Marianne Wallenius

State of the art: reproduction and pregnancy in rheumatic diseases

Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their childrens birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes.

Work disability and health-related quality of life in males and females with psoriatic arthritis

Objectives: To compare health status, demographic variables and work disability (WD) between males and females with psoriatic arthritis (PsA) in the 18–45 age group, and further to compare health status between those with and without WD for each gender and to identify variables associated with WD. Methods: A cross-sectional study was carried out of patients with PsA with peripheral arthritis at the time at which they started disease-modifying antirheumatic drug therapy (DMARD) and/or biological treatment. Patients receiving a permanent national WD pension corresponding to ⩾50% were defined as work disabled. Gender differences were examined with regard to health status, demographic variables and WD. Mann–Whitney U test and Pearson χ2 were applied for group comparisons between males and females and work disabled versus not work disabled for each gender. Multiple logistic regression analyses with adjustments for duration of education, disease duration, age, erosive disease, disability score (Modified Health Assessment Questionnaire; MHAQ), the short form-36 (SF-36) mental health score, and gender were used to identify variables associated with WD. Results: Out of 271 (102 females) patients, the number (%) of work-disabled females/males was 33 (32.7%)/29 (17.4%) (p = 0.004). Work-disabled patients had generally worse health status than non-work-disabled patients, and these differences were generally more pronounced in males than in females. In the multiple logistic regression model, low educational level, increasing disability score (MHAQ), presence of erosive disease, female gender and disease duration were independently associated with WD. Conclusions: WD in patients with PsA below 45 years of age was independently associated with educational level, disability score, erosive disease, female gender and disease duration.

Pregnancy and delivery in women with chronic inflammatory arthritides with a specific focus on first birth.

OBJECTIVE To examine possible associations between chronic inflammatory arthritides and pregnancy outcomes with separate analyses of first and subsequent births before and after diagnosis. METHODS Linkage of data from a registry of patients with chronic inflammatory arthritides and the Medical Birth Registry of Norway enabled a comparison of pregnancy outcomes in women with chronic inflammatory arthritides and pregnancy outcomes in reference subjects. Outcomes of first birth and subsequent births before and after diagnosis were analyzed separately. Associations between chronic inflammatory arthritides and the womens health during pregnancy and delivery as well as perinatal outcomes were assessed in logistic regression analyses with adjustments for maternal age at delivery and gestational age. RESULTS We analyzed 128 first births and 151 subsequent births after diagnosis and 286 first births and 262 subsequent births before diagnosis in patients and compared them with first and subsequent births in reference subjects. Firstborn children of women diagnosed as having chronic inflammatory arthritides were more often preterm (odds ratio [OR] 1.85 [95% confidence interval (95% CI) 1.09-3.13]) and small for gestational age (OR 1.60 [95% CI 1.00-2.56]). They also had lower mean birth weight (P=0.01) and higher perinatal mortality (OR 3.26 [95% CI 1.04-10.24]). Birth by caesarean section (all classifications) was more frequent in patients than in reference subjects, and elective caesarean section was 2-fold more frequent in patients, both in first birth (OR 2.60 [95% CI 1.43-4.75]) and in subsequent births (OR 2.18 [95% CI 1.33-3.58]). No excess risks of clinical importance were observed prior to diagnosis of chronic inflammatory arthritides. CONCLUSION Excess risks were related to first birth in women diagnosed as having chronic inflammatory arthritides, including a higher rate of perinatal mortality. A higher caesarean section rate was related to all patient deliveries. Mainly, pregnancy outcomes before diagnosis did not differ from those in reference subjects.

Drug insight: Anti-tumor necrosis factor therapy for inflammatory arthropathies during reproduction, pregnancy and lactation.

Tumor necrosis factor (TNF) antagonists are widely used to reduce disease activity and joint damage, and to improve health-related quality of life in patients suffering from rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. To date, no increased risk of embryotoxicity or teratogenicity, or adverse pregnancy outcome (such as birth defects, premature birth, and low birth weight) has been reported in patients with inflammatory arthropathies treated with anti-TNF therapy, compared with the general population. However, the available data are limited, and methotrexate, which is commonly used in combination with anti-TNF drugs, is teratogenic. Until more data are available, no firm conclusions can be reached regarding the safety of anti-TNF therapy in pregnancy. Nevertheless, in selected cases where there is high disease activity, anti-TNF therapy might be recommended, depending on the results of individual risk–benefit analyses. Fully informed consent from the mother is needed in such cases. Anti-TNF agents are not usually used during lactation, although the risk of toxicity is probably negligible.

Fertility in women with chronic inflammatory arthritides

OBJECTIVE To compare fertility rates in women with RA, other chronic arthritides (OCAs) and JIA with reference women from the general population. METHODS Each woman from a Norwegian patient registry was matched by year of birth with 100 reference women randomly selected from the National Population Registry. Data linkage of patients and references with the Medical Birth Registry of Norway (MBRN) identified all offspring in patients and references until October 2007, and indirectly also nulliparous (childless) women. Groups were compared with Mann-Whitney U-test for continuous variables and chi-squared tests for categorical variables. Poisson regression analysis was applied to calculate relative fertility rates in the diagnostic groups vs references. RESULTS Among 631 patients 849 children were registered in MBRN. Of these, 289 children (34.0%) were born after time of diagnosis vs 44.3% in references. Altogether, 206 of 631 patients (32.6%) were nulliparous vs 26.4% in references (P < 0.001). Among RA patients, 28.4% (96 of 338) were nulliparous vs 24.5% in references (P = 0.09), 30.7% (67 of 218) in OCA patients vs 24.5% in references (P = 0.03) and 57.3% (43 of 75) in JIA patients vs 40.9% in references (P = 0.004). Adjusted relative fertility rates in RA, OCA and JIA after diagnosis were 0.88, 0.84 and 0.84, respectively, compared with references. CONCLUSION A higher proportion of women with chronic inflammatory arthritides were nulliparous compared with references, and relative fertility rates were reduced in all patient groups.

