Clinical:Rheumatoid Arthritis and The Menstrual Cycle

Original materials created in December 2004 by Carmen Hering, M.D. and Justina Trott, M.D.

Rheumatoid Arthritis (RA) affects 1-3% of the general US population making it the most prevalent autoimmune disorder. The etiology is unknown, but both genetics and environment seem to be involved. The disease also has sex, and possibly genderspecific influences, because we know that women are three times more likely than men to develop the disease. Not surprisingly, recent research has shown that female reproductive hormones have an immunomodulatory effect, and consequently, can impact rheumatoid arthritis and its course.

Hx:

DH is a 38 y/o female who comes in to meet you as her new doctor. Her medical history is significant for Rheumatoid Arthritis (RA). She is hesitant to say so, but feels that her RA fluctuates with her menstrual cycle. She notes that other times she had brought this up she was told that she simply perceives worse symptoms a part of her “PMS.”

PMHx:

4 year history of mild to moderate RA, always well controlled with NSAIDs; Otherwise healthy

FamHx:

Mother with RA, with severe deformities in later life Exam: Normal, with no joint findings, and no systemic manifestations of RA Studies: PAP normal, RF+

Discussion

While Rheumatoid Arthritis has historically been identified as an immune phenomenon, it is actually a product of complex interactions among multiple systems. RA and other autoimmune diseases should be viewed in the context of the neuroendocrine axis, which includes the hypothalamus, pituitary and adrenal glands, and the ovaries. These axes are often divided (arbitrarily) into the Hypothalamic-Pituitary- Adrenal Axis (HPA), and the Hypothalamic-Pituitary-Ovarian Axis (HPO). Any factors affecting these complex feedback loops, whether intrinsic or extrinsic, can impact RA. External stressors can affect the neuroendocrine axis in many ways. One important effect is through stimulation of beta-endorphin release. Beta endorphins then trigger a cascade starting at the hypothalamus, and activating both the HPA and HPO axes. This cascade results in adrenal gland release of cortisol into the blood, which is the stress response with which we are all familiar. Cortisol functions as immunosuppressant, which can lessen the inflammatory course of RA. Intrinsic factors affecting RA are many. One of the most important intrinsic factors is gonadal steroid production. Doctors have long recognized improvements in RA during pregnancy, with postpartum exacerbations. This has been postulated to result from high, steady levels of gonadal steroids, with abrupt decline after delivery. ^{[1] [2]} Less well-recognized and characterized are the effects of normal, biorhythmic hormone fluctuations, such as those associated with the menstrual cycle. Symptoms of RA are often reported to be minimized during the luteal phase of the menstrual cycle, when gonadal steroid production is at a maximum. During menses and early follicular phase, when hormonal levels are at their lowest, RA has been reported to be more severe. For example, studies have reported that symptoms such as morning stiffness and joint pain are increased during menses. ^[3] One study documented that size of finger joints is highest, and demonstrated grip strength to be the lowest at the start of menstruation.^[4] The relationship between the menstrual cycle and RA has recently become a subject for study. Focus has been on the relationship between ovarian hormones and the immune system, as the cause. While the interactions of gonadal steroids (in particular estrogens and progestins) with the immune system are complex, some relationships have been characterized. The physiologically low levels of estrogen during menses (or during the postpartum period), result in important changes. For example, dehydroxyepiandrosterone (DHEA) levels decrease, resulting in increases in inflammatory mediators such as interleukins, cytokines, and tumor necrosis factor (TNF). Cytokines and TNF stimulate a host of inflammatory mediators, which ultimately stimulate production of nitric oxide and superoxides producing an acute inflammation response. These findings can correlate with the post-partum “flare” seen in RA patients and with menstrual RA flares. ^{[5] [6] [7]} The menstrual cycle also impacts other components of the immune system active in RA. While it is less well characterized, the impact of gonadal steroids on humoral (antibody) response has been documented. ^[8] It is clear that antibody release is cyclic, but the relationship to estrogen and progestin levels, or to abrupt changes in these levels, is still unelucidated. White blood cell subpopulations also change in a cyclic fashion in relation to the menstrual cycle. ^[9] Any, or all of the immunomodulatory effects of the menstrual cycle can affect DH’s RA symptoms in a rhythmic fashion. Current knowledge and experience are in the beginning stages, but suggest the following course of action.

Plan

As DH’s physician, her experience of her symptoms as biorhythmic and coincident with her menses should be validated. DH should keep a detailed symptom diary to document which symptoms occur at which phases. If DH feels that her symptom exacerbations are severe enough to consider medication changes, cautious dosage adjustment in her NSAIDS in a cyclic fashion might be warranted. Another consideration might be addition of combination hormonal contraception to minimize hormonal fluctuations. In fact, addition of oral contraceptive pills has been shown to be beneficial for symptom control in some women ^[10] but it does not significantly influence outcome in long term RA. There is, however, a trend for patients with multiple pregnancies and long term OC use to have less radiographic joint damage and a better functional level. ^[11] If fluctuations are severe enough to warrant additional medications, such as methotrexate or biologicals, consultation with rheumatology is in order before changes are made.

References

1. ↑ Ann Rheum Dis, 1953;12:227-229
2. ↑ Arthritis Rheum, 1990;33:1770-1775
3. ↑ Am J Med, 1983;74:957-60
4. ↑ Ann Rheum Dis, 1983;42:425-30
5. ↑ J Clin Endo Met, 2001;86:4933-493
6. ↑ Sem Arthritis & Rheum, 1999;29:65-81
7. ↑ Brain Behav & Immun, 1999;14:49-61
8. ↑ Am J Obstet Gyn, 1969;104:440-42
9. ↑ Hum Reprod Upd, 2000;1:1-15
10. ↑ J Clin Epidemiol, 1990;1230
11. ↑ Ann Rheum Dis 2002;405