Johns Hopkins Arthritis Center

Home / Arthritis News / Rheumatoid Arthritis News

Rheumatoid Arthritis News

Pregnancy Concerns Among Women with Rheumatoid Arthirits and Lupus

Pregnancy Concerns Among Women with Rheumatoid Arthirits and Lupus

Many autoimmune diseases have a female predominance. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are no exception. Both of these diseases can affect young women in their reproductive years, but little is known about the impact of RA and SLE on a woman’s opinion regarding pregnancy or, further, how this translates into family planning. This study [Clowse ME, et al. Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care & Research 2012; 64(5):668-74] sought to determine if women with RA or SLE had fewer children than those diagnosed later in life, and if so, the reasons and causes behind such differences.

Methods:

Adult female participants with RA or SLE in the National Data Bank for Rheumatic Diseases were mailed a comprehensive reproductive questionnaire. This questionnaire asked participants about their reproductive history (ever pregnant, number of pregnancies, number of miscarriages, etc) and if they had a personal history of infertility. Additional questions were included that addressed issues of reproductive intent. Based on the participants’ responses, women were categorized as: A) those who had fewer children than they had intended; B) those who had the same number of children as they had intended; C) those who had completed childbearing at the time of diagnosis.

Results:

578 (68%) RA patients and 114 (69%) SLE patients completed the reproductive questionnaire. Women with SLE were younger at age of symptom onset than RA (35.7 vs 38.4 years, p=0.07) and younger at age of reproductive questionnaire completion (53.8 vs 58.6 years, p<0.01). The percentage of women in Group A, B, or C was similar for RA and SLE (A: 21% RA, 25% SLE; B: 16% RA, 14% SLE; C: 63% RA, 60% SLE). For both RA and SLE, women who developed symptoms of their disease prior to the completion of having children ended up with fewer children than they had planned. The mean number of pregnancies, children, and terminations was similar between RA and SLE women; however, SLE women had a higher rate of miscarriages. Among women with RA, those in Group A had on average 1 less pregnancy and 1 less child than women in Group B or C. RA women in Group A, as expected, reported the highest infertility rate (42%) with causes including ovulatory dysfunction, unexplained, and endometriosis. However, 58% of RA women in Group A did not report infertility but had fewer pregnancies and children than they had hoped. Reasons reported for this discrepancy included: concern about their ability to care for children; concern that their disease or medications would harm the baby; and concern their children would develop RA. Among women with SLE, 21.7% of the pregnancies ended with miscarriage. Among women with RA, older age at diagnosis was associated with a higher number of pregnancies and infertility – and reporting more reasons for avoiding conception was associated with fewer pregnancies. Infertility, age of SLE onset, and miscarriage did not impact the number of pregnancies or live births for women with SLE.

Conclusions:

More than a half of the women with RA and SLE in this cohort diagnosed with their disease prior to completing child bearing had fewer children than they originally planned. Contributing factors include reported infertility (particularly among RA), pregnancy loss (particularly in SLE), and concerns about the impact of their autoimmune disease on their children.

Editorial Comment:

Decisions about family planning are very personal and are an important part of the overall health care of our female patients with RA and SLE. As a health care community, it is critical we address patients’ concerns about fertility and family in the context of their inflammatory disease. This study clearly demonstrates that our patients are dealing with these issues, and it is our responsibility to educate our patients so they can make well-informed decisions based on data and facts and not fears or fallacies. Infertility in RA and SLE is an understudied area that deserves more attention to understand causes and optimal management.     Rebecca L Manno, MD, MHS

Don’t Stop Exercising!

Don’t Stop Exercising!

It has been established that patients with rheumatoid arthritis (RA) have decreased muscle and increased fat compared to those without RA. A randomized-controlled trial of 24-weeks of high-intensity resistance exercise among patients with RA published in 2009 [Lemmey AB, et al. Effects of high-intensity resistance training in patients with rheumatoid arthritis patients: A randomized controlled trial. Arthritis Care & Research 2009;61(12):1726-34] demonstrated significant gains in strength, function, and lean body mass among RA patients who exercised compared to those who did not. Further, the intervention improved gait speed (an important predictor of morbidity and mortality) and decreased fat mass. However, it is not known if these benefits can be sustained over time. A 3-year follow up of this resistance exercise trial [Lemmey AB, et al. Are the benefits of a high-intensity progressive resistance program sustained in rheumatoid arthritis patients? A 3-year follow up study. Arthritis Care & Research 2012;64(1):71-75] seeks to answer this question and determine if the positive effects of resistance exercise persist despite the study population returning to their sedentary lifestyles.

