Article

Safety issues of biologics in pregnant patients with rheumatic diseases

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Abstract

The safety of biologic agents during pregnancy is still being investigated. Tumor necrosis factor α (TNF-α) inhibitors are the only well-studied biological drugs in pregnancy; they do not appear to be teratogenic but increase the risk of infection after birth when given in late pregnancy. The long-term effects in exposed children are, at present, unknown. An increased risk of infection is a concern for all biologics and the risk increases further should combination with glucocorticoids be necessary. Experiences with rituximab, abatacept, anakinra, tocilizumab, and belimumab in pregnancy are limited. These drugs should be avoided during pregnancy or used only when no other option is available for treatment of serious maternal disease.

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... Schwangerschaftswoche. Die Behandlung der Mutter im 2. Trimester kann bereits zu hohen Wirkstoffkonzentrationen beim Feten führen, der Übertritt im dritten Trimenon überschreitet, v. a. bei Adalimumab und Infliximab, z. T. die mütterliche Serumkonzentration [2]. Immunglobuline haben bei Neugeborenen mit bis zu sechs Monaten eine verlängerte Halbwertszeit. ...
... 200 evaluierten Schwangerschaften kein Hinweis auf teratogene Effekte. Es wurden weder gehäuft Malformationen noch Aborte berichtet [2]. Im 2.-3. ...
... Trimenon geht Adalimumab wie das mütterliche IgG1 diaplazentar auf das Kind über. Durch den aktiven Transport über den F c -Rezeptor an den Trophoblastzellen in die fetale Zirkulation wurden direkt postnatal im kindlichen Nabelschnurblut höhere Serumspiegel (Median 179 %) als im mütterlichen Serum gemessen [2]. Damit besteht für Säuglinge nach einer intrauterinen Exposition im 2./3. ...
Article
Mit Einführung zahlreicher neuer, überwiegend biologischer Systemtherapien in der Dermatologie stellt sich im klinischen Alltag regelmäßig die Frage, inwieweit eine Anwendung bei Kinderwunsch oder in Schwangerschaft und Stillzeit möglich ist und welche Risiken ggf. damit verbunden sind. Seriöse Informationen liefern neben Fachinformation und Roter Liste Datenbanken wie die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie der Charité Berlin (https://www.embryotox.de) oder eine Literaturrecherche (z. B. über http://www.ncbi.nlm.nih.gov/pubmed). Den aktuellen Wissensstand aus o. g. Quellen zum Einsatz bei Kinderwunsch oder in Schwangerschaft und Stillzeit fasst dieser Artikel für Biologika bei Psoriasis (Infliximab, Adalimumab, Etanercept, Ustekinumab), für die neuen Systemtherapien des metastasierten Melanoms (Vemurafenib, Dabrafenib, Imatinib, Ipilimumab), des inoperablen bzw. metastasierten Basalzellkarzinoms (Vismodegib) und kutaner Lymphome (Rituximab) sowie für weitere Präparate aus dem Bereich Allergologie (Omalizumab, Anakinra) zusammen. © 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.
... This active placental transport starts during the 14th week of gestation. Treating the mother in the 2nd trimester may already lead to high drug concentrations in the fetus, sometimes exceeding maternal serum concentrations in the third trimester, especially in the case of adalimumab and infliximab [2]. Immunoglobulins have a longer half-life in neonates of up to six months. ...
... Although there is registry data on approximately 450 prospectively registered pregnancies on Remicade ® and, in line with data obtained from animal studies, no embryotoxic effects of the drug have been detected, the SPC nevertheless recommends that women of childbearing age use adequate contraception during therapy with Remicade ® and for six months after the last infusion. Overall, 1,000 pregnancies while on Remicade ® have been documented, most of them in the 1st trimester [2]. ...
... After the 30th gestational week, therapy with infliximab should be discontinued, as fetal serum levels are very high from this point onwards. Median values in the cord blood of newborns were 160% of the corresponding infliximab serum levels in the mother [2]. The drug remained detectable in the serum of infants for another 6 months, exposing them to a significantly increased risk of infection. ...
Article
With the increasing use of new, predominantly biologic drugs in dermatology, questions frequently arise in clinical practice as to their safety in women wishing to conceive as well as during pregnancy and lactation. Apart from the Summary of Product Characteristics and the Physician's Desk Reference, reliable information may be obtained from databases such as the one compiled by the Center for Pharmacovigilance and Consultation on Embryonal Toxicology at Charité University Medical Center Berlin (https://www.embryotox.de). Another source of information is researching recent publications, for example via PubMed (http://www.ncbi.nlm.nih.gov/pubmed). This article presents current knowledge from the sources mentioned above, and gives detailed information about the use of new biologic agents in women wishing to conceive as well as during pregnancy and lactation. Drugs reviewed include: infliximab, adalimumab, etanercept, metastatic for psoriasis, vemurafenib, dabrafenib, imatinib, ipilimumab for melanoma, vismodegib for basal cell carcinoma, rituximab for cutaneous lymphoma as well as omalizumab and anakinra used in the treatment of allergies. © 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.
... Additionally, they are detectable in blood of the infant for more than six months after the birth, reducing the safety of vaccination [16] . Certolizumab does not contain Fc region, thus it does not actively cross the placenta [18] . Use of TNF inhibitors has been reported in almost 2000 pregnancies of the patients with rheumatic diseases, inflammatory bowel diseases and psoriasis. ...
... It has been rated as FDA pregnancy category B. It has a halflife of 46 h. Because of its short halflife, discontinuance of anakinra before conception is not necessary [18] . Experiences with use of anakinra during pregnancy are limited. ...
... Tocilizumab is a humanized IL-6 receptor inhibitor used in the therapy of moderate to severe RA and polyarticular and systemic JIA. It is categorized as FDA pregnancy category C. Tocilizumab should be discontinued three months before conception [18] . Experiences with use of tocilizumab during pregnancy were reported by Rubbert-Roth et al [60] at the ACR Annual Meeting in 2010. ...
Article
Full-text available
Biologic agents have ushered a new era in the treatment of inflammatory rheumatic diseases. In recent years, several biologic agents have been approved by Food and Drug Administration (FDA) and have significantly improved outcomes for patients with immune mediated inflammatory disorders including rheumatic and inflammatory bowel diseases. The most common used biologic therapeutic agents are tumor necrosis factor inhibitors (etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab), an interleukin (IL)-6 inhibitor (tocilizumab), an IL-1 receptor antagonist (anakinra), an anti-CD-20 antibody (rituximab), and a T cell co-stimulation modulator (abatacept). Their use during pregnancy has been controversial because of absence of controlled studies which have enrolled pregnant women. This brief overview provides published data on use of biologic agents for the treatment of rheumatic diseases in pregnancy.
... 5 Table 1 The long-term safety of SC abatacept showed a low incidence of serious infections, malignancies, autoimmune events, and injectionsite reactions. 6,12,[17][18][19][20][21][22][23][24][25][26] Due to the limited budget, we had only four vials of SC abatacept and to decrease the risk of side effects, we extended the intervals between doses using the frequency of initial IV abatacept doses, biweekly for three doses (i.e. a dose at weeks zero, two, and four) and the fourth dose administered at week eight. 15 However, in the current study, mortality rate was 30% in the abatacept-treated mice despite using the recommended dose for juvenile idiopathic arthritis (as per body weight category above). ...
