go back and review:

• At six weeks......The most significant clinical improvement was seen in fatigue. Most definitely true in my case. 
• By week 16, rituximab was still associated with a greater improvement in fatigue. Let's see, that would be four months out. Yup. Sounds right.
• ....by week 24, even that difference (decrease in fatigue) was gone. At six months, I needed to have my infusions repeated. Which is exactly what Dr. Young Guy had told me would happen, which is what we did, and my energy rebounded right on schedule.

I'm confused. The study authors felt that these clinical improvements were significant but lasted less than six months. The patients were never given a second cycle of the drug. Were they expecting that one set of infusions would create clinical improvements that would last indefinitely?

Really?

The fact that the B cell depletion action of rituximab is considered only to last six to twelve months was surely not unknown to the researchers since the target antigen (CD20) is not found on hematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissues. (Translation: Although rituximab decreases peripheral CD20 B lymphocytes, they eventually grow back since the tissues that create them (hematopoietic cells) are not targeted by the drug).

Let's repeat that: The desired effect of rituximab is in it's depletion of mature B lymphocytes with a CD20 antigen. Since the drug does not deplete the tissues that produce these lymphocytes, and since it takes the body six to twelve months to replenish these cells, it would appear only logical that the effects of the drug would diminish once the B lymphocytes regained their pre-rituximab numbers.

Am I being too simplistic here?

Apparently, other folks share my skepticism of this study:

At least one outside expert was less surprised. "The length of this study was short, considering that Sjögren syndrome is a lifelong condition," said Solomon Forouzesh, MD, associate clinical professor of medicine and rheumatology, University of California, Los Angeles, Geffen School of Medicine and Cedars-Sinai Hospital. "And although it is a relatively rare condition, 120 patients is not a lot. The authors needed a larger sample size." Dr. Forouzesh also questioned the study design. "This is not a disease you can control with 2 infusions. The study should have been designed more like a study for rheumatoid arthritis, in which the infusions are ongoing. You must give this drug continuously over time in order to see improvements in lacrimal glands or salivary flow. A chronic disease like Sjögren syndrome requires ongoing suppression."

Hm. "A chronic disease like Sjogren syndrome requires ongoing suppression."

Well. French study notwithstanding, this sjoggie plans on re-starting rituximab therapy in March to provide that "ongoing suppression".

I took a year long hiatus from the drug since my last cycle produced a significant neutropenia, an unusual side effect of ritux. But after lengthy discussions with Dr. Young Guy and a new plan of increased monitoring of lab values, I have decided to give it another try in the hopes that the neutropenia will not reoccur. If it does -- dang. I don't get any more chances with rituximab. But I'm willing to try. Living for the past year with the return of truly bone crunching fatigue has convinced me of the value of B cell depletion therapy.