Abstract
We report here an unusual case of rheumatoid arthritis presenting for the first time in a 32-week pregnant patient. Despite thorough evaluations from different specialties, the patient’s diagnosis went undiscovered originally being attributed to orthopedic issues and then to normal symptoms of pregnancy. The patient’s symptoms progressively worsened until she was no longer able to ambulate and complete her daily activities. A primary diagnosis of rheumatoid arthritis is exceedingly rare during pregnancy due to changes in the body’s immune system that accommodate the foreign fetus. Also physiologic changes that occur during pregnancy can often cloud the clinical picture of a patient presenting with joint pain and weakness. Nonetheless, a thorough workup should be conducted to rule out underlying rheumatologic disease.
Introduction
Rheumatoid arthritis (RA) is a chronic autoimmune disorder that primarily affects the joints, but can also involve other organ systems, including the eyes, lungs, and peripheral nerves. Left untreated, it may ultimately lead to a symmetric erosive polyarthritis. It is one of the more common autoimmune diseases, with a prevalence greater than psoriasis, Crohn’s disease, multiple sclerosis or lupus. 1 The disease affects approximately 1% of the world population 2 and 1.3–1.4 million adults in the United States.3,4 RA has a female predominance, occurring twice as frequently in women than in men. 2 The age-standardized prevalence of RA among women, according to the Rochester Epidemiology Project, has increased from 0.8% (7.7 per 1000) in 1995 to 1% (9.8 per 1000) in 2005. 5 Many women who have RA are of childbearing age and therefore pregnancy presents a unique challenge to disease management.
During pregnancy, as is true for many other chronic autoimmune diseases, there may be a temporary resolution of symptoms. Because the fetus is a natural allograft that expresses paternal antigens, several changes occur in the mother’s body to suppress the immune system in order to maintain the viability of that fetus. Some of these immunologic alterations include a switch in T-helper cell cytokine secretion from a Th1 (proinflammatory) predominance to a Th2 (allergic and anti-inflammatory) predominance, 6 an increase in T-regulatory cells within the CD4+ population, 7 the inhibition of complement activation by CR1-related gene/protein Y, 8 estradiol-induced reduction in cytokine production, 9 M2 polarization of decidual macrophages, 10 dampening of Th17 activity by decidual natural killer cells, 11 and increased soluble tumor necrosis factor (TNF) receptors. Research has shown that, to varying degrees, approximately 75%–90% of women with RA improve during pregnancy. 12
It is in the postpartum period that the female is particularly vulnerable to RA flares as well as primary development of RA. There is an increased incidence of RA following the first pregnancy, especially in the first 9 months. Postpartum flares may occur in up to 90% of RA patients, usually in the first 3 months, also more often after the first pregnancy.12,13
Because of the dynamics of the immune system during pregnancy, the initial appearance of RA during pregnancy is very uncommon. Here, we report a novel case of RA development and diagnosis in the third trimester of pregnancy.
Presentation of case
Informed consent was obtained from our patient to discuss the following case.
A 32-year-old Hispanic woman presented to the emergency department (ED) with a chief complaint of joint pain and swelling. She had a past medical history significant for a chlamydial infection at age 19 years which was appropriately treated and a past surgical history of rhinoplasty in her teenage years. The patient was an overall healthy female at 32 weeks gestation with a previous cesarean section for her first child 10 years prior. Her current pregnancy to date had been uncomplicated. She had gained 15 pounds in the first two trimesters and had recently been diagnosed with gestational diabetes which was under adequate control with diet modification. The patient was never a smoker and was not drinking alcohol for the past 8 months.
The patient’s joint pain and swelling had begun suddenly 1 month prior to her admission. The pain and swelling were initially localized to the knees and were associated with 30 min of morning stiffness, myalgias, and fatigue. The onset of her pain was not related to any known trauma and non-steroidal anti-inflammatory drugs (NSAIDs) provided minimal relief. Her symptoms were mildly relieved by topical IcyHot and acetaminophen/codeine, which were suggested by her primary care physician. The pain and stiffness in her knees had worsened bilaterally over the course of a few days prompting the patient to present to the ED. She was evaluated and told to follow-up with outpatient orthopedics. She underwent bilateral knee arthrocentesis by orthopedics with removal of cloudy yellow fluid, as per the patient. Fluid analysis and culture were insignificant for any underlying infectious process. Despite several outpatient appointments with orthopedics, the etiology of her pain and stiffness remained unresolved and she began using a cane to ambulate.
Shortly afterward, she began noticing pain in both shoulders. She presented to the ED again due to worsening pain but was discharged after an evaluation by labor and delivery which cited symptoms of pregnancy. One week prior to admission, the patient presented to the ED for the third time. She began to have pain and swelling in her hands, wrists, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints bilaterally. In addition, the patient complained of sharp shooting pain originating in her left hand and wrist that propagated proximally to her left elbow. The patient noted that her morning stiffness was now lasting 1.5 h each morning and that she had lost five pounds since the onset of her symptoms. At the time of her admission, the patient’s symptoms had progressed so significantly that the patient required assistance with her usual activities of daily living.
Initial diagnosis/assessment
Upon physical examination, it was noted that the patient had several tender and inflamed joints which included her shoulders, knees, wrists, MCPs, and PIPs bilaterally. Range of motion was significantly restricted: she was unable to close either hand secondary to severe stiffness and pain and had difficulty extending her arms and raising them vertically.