... Studies of the effects of disease-modifying antirheumatic drugs on the male reproductive system have been limited. 6,12,[18][19][20][21][22][23][24][25][26][29][30][31] On the other hand, monotherapy with methotrexate does not, as a rule, induce infertility in men. Sperm abnormalities may occur in rare cases, as in a young male patient with severe psoriasis treated with methotrexate. ...
... A mild semen abnormality was shown in two of three ankylosing spondylitis patients receiving anti-TNF-a inhibitors, contrasting with a recent report of four ankylosing spondylitis patients who had six healthy children during infliximab therapy. 6,7,12,[18][19][20][21][22][23][24][25][26] Whether abatacept exerts harmful effects on reproduction has not been studied. 7,10,24 Absence of significant changes in testicular histology with normal spermatogenesis in abatacept-tested group indicates that abatacept may not be considered as toxic to the testicles of BALB/c mice. ...
Article
Objectives: This study aims to demonstrate the effect of subcutaneous injections of abatacept on the histology of testes in mice. Materials and methods: The study included 20 male BALB/c mice (average weight, 25 g; aged 12-14 weeks). Ten mice received subcutaneous (SC) injections of abatacept [0.25 mg per 25 g body weight per 0.03 mL normal saline (NS)] at zero, two, four and eight weeks. As the control group, 10 mice received SC injections of NS (0.03 mL). At the post-injection 10th week, the mice were sacrificed, and histopathological studies were conducted. Results: The results showed that 3/10 mice died of the abatacept-treated group. Testicular histology for the abatacept-treated group showed that 7/7 displayed no histopathological changes. Conclusion: To our knowledge, this is the first control-blinded study of BALB/c mice suggesting that abatacept may not have testicular toxicity. Further fertility and testicular toxicology evaluations including semen analysis and gonadal hormones should be performed to clarify our findings.
... La mayoría de los varones con espondiloartropatías se diagnostican durante la edad reproductiva, estando muchos de ellos en tratamiento con fármacos bloqueantes del TNF-␣. Existe evidencia de que prácticamente todos estos fármacos alcanzan los testes, no modificando o incluso potenciando la espermatogénesis a dosis bajas, e inhibiéndola a dosis altas [16][17][18][19] . No se han demostrado alteraciones de la calidad espermática en pacientes tratados entre 3 y 12 meses con bloqueantes del TNF-␣. ...
... MTX no afecta a la capacidad fértil del varón 17 . En un estudio posterior que incluye datos de 113 gestaciones tras exposición paterna a MTX, Weber-Schoendorfer et al. 30 tampoco identifican un aumento de complicaciones fetales. ...
... Si se decide cambiar de fármaco/s hay que considerar el tiempo necesario hasta que sean efectivos. En pacientes con afectación renal, deberían asociarse dosis bajas de aspirina a fin de disminuir el riesgo de preeclampsia 47 17 . ...
Article
Rheumatic and systemic autoimmune diseases occur in women and, to a lesser degree, men of reproductive age. These disorders have to be clinically nonactive before conception, which is usually only possible after anti-inflammatory and immunosuppressive treatment. We must be alert since 50% of pregnancies are unplanned. Physicians should know the embryo-foetal toxicity of these drugs during pregnancy and lactation. This January 2016-updated review allows us to conclude that the majority of immunosuppressives available -anti-TNF inhibitors included- can be used before and during pregnancy, with the exception of cyclophosphamide, methotrexate, mycophenolate and leflunomide. Lactation is permitted with all drugs except methotrexate, leflunomide, mycophenolate and cyclophosphamide. Although data on abatacept, belimumab, rituximab, tocilizumab and anakinra are scant, preliminary reports agree on their safety during pregnancy and, probably, lactation. Cyclophosphamide and sulfasalazine apart, no negative effects on sperm quality, or embryo-foetal anomalies in men treated with immunosuppressives have been described. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.
... Sertolizumab: Transplasental geçişi minimaldir. Sertolizumab'a maruz kalan gebelerde sağlıklı kontrollerle karşılaştırıldığında, gebelikte olumsuz etkisi olmadığı belirlenmiştir (49). ...
... haftadan önce kesilmelidir. Ayrıca, bu ilaçların yarı ömrü uzun olduğu için infantlara yapılacak canlı aşıların ilk 6 ay içerisinde yapılmaması gerekmektedir (49). ...
... Her ne kadar gebeliğin erken dönemlerinde güvenilir gibi görünse de 2. ve 3. trimesterde kullanımı fetusta B hücre deplesyonuna neden olduğu ve bu durumun uzun süreli etkileri bilinmediği için gebelikte kullanımı önerilmez. Uzun yarılanma süresine sahip olduğu için gebe kalmadan 6 ay önce kesilmesi gereklidir (49). Global ilaç güvenlik verilerine göre rituksimab kullanırken gebe kalan 153 kişiden, 90'ı canlı doğum, 33'ü spontan, 28'i terapötik abortus yapmıştır. ...
Article
Many rheumatic diseases affect women of childbearing age. It is well known that during pregnancy, some patients with inflammatory arthritis such as rheumatoid arthritis go into remission, whereas in others, pregnancy aggravates disease activity. Unfortunately, the flares of rheumatic diseases during pregnancy may result in fetal loss, intrauterine growth retardation, and premature delivery. Furthermore, during pregnancy, anti-rheumatic drugs used to control disease activity may lead to fetal complications. In this review, the effects of pregnancy on the disease and the effects of disease on the fetus are discussed first. The effects of biological and non-biological disease-modifying anti-rheumatic drugs on fertility, pregnancy, and lactation are then summarized. Physicians dealing with rheumatic diseases need to be aware of the potential adverse effects of these medications and discuss the risks and benefits of drugs during pregnancy and lactation with their patients in detail. © 2015 by Turkish Society of Physical Medicine and Rehabilitation.
... In the past few years, numerous new pregnancies, with a first trimester exposure to these drugs, have been reported with a good pregnancy outcome. 24 According to the majority of the experts, anti-TNF-α agents can be considered safe in the early stage of pregnancy. If maternal disease is in remission, the treatment could be discontinued after the pregnancy test turns positive in order to limit the transplacental passage of the drug. ...
... In these cases, to avoid an impaired immune response and a higher infective risk in the babies, TNF-α inhibitors should be discontinued at latest at gestational week 30, especially if they are complete monoclonal antibodies. 24 In a study assessing the course of inflammatory bowel disease in pregnant women, the authors demonstrated that cord blood concentrations of infliximab were lower among women who received the drug 10 weeks or less before delivery than those treated closer to it. 39 In our experience, between 1999 and 2013, we identified 74 exposed pregnancies in women affected by different rheumatic diseases with peripheral chronic arthritis and treated with TNF-α inhibitors. ...