Postpartum onset of rheumatoid arthritis and other chronic arthritides: results from a patient register linked to a medical birth registry

Background: It is known that onset of rheumatoid arthritis (RA) is increased post partum. Objective: To compare incidence rates between RA and other chronic arthritides (OCA) 0–24 months after delivery, and to compare the incidence rates within each group 0–24 versus 25–48 months post partum. Methods: Premenopausal women from a Norwegian patient register were linked with the Medical Birth Registry of Norway to study the interval between delivery and time of diagnosis. Cox regression analysis with adjustments for age at delivery and birth order was applied to compare proportions of incident cases of RA and OCA with onset 0–24 months post partum. Poisson regression analysis with adjustment for the population at risk was applied to estimate the incidence rate ratio (IRR) 0–24 versus 25–48 months post partum. Results: Of 183 RA and 110 patients with OCA diagnosed after delivery, 69 (37.7%) had RA and 31 (28.2%) OCA during the first 24 months post partum (p = 0.09). The IRR (95% CI) for diagnosis during 0–24 months versus 25–48 months was 1.73 (1.11 to 2.70) (p = 0.01) for RA, 1.05 (0.59 to 1.84) (p = 0.86) for OCA. The IRR was 2.23 (1.06 to 4.70) and 1.87 (0.67 to 5.21), respectively, when only considering diagnoses after the first pregnancy. Clinical characteristics were similar within each diagnostic group. Conclusion: The proportions of incident cases with onset 0–24 months after delivery were not different between RA and OCA. A peak in incidence during 0–24 months was seen in the RA group, both when considering all pregnancies and only the first pregnancy.

Rheumatoid arthritis and outcomes in first and subsequent births based on data from a national birth registry

To examine associations between rheumatoid arthritis (RA) and pregnancy outcomes in first and subsequent births.

Comparison of work disability and health‐related quality of life between males and females with rheumatoid arthritis below the age of 45 years

Objectives: To compare work disability (WD) and health status between males and females with rheumatoid arthritis (RA) in the age group 18–45 years, and to compare health status between patients with and without WD within each gender, and finally to identify factors independently associated with WD in this age group. Methods: A cross‐sectional study of RA patients at the time starting with disease‐modifying antirheumatic drug (DMARD) therapy and/or biological treatment. Patients receiving a permanent, national WD pension corresponding to ⩾ 50% were defined as work disabled. We examined gender differences with regard to disease characteristics, health status and WD. The Mann–Whitney U‐test and Pearson’s χ2‐test were applied for group comparisons. Multiple logistic regression analyses with adjustments for duration of education, disease duration, age, erosive disease, disability score [using the Modified Health Assessment Questionnaire (MHAQ)], Disease Activity Score‐28 (DAS‐28), the Short Form Health Survey (SF‐36) mental health score and gender were used to identify variables associated with WD. Results: Out of 474 (372 females) patients, the number (%) of work‐disabled females/males was 91 (24.7)/8 (8.1) (p<0.001). WD was associated with worse health status in both genders. The odds ratio (95% confidence interval) [OR (95% CI)] for WD in females vs. males was 4.84 (1.85–12.65) in the multivariate analyses. Other factors independently associated with WD were worse mental health, disease duration and low level of education. Conclusion: Females with RA had a fourfold increased risk of WD compared to men. Low level of education, disease duration and worse mental health were also independently associated with WD.

Systemic Lupus Erythematosus and Outcomes in First and Subsequent Births Based on Data From a National Birth Registry

To examine the associations between systemic lupus erythematosus (SLE) and outcomes in first and subsequent births.

Parity in patients with chronic inflammatory arthritides childless at time of diagnosis.

Objective: To assess parity in women with chronic inflammatory arthritides (CIA) childless at time of diagnosis. Methods: Patients were selected from the Norwegian Disease-Modifying Anti-Rheumatic Drug (NOR-DMARD) registry. Each patient was matched by year of birth with 100 reference women from the Norwegian Population Registry. Data linkage for patients and references with the Medical Birth Registry of Norway (MBRN) identified all offspring until time of linkage (October 2007). Patients and corresponding references childless at the time of diagnosis were included in the analyses. Kaplan–Meier curves visualized the proportion of childless women and were compared by a log rank test. Results: In all, 156 rheumatoid arthritis (RA), 107 other chronic arthritides (OCA), and 75 juvenile idiopathic arthritis (JIA) patients were childless at time of diagnosis. At the time of data linkage, the proportions (%) of childless RA/OCA/JIA patients versus references were 61.5/62.6/57.3 versus 46.9/42.9/41.0, respectively, all differences statistically significant. The log rank test showed lower parity in all diagnostic groups compared with references (p < 0.001 for RA and OCA and p = 0.002 for JIA). No difference in parity was observed between RA and OCA patients, but both diagnostic groups had lower parity than JIA patients (p = 0.001). Disease characteristics were similar between childless and fertile patients. Conclusions: Reduced parity was observed in all diagnostic groups compared with references. RA and OCA patients had lower parity than JIA patients, indicating that having the disease as a young adult may influence parity more than having the disease in childhood.