Do Treatment Outcomes Differ Between Seronegative RA and Seropositive RA?

My diagnosis of rheumatoid arthritis was not immediate upon reporting vague symptoms to my primary care doctor as early as 2004. The main reason is that my laboratory results did not show elevated levels of rheumatoid factor (RF). At the same time, my erythrocyte sedimentation rate (ESR), otherwise known as SED rate, was barely elevated. It wasn’t until 2007 that I was finally diagnosed with seronegative RA.

Seronegative RA compared to seropositive RA

Researchers from the Netherlands have recently published a retrospective study in PLoS Medicine (2020) that suggests there are distinct differences between disease outcomes and response to treatment between RA patients who are seropositive versus those who are seronegative.1 The researchers refer to these two groups of patients as having autoantibody-positive RA or autoantibody-negative RA.

The study included 1285 patients diagnosed with RA between 1993 and 2016. The study participants were followed yearly, making this a very long-duration study, with 36 percent presenting with autoantibody-negative RA compared to 64 percent presenting with autoantibody-positive RA. The autoantibody-negative group was slightly older than the autoantibody-positive group at time of diagnosis with mean ages of 60 and 55 years, respectively.

Autoantibody-positive and autoantibody-negative RA groups

The autoantibodies used to distinguish groups of patients included rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). If results were positive for either test, the patient was categorized as autoantibody-positive RA. The autoantibody-negative RA category required negative results for both tests. The variety of biomarkers used in the modern VECTRA test were not used in this study.

In the published paper, researchers emphasize that it is very rare for patients to convert from autoantibody-negative RA to autoantibody-positive RA, or vice versa. Authors point out that only 2 percent converted after 1 year and 5 percent converted after 2 years.1 This could be explained by borderline test results at the beginning of the study.

Changes in RA treatment approaches and options

A lot about RA diagnosis and treatment approaches have changed during this time period, so data was analyzed to take this into consideration. In this study, patients diagnosed between 1993-1996 basically only received NSAIDs (non-steroidal anti-inflammatory drug) as treatment.

Those diagnosed between 1997-2000 received DMARDs (disease-modifying anti-rheumatic drugs) such as sulfasalazine or hydroxychloroquine (but not methotrexate) and those diagnosed between 2001-2005 received methotrexate as initial treatment.

Patients diagnosed between 2006-2010 typically received methotrexate followed by a biologic in a treat-to-target approach.

Those diagnosed between 2011-2016 received similar treatment to the previous group, but were often diagnosed earlier in their disease due to increased primary care education, outreach, and referral.

The Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR; a combined count of swollen/tender joints and SED rate results) was used to measure short-term outcomes and treatment response. Long-term outcomes that were studied include sustained DMARD-free remission (SDFR), mortality, and functional disability.

The start of my seronegative RA treatment

When I was diagnosed with seronegative RA, the first thing my rheumatologist did was prescribe DMARDs, including methotrexate, sulfasalazine, and hydroxychloroquine. These drugs take a few months to really kick in, and once this happened my disease severity definitely improved. My experience aligns well with what happened to patients with either type of RA in this study. My DSA28-ESR definitely improved and I achieved drug-induced near-remission of my RA with treatment.

But a few years into my RA journey, I attempted to taper off and stop methotrexate with the idea of potentially having children. That didn’t last very long because the pain and disability associated with RA started to rush back with a vengeance. That experiment failed and my near-remission ended.

Sustained DMARD-free remission

I found results of one of the long-term outcomes measured in this study — sustained DMARD-free remission (SDFR) — to be very interesting, particularly considering my own failed attempt to go off methotrexate.

Researchers found that in autoantibody-positive RA patients, SDFR increased significantly over time, especially since the introduction of the treat-to-target approach.1 However, no such significant increase in SDFR was noted in the autoantibody-negative RA group.1

Sustained remission in the seronegative RA group

In my own comparison of the percentages of patients in either group who achieved SDFR, it is apparent that a larger percentage of patients with seronegative RA were able to achieve SDFR and in a shorter period of time than those with seropositive RA. There was just less improvement in SDFR rates over time in the autoantibody-negative RA group. That which was already okay had less room to get better.

But I find it discouraging to see that only a rough estimate of 10-20 percent of people with seropositive RA and 30-50 percent of people with seronegative RA could achieve SDFR in 5-10 years. It would be more encouraging to see that treatments were so effective that a large majority of people with either form of RA could achieve sustained remission in under 10 years.

My personal experience

I’ve heard anecdotally that people with seronegative RA have less severe disease activity and this study seems to support that notion. Once methotrexate and Rituxan got my RA under control, my disease went from severe to mild with drug-induced near remission status. However, if I remove methotrexate as I tried in the past, my disease definitely does not maintain SDFR status and it doesn’t take long before it becomes active again.

To stop treatment is not a current treatment goal

The point of the study was not to compare or optimize treatment choices for people with RA. In clinical practice, SDFR is not a current treatment goal. Authors suggest that “although innovative, [sustained DMARD-free remission] is an interesting outcome from an immunological perspective that resembles ‘cure.’”1 If this were achievable in the majority of patients, I could begin to hope that a cure might be possible.

Authors note that improved treatment strategies, which have evolved over the past 2+ decades, resulted in reduced disease activity in both groups of RA patients, which is great news. However, significant improvements in long-term outcomes — SDFR, mortality, and functional disability — were present in autoantibody-positive RA patients but not in autoantibody-negative RA patients.

Again, when baseline measurements are already better in one group - in this case, the seronegative RA group - it’s harder to detect significant improvements. Just because the observed improvement wasn’t as dramatic in patients with seronegative RA, I wouldn’t want to risk losing some of those improvements by stopping medication.

A need to tailor treatment approaches to autoantibody status

As we know, there’s more to RA than painful joints and underlying disease activity can be brewing even if swollen joint counts and SED rates are down. What this study suggests to me is that perhaps researchers need to explore what makes seronegative RA so different from seropositive RA aside and to ultimately be able to tailor treatment approaches to autoantibody status.

What’s your seronegative RA experience?

For those of you in the community who have seronegative RA, has your rheumatologist suggested a less aggressive treatment approach? Have you and your rheumatologist tried to stop DMARD or biologic treatment for a period of time? If so, what happened?

I’d love to hear your stories.

Be well,

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