Article
Full-text available
The impact of rheumatic disease on fertility and reproduction can be remarkable. Many disease-related factors can influence patients' sexual functioning, perturb fertility and limit family planning. Antirheumatic pharmacological treatment can also have a crucial role in this field. Proper counselling, preferably provided by a multidisciplinary team of rheumatologists, obstetricians, gynaecologists and neonatologists, is recommended for patients taking antirheumatic drugs, not only at the beginning, but also during the course of treatment. Paternal exposure to antirheumatic drugs was not found to be specifically associated with congenital malformation and adverse pregnancy outcome, therefore discontinuation of these drugs while planning for conception should be weighed against the risk of disease flare. Drugs in Food and Drug Administration (FDA) category 'X' should be withdrawn in a timely manner in women who desire a pregnancy. Meanwhile, disease control can be achieved with anti-tumour necrosis factor (TNF)-α agents, which are not teratogenic drugs. If maternal disease control is permissive, they can be stopped as soon as the pregnancy test turns positive and be resumed during pregnancy in case of a flare.
... RTX is an approved biologic agent for induction of remission in patients with juvenile idiopathic arthritis, RA, granulomatosis with polyangiitis, and microscopic polyangiitis. [26][27][28][29][30][31][32][33][34][35][36][37][38][39] RTX is generally well tolerated, independently of the time or course of the treatment. A long-term study for the use of RTX over 9½ years did not detect increased safety risk or side effects. ...
... [43] Some observational studies have demonstrated that treatment with anti-TNF drugs including infliximab, etanercept, and adalimumab did not increase the risk of male infertility, as these anti-TNF drugs apparently did not produce abnormalities with regard to the quantity and quality of sperms. [20,24,[27][28][29][30][31][32][33][34][35] No clinical trials or animal studies investigating the direct effect of RTX on the testicles have been reported. [24] Drug toxicity might be on target or mechanism-based toxicity (e.g., anti-CD20). ...
Article
Full-text available
Objectives: Rituximab (RTX) is a biologic agent used for rheumatic and autoimmune disorders. RTX is a drug indicated for the treatment of patients with refractory rheumatoid arthritis patients who have not responded to nonbiological therapy and one or more anti-tumor necrosis factor-α drugs. The purpose of this trial was to investigate the RTX effects on testes in BALB/c mice by histology. Materials and Methods: A total of 20 mice were divided into two groups. Ten mice were subjected to weekly subcutaneous (SC) injection of RTX (0.31 mg/25 g body weight, in a final volume of 0.03 ml normal saline [NS] solution) for only the first 4 weeks. For the control group, ten mice were subjected to weekly SC injection of 0.03 ml NS solution. At the 10th week after first SC injection, mice were sacrificed, and histological analysis of tests was performed. Results: One out of ten mice died in the RTX-tested group; meanwhile, the remaining mice and the NS-tested group mice showed no abnormal histological findings. Conclusion: This is the first experimental animal trial which demonstrated that RTX treatment may not elicit testicular toxicity.
... Multiple studies of > 1000 pregnancies do not show patterns of malformation or prematurity ( Ostensen, 2014 ). Manufacturer recommends contraception during therapy and for 6 months after last infusion. ...
... † Limited data. Eight case reports in literature of men on rituximab at the time of conception; 7 of 8 pregnancies resulted in healthy children, and 1 was a spontaneous abortion ( Ostensen, 2014 . ...
Article
Full-text available
Background: The U.S. Food and Drug Administration has published new pregnancy and lactation labelling rules that set standards on the presentation of information with regard to drug usage during pregnancy and breastfeeding, as well as the effects on fertility. These guidelines became effective June 30, 2015, and classified the risks of using prescription drugs during pregnancy in three detailed subsections: Pregnancy, Lactation, and Females and Males of Reproductive Potential. These sections describe the risks within a real-world context of caring for these patients. Objective: In this study, we reclassified and categorized drugs and treatments commonly used in dermatology according to these new guidelines. Methods: We performed a search of the medical literature about the use of relevant prescription drugs during pregnancy and breastfeeding and their effect on fertility. The search included prospective and retrospective studies, review articles from PubMed-indexed journals (from inception to November 2018), U.S. Food and Drug Administration records, pregnancy exposure registries, relevant information and studies provided in drug labeling by companies, and updated pharmacologic texts and guidelines up to 2018. Results: Topical immunomodulators, systemic immunomodulators (including biologics), systemic antipruritic agents, antimicrobials, as well as acne, hair, and cosmetic agents were included. We have made best attempts to review and consolidate existing and new data and include them in our guide. Conclusion: This new narrative format facilitates prescribing by considering a variety of factors. One previously overlooked aspect was the impact on the reproductive potential of both male and female patients. Rather than depending on overly simplistic letter risk categories, dermatologists will now need to make prescribing decisions based on each patient and the information provided, which will allow for better decision making and patient care.
... For ethical issues, well-conducted studies have not been performed in pregnant women, and the published experiences mainly consist of preclinical/animal reproduc- tion studies, single case reports and reg- istries of pregnant patients with arthritis or inflammatory bowel disease. The experience with some biologic drugs (anakinra (4, 5), rituximab (6), abata- cept (7), tocilizumab (8)) is now insuffi- cient to claim their safety during gesta- tion (9,10), whereas human and animal data on anti-TNF-alpha agents exposed pregnancies seem to be reassuring (11). Whilst most of the available data come from retrospective studies, here we pre- sent our prospectively collected data on pregnancy course and outcome in women with inflammatory arthritis tak- ing biological drugs immediately before or during gestation, particularly focus- ing on obstetrical and foetal outcomes. ...
Article
Information on new drugs does not include their possible effects on pregnancy because pregnant women are excluded from clinical trials. Although not classified as teratogenic in animals, limited data is available on biological anti-rheumatic agents and their safety in human pregnancy. The aim of the study is to evaluate the safety of biological drugs in pregnant patients with chronic arthritis. Pregnancy outcome and maternal disease variations were prospectively followed in six Italian Rheumatology Centres. Patients exposed to biological agents during the periconceptional period or during pregnancy were included in the study. The occurrence of congenital malformations as well as the obstetric and neonatal outcomes were assessed. Between 1999 and 2013 we identified 79 exposed pregnancies in 67 women affected by different rheumatic diseases with peripheral chronic arthritis. At the time of the start of pregnancy, 56 patients were taking etanercept, 13 adalimumab, 3 infliximab, 2 each certolizumab-pegol and rituximab, 1 each golimumab, anakinra and abatacept. Biological treatment was stopped after a mean of 41 days since documented pregnancy. Live births were reported in 66% of pregnancies. The rate of spontaneous pregnancy loss was 20%. Only one congenital malformation was reported. TNF-alpha inhibitors can be considered safe in the periconception period, representing a possible therapeutic choice also in young women affected by an aggressive form of chronic arthritis and hoping for a pregnancy. Reports of exposure during 2nd/3rd trimester are still limited and suggest caution. Experience with abatacept, tocilizumab, anakinra and rituximab in pregnancy is insufficient.
... 8 Por otro lado, existe información creciente de que el uso de agentes biológicos no se asocia con mayores complicaciones materno-fetales, aunque la recomendación actual es administrarlos solo si los benefi cios superan claramente a los riesgos. 22,23 El desenlace fetal en nuestra serie se puede considerar satisfactorio, ya que hubo una alta tasa de éxito en los nacidos vivos, la mayoría a término y con buen peso al nacer. Nuestros resultados son consistentes con lo observado por algunos autores [24][25][26] pero no por otros. ...