Methods:

All patients (adult RA) who participated in the original RCT were eligible for inclusion. These patients had been randomized either to receive supervised high-intensity resistance exercise (for 24-weeks) or home-based low-intensity range of movement exercise. Of note the original RCT did not continue to provide an exercise program for participants outside the 24-weeks of the original study. Follow up (3 years post-study) measures included: body composition by DEXA, knee strength, functional measures (20-second chair stand, 20-second arm cur., 50-foot walk), and RA disease activity (DAS28). Participants were asked about their physical activity, medications, diet, and leisure activities as well.

Results:

18 RA patients from the original study (n=28) participated in the 3 year follow up measures (n=9 intervention; n=9 controls). None of the subjects were performing high-intensity progressive resistance training at follow up or any other form of regular high-intensity exercise. Body weight was unchanged in the group who previously participated in the exercise program, but the gains in lean made during the study were lost. There was some preservation of body composition change regarding loss of fat mass. Gains in gait speed did persist among the exercise group resulting in 66% retention in walking speed improvements for those who had exercised compared to those in the control group.

Table 1.

Variable Intervention(exercise) GroupControl GroupP-value
Appendicular Mass
Baseline14.23 ± 2.1015.24 ± 4.49
Postintervention15.44 ± 2.2415.21 ± 4.830.030
3-year FUP14.15 ± 1.9214.93 ± 4.610.738
Total Fat Mass
Baseline28.18 ± 14.3527.92 ± 6.71
Postintervention24.96 ± 12.7928.11 ± 8.560.045
3-year FUP27.20 ± 14.4930.34 ± 6.400.032
50-foot walk, seconds
Baseline9.68 ± 2.778.80 ± 2.96
Postintervention7.90 ± 1.388.97 ± 3.820.011
3-year FUP8.50 ± 1.779.06 ± 3.510.033

Conclusions:

Changes in fat mass and improvements in gait speed achieved through a 24 week program of high-intensity resistance exercise in RA patients were sustained up to 3 years in follow up, even without continuing the exercise program. Gains in lean mass and strength measures, however, did not persist. Importantly, no patients continued to participate in any structured resistance exercise training programs.

Editorial Comment:

This 3-year follow up of resistance exercise in patients with RA puts real data behind the commonly used term “use it or lose it.” RA patients made impressive gains in lean muscle, fat loss, strength and function (as evidenced by gait speed) with resistance exercise – only to lose most if it by stopping exercising altogether with the end of the study. Further investigation into the barriers that RA patients face regarding participation in routine exercise programs (is the problem access? pain? cost? time?) needs to be conducted so we can help our patients overcome these obstacles. Exercise is an important part of the overall treatment of RA due to the many benefits to joint, muscle, and overall health.

Vaccinations in RA: Stay Healthy!

Vaccinations in RA: Stay Healthy!
Vaccinations

Vaccinations are a critical component of RA clinical management, and their importance in preventing infection cannot be stressed enough. The majority of patients with RA are on immunosuppressive treatment, and a data driven approach to vaccinations in this high-risk population is essential.  In Arthritis News on 2/28/10 [“Immunization Responses with Rituximab Explored”] we reviewed two studies that explored immunization responses after influenza vaccination among RA patients being treated with rituximab. It was concluded that patients should not be vaccinated around the time of rituximab infusion to ensure maximal response.

Below we summarize a recent study [Coulson E, et al. Pneumococcal antibody levels after pneumovax in patients with rheumatoid arthritis on methotrexate. Ann Rheum Dis 2011;70:1289-1291] that measured the response to the vaccination for Streptococccus pneumoniae in RA patients on methotrexate over a 10  year period.

The pneumovax vaccine prevents severe infections from a virulent bacterium (Streptococcus pneumoniae) that can cause pneumonia, meningitis, sinusitis, and other serious infections. This vaccine is currently recommended for children, adults  ≥65 years old, adult smokers, adults with asthma, and any adult with a chronic disease that lowers the immune system or who is on medications that lowers the immune system (http://www.cdc.gov/vaccines/vpd-vac/pneumo/default.htm#notvacc). A one-time re-vaccination with pneumonvax five years after the first dose is recommended for: 1) individuals <65 years at highest risk for serious pneumococcal infections or who are likely to have a rapid decline in antibody levels (patients on chronic immunosuppression and corticosteroids are included in this group), and 2) individuals ≥65 years old who received their first dose for any indication when they were <65 years old (http://www.immunize.org/askexperts/experts_ppv.asp).