On a thorough laboratory workup, the patient was found to have elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) antibodies (Table 1). According to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA, our patient achieved a total score of 9/10, since at the time symptom duration was <6 weeks. Based on her presentation, examination, and laboratory findings, she was diagnosed with typical or “classic” RA. As there was also concern for systemic lupus erythematous (SLE), additional workup was conducted to rule out this disease process. In addition to negative anti-nuclear antibody (ANA), the patient did not satisfy 4/11 criteria for SLE diagnosis; she had no rash, ulceration, renal, hematologic, or neurologic disorder.
Initial RA workup.
RA: rheumatoid arthritis; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; RF: rheumatoid factor; CCP: cyclic citrullinated peptide; ACE: angiotensin-converting enzyme; ANA: anti-nuclear antibody.
Treatment/management
After a joint discussion between the medicine and rheumatology services, the patient was started on methylprednisolone 16 mg, a dose that would both alleviate her symptoms and be safe for the growing fetus. It is standard rheumatologic practice to initiate therapy with low-dose corticosteroids as opposed to intraarticular injection with crystalline glucocorticoids to reduce the systemic inflammation immediately when there is polyarticular involvement. In addition to medication, the patient engaged in physical therapy daily. A gradual improvement was noted and by day 3 of admission, the patient was ambulating without her cane.
Also noted on admission were elevated liver function tests (LFTs), which continued to trend upward (Figure 1). A thorough workup was initiated to look for autoimmune hepatitis, cholestasis of pregnancy, infection, or fatty liver since elevated LFTs are not seen in RA (Table 2). Abdominal ultrasound showed prominent biliary sludge and a dilated common bile duct (CBD) (6 mm). Autoimmune hepatitis was unlikely as all other autoimmune markers were negative, there was no IgG elevation, and the transaminase elevation did not respond to methylprednisolone. Cholestasis of pregnancy was the primary diagnosis in light of elevated bile acid levels but normal gamma-glutamyl transpeptidase (GGT).
Serial LFTs.
Elevated LFT etiology workup.
ASMA: anti-smooth muscle antibody; AMA: anti-mitochondrial antibody; GGT: gamma-glutamyl transpeptidase.
Outcome/implications
The patient was discharged on hospital day 7 to be followed up by hepatology and rheumatology postpartum for the initiation of disease-modifying anti-rheumatic drugs (DMARDs). Two weeks postpartum, the patient presented for rheumatology follow-up where she was found to be minimally symptomatic with no significant joint edema or restriction in movement and her dose of methylprednisolone was decreased to 12 mg. One month later, the patient complained of 1–2 h morning stiffness and displayed generalized puffiness of her hands with decreased grip strength. DMARDs were deferred until the infant was weaned off of breastfeeding. At 2 months postpartum, the patient was started on sulfasalazine, three times daily, and methylprednisolone was decreased to 8 mg. Her laboratory reports showed elevated ESR and CRP with continued hand stiffness and swelling (Figure 2). Three months postpartum, the patient reported a significant flare, with increased stiffness and pain. She was advised to increase sulfasalazine to 1000 mg bid. Consideration will be given to adding a second DMARD at the next follow-up visit.
Four-month trend of inflammatory markers.
Discussion/conclusion
RA flares during pregnancy are uncommon, and a new diagnosis of RA is even rarer. This is the first report in the medical literature of a primary diagnosis of RA during pregnancy.
The immunosuppression that occurs in pregnancy generally causes resolution of symptoms of chronic inflammatory diseases. The amelioration of RA symptoms during pregnancy was first described by Hench in 1938 14 who noted that 90% of women in his 34 patient cohort described relief of symptoms. A more recent prospective study used an RA validated instrument, the disease activity score 28 (DAS28), as well as laboratory results to show a statistically significant decrease in disease activity during pregnancy and an increase postpartum. 15 In addition, they speculated, postpartum flares may be underestimated because medication use is often remarkably increased after delivery.
The disease’s ability to evade the immune suppression associated with pregnancy, as in the case of our patient, may serve as a predictive factor for a more rapidly progressive and severe disease course. In patients diagnosed with RA before pregnancy, deterioration of RA postpartum was present in 40%–60% of patients with at least a moderate flare. 15 One study showed that 70% of women had self-reported deterioration in disease activity in the postpartum period. 16 In all, 66% of the women in this study reported an increase in joint swelling and 62% of patients had an increase in the number of affected joints. The median number of affected joints increased from 6 during pregnancy to 10 joints at 6 months postpartum. 16 In our patient, postpartum follow-up revealed a course that progressively worsened up to 4 months postpartum. She required intervention with DMARDs and an increase in methylprednisolone dosage after an initial taper due to transient and temporary alleviation of symptoms that lasted only a few weeks postpartum.
In RA cases that present for the first time during pregnancy or flare, early intervention with appropriate medication is crucial to prevent a severe disease course. 17 Physiologic changes that occur during pregnancy (especially in the third trimester) can make it hard to distinguish the physical symptoms of RA presentation. In addition, the ESR, an important inflammatory marker in the diagnosis of RA, rises from 10 mm/h in the first trimester to 33 m/h in the third trimester secondary to increased circulating fibrinogen, plasma expansion, and decreased hemoglobin concentration.18,19 While most women with RA tend to improve during pregnancy, disease flare and particularly primary diagnosis should not be overlooked or attributed to pregnancy symptoms. Patients presenting with typical and atypical features of RA should have a comprehensive evaluation for different rheumatologic diseases, in order to reach a correct diagnosis and initiate appropriate therapy. Primary presentation of RA during pregnancy may portend a more severe clinical course. Additional research on this very unique patient population is necessary to further delineate the prognosis of their disease.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.