Article
Full-text available
To compare the maternal and fetal outcomes between childhood-onset and adult-onset systemic lupus erythematosus (SLE), we reviewed the medical records of SLE pregnant women treated from January 2005 to August 2013. For comparison, patients were allocated to one of the two groups, those pregnant patients with SLE onset before 18 years of age (childhood-onset) and ≥18 years (adult-onset). The patients were evaluated at least once in each trimester and postpartum. Relevant maternal and fetal outcomes were extracted, such as lupus flare, preeclampsia/eclampsia, rate of liveborns, fetal loss (spontaneous abortion and stillbirth), term delivery, preterm birth, neonatal death, low birth weight, low birth weight at term, and congenital malformations. We studied 186 pregnancies (in 180 women), 58 of them had childhood-onset SLE, and the remaining 128 had adult-onset SLE. The rate of maternal and fetal complications was similar in both groups. Multivariate analysis showed that active SLE before pregnancy, primigravida, renal flare, preeclampsia, lupus flare, anticardiolipin antibodies, and low serum complement were associated with an increased risk of poor maternal and fetal outcomes. The diagnosis of childhood-onset had no impact on maternal-fetal outcome. The maternal and fetal outcome in women with childhood-onset SLE is similar to that reported in women with adult-onset SLE. Pregnancy in women with childhood-onset SLE should not be contraindicated if the disease is well controlled.
... Alors que l'efficacité et l'innocuité de ces agents ont été étudiées dans les essais cliniques et, de plus en plus, dans les études observationnelles à long terme, il y a peu de données dans la littérature sur leur utilisation pendant la grossesse. Les données sur plus de 2000 grossesses centrées pour l'essentiel dans les maladies inflammatoires chroniques intestinales (MICI) proviennent de cas cliniques/ou de petites séries de cas, en plus des registres de sécurité [1][2][3][4][5][6]. Ces données ne rapportent pas d'augmentation du risque d'avortement spontané, d'insuffisance pondérale, de prématurité, ou de malformation congénitale. ...
Article
Résumé Objectif Comme de nombreux rhumatismes inflammatoires affectent les patients en âge de procréer, un certain nombre de questions se posent au sujet de la sécurité des biothérapies pendant la grossesse. Cette étude a évalué les effets des agents anti-TNF alpha sur le devenir de la grossesse et de l’enfant. Méthodes Trente-huit grossesses ont été suivies de façon prospective de novembre 2008 à février 2015. Les renseignements sur l’exposition des patients aux anti-TNFα, l’activité de la maladie, le traitement de fond, le devenir de la grossesse et de l’enfant ont été enregistrés. Résultats Vingt-quatre sur trente-huit (71,1 %) grossesses ont été exposées aux anti-TNFα à la conception/1er trimestre, 11/38 (28,9 %) avant la conception et 3 (11,1 %) après exposition paternelle. Il y avait deux malformations congénitales : un enfant (4,2 %) avait une hernie diaphragmatique congénitale et un méga uretère obstructif ; la mère avait été exposée à l’adalimumab à la conception/1er trimestre. Tandis qu’un fœtus (9,1 %) avait une trisomie 16, la mère de 38 ans avait suspendu l’étanercept 4 semaines avant la conception. Il n’y avait aucune différence significative sur le devenir de la grossesse et de l’enfant entre les deux groupes. Il n’y avait pas non plus de différence significative sur le devenir de la grossesse et de l’enfant dans les différents groupes traités par différents antagonistes anti-TNFα. Aucune malformation congénitale ne fut constatée après exposition paternelle. Conclusion Les résultats suggèrent que les médicaments anti-TNFα peuvent être sans danger lorsqu’ils sont administrés après exposition paternelle, autour de la conception ou au cours du premier trimestre.
... 8 Por otro lado, existe información creciente de que el uso de agentes biológicos no se asocia con mayores complicaciones materno-fetales, aunque la recomendación actual es administrarlos solo si los benefi cios superan claramente a los riesgos. 22,23 El desenlace fetal en nuestra serie se puede considerar satisfactorio, ya que hubo una alta tasa de éxito en los nacidos vivos, la mayoría a término y con buen peso al nacer. Nuestros resultados son consistentes con lo observado por algunos autores [24][25][26] pero no por otros. ...
Article
Full-text available
To report our experience in maternal-fetal outcome in women with RA in a national medical referral center. A retrospective analysis of the records of pregnant women with rheumatoid arthritis attending at a Pregnancy and Autoimmune Rheumatic Diseases Clinic was performed. Maternal-fetal outcomes such as disease activity, preclampsia/eclampsia, rate of live births, abortions, stillbirths, preterm birth, weeks of gestation, birth weight, congenital malformations and use of anti-rheumatic drugs were studied. We included 73 pregnancies in 72 patients. Disease activity was documented in 47.2% of patients during pregnancy and/or postpartum and 87.7 % of patients received some antirheumatic drug. Preclampsia developed in 8.2 % of cases. The live birth rate was 98.6 %, with preterm delivery in 15.9 % and low weight at term in 17.6% of cases. Cesarean section was performed in 77.1 % of cases. The disease activity was not associated with a higher percentage of maternal-fetal complications. Our study showed that most patients do not experience significant activity of RA during pregnancy, fetal outcome is satisfactory and disease activity did not appear to influence significantly the obstetric outcome.
... Of the 11 term deliveries, 10 were healthy newborns and 1 died of acute respiratory distress syndrome after emergency C-section due to placenta previa [66]. The analysis of these cases, in addition to six other reported, showed no conclusive data in humans [67]. ...
Article
Introduction: Since most of the autoimmune diseases (AID) affect mostly women in their fertile years, and fertility is in general preserved, the use of disease modifying anti-rheumatic drugs (DMARDs) during conception, pregnancy and lactation has been a matter of concern in the treatment of women affect by AID. Areas covered: We performed a comprehensive review of the latest and most relevant research papers published in the field and discussed different aspects related to the use of synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) and immunosuppressants in the preconceptional period, during pregnancy and lactation in AID patients, both in males and females. Expert commentary: Active AID impose an increased risk for adverse maternal and fetal outcomes, such as preeclampsia, miscarriage, intrauterine growth restriction, prematurity, low birth weight, and stillbirth. Family planning with proper contraception and shared decision-making on the ideal time to conceive with treatment adjustment must be a rule. One of the main challenges when counseling and/or adjusting treatment of patients that are planning a pregnancy is to provide a medication that is at the same time efficacious and safe at the conceptional period and to developing the fetus.
... While the efficacy and safety of these agents have been investigated in clinical trials and, increasingly, in long-term observational studies, limited data about their use in pregnancy can be found in the literature. Data from more than 2000 pregnancies focusing for the most part in inflammatory bowel diseases (IBD) comes from case reports/small case series besides safety registries [1][2][3][4][5][6]. These data reported no increased risk of spontaneous abortion, low birth weight, prematurity, or congenital malformations. ...