Methods:

To be included in the study, patients had to meet the 1987 criteria for RA and be on a stable dose of methotrexate for >12 months. The following data were collected for each patient: dose/duration of methotrexate therapy, dose/duration of steroid therapy, pneumovax status in preceding 10 years (date of administration), and the presence of serious pulmonary infections in the preceding 10 years. All patients had blood drawn to determine pneumococcal antibody levels.

Results:

180 consecutive outpatients with RA were identified, although reliable vaccination data was only available on 152 patients and these 152 individuals were included in the final analyses (vaccinated = 124, non-vaccinated = 28). No correlation was found between pneumococcal antibody levels and methotrexate dose (r= -0.01), duration (r= -0.03) or time since vaccination (r= -0.07) in the vaccinated group. There was a trend for levels to fall 7 years after vaccination. The mean methotrexate dose was similar between the two groups (vaccinated = 18 mg/week, non-vaccinated = 17 mg/week, p=0.94). In the preceding 10 years, 11 patients had pulmonary infections [vaccinated = 1 (vaccine administered after pneumonia), non-vaccinated = 7, p=0.0007]. Among RA patients who developed pneumonia, there was a greater percentage on oral steroids (pneumonia = 45%, no pneumonia = 9%, p=0.004). The relative risk for developing pneumonia among non-vaccinated patients was 9.7 (p=0.005) and among patients on oral steroids was 6.5 (p=0.001) after adjusting for age, gender, disease duration, and co-morbidities.

Conclusions:

These data demonstrate that vaccination of RA patients on methotrexate did not impair an antibody response to pneumovax (mean doubling of pneumococcal titers among those vaccinated). RA patients on oral steroids had a significantly increased risk of developing pneumonia, but patients with RA on methotrexate who received pneumonvax were 10-times less likely to develop pneumonia over a 10-year period than those not vaccinated. Finally, the antibody response was sustained for 10 years, although there was a trend for levels to fall after 7 years.

Editorial Comment:

These data re-emphasize the importance of vaccinations in preventing serious infections in patients with RA. Further, it suggests that prednisone, not methotrexate, is the culprit which may lead to an increased risk of pneumonia among these patients. Neither dose nor duration of methotrexate therapy had an impact on pneumoncoccal antibody titers over 10 years of follow up. Although this study cannot definitively answer the question regarding the need for re-vaccination after 5 years, it does suggest that the protective effects (at least the antibody response) may be sustained for at least this long in the setting of ongoing treatment with methotrexate. We recommend that all patients with RA discuss the pneumovax with their primary care physician and rheumatologist.

Does Antioxidant Intake Protect Against the Development of Rheumatoid Arthritis or Lupus?

Pills

Antioxidants may protect tissues against damage, reduce systemic inflammation, and modulate antigen presentation by inflammatory cells.  However, no large-scale investigation on whether dietary and/or supplement intake of antioxidants is protective against the development of autoimmune rheumatic disease.  Here, Costenbader et al (American Journal of Epidemiology 2010; 172(2): 205) explore antioxidant intake and the risk of developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in women enrolled in the Nurse’s Health Study.

Methods

Participants in the Nurses’ Health Study, a prospective cohort study of U.S. female nurses enrolling between 1976 – 2004, had food frequency questionnaires administered every four years that included quantifiable data on multivitamin intake and antioxidant intake from dietary sources.  A total antioxidant intake composite score [called the “ferric-reducing ability of plasma” score (FRAP)] was calculated for each participant.  The association with antioxidant exposure with incident RA and SLE was examined.

Results

A total of 184,643 women without RA or SLE at baseline were studied.  The majority of participants (95%) were Caucasian with an average age of approximately 40 years.  Higher intakes of antioxidants were associated with a lower frequency of smoking, higher levels of physical activity, lower intakes of alcohol and caffeine, and higher intakes of calcium and protein.   There were 787 incident cases of RA and 192 incident cases of SLE over a mean follow-up time of 11 – 21 years (depending on the enrollment cohort).  There was no difference in the incidence of RA or SLE according to level of intake of any individual antioxidants (vitamins A, C, E, α-carotenoid, β-carotene, β-cryptoxanthine, or leutein) either from dietary sources, supplements, or combined, in crude analyses or those adjusted for age at menarche, menopausal status, use of oral contraceptives and hormone replacement, smoking, physical activity, body mass index or race.  The incidence of RA or SLE was also not different according to low vs. high levels of the composite FRAP score in crude or adjusted analyses.

Conclusions

Female U.S. nurses with low intakes or antioxidants were not more susceptible to developing RA or SLE than their counterparts with higher intake levels.

Editorial Comment

This large, carefully analyzed study is very clear in its message of no effect of antioxidant intake on RA and SLE risk.  It remains possible that misclassification of the exposures or the outcome could have nullified any association.  However, it is unlikely that an interventional study in which antioxidants intake is regulated in patients without RA or SLE who are followed for development of disease will be performed.  This is not the first instance of compelling preclinical information about the beneficial effect of antioxidants on immune mediated disease not being validated in clinical investigation, with examples in cancer and heart disease not demonstrating strong protective effects.

Antioxidant supplementation remains popular among the general population solely based on purported health benefits.  In this instance, this study is convincing enough to discourage high antioxidant intakes solely for the purpose of reducing the risk of RA or SLE.  In particular, high levels of supplementation of some antioxidant vitamins (e.g. E and β-carotene) have even been associated with increased risk of adverse outcomes (e.g. mortality) in some populations.

Leflunomide and Pregnancy Outcomes Explored

Interleukin-17

Leflunomide use during early pregnancy is associated with fetal malformations in animal studies and is classified as a pregnancy category X by the U.S. Food and Drug Administration.  However, little is known about pregnancy outcomes in humans exposed to leflunomide in early pregnancy, particularly in those who receive “wash-out” with cholestyramine (a drug sequestrant).   Here, Chambers et al (Arthritis Rheum 2010; 62(5):1494) present birth outcomes for the largest series of women exposed to leflunomide during early pregnancy.

Methods

Participants were women enrolled in the Organization of Teratology Information Specialists (OTIS) Collaborative Research Group.  Clinical data and birth outcomes for women with rheumatoid arthritis (RA) or juvenile rheumatoid arthritis (JRA) who took at least one dose of leflunomide after their estimated date of conception and were compared to disease-matched women unexposed to any teratogen during pregnancy and to a group of healthy-control pregnant women.  Cases were collected between 1999-2009.

Results

A total of 250 women were enrolled (64 in the leflunomide exposed group; 108 in the disease-matched group; and 78 in the healthy control group).  There were imbalances among the groups in baseline characteristics.  Compared to the healthy control group, leflunomide treated patients were of lower socioeconomic status, less likely to be on multivitamin or folate supplementation, and more likely to report tobacco use during pregnancy (25% vs. 10%; p<0.01).  The average gestational timing of leflunomide after conception was 3.1 weeks.  The longest exposure after conception was 8.6 weks.  Cholestyramine wash-out was performed in 61 leflunomide treated women (95%).  There was no significant difference between the groups in the proportion of liveborn or miscarried pregnancies.  Only one pregnancy to leflunomide exposed mother was electively terminated.  Among the live births, delivery by cesarean section was significantly more common among leflunomide exposed mothers (48%) compared to disease-matched non-exposed mothers (29%) or healthy control mothers (25%).  Preeclampsia was not significantly higher in leflunomide exposed mothers.

Major structural defects occurred in 3 of 63 leflunomide exposed women (5%), all in the liveborn offspring, compared to 7% in the disease-matched control group and 4% in the healthy control group.  These consisted of one occult spinal dysraphism, one uretero pelvic junction obstruction and multicystic kidney disease; and one microcephaly.  There was a trend to higher number of minor abnormalities in the offspring of leflunomide exposed women (i.e. the proportion with ≥ 3 minor abnormalities was 47, 32, and 29% for the leflunomide-exposed, disease-matched control, and healthy-control groups, respectively; p=0.10).

Compared to the control groups, gestational age was significantly lower in leflunomide exposed women, with significantly lower birthweight compared to disease-matched controls.  After adjusting for differences in maternal age, socioeconomic status, smoking, and preeclampsia, leflunomide was no longer significantly associated with lower gestational age or lower birth weight.

Among 19 leflunomide exposed women not-eligible for the cohort study, two malformations were encountered: aplasia cutis in the surviving member of a twin pair, and a birth resulting in multiple malformations in a mother treated with leflunomide for lupus.

