Oral Contraceptives Play Positive Role in Rheumatoid Arthritis
An interview with Rainer H. Straub, MD
For over 10 million American women taking oral contraceptives (OC), the intention is safe birth control. However, there could be another positive, tangent effect: managing early rheumatoid arthritis (RA) symptoms.
Since the 1970s, doctors have been debating the notion that hormonal therapy could offer a protective effect over the incidence and development of RA. However, a new study shows RA patients who are taking, or have taken, oral contraceptives (OC) have much better outcomes than controls.
The study, which was published online in Arthritis Care & Research, examined 273 women, aged 18 to 60, in an early RA cohort.1 The German researchers tried to see if there were any associations between OC exposure (current, past, or never) and RA disease activity and patient-reported outcomes.
The study found that a majority of the patients did have some form of exposure to OCs, either in the past (63%) or currently (19%). Over the course of 12 months, those patients who have taken OC showed better outcomes than the 18% who never used an OC. Positive outcomes were defined as scoring higher on the Rheumatoid Arthritis Impact of Disease Score (RAID), the Rheumatoid Arthritis Disease Activity Index (RADAI), the Profile of Mood and Discomfort (PROFAD), and the Hannover Functional Assessment (FFbH) (all P<0.05). After 2 years, current/past OC users had significantly better RAID scores (P<0.001).
The Debate Behind Oral Contraceptives
However, the notion that OCs could serve a protective role against RA has been a source of debate since 1978.2 Numerous studies have found conflicting results, making any chance at developing a uniform explanation of OC's association to RA rather elusive. The positive role for OC centers around the idea that birth control products may have some kind of protective, immunoinhibitory effect that could alter RA progression by modifying the body’s complex relationship between its reproductive and immune systems.3
There are complications to consider, however. Contraceptive products feature varying formulations of estrogen and/or progestin cocktails (among other possible additives), so there could be variation by product. It is also not fully understood why there is not a difference in risk factor between current or past use of OCs—something this latest study also failed to answer.4
Further adding to this confusion, some studies have concluded the association between OC-use and RA is simply a byproduct of a lifestyle difference pointing to something else entirely—like smoking or pregnancy—and yet those environmental factors are still clouded by their own developing theories, as well.5
Oral Contraceptives: A Neurological Hypothesis
Indeed, the complexities and contradictions have created an air of skepticism around the subject, but according to Rainer H. Straub, MD, one of the study’s authors and a professor at the University Hospital Regensburg in Regensburg, Germany, past studies may have been looking at the idea from the wrong angle.
For years, studies have focused on biomarkers of inflammation, like erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) levels, in a fruitless search for associational data.6,7 The current study similarly found no association between inflammatory markers and OC-use. However, according to Dr. Straub, this could mean doctors have been overlooking something essential all along—the brain.
“The brain is much more plastic than we earlier thought,” made possible through neuronal stem cells, Dr. Straub explained in an email interview. “We more and more recognize that fatigue and other central nervous system (CNS) symptoms are mainly dependent on pain. Thus, the sensory nervous input to the brain is probably much more important than the cytokine-driven input to the brain. Exactly here, OCs might act because they might change the CNS locally."
“From studies in developmental plasticity in utero, one knows that hormones can have a long-term effect on later gender (not on sex). It is a kind of long-term programming initiated by epigenetic imprinting. Therapy with hormones over longer time might have a similar epigenetic reprogramming,” he noted
Epigenetics refers to the study of heritable changes in gene activity that are influenced by environmental factors, like taking OCs, not by any alteration in the primary DNA sequence.8 As clinicians continue to uncover details about RA’s polygenic profile, both genetic and epigenetic factors seem to play increasingly significant roles in the disease’s pathogenesis.5,9
So Dr. Straub’s epigenetic theory could help explain how hormonal therapy seems to influence a protective effect on RA, although important questions do remain. For instance, if hormone therapy displays a “long-term effect” of epigenetic changes, how can we explain the fact that both current and past users of OC seem to show equal results?
There are many other questions to ask, and Dr. Straub is positive about designing future studies to further explore the possible epigenetic mechanisms at play. Incorporating a more purposed genetic evaluation of cohorts, along with the OC-use and RA outcome data, could give more valuable insights and reveal more explicit connections—something researchers are eager to achieve. “Presently, such an idea is the future,” he noted.
This study was sponsored by the German arm of Pfizer, a biopharmaceutical company. The authors reported no conflicts of interest.