Article
Full-text available
Objective: As many inflammatory rheumatic diseases affect patients in childbearing age, some concern has been expressed about the safety of biologic drugs during pregnancy. This study evaluated the effects of anti-tumor necrosis factor alpha (TNFα) agents on pregnancy/foetal outcomes. Methods: Thirty-eight pregnancies were followed prospectively from November 2008 to February 2015. Information about the patients' exposure to anti-TNFα, disease activity, DMARD therapy, pregnancy/foetal outcomes were registered. Results: Twenty-four/38 (71.1%) pregnancies were exposed to anti-TNFα at conception/I trimester, 11/38 (28.9%) prior to conception and 3 (11.1%) following paternal exposure. There were two congenital malformations: one infant (4.2%) was diagnosed with congenital diaphragmatic hernia and obstructive megaureter; the mother was exposed to adalimumab at conception/I trimester. While one foetus (9.1%) showed a trisomy 16, the mother 38 year-old had suspended etanercept 4 weeks before conception. There was no significant difference in pregnancy/foetal outcome between the two groups. Nor were there any significant differences in pregnancy/foetal outcomes in the various groups being treated with different anti-TNFα antagonists. No congenital malformations were found in connection to paternal exposure. Conclusion: Study results suggest that anti-TNFα drugs could be safe when administered during conception/I trimester and following paternal exposure.
... According to the present counselling, women should avoid pregnancy for about 6 months after RTX exposure. The administration of RTX to a pregnant woman should be discouraged unless the benefits outweigh the potential risk for the fetus [73][74][75]. There are no data on RTX use in breastfeeding. ...
Article
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Women affected by autoimmune diseases, organ transplantation, or neoplasia need to continue immunosuppressive treatment during pregnancy. In this setting, not only a careful planning of pregnancy, but also the choice of drugs is critical to preventing maternal complications and minimizing the fetal risks. Some immunosuppressive drugs are teratogenic and should be replaced even before the pregnancy, while other drugs need to be managed with caution to prevent fetal risks, including miscarriage, intrauterine growth restriction, prematurity, and low birth weight. In particular, the increasing use of biologic agents raises the question of their compatibility with reproduction. In this review we present data on the indication and safety in pregnancy of the most frequently used immunosuppressive drugs.
... The long-term effects of in utero exposure to RTX are unknown. There is agreement that the administration of RTX to a pregnant woman should be discouraged unless the benefits outweigh the potential risk for the fetus [112,113]. ...
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Pregnancy is not contraindicated in kidney transplant women but entails risks of maternal and fetal complications. Three main conditions can influence the outcome of pregnancy in transplant women: preconception counseling, maternal medical management, and correct use of drugs to prevent fetal toxicity. Preconception counseling is needed to prevent the risks of an unplanned untimely pregnancy. Pregnancy should be planned ≥2 years after transplantation. The candidate for pregnancy should have normal blood pressure, stable serum creatinine <1.5 mg/dL, and proteinuria <500 mg/24 h. Maternal medical management is critical for early detection and treatment of complications such as hypertension, preeclampsia, thrombotic microangiopathy, graft dysfunction, gestational diabetes, and infection. These adverse outcomes are strongly related to the degree of kidney dysfunction. A major issue is represented by the potential fetotoxicity of drugs. Moderate doses of glucocorticoids, azathioprine, and mTOR inhibitors are relatively safe. Calcineurin inhibitors (CNIs) are not associated with teratogenicity but may increase the risk of low birth weight. Rituximab and eculizumab should be used in pregnancy only if the benefits outweigh the risk for the fetus. Renin–angiotensin system inhibitors, mycophenolate, bortezomib, and cyclophosphamide can lead to fetal toxicity and should not be prescribed to pregnant women.
... Since few data are available about TCZ during pregnancy, women in reproductive age should be advised to stop TCZ three months before conception [98]. ...
Article
Introduction: Rheumatoid arthritis (RA) can spontaneously improve during pregnancy. However, a considerable proportion of patients can experience a flare and high disease activity has been associated with an increased risk of adverse pregnancy outcome. Thus, the treatment of RA in pregnant women should be selected taking into account both the potential harmful effects of the treatment and the risk associated with discontinuation. Areas covered: Recent publications regarding safety of the most important disease modifying anti-rheumatic drugs (DMARDs) during pregnancy has been reviewed. A systematic literature search of MEDLINE was conducted using pregnancy, teratogenicity, adverse effects, embryo/foetal-toxicity as key search terms for each DMARD. Expert opinion: A great body of evidence suggest that hydroxychloroquine, sulfasalazine, and non-fluorinated steroids can be continued throughout pregnancy, while methotrexate and leflunomide should be discontinued 3 months before pregnancy. Continuation of TNFi during the first part of pregnancy should be considered when benefits outweigh the potential risk of teratogenicity. Data regarding other biologics are scant and, at present, they should be stopped before pregnancy.
... Questions regarding therapy before and during pregnancy and lactation are of great concern for patients and their treating physicians. Special interest has focused on inhibitors of tumor necrosis factor-alpha (TNF-alpha) because of their frequent use both in female and male patients with rheumatic disease [114]. Measurements of transplacental passage of four TNF inhibitors in an ex vivo human placental perfusion model, and in patients showed differences among adalimumab (ADA), etanercept (ETA), infliximab (IFX) and certolizumab (CZP). ...
Article
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 aetiology 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 children's 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 counselling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes. Copyright © 2014. Published by Elsevier B.V.
... A systematic review on pregnant patients with inflammatory bowel diseases revealed that the rate of adverse pregnancy outcome and malformation in patients treated with TNF-a antagonists is not significantly higher than expected in the general population (Nielsen et al., 2013). However, possible increased risk of neonatal infections has been suggested if these drugs are administered during the third trimester (Ostensen, 2014). The EULAR task force recommended continuation of TNF-a antagonists during the first part of pregnancy and suggested etanercept and certolizumab for use throughout pregnancy due to low rate of transplacental passage (Götestam Skorpen et al., 2016). ...
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Pregnancy may induce the onset or exacerbation of autoimmune bullous diseases such as pemphigus or pemphigoid gestationis. A shift toward T helper (Th) 2 immune response and the influence of hormonal changes have been evoked as possible triggering factors. Therapeutic management of this setting of patients may represent a challenge, mainly due to safety concerns of some immunosuppressive drugs during pregnancy and lactation. In this narrative review, we provided a comprehensive overview of the therapeutic management of autoimmune bullous diseases in pregnant and breastfeeding women, focusing on pemphigus and pemphigoid gestationis.
... This should require the measurement of B-cells at birth and a close interaction with pediatricians to time vaccinations accordingly. 1,31 Our data that all women with RRMS who had been treated with anti-CD20 mAbs before pregnancy experienced a stable DA during pregnancy are very reassuring and in line with a recent observation in a retrospective cohort of 27 patients with MS from Sweden 16 and both Californian studies. 1,2 Of note, women who were treated >6 months before the LMP were effectively untreated by the end of pregnancy. ...