Conclusions

Leflunomide exposure early in pregnancy was not associated with an increase in the number of major malformations, or adverse delivery outcomes compared to unexposed mothers with RA or JRA or healthy control mothers.  Lower gestational age and birth weight were explained not by leflunomide exposure itself, but to sociodemographic factors linked to leflunomide use in the cohort.

Editorial Comment

It is actually quite surprising and reassuring that major malformations were not higher than what was observed in this study.  This could indicate that leflunomide is not as teratogenic in humans as what was observed in animal studies, or that leflunomide washout with cholestyramine is very effective in limiting teratogenic effects.  These data are clinically applicable for counseling women who may have been exposure during early pregnancy, particularly regarding issues of elective termination.   Regardless, many practitioners will still choose not to use leflunomide in women of childbearing potential if there are other alternatives available.

Targeting Interleukin-17 Studied in Rheumatoid Arthritis

Interleukin-17

Recently, it has been recognized that a subset of T cells producing the cytokine IL-17 contribute to the pathogenesis of rheumatoid arthritis (RA).  Animal studies have suggested that blockade of IL-17 may reduce the inflammatory signs and symptoms of inflammatory arthritis and reduce bone erosion.  Here, Genovese et al report Phase I/II data for LY2439821, a novel humanized monoclonal IL-17 antagonizing antibody in patients with RA.

Methods

Adult patients with active RA despite stable background non-biologic DMARDs (methotrexate, sulfasalazine, and hydroxychloroquine) were randomized to receive a single escalating dose of LY2439821 or placebo (Part A-safety assessment).  In Part B, patients were randomly assigned to LY2439821 0.2, 0.6, or 2.0 mg/kg or placebo administered every 2 weeks for a total of 5 treatments.  The primary efficacy and safety endpoints were at week 10.  The study was conducted at 17 sites in Australia, Belgium, and Romania.

Results

A total of 20 RA patients were randomized in Part A (single dose escalation): four to each group of LY2439821 0.06, 0.2, 0.6, and 2.0 mg/kg or placebo.  A total of 77 RA patients were randomized in part B (multiple doses): 19 to LY2439821 0.2 mg/kg every 2 weeks, 20 to 0.6 mg/kg every two weeks, and 20 to 2.0 mg/kg every two weeks.  Randomization to placebo infusion s occurred in 18 patients in Part B.  In Part B, the average age of the participants was approximately 57 years, with the majority being female with approximately 8 years of RA duration.  Average DAS28 at baseline was approximately 6.0.  most of the patients were receiving two concomitant non-biologic DMARDs.  With the exception of average weekly methotrexate dose, there were no significant differences in baseline characteristics between the groups.

For safety outcomes, no patients withdrew from Part A due to adverse events.  Three patients withdrew from Part B due to adverse events [one for worsening of arthritis, and two for leukopenia (both were in the highest study drug dosing group)].  In Part A, headache and diarrhea were the most common treatment-related adverse events.  In Part B, adverse events were uncommon –with leukopenia being the most common and observed in 7%.  Neutrophil counts <1,500 were observed in 5 patients, all receiving study drug; however, there were no study discontinuations due to neutropenia.  Infections were not more common in patients receiving study drug compared to placebo.  One serious adverse event, a skin ulcer, occurred in one patient and was not felt to be related to the study drug.  One patient experienced an allergic skin rash felt to be related to the study drug; however, the patient did not develop antibodies to the study medication.

For efficacy outcomes, significant differences in ACR20 responses between patients receiving all doses of LY2439821 and placebo were observed at as early as 2 weeks.  The proportions of patients meeting response criteria increased over the study duration, with approximately 90% of patients in the highest LY2439821 dose achieving an ACR20 response at 16 weeks compared to approximately 50% in the placebo group.

Conclusions

LY2439821, a fully-humanized monoclonal antibody targeting IL-17, was tolerated and demonstrated short-term efficacy in RA patients with active disease with inadequate control with other DMARDs

Editorial Comment

The recent studies linking IL-17 to several of the key inflammatory pathways of RA and other autoimmune diseases make it an attractive candidate for antagonism.  Even more compelling are the preclinical studies suggesting that the IL-17 pathway is non-redundant.  Thus, this report is reassuring in that efficacy was demonstrated, albeit in a small cohort and for a short period.  Also reassuring was the observation of few safety signals, although the issues of leukopenia and neutropenia appear the primary ones to monitor in future trials.  The results of larger, longer-term follow-up studies with this agent are eagerly awaited.