Characteristics and Obstetric Outcomes in Women With Autoimmune Rheumatic Disease During the COVID-19 Pandemic in Qatar.

OBJECTIVE: Pregnant women with autoimmune rheumatic diseases are considered to have a high risk of obstetric complications with the emergence of the Coronavirus disease (COVID-19) pandemic. Therefore, we aimed to assess the impact of COVID-19 on this high-risk group. METHODS: This cross-sectional cohort study (March to December 2020) was conducted at the largest tertiary center in Qatar (Hamad Medical Corporation). Eighty consecutive patients following up at the center during pregnancy were surveyed through telephonic interviews. Data on COVID-19 and pregnancy outcomes were extracted from electronic hospital records. RESULTS: Eighty pregnant women with autoimmune rheumatic diseases were included. Among them, 17 (21.3%) (95% confidence interval [CI]: 12.9-31.8%) were diagnosed with COVID-19, five were hospitalized, and only one required intensive care unit admission. The proportion of adverse obstetric outcomes in the cohort was 29.5% (n = 23; 95% CI: 19.7-40.9%). Prematurity (n = 14; 19.4%) and caesarean section (n = 30; 41.1%) were the most prevalent adverse events. There was no statistical difference in adverse pregnancy outcomes between women with and without COVID-19. CONCLUSION: COVID-19 did not affect pregnancy outcomes in women with autoimmune rheumatic diseases.

Biologics and small molecules in the management of psoriatic arthritis: Reproduction related issues in female and male patients.

STRACTBackground: Psoriatic arthritis (PsA) is the musculoskeletal manifestation of psoriatic disease, an inflammatory systemic disease with a high incidence in the reproductive years. Biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) as well as 'small molecules', are increasingly used to treat subtypes of PsA. Safety concerns exist in the field of fertility for PsA patients since the literature shows discordant results toward the influence of anti-psoriatic drugs.Areas covered: This comprehensive review critically reviews the available data on the safety of biologics and small molecules in PsA including pregnancy and lactation and men who want to father a child. TNF inhibitors (TNFi) are best studied in relation to reproduction. For other biologics and small molecules, no prospective, controlled studies are available.Expert opinion: No contraindications appear for TNFi in pregnancy, lactation, and paternal exposure. For biologics other than TNFi and small molecules, prospective controlled studies on outcomes after exposure in early and late pregnancy are urgently needed. Potential effects of all biologics on immune function, infection rates, and vaccine responses in prenatally exposed children need to be expanded. Until more data become available, small molecules should be avoided during pregnancy and breastfeeding. More reproduction-related data are expected from various national and international registries in the future.

Increased proportion of comorbidities but no deterioration of sexual quality of life during a 5-year follow-up in patients with axial spondyloarthritis in the biologic treatment era.

OBJECTIVE: To explore patient perception of sexual quality of life (SQOL), an important category of QOL, in male and female patients with axial SpA (axSpA) after a 5 year follow-up. METHODS: A broad spectrum of demographic, disease-related, treatment and SQOL data was collected at baseline and at the 5 year follow-up. SQOL was assessed by the SQOL-Female (SQOL-F) questionnaire. For statistical analysis, McNemar's tests, paired t-tests and multiple regression analyses were applied. RESULTS: A total of 245 axSpA patients (168 men and 77 women) from outpatient clinics were examined (mean age 46 years, mean disease duration 11.9 years at baseline). Compared with baseline, the patients had lower CRP, lower Maastricht Ankylosing Spondylitis Enthesitis Scores, lower BASFI scores, less use of smoking and significantly more patients were treated with biologic DMARDs at the 5 year follow-up. Patient perception of SQOL was basically unchanged at the 5 year follow-up despite a significantly increased proportion of comorbidities, including cardiovascular, endocrine and gastrointestinal disease. A decrease in SQOL after 5 years was observed only in patients exercising <1 h/week at baseline (P = 0.048) and in patients >65 years old. CONCLUSION: In our axSpA patients, no statistically significant changes in SQOL were observed over 5 years, despite a significant increase in comorbidities. Overall disease symptoms decreased, indicating better disease control. Increased use of biologic drugs at the 5 year follow-up may have contributed to this favourable outcome.

A questionnaire-based study on contraceptive practice in patients with rheumatic disease found no significant difference in age-matched healthy controls.

OBJECTIVE: Birth control is crucial in preventing unplanned pregnancy. The study analyzed contraceptive practice in women and men with rheumatic disease. METHODS: A questionnaire-based study investigated the actual contraceptive practices in patients of reproductive age from three European countries and compared them to age-matched healthy women and men. Associations between patient characteristics and contraception behavior were analyzed by association analysis. RESULTS: No significant difference in the frequency of contraception use was found in 133 rheumatic patients compared to 122 healthy controls. The main reason for not using contraception was lack of partner or the wish to become pregnant, whereas the current use of contraception was predominantly to limit family size in general or at this stage of life. Both patients and controls preferred barrier methods (48% and 45%, respectively) followed by hormonal contraceptives (31% and 38%, respectively). Characteristics associated with less use of contraception in patients were living single, having no children, and for being religious, whereas gender and education had no influence. Treatment with teratogenic drugs was no major patient concern, and 13 of 30 female patients using methotrexate, mycophenolate mofetil, or leflunomide did not practice birth control. CONCLUSION: Patients used contraception less frequently than healthy individuals, and the main reason for use was to limit family size. Contraception should be an integral part of counseling patients of fertile age, since the patient-preferred methods in case of active disease or therapy with teratogenic drugs were unreliable for the prevention of pregnancy.

Pregnancy Outcomes in Couples with Males Exposed to Longterm Anti-tumor Necrosis Factor-α Inhibitor Therapies: A Prospective Study.

OBJECTIVE: To examine the pregnancy achievement and outcomes in couples in which men with spondyloarthritis (SpA) were exposed to tumor necrosis factor inhibitors (TNFi). METHODS: Information about pregnancies involving fathers with SpA was prospectively collected by 6 Romanian rheumatology centers. RESULTS: Twenty-seven patients achieved 33 pregnancies and fathered 30 healthy children. Three elective abortions (personal reasons) and no spontaneous abortions, preeclampsia/eclampsia, stillbirths, congenital malformations, or pathologies in the children were recorded. Five patients showed normospermia before and after longterm TNFi treatment. CONCLUSION: Pregnancy and child outcomes in male patients with SpA exposed to longterm TNFi therapy were reassuring.

Sexual Quality of Life in Patients with Axial Spondyloarthritis in the Biologic Treatment Era.

OBJECTIVE: To examine the relationship between demographics, disease-related variables, treatment, and sexual quality of life (SQOL) in men and women with axial spondyloarthritis (axSpA). METHODS: AxSpA patients were consecutively recruited from 2 rheumatology outpatient clinics in southern Norway. A broad spectrum of demographics, disease, treatment, and QOL data were systematically collected. SQOL was assessed using the SQOL-Female (SQOL-F) questionnaire (score range 18-108). Appropriate statistical tests were applied for group comparison, and the association between independent variables and SQOL-F was examined using multiple linear regression analysis. RESULTS: A total of 360 (240 men, 120 women) axSpA patients with mean age 45.5 years and disease duration 13.9 years were included. Seventy-eight percent were married/cohabiting, 26.7% were current smokers, 71.0% were employed, 86.0% performed > 1-h exercise per week, and 88.0% were HLA-B27-positive. Mean (SD) values for disease measures were C-reactive protein (CRP) 8.5 (12.1) mg/l, Bath Ankylosing Spondylitis Disease Activity Index 3.1 (2.1), Bath Ankylosing Spondylitis Global Score (BAS-G) 3.8 (2.5), Bath Ankylosing Spondylitis Functional Index 2.7 (2.2), and Health Assessment Questionnaire 0.6 (0.5). The proportion of patients using nonsteroidal antiinflammatory drugs was 44.0%, synthetic disease-modifying antirheumatic drugs (DMARD) 5.0%, and biologic DMARD 24.0%. Mean (SD) total sum score for SQOL was 76.6 (11.3). In multivariate analysis, female sex, increased body mass index, measures reflecting disease activity (BAS-G and CRP), and current biologic treatment were independently associated with a lower SQOL. CONCLUSION: Our data suggest that inflammation in patients with axSpA even in the biologic treatment era reduces SQOL.

From mother to baby: antenatal exposure to monoclonal antibody biologics.

INTRODUCTION: More women with autoimmune and inflammatory conditions are being treated with monoclonal antibody biologics (mAbs) during their pregnancy, to maintain clinical remission. The use of anti-tumor necrosis factor alpha agents in pregnancy appears to be safe but less is known regarding other mAbs, such as anti-integrins and anti-cytokine agents. There are currently no comprehensive guidelines on how to manage the exposed infants. Areas covered: We review recent literature to assess the impact of mAbs on birth and early infant outcomes, including what is currently known about maternal and infant drug levels at birth and drug clearance in the infant. We describe the potential risks of infections and reported hematological and immunological effects of antenatal mAbs exposure on the infant and provide guidance on the management of the exposed infant. Expert opinion: Exposed infants should be monitored closely. Certain mAb exposures require specific testing and management. Safety monitoring should be done in a multidisciplinary approach and should include pediatric care providers. The current clinical experience with anti-tumor necrosis factor agents in pregnancy cannot be extrapolated to other mAbs. Long-term observational studies and a multicenter international registry are needed to better appreciate the impact of exposure, especially to newer mAbs.

Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters.

OBJECTIVE: To analyse pregnancy outcome and delivery mode in patients with RA and axial spondyloarthritis (axSpA) in relation to disease activity and anti-rheumatic drugs. METHODS: Patients with RA and axSpA were compared with age-matched healthy controls (HCs) with respect to pregnancy outcome and delivery mode. Disease activity (DAS28, ASDAS, CRP) and medication use of patients was assessed once at each trimester. ORs with 95% CI were calculated with univariate and multivariate regression models. RESULTS: We analysed 244 pregnancies, of which 96 occurred in patients with RA, 78 in patients with axSpA and 70 in HCs. The adjusted analysis showed that pregnant women with RA and axSpA had a higher risk of pregnancy complications (gestational diabetes, preeclampsia, infection, preterm premature rupture of membranes), small for gestational age infants and preterm deliveries (all P < 0.05). Active disease was a predictor for preterm delivery in both RA [odds ratio (OR) = 3.9, 95% CI: 1.25, 12.15] and axSpA (OR = 13.8, 95% CI: 1.33, 143.94). Regarding delivery mode, most patients had vaginal deliveries. However, women with RA revealed an increased risk of caesarean section compared with HC (P < 0.05), which was not seen in patients with axSpA. CONCLUSION: Our findings show that disease activity of RA and axSpA during pregnancy influences pregnancy outcome. To allow for successful pregnancy a treatment strategy that targets inactive disease beyond conception should be followed.

Sexual and reproductive health in rheumatic disease.

Family size is reduced among patients with rheumatic diseases. The causes for the low number of children are multifactorial and include impaired sexual function, decreased gonadal function, pregnancy loss, therapy and personal choices. Sexuality contributes to quality of life in patients with rheumatic disease, but is often ignored by health professionals. Both disease-related factors and psychological responses to chronic disease can impair sexual functioning. Toxic effects of anti-inflammatory and immunosuppressive drugs can induce transient or permanent gonadal failure in women and men. Furthermore, permanent infertility can be a consequence of treatment with cyclophosphamide, whereas transient infertility can be caused by NSAIDs in women and sulfasalazine in men. These adverse effects must be communicated to the patients, and measures to preserve fertility should be initiated before the start of gonadotoxic therapy. Management of patients of both genders should include regular family planning, effective treatment of high disease activity, sexual counselling, and, if necessary, infertility treatment.

Preconception Counseling.

Chronic rheumatic disease may interfere with procreation in women of childbearing age. Female patients should have counseling in regard to family planning and parenting. Preconception counseling requires risk assessment of possible maternal or fetal risks, screening for biomarkers with predictive value for adverse pregnancy outcomes, adjustment of therapy, and a schedule for monitoring and follow-up during pregnancy. Delivering comprehensive information and addressing all patient concerns are both essential for enabling patients to engage actively in decision making.

The use of biologics in pregnant patients with rheumatic disease.

INTRODUCTION: An increasing number of female patients with autoimmune diseases are treated with biologic drugs. Concerns in regard to safety of biologics during pregnancy arise in patients who have not completed their families. Areas covered: A review of the literature dealing with child outcomes of pregnancies exposed to biologics shows that TNF inhibitors (TNFi) are the best studied in regard to human pregnancy. In studies comparing exposed pregnancies to disease-matched controls no increased risk of spontaneous abortion, low birth weight, prematurity or congenital malformations has been observed. For rituximab, tocilizumab, anakinra, belimumab and ustekinumab no prospective, controlled studies are available, and firm conclusions about their safety during pregnancy cannot be drawn. Expert commentary: TNFi appear fairly safe when given in early pregnancy. For biologics other than TNFi prospective, controlled studies on outcomes after early and late pregnancy exposure are urgently needed. Possible effects of TNFi and all other biologics on children's immune function, infection rate and vaccination responses are either limited or absent and need to be extended. Development of laboratory tests to measure concentrations of biologics routinely in children exposed in utero would facilitate decisions in regard to the time point of vaccination with live vaccines.

Risk factors for flare and treatment of disease flares during pregnancy in rheumatoid arthritis and axial spondyloarthritis patients.

BACKGROUND: During pregnancy, patients with rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) can experience active disease, which might be influenced by adjustment of treatment around conception. The aim of this study was to identify possible risk factors of disease flares during pregnancy and to evaluate the effect of treatment in pregnant patients experiencing a flare. METHODS: Pregnant patients with RA and axSpA were prospectively followed before, during, and after pregnancy. Disease activity and flares of disease activity were analyzed in regard to medication. RESULTS: Among 136 pregnant patients, disease flares during pregnancy occurred in 29% of patients with RA and in 25% of patients with axSpA. In both diseases, active disease and tumor necrosis factor inhibitor (TNFi) discontinuation in early pregnancy were identified as risk factors for disease flares during pregnancy. Of 75 patients with RA, 15 patients were on TNFi and discontinued the treatment at the time of the positive pregnancy test. After stopping TNFi, disease activity increased, which was reflected by peaking C-reactive protein levels at the first trimester. The relative risk of flare in patients with RA stopping TNFi was 3.33 (95% CI 1.8-6.1). Initiation of TNFi or glucocorticosteroid (GC) treatment in 60% of these patients resulted in disease improvement at the second and third trimesters. In comparison, patients with RA without TNFi in the preconception period, most of whom had used pregnancy-compatible antirheumatic drugs, showed mild and stable disease activity before and during pregnancy. Of 61 patients with axSpA, 24 patients were on TNFi and discontinued the treatment at the time of the positive pregnancy test. In patients with axSpA stopping TNFi, a disease aggravation at the second trimester could be observed. The relative risk of flare in this group was 3.08 (95% CI 1.2-7.9). In spite of initiated TNFi or GC treatment in 62.5% of these patients, disease activity remained elevated throughout pregnancy. Patients with axSpA without TNFi in the preconception period showed persistent high disease activity from prepregnancy until the postpartum period. CONCLUSIONS: On the basis of a risk-benefit analysis, to stabilize disease activity and to prevent a flare during pregnancy in patients with RA and axSpA, tailored medication including TNF inhibitors should be considered beyond conception.

Methotrexate Use and Monitoring in Patients with Psoriasis: A Consensus Report Based on a Danish Expert Meeting.

Methotrexate (MTX) has been used in the treatment of psoriasis and other dermatological diseases for more than 50 years. However, there is limited evidence regarding its effect, dose and monitoring, and a lack of consensus regarding how the drug should be used in daily practice. Although the use of MTX is governed by guidelines, such as the European S3-Guidelines and the National Institute for Health and Care Excellence (NICE) guideline, it is important to discuss and adjust these guidelines to national standards. An expert meeting was held in Denmark at the end of 2014, in order to reach consensus regarding the use of MTX in dermatological practice in Denmark. Participants included dermatologists, hepatologists, paediatricians, clinical biochemists and a rheumatologist. Topics discussed were: liver disease monitoring, teratogenic effects of MTX, risk of cancer, and use of MTX in children. We report here the conclusions of this expert meeting regarding use of MTX in dermatological practice.

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data.

OBJECTIVES: Analyze the cumulative evidence for pregnancy outcomes after maternal exposure to tocilizumab, an anti-interleukin-6-receptor monoclonal antibody used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. At present, published experience on tocilizumab use during pregnancy is very limited. METHODS: We have analyzed all pregnancy-related reports documented in the Roche Global Safety Database until December 31, 2014 (n = 501). RESULTS: After exclusion of ongoing pregnancies, duplicates, and cases retrieved from the literature, 399 women were found to have been exposed to tocilizumab shortly before or during pregnancy, with pregnancy outcomes being reported in 288 pregnancies (72.2%). Of these 288 pregnancies, 180 were prospectively reported resulting in 109 live births (60.6%), 39 spontaneous abortions (21.7%), 31 elective terminations of pregnancy (17.2%), and 1 stillbirth. The rate of malformations was 4.5%. Co-medications included methotrexate in 21.1% of the prospectively ascertained cases. Compared to the general population, an increased rate of preterm birth (31.2%) was observed. Retrospectively reported pregnancies (n = 108) resulted in 55 live births (50.9%), 31 spontaneous abortions (28.7%), and 22 elective terminations (20.4%). Three infants/fetuses with congenital anomalies were reported in this group. No increased risks for adverse pregnancy outcomes were observed after paternal exposure in 13 pregnancies with known outcome. CONCLUSIONS: No indication for a substantially increased malformation risk was observed. Considering the limitations of global safety databases, the data do not yet prove safety, but provide information for physicians and patients to make informed decisions. This is particularly important after inadvertent exposure to tocilizumab, shortly before or during early pregnancy.

The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation.

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.

Differential influence of maternal and fetal pregnancy factors on the in-vitro induction of human regulatory T cells: a preliminary study.

PROBLEM: Given the important role of regulatory T cells (Treg) for successful pregnancy, the ability of soluble maternal and fetal pregnancy factors to induce human Treg was investigated. METHOD OF STUDY: Peripheral blood mononuclear cells (PBMCs) or isolated CD4+CD25‒ cells were cultured in the presence of pooled second or third trimester pregnancy sera, steroid hormones or supernatants from placental explants, and the numbers and function of induced CD4+CD25+FOXP3+ Treg were analysed. RESULTS: Third trimester pregnancy sera and supernatants of early placental explants, but not sex steroid hormones, induced an increase of Tregs from PBMCs. Early placental supernatant containing high levels of tumour necrosis factor-α, interferon-γ, interleukins -1, -6 and -17, soluble human leucocyte antigen-G, and transforming growth factor-ß1, increased the proportion of Treg most effectively and was able to induce interleukin-10-secreting-Treg from CD4+CD25‒cells. CONCLUSIONS: Compared with circulating maternal factors, placental- and fetal-derived factors appear to exert a more powerful effect on numerical changes of Treg, thereby supporting fetomaternal tolerance during human pregnancy.