Pregnancy and neonatal outcomes in women with axial spondyloarthritis: pooled data analysis from the European Network of Pregnancy Registries in Rheumatology (EuNeP).

OBJECTIVE: To investigate outcome and course of pregnancies in women with axial spondyloarthritis (axSpA) in a pooled data analysis of pregnancy registries in rheumatology. METHODS: Prospectively followed women with axSpA, fulfilling ASAS classification criteria and for whom a pregnancy outcome was reported, were eligible for the analysis. Anonymised data of four registries was pooled. Rates of adverse pregnancy outcomes were calculated. Systemic inflammation, disease activity and treatment patterns with tumour necrosis factor inhibitor (TNFi) before, during and after pregnancy were analysed. RESULTS: In a total of 332 pregnancies from 304 axSpA women, 98.8% of the pregnancies resulted in live birth. Mean maternal age was 31 years and disease duration 5 years. Most of these patients received pre-conception counselling (78.4%). Before pregnancy, 53% received TNFi treatment, 27.5% in first and 21.4% in third trimester. Pregnancy and neonatal outcomes were favourable with rates of 2.2% for pre-eclampsia, 4.9% for preterm birth, 3.1% for low birth weight and 9.5% for small for gestational age. Neonates were delivered by caesarean section in 27.7% of pregnancies, of which 47.4% were emergencies. Pooled mean CRP was 4 mg/L before conception peaking in the second trimester at 9.4 mg/L. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was below 4 at all time-points. CONCLUSIONS: Pooled rates of most outcomes were better than what had been reported in the literature and within expected rates of those reported for the general population. Pre-conception counselling, planned pregnancies and a tight management in expert centres applying a tailored treatment approach may have contributed to the favourable pregnancy outcomes.

Pharmacovigilance pregnancy data in a large population of patients with chronic inflammatory disease exposed to certolizumab pegol.

Introduction: Chronic inflammatory diseases (CIDs), including rheumatic diseases and other inflammatory conditions, often affect women of reproductive age. Tumor necrosis factor inhibitors (TNFi) are widely used to treat CID, but there is limited information on outcomes of TNFi-exposed pregnancies. We evaluated pregnancy outcomes from 1392 prospectively reported pregnancies exposed to certolizumab pegol (CZP), a PEGylated, Fc-free TNFi with no to minimal placental transfer. Methods: CZP-exposed pregnancies in patients with CID from the UCB Pharmacovigilance global safety database were reviewed from the start of CZP clinical development (July 2001) to 1 November 2020. To limit bias, the analysis focused on prospectively reported cases with known pregnancy outcomes. Results: In total, 1392 prospective pregnancies with maternal CZP exposure and known pregnancy outcomes (n = 1425) were reported; 1021 had at least first-trimester CZP exposure. Live birth was reported in 1259/1425 (88.4%) of all prospective outcomes. There were 150/1425 (10.5%) pregnancy losses before 20 weeks (miscarriage/induced abortion), 11/1425 (0.8%) stillbirths, and 5/1392 (0.4%) ectopic pregnancies. Congenital malformations were present in 30/1259 (2.4%) live-born infants, of which 26 (2.1%) were considered major according to the Metropolitan Atlanta Congenital Defects Program criteria. There was no pattern of congenital malformations. Discussion and conclusion: No signal for adverse pregnancy outcomes or congenital malformations was observed in CZP-exposed pregnancies. Although the limitations of data collected through this methodology (including underreporting, missing information, and absence of a comparator group) should be considered, these data provide reassurance for women with CID who require CZP treatment during pregnancy, and their treating physicians.

Fertility and pregnancy outcomes in women with spondyloarthritis: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to determine the impact of SpA and its treatments on fertility and pregnancy outcomes, as well as the impact of pregnancy on disease activity. METHODS: A systematic review and meta-analyses were performed, including studies in women with SpA [axial (axSpA) and peripheral SpA, including PsA]. The heterogeneity between studies was quantified (I2), and in the case of substantial heterogeneity, the results were reported in a narrative review. RESULTS: Of 4397 eligible studies, 21 articles were included, assessing a total of 3566 patients and 3718 pregnancies, compared with 42 264 controls. There is a lack of data on fertility in the literature. We found an increased risk of preterm birth [pooled odds ratio (OR) 1.64 (1.15-2.33), I2 =24% in axSpA and 1.62 (1.23-2.15), I2 =0.0% in PsA], small for gestational age [pooled OR 2.05 (1.09-3.89), I2 =5.8% in axSpA], preeclampsia [pooled OR 1.59 (1.11-2.27], I2 =0% in axSpA] and caesarean section [pooled OR 1.70 (1.44-2.00), I2 =19.9% in axSpA and 1.71 (1.14-2.55), I2 =74.3% in PsA], without any other unfavourable pregnancy outcome. Further analysis showed a significantly higher risk of elective caesarean section [pooled OR 2.64 (1.92-3.62), I2 =0.0% in axSpA and 1.47 [1.15-1.88], I2 =0,0% in PsA), without increased risk of emergency caesarean section in PsA. During pregnancy, there appears to be a tendency for unchanged or worsened disease activity in axSpA and unchanged or improved disease activity in PsA. Both conditions tend to flare in the postpartum period. CONCLUSION: SpA seems to be associated with an increased risk of preterm birth, small for gestational age, preeclampsia, and caesarean section.

No Association of Discontinuing Tumor Necrosis Factor Inhibitors Before Gestational Week Twenty in Well-Controlled Rheumatoid Arthritis and Juvenile Idiopathic Arthritis With a Disease Worsening in Late Pregnancy.

OBJECTIVE: To investigate whether the discontinuation of tumor necrosis factor inhibitors (TNFi) during pregnancy is associated with any changes of the disease course in women with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). METHODS: Pregnant women with RA and JIA from the US and Canada were enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project, a prospective cohort study. Information about medication and disease activity (patient-reported outcome measures) was collected prior to gestational week 20 and at gestational week 32. Associations between patterns of TNFi continuation or discontinuation and disease activity changes were tested in unadjusted and multivariate analyses. RESULTS: Among 490 women (397 with RA, 93 with JIA) enrolled between 2005 and 2017, 122 (24.9%) discontinued a TNFi before gestational week 20, 201 (41.0%) received a TNFi beyond week 20, and 167 (34.1%) did not receive a TNFi during pregnancy. At the time of enrollment, disease activity was low to minimal in 72.9% of women. TNFi discontinuation was not associated with a clinically important worsening of patient reported outcome measures at the third trimester. Univariate but not multivariate analysis showed that women receiving TNFi beyond week 20 were more likely to experience improved disease activity scores at the third trimester. CONCLUSION: Discontinuing TNFi before gestational week 20 seems feasible in women with RA and JIA who enter pregnancy with well-controlled disease.

Pregnancy Outcomes After Exposure to Certolizumab Pegol: Updated Results From a Pharmacovigilance Safety Database.

OBJECTIVE: Anti-tumor necrosis factor (anti-TNF) medications are effective in controlling chronic inflammatory diseases, but information about their use and safety in pregnancy is limited. Consequently, anti-TNF agents are often discontinued early in gestation. Certolizumab pegol (CZP), a PEGylated, Fc-free anti-TNF agent approved for the treatment of rheumatic diseases and/or Crohn's disease, has minimal to no active placental transfer. This analysis was undertaken to evaluate pregnancy outcomes in women receiving CZP, especially those exposed during early pregnancy. METHODS: Prospective and retrospective data on maternal CZP exposure were extracted from the UCB Pharma safety database through March 6, 2017. Analysis was limited to prospective reports to avoid potential bias associated with retrospective submissions. The numbers of live births, miscarriages, elective abortions, stillbirths, and major congenital malformations were ascertained. RESULTS: Of 1,137 prospectively reported pregnancies with maternal exposure to CZP, 528 (including 10 twin pregnancies) had 538 known outcomes: 459 live births (85.3%), 47 miscarriages (8.7%), 27 elective abortions (5.0%), and 5 stillbirths (0.9%). There were 8 major congenital malformations (1.7%) among the 459 infants. First trimester exposure occurred in 367 (81.2%) of 452 pregnancies resulting in 459 live births. Exposure during all 3 trimesters occurred in 201 (44.5%) of 452 pregnancies. CONCLUSION: This analysis represents the largest cohort of pregnant women exposed to an anti-TNF agent for management of chronic inflammatory diseases. Analysis of pregnancy outcomes does not indicate a teratogenic effect of CZP, compared to the general population, nor an increased risk of fetal death. The data are reassuring for women of childbearing age considering treatment with CZP.

Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study.

OBJECTIVES: There is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants. METHODS: CRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 µg/mL). RESULTS: Sixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0-49.4] µg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 µg/mL), and 1 had a minimal CZP level of 0.042 µg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 µg/mL). CONCLUSIONS: There was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary. TRIAL REGISTRATION NUMBER: NCT02019602; Results.

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.

Treatment of rheumatoid arthritis during pregnancy: present and future.

INTRODUCTION: For the management of rheumatoid arthritis patients who plan to become pregnant, both disease activity and therapeutic regimens have to be taken into consideration. In the case of stable inactive disease, pregnancy can be planned and therapy can be adjusted with drugs compatible with pregnancy. AREAS COVERED: Drugs to be discontinued before pregnancy are methotrexate, leflunomide, tocilizumab, rituximab, abatacept and tofacitinib. Pregnancy compatible disease modifying drugs are antimalarial drugs and sulfasalazine. TNF-inhibitors can be continued during the first half of pregnancy, yet if indicated during the third trimester TNF-inhibitors with a low rate of transplacental passage should be used. Glucocorticoids may be considered at the lowest effective dose throughout pregnancy. Non-selective COX-inhibitors can be continued until gestational week 32. Expert commentary: Together, a tailored treatment throughout pregnancy is possible with reasonable safety. Controlling disease activity during pregnancy is important for both, maternal and fetal health.

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.

Reduced pro-inflammatory profile of γδT cells in pregnant patients with rheumatoid arthritis.

BACKGROUND: During pregnancy, many patients with rheumatoid arthritis (RA) experience disease improvement, whereas patients with ankylosing spondylitis often suffer from persistent active disease. Here we investigated whether pregnancy-related changes in disease activity were associated with changes in the proportion and function of γδT cells. METHODS: The study population comprised 55 patients with RA, 31 patients with ankylosing spondylitis, and 35 healthy controls. Among these participants, 28 RA patients, 21 ankylosing spondylitis patients, and 23 healthy controls were investigated once before conception when possible, at each trimester of pregnancy, and at 8 weeks postpartum. Data were compared with age-matched non-pregnant patients to obtain disease-related background. In all subjects, peripheral Vδ1 and Vδ2 T cells were analyzed for cell frequencies, the activation marker CD69, the cytotoxicity markers NKG2D and NKG2A, and the intracellular cytokines tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-17 and IL-10. RESULTS: Pregnant patients showed a decreased Vδ2/Vδ1 ratio in the third trimester, which resulted from a slightly reduced proportion of Vδ2 cells. Changes in RA disease activity during pregnancy and postpartum were not associated with numerical proportions of γδT cells but with changes of the cell activation marker CD69 on Vδ1 and Vδ2 cells. Only RA patients showed reduced proportions of TNFα-positive Vδ1and Vδ2 cells and IFNγ-positive Vδ2 cells at the third trimester of pregnancy, a finding that was not apparent in the entire population of CD3 T cells. The proportions of IL-17-positive γδT cells and IL-10-positive γδT cells did not differ between pregnant and non-pregnant women of the different groups. CONCLUSIONS: Changes of disease activity in pregnant RA patients were associated with functional changes in both γδT cell subsets. This reduced pro-inflammatory profile of γδT cells might contribute to the immunomodulation resulting in pregnancy-induced improvement of RA.

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.

Cyclophosphamide: As bad as its reputation? Long-term single centre experience of cyclophosphamide side effects in the treatment of systemic autoimmune diseases.

OBJECTIVES: Despite new treatment modalities, cyclophosphamide (CYC) remains a cornerstone in the treatment of organ or life-threatening vasculitides and connective tissue disorders. We aimed at analysing the short- and long-term side-effects of CYC treatment in patients with systemic autoimmune diseases. METHODS: Chart review and phone interviews regarding side effects of CYC in patients with systemic autoimmune diseases treated between 1984 and 2011 in a single university centre. Adverse events were stratified according to the "Common Terminology Criteria for Adverse Events" version 4. RESULTS: A total of 168 patients were included. Cumulative CYC dose was 7.45 g (range 0.5-205 g). Gastro-intestinal side effects were seen in 68 events, hair loss occurred in 38 events. A total of 58 infections were diagnosed in 44/168 patients (26.2%) with 9/44 suffering multiple infections. Severity grading of infections was low in 37/58 cases (63.8%). One CYC-related infection-induced death (0.6%) was registered. Amenorrhoea occurred in 7/92 females (7.6%) with 5/7 remaining irreversible. In females with reversible amenorrhoea, prophylaxis with nafarelin had been administered. Malignancy was registered in 19 patients after 4.7 years (median, range 0.25-22.25) presenting as 4 premalignancies and 18 malignancies, 3 patients suffered 2 premalignancies/malignancies each. Patients with malignancies were older with a higher cumulative CYC dose. Death was registered in 28 patients (16.6%) with 2/28 probably related to CYC. CONCLUSIONS: Considering the organ or life-threatening conditions which indicate the use of CYC, severe drug-induced health problems were rare. Our data confirm the necessity to follow-up patients long-term for timely diagnosis of malignancies. CYC side-effects do not per se justify prescription of newer drugs or biologic agents in the treatment of autoimmune diseases.

Anaemia may add information to standardised disease activity assessment to predict radiographic damage in rheumatoid arthritis: a prospective cohort study.

OBJECTIVE: Anaemia in rheumatoid arthritis (RA) is prototypical of the chronic disease type and is often neglected in clinical practice. We studied anaemia in relation to disease activity, medications and radiographic progression. METHODS: Data were collected between 1996 and 2007 over a mean follow-up of 2.2 years. Anaemia was defined according to WHO (♀ haemoglobin<12 g/dl, ♂: haemoglobin<13 g/dl), or alternative criteria. Anaemia prevalence was studied in relation to disease parameters and pharmacological therapy. Radiographic progression was analysed in 9731 radiograph sets from 2681 patients in crude longitudinal regression models and after adjusting for potential confounding factors, including the clinical disease activity score with the 28-joint count for tender and swollen joints and erythrocyte sedimentation rate (DAS28ESR) or the clinical disease activity index (cDAI), synthetic antirheumatic drugs and antitumour necrosis factor (TNF) therapy. RESULTS: Anaemia prevalence decreased from more than 24% in years before 2001 to 15% in 2007. Erosions progressed significantly faster in patients with anaemia (p<0.001). Adjusted models showed these effects independently of clinical disease activity and other indicators of disease severity. Radiographic damage progression rates were increasing with severity of anaemia, suggesting a 'dose-response effect'. The effect of anaemia on damage progression was maintained in subgroups of patients treated with TNF blockade or corticosteroids, and without non-selective nonsteroidal anti-inflammatory drugs (NSAIDs). CONCLUSIONS: Anaemia in RA appears to capture disease processes that remain unmeasured by established disease activity measures in patients with or without TNF blockade, and may help to identify patients with more rapid erosive disease.

Evaluation of histologic, serologic, and clinical changes in response to abatacept treatment of primary Sjögren's syndrome: a pilot study.

OBJECTIVE: To prospectively evaluate histopathologic, blood cellular, serologic, and clinical changes in response to abatacept treatment in patients with primary Sjögren's syndrome (SS). METHODS: Blood, saliva, and minor salivary gland biopsy samples were obtained before and after the last of 8 doses of abatacept in 11 primary SS patients. The histologic data evaluated the numbers of lymphocytic foci and B and T cell subtypes (CD20+, CD3+, CD4+, and CD8+). The numbers of FoxP3+ regulatory T cells were measured and the FoxP3:CD3 ratio was calculated. Histologic data were compared with results from peripheral blood and with changes in saliva secretion. RESULTS: The numbers of lymphocytic foci decreased significantly (P = 0.041). Numbers of local FoxP3+ T cells decreased significantly in percentage of total lymphocytic infiltrates (P = 0.037). In the peripheral blood, B cells increased (P = 0.038). This was due to an expansion of the naive B cell pool (P = 0.034). When adjusting for disease duration, an increase was also noted for total lymphocytes (P = 0.044) and for CD4 cells (P = 0.009). Gamma globulins decreased significantly(P = 0.005), but IgG reduction did not reach significance. Adjusted for disease duration, saliva production increased significantly (P = 0.029). CONCLUSION: CTLA-4Ig treatment significantly reduces glandular inflammation in primary SS, induces several cellular changes, and increases saliva production. Remarkably, this increase in saliva production is significantly influenced by disease duration.

Evaluation of smell and taste in patients with Wegener's granulomatosis.

Although a reduced olfactory/gustatory function affects patients in all parts of life, this problem has not received much attention in Wegener's granulomatosis (WG). The aim of this study was to assess the smell/taste function of WG patients. Demographic data of 16 WG patients (9 males, 7 females) were obtained. They all subjectively assessed their taste/smell function on visual analogue scale. Olfactory/gustatory functions of the patients were tested with 'Sniffin' Sticks and 'Taste' strips, respectively. The results were then compared with those from sex and age-matched control group (n = 16) and normative data. WG patients subjectively assessed their olfactory (p = 0.03) and gustatory (p = 0.02) function to be lower than control group. All the olfactory scores (odour identification, odour discrimination and threshold) in both genders were significantly below the scores in the control group. WG patients were hyposmic. For taste (total taste score, as well as scores for the qualities sweet, sour, salty and bitter), WG patients did not significantly differ from controls and were normogeusic. However, the gustatory scores showed the tendency of reduction as compared to the control group. In conclusion, WG patients truly suffer from olfactory/taste dysfunction, but this is worse with olfaction. It is, therefore, imperative that physicians should make their patients to be aware of these sensory dysfunctions and educate them on methods to cope with it for better quality of life.

Treatment with biologics of pregnant patients with rheumatic diseases.

OBJECTIVE: Due to limited human pregnancy experience safety issues in regard to children exposed antenatally to biological drugs are still under debate. A survey of new published experience on biological agents during pregnancy is necessary to assist clinicians with adequate counseling and management of patients who desire children. RECENT FINDINGS: No controlled study has been published on use of TNFα inhibitors, rituximab, abatacept, tocilizumab or anakinra in pregnancy during the years 2009-2010. New case reports confirm that all monoclonal antibodies expose the child to the full adult dose when administered in late pregnancy with a risk for adverse effects in the newborn and perinatally. Data from a drug registry show that preconceptional and early first-trimester use of rituximab appears to confer no serious side effect to the child. Case reports on abatacept, tocilizumab or anakinra in pregnancy are not conclusive. SUMMARY: Differences in molecular structure of TNFα inhibitors may turn out to favor the use of agents that are not complete monoclonal antibodies in women who consider pregnancy. The very limited experience with abatacept, tocilizumab or anakinra in pregnancy allows no statement as to their compatibility with pregnancy. At present use of biological agents throughout pregnancy cannot be recommended.

Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis.

OBJECTIVE: To study the influence of tumour necrosis factor (TNF) antagonists on spermatogenesis in a cohort of patients with spondyloarthritis (SpA). PATIENTS AND METHODS: Semen samples of 26 patients with SpA were analysed according to WHO 1999 guidelines with and without TNF blocking agents (infliximab, etanercept or adalimumab). RESULTS: were compared with semen samples of 102 healthy volunteers. Results Sperm abnormalities were found in 10/11 patients without anti-TNF therapy. The sperm of these 11 patients had significantly poorer motility (p=0.001) and vitality (p=0.001) than found in 15 patients tested during longstanding anti-TNF therapy, but sperm concentration and morphology were similar in the two groups. There was no significant difference of sperm quality between healthy controls and anti-TNF treated patients with SpA. Notably, sperm abnormalities were also found in 102 healthy controls. CONCLUSION: Sperm abnormalities are a common finding in healthy men, they are more pronounced in patients with active SpA. The sperm quality of patients with SpA with inactive disease receiving long-term TNF inhibition is comparable to that in healthy controls. The data support continuation of anti-TNF treatment when fatherhood is planned.

Management of RA medications in pregnant patients.

A desire for children or the presence of pregnancy limits the drug therapy options for a woman with rheumatoid arthritis. Combination therapies that include methotrexate or new drugs that have not been studied or used in pregnant patients must be excluded, even though they might be highly efficacious. With few exceptions, the reason for this exclusion is not the proven teratogenicity of the drugs, but the absence of proven safety for the fetus. Whereas methotrexate, leflunomide, abatacept and rituximab must be withdrawn before a planned pregnancy, tumor necrosis factor inhibitors and bisphosphonates can be continued until conception. Antimalarial agents, sulfasalazine, azathioprine and ciclosporin are compatible with pregnancy, and so can be administered until birth. Corticosteroids and analgesics such as paracetamol (acetaminophen) can also be used throughout pregnancy. NSAIDs can be safely administered until gestational week 32. The most important consideration when managing rheumatoid arthritis medications during pregnancy is that therapy must be tailored for the individual patient according to disease activity.

Pregnancy in patients with ankylosing spondylitis: do regulatory T cells play a role?

OBJECTIVE: To investigate the numerical and functional changes of CD4+CD25(high) regulatory T (Treg) cells during pregnancy and postpartum in patients with ankylosing spondylitis (AS). METHODS: The frequency of CD4+CD25(high) T cells was determined by flow cytometry in 10 pregnant and 5 nonpregnant patients with AS as well as in 14 pregnant and 4 nonpregnant healthy controls. Pregnant individuals were investigated at the third trimester and 8 weeks postpartum. Treg cells and CD4+CD25- effector T (Teff) cells separated by fluorescence-activated cell sorting were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies, alone or in coculture, to investigate proliferation and cytokine secretion. RESULTS: The frequency of CD4+CD25(high) Treg cells was significantly higher during pregnancy than postpartum in both healthy control subjects and patients with AS. In contrast to Treg cells in healthy pregnant women, Treg cells in pregnant women with AS secreted only small amounts of interleukin-10 and showed lower suppression of tumor necrosis factor alpha and interferon-gamma secretion by CD4+CD25- Teff cells. At the postpartum time point, proinflammatory cytokine levels in the Treg/Teff cell cocultures and Teff cell monocultures were significantly higher in patients with AS than in healthy controls. CONCLUSION: Pregnancy influenced the expansion and cytokine secretion of Treg cells in both patients with AS and control subjects. However, the Treg cells of pregnant patients with AS failed to support an antiinflammatory cytokine milieu, thereby possibly contributing to the persistent disease activity of AS during pregnancy.