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Objective To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy. Methods Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group. Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8); <6M group = RTX/OCR <6 months before the LMP (n = 47); preg group = RTX/OCR after the LMP (n = 13). Results Pregnancy outcomes were similar between groups, but significantly more preterm births (9.8% vs 45%) occurred after exposure during pregnancy. Overall, 2 major congenital abnormalities (3.3%), both in the preg group, were observed. Three women had severe infections during pregnancy. All women with MS (35) and 12/13 women with NMOSD, RTX/OCR exposure before the LMP and known pregnancy outcomes after gestational week 22 were relapse free during pregnancy. Five of 29 (17.2%) women with relapsing-remitting MS (RRMS) and 1 of 12 (8.3%) with NMOSD and at least 6 months postpartum follow-up experienced a relapse postpartum. Duration of RTX/OCR and early retreatment but not detection of B-cells were possible predictors for postpartum relapses in patients with RRMS/NMOSD. Conclusions Although RTX/OCR might be an interesting option for women with RRMS/NMOSD who plan to become pregnant to control DA, more data on pregnancy outcomes and rare risks are needed.
... For example, the treatment goal for rheumatoid arthritis is to have little or no pre-conception activity, as negative effects of steroids and non-steroidal anti-inflammatory drugs must be considered [106]. Experiences from case reports and registry data with TNF antagonists, which have been approved for many years for the treatment of rheumatological diseases and psoriasis vulgaris, have so far shown no evidence of an increased number of spontaneous abortions or malformations [107]. As a result, the use of TNF inhibitors such as infliximab, adalimumab, and etanercept is recommended in pregnancy up to week 20. ...
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With the advent of biologicals, more and more therapeutics are available that specifically address specific switch points in the pathomechanism of immunologically dominated diseases. Thus, the focus of diagnostics and therapy (precision medicine) is more on the individual disease characteristics of the individual patient. Regarding the different phenotypes of atopic diseases, severe asthma was the first entity for which biologicals were approved, followed by urticaria, and finally atopic dermatitis and chronic rhinosinusitis with nasal polyps. Experience in the treatment of severe bronchial asthma has shown that the intensity of the response to biological therapy depends on the quality of clinical and immunological phenotyping of the patients. This also applies to different diseases of the atopic form, as patients can suffer from several atopic diseases at the same time, each with different characteristics. Biologics are already emerging that may represent a suitable therapy for allergic bronchial asthma, which often occurs together with severe neurodermatitis, and chronic rhinosinusitis with nasal polyps. In practice, however, the question of possible combinations of biologicals for the therapy of complex clinical pictures of individual patients is increasingly arising. In doing so, the side effect profile must be taken into account, including hypersensitivity reactions, whose diagnostic and logistical management must aim at a safe and efficient therapy of the underlying disease. Increased attention must also be paid to biological therapy in pregnancy and planned (predictable) vaccinations as well as existing infections, such as SARS-CoV-2 infection. Before starting a biological therapy, the immune status should be checked with regard to chronic viral and bacterial infections and, if necessary, the vaccination status should be refreshed or missing vaccinations should be made up for before starting therapy. Currently, reliable data on the effect of biologicals on the immunological situation of SARS-CoV-2 infection and COVID-19 are not available. Therefore, research and development of suitable diagnostic methods for detection of immunologically caused side effects as well as detection of potential therapy responders and non-responders is of great importance.
... For example, the treatment goal for rheumatoid arthritis is to have little or no pre-conception activity, as negative effects of steroids and non-steroidal anti-inflammatory drugs must be considered [106]. Experiences from case reports and registry data with TNF antagonists, which have been approved for many years for the treatment of rheumatological diseases and psoriasis vulgaris, have so far shown no evidence of an increased number of spontaneous abortions or malformations [107]. As a result, the use of TNF inhibitors such as infliximab, adalimumab, and etanercept is recommended in pregnancy up to week 20. ...
Article
With the advent of biologicals, more and more therapeutics are available that specifically address specific switch points in the pathomechanism of immunologically dominated diseases. Thus, the focus of diagnostics and therapy (precision medicine) is more on the individual disease characteristics of the individual patient. Regarding the different phenotypes of atopic diseases, severe asthma was the first entity for which biologicals were approved, followed by urticaria, and finally atopic dermatitis and chronic rhinosinusitis with nasal polyps. Experience in the treatment of severe bronchial asthma has shown that the intensity of the response to biological therapy depends on the quality of clinical and immunological phenotyping of the patients. This also applies to different diseases of the atopic form, as patients can suffer from several atopic diseases at the same time, each with different characteristics. Biologics are already emerging that may represent a suitable therapy for allergic bronchial asthma, which often occurs together with severe neurodermatitis, and chronic rhinosinusitis with nasal polyps. In practice, however, the question of possible combinations of biologicals for the therapy of complex clinical pictures of individual patients is increasingly arising. In doing so, the side effect profile must be taken into account, including hypersensitivity reactions, whose diagnostic and logistical management must aim at a safe and efficient therapy of the underlying disease. Increased attention must also be paid to biological therapy in pregnancy and planned (predictable) vaccinations as well as existing infections, such as SARS-CoV-2 infection. Before starting a biological therapy, the immune status should be checked with regard to chronic viral and bacterial infections and, if necessary, the vaccination status should be refreshed or missing vaccinations should be made up for before starting therapy. Currently, reliable data on the effect of biologicals on the immunological situation of SARS-CoV-2 infection and COVID-19 are not available. Therefore, research and development of suitable diagnostic methods for detection of immunologically caused side effects as well as detection of potential therapy responders and non-responders is of great importance.
... Because etanercept is a fusion protein, there is less transplacental passage than of complete antibodies. 35 Certolizumab lacks an Fc component and thus cannot be actively transported across the placenta. 36 There was initial concern stemming from a 2009 uncontrolled study of voluntarily reported events that infliximab and etanercept were associated with the VACTERL spectrum of anomalies (vertebral abnormalities, anal atresia, cardiac defects, tracheo-esophageal, renal and limb abnormalities). ...
Article
Women with rheumatoid arthritis (RA) are often of childbearing age and therefore questions regarding reproductive health and the use of medications, including disease-modifying anti-rheumatic drugs (DMARDs) may arise during the clinical consultation. Each patient requires individual assessment in order to effectively manage the disease while minimizing any treatment-associated risks to the fetus. Although good-quality controlled trials are lacking, there is an increasing volume of evidence surrounding the use of immunosuppressive therapies in pregnancy and lactation. This review summarizes the currently available information which can be of benefit to clinicians guiding patients and their families through the risks and benefits of continuing RA therapy during pregnancy and lactation. Further studies and ongoing surveillance of drug safety in pregnancy are required to resolve the uncertainties that remain regarding synthetic and biologic DMARDs.
... Even though the studies have been limited, and in general open labeled with active SLE and with flares, the results are worthwhile to review carefully [42][43][44]. In these reports no major adverse effects were recorded although safety issues of concern have to be taken into account [45,46]. Most probably, a new scheme of treatments should be possible taking into the account the high number of young women that may suffer SLE in the near future. ...
Article
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There have been few changes over the last 50 years in the treatment of Systemic lupus erythematosus (SLE), using non-specific anti-inflammatory agents such as: non-steroidal anti-inflammatory drugs along with the immune cell modulating agent hydroxychloroquine for mild disease, and broad spectrum immunosuppressants plus anti-inflammatories such as corticosteroids, azathioprine, cyclophosphamide, or mycophenolate during flares or severe disease with organ involvement. In some patients, the response is inadequate and side effects appear from mild unpleasant up to severe toxicity. Drug metabolism and clearance may be severely compromised. Therefore, it is a priority to develop better treatments with fewer adverse events that can be used at different stages of disease activity. In recent years, a member of the tumor necrosis factor (TNF) family, soluble human B Lymphocyte Stimulator protein (BLyS), also referred to as B-cell activating factor (BAFF) and TNFSF13B has been studied extensively. This protein is synthesized by myeloid cell lines, specifically interacts with B lymphocytes and increases their life-span. BlyS plays a key role in the selection, maturation and survival of B cells and it has a significant role in the pathogenesis of SLE. In this review, we analyzed the role of BLyS as a diagnostic/prognostic marker and/or therapeutic target for lupus patients, and the different clinical studies published using belimumab.
Article
Preeclampsia (PE) is associated with altered immune activation during pregnancy. We have previously shown that adoptive transfer of CD4(+) T cells from the reduced uterine perfusion pressure (RUPP) rat model of PE increases blood pressure, oxidative stress (ROS), and inflammation in normal pregnant recipient rats. The objective of this study was to determine if blockade of communication via the CD40-CD40 ligand interaction between placental ischemia-induced CD4(+) T cells with endogenous normal pregnant (NP) cells would improve pathophysiology that was previously observed in NP recipient rats of RUPP CD4(+) T cells. Splenic CD4(+) T lymphocytes were magnetically separated, incubated with 2.5 µg/mL anti-CD40 ligand (αCD40L) overnight and transferred into NP rats on day 12 of gestation (NP+RUPP CD4(+)T cells+CD40L). On day 19 of gestation, blood pressure (MAP), blood, and tissues were collected. MAP was 99±2 in NP (n=13), 116±4 in NP+RUPP CD4(+) T cells (n=7; p<0.01); MAP only increased to 104 ±2 in NP+RUPP CD4+Tcells+CD40L (n=24) (p<0.05 vs NP+RUPP CD4(+)T cells). Mechanisms of hypertension in response to RUPP CD4(+) T cells include ET-1, ROS, and AT1-AA were analyzed. Inhibition of CD40 ligand binding reduced placental ET-1 to 2.3 fold above NP rats, and normalized placental ROS from 318.6 ±89 in NP+RUPP CD4(+)T cells (p<0.05) to 118.7 ±24 in NP+RUPP CD4(+)T cells+CD40L (p<0.05). AT1-AA was also normalized with inhibition of CD40 ligand. This data suggests that placental ischemia-induced T cell communication via the CD40 ligand is one important mechanism leading to much of the pathophysiology of preeclampsia. Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
Article
Introduction: Management of patients with severe immune-mediated uveitis requires the use of immunosuppressive drugs in selected cases. This may be especially challenging in certain patients with concomitant conditions, which could increase the risk of side effects or modify guidelines for the use of such drugs. Therapeutic decision-making and management may be of particular difficulty in pregnancy as well as in patients with associated malignancies unrelated to a specific ophthalmic inflammatory condition. Areas covered: The main aim of this review is to provide an updated comprehensive practical guide for practitioners regarding the therapeutic decision-making and management of patients with severe immune-mediated uveitis in the context of pregnancy and malignancies. Expert opinion: Management of patients with immune-mediated uveitis requiring immunosuppressive/immunomodulatory drugs might be particularly complicated by other conditions affecting their health and immune status. Clinicians should take into account such conditions, which might influence treatment response and the clinical outcome of these patients.
Article
Biosimilars for psoriasis treatment are currently being developed. Comparison of their efficacy and safety is a challenge. For approval, the European Medicines Agency (EMA) considers indirect evidence from other indications (for example, rheumatoid arthritis) as sufficient. Systematic review of biosimilars for psoriasis and other indications, review of ongoing trials in trial registers. Systematic search for randomized controlled trials (RCT) on biosimilars to adalimumab, etanercept, infliximab, and ustekinumab compared to their reference medication: (1) Publications in Medline, Medline In-Process, Embase, Cochrane Library (efficacy, safety, immunogenicity) and (2) ongoing studies in clinical trial registers. No trials on biosimilars in psoriasis patients were identified. As to the infliximab biosimilar, there is data on patients with ankylosing spondylitis and rheumatoid arthritis, indicating no clinically relevant differences regarding efficacy and safety. Currently, there are two registered studies of an adalimumab biosimilar and one study of an etanercept biosimilar in psoriasis patients. Further ongoing studies on biosimilars to adalimumab, etanercept, and infliximab - all in rheumatoid arthritis patients - were identified. There is currently only limited data regarding RCTs with biosimilars. Provision of further clinical data and inclusion of patients in patient registers will be crucial. © 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.
Article
Rheumatoid arthritis (RA) affects mainly women during their childbearing years. As aging of childbirth advances in Japan, women who plan pregnancy would increase after they developed RA. Recent findings showed that high disease activity of RA might impair fertility. Planning pregnancy is preferable after female patients achive and maintain low disease activity or remission of RA. Women on methotrexate, which is the anchor drug for RA, need to discontinue the medication with a high risk of causing birth defects during conception and pregnancy. Data of RA patients exposed TNF inhibitors during pregnancy has been accumulating in recent years. These data suggest that increased risk of spontaneous abortion and congenital abnomalies has not been observed. Although there is insufficient data about safety of breastfeeding while using TNF inhibitors, the secretion of the drugs in breast milk is very little and fetal toxicity has not been observed. Since long term safety of children exposed TNF inhibitors in uterus has not been established, we should discontinue the drugs as soon as pregnancy is recognized. TNF inhibitors may be an useful tools for management of active RA resistant to conventional DMARDs in women who desire to bear children.
Article
In recent years, there has been a growing interest in the role of immune, alloimmune and autoimmune processes in the pathogenesis of spontaneous preterm birth and recurrent pregnancy loss. The association between an inflammatory response and preterm labor has been established. Indeed, many women suffering from preterm labor have elevated inflammatory markers such as tumor necrosis factor alpha, interleukin 6 and matrix metaloproeinase 8. The role of immune processes in the pathogenesis of recurrent pregnancy loss has also been widely researched. Progesterone induces many physiologic effects necessary for healthy pregnancy, and progestagens supplementation has been used as an approach to prevent preterm labor and recurrent pregnancy loss. Progestagens also have potent anti-inflammatory and immunomodulatory actions. Because preterm labor and recurrent pregnancy loss are associated with abnormal inflammation, progestagens may maintain healthy pregnancy through both endocrine and immunologic actions. These immunologic actions, such as suppression of Th1- and Th17-related responses, enhancement of regulatory T cell (Tregs) activity and suppression of inflammation, may also be involved in pregnancy-induced remission of certain autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). Accordingly, there is growing interest in the potential therapeutic role of progestagens in the treatment of MS and RA. In this review, we suggest that biologic autoimmune modulators, especially those which affect immune pathways similar to progestagens, may provide more potent and specific effects, and hence better results than progestagens, in preventing preterm labor and recurrent pregnancy loss.
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While immunoglobulin biologicals are increasingly used during pregnancy, there have been concerns on the immune function and vaccination of infants born to mothers taking immunoglobulin biologicals. In addition to the detection of biologicals in cord blood, cases of severe neonatal neutropenia and fatal dissemination of Bacillus Calmette-Guérin (BCG) have been reported. With increasing number of infants exposed to immunoglobulin biologicals in utero, there is a need to address the challenges in vaccinating these infants. This review summarizes the available evidence to discuss the issues of immunoglobulin biological exposure in utero, neonatal immune function, long-term immune development, and the challenges and strategies of vaccinating newborns and infants who were born to mothers taking biologicals during pregnancy.
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Systemic lupus erythematosus (SLE) mostly affects young women of reproductive age group. SLE patients may conceive as any normal woman but complication may occur in these patients if the disease is active. Pregnancy in SLE may lead to 1. Aggravation of SLE (Lupus flare) 2. Pre-term delivery, intrauterine growth retardation and foetal loss (in presence of antiphospholipid antibodies) 3. Neonatal lupus especially in presence of Anti-Ro / La antibody. For a successful pregnancy, both from maternal and foetal aspects, disease should be quiescent for at least six months before the conception. Lupus patients with pregnancy require specific management to improve the maternal and fetal outcomes. Many safe drugs are available for the management of pregnancy in SLE.
Article
Tocilizumab (TCZ) is not recommended for use during pregnancy due to limited data, but pregnancies nevertheless occur and pregnant women need to be counseled about potential fetal risks. Participants of this study were recruited from the pool of callers who spontaneously contact the pharmacovigilance center “Embryotox” Berlin for risk assessment during pregnancy. Of 22 identified cases with TCZ exposure during pregnancy, 16 prospectively enrolled cases with maternal and two cases with paternal TCZ therapy could be completed. The outcomes of the 16 maternal cases were: four spontaneous abortions (SAB), one induced abortion for personal reasons and 11 live-born infants. Congenital malformations were not recorded, but one SAB at week 15 + 3 days was complicated by hydrops fetalis of unknown origin. An incidental continuation of TCZ into early pregnancy does not justify an elective termination. However, a detailed prenatal ultrasound should be offered.
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Multiple sclerosis (MS) is a major acquired neurologic disease of young adults. The prototypic patient is a young woman of reproductive age. Gender preference is becoming more pronounced, since MS is increasing specifically among women. Any healthcare provider who deals with MS must be prepared to discuss pregnancy issues, and provide appropriate counseling. This is now complicated by the availability of multiple treatment options. There is growing literature on which to base recommendations, particularly regarding washout periods. After a brief background introduction, this review will discuss state-of-the-art family planning counseling in the treatment era, divided into prepregnancy, pregnancy, and postpartum MS issues.
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Systemic lupus erythematosus (SLE) mostly affects young women of reproductive age group. SLE patients may conceive as any normal woman but complication may occur in these patients if the disease is active. Pregnancy in SLE may lead to 1. Aggravation of SLE (Lupus flare) 2. Pre-term delivery, intrauterine growth retardation and foetal loss (in presence of antiphospholipid antibodies) 3. Neonatal lupus especially in presence of Anti-Ro / La antibody. For a successful pregnancy, both from maternal and foetal aspects, disease should be quiescent for at least six months before the conception. Lupus patients with pregnancy require specific management to improve the maternal and fetal outcomes. Many safe drugs are available for the management of pregnancy in SLE. © 2016, Journal of Association of Physicians of India. All rights reserved.
Article
Rheumatic and systemic autoimmune diseases occur in women and, to a lesser degree, men of reproductive age. These disorders have to be clinically nonactive before conception, which is usually only possible after anti-inflammatory and immunosuppressive treatment. We must be alert since 50% of pregnancies are unplanned. Physicians should know the embryo-foetal toxicity of these drugs during pregnancy and lactation. This January 2016-updated review allows us to conclude that the majority of immunosuppressives available – anti-TNF inhibitors included – can be used before and during pregnancy, with the exception of cyclophosphamide, methotrexate, mycophenolate and leflunomide. Lactation is permitted with all drugs except methotrexate, leflunomide, mycophenolate and cyclophosphamide. Although data on abatacept, belimumab, rituximab, tocilizumab and anakinra are scant, preliminary reports agree on their safety during pregnancy and, probably, lactation. Cyclophosphamide and sulfasalazine apart, no negative effects on sperm quality, or embryo-foetal anomalies in men treated with immunosuppressives have been described.
Article
Während der Schwangerschaft ist ein erfolgreiches und sicheres therapeutisches Management der Patienten zur Verringerung der Krankheitslast möglich. Meist reicht eine topische Therapie, ggf. begleitet von einer Basistherapie. Darüber hinaus können Systemtherapien z. B. bei Autoimmunerkrankungen oder Psoriasis durchaus sicher eingesetzt werden. Hier gilt es, auch bei geplanten Schwangerschaften frühzeitig Medikamente abzusetzen, zu reduzieren, mögliche alternative Therapien zu besprechen bzw. ein frühes Monitoring zu starten. Zu bedenken ist immer, dass Medikamente in möglichst geringer Dosis (ohne Okklusion bei Lokaltherapien) und kurzzeitig (Ausnahme: Autoimmun- oder maligne Erkrankungen) anzuwenden sind. Eine interdisziplinäre Zusammenarbeit zwischen Gynäkologen, Rheumatologen, Internisten und Dermatologen sowie Pharmazeuten ist unabdingbar.
Article
Autoimmune inflammatory rheumatic diseases (AIIRD) such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are often complicated by infection, which results in significant morbidity and mortality. The increased risk of infection is probably due to a combination of immunosuppressive effects of the AIIRD, comorbidities, and the use of immunosuppressive conventional synthetic disease modifying anti-rheumatic drugs (DMARDS) and more recently, targeted synthetic DMARDS and biologic DMARDS which block specific pro-inflammatory enzymes, cytokines or cell types. The use of these various DMARDS has revolutionized the treatment of AIIRD. This has led to a marked improvement in quality of life for AIIRD patients, who often now travel for prolonged periods. Many infections are preventable with vaccination. However, as protective immune responses induced by vaccination may be impaired by immunosuppression, where possible, vaccination may need to be performed prior to initiation of immunosuppression. Vaccination status should also be reviewed when planning overseas travel. Limited data regarding vaccine efficacy in patients with AIIRD makes prescriptive guidelines difficult. However, a vaccination history should be part of the initial work-up in all AIIRD patients. Those caring for AIIRD patients should regularly consider vaccination to prevent infection within the practicalities of routine clinical practice.
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There are a number of barriers that result in cancer patients not being referred for oncofertility care, which include knowledge about reproductive risks of antineoplastic agents. Without this information, clinicians do not always make recommendations for oncofertility care. The objective of this study was to describe the level of reproductive information and recommendations that clinicians have available in clinical trial protocols regarding oncofertility management and follow-up, and the information that patients may receive in clinical trials patient information sheets or consent forms. A literature review of the 71 antineoplastic drugs included in the 68 clinical trial protocols showed that 68% of the antineoplastic drugs had gonadotoxic animal data, 32% had gonadotoxic human data, 83% had teratogenic animal data, and 32% had teratogenic human data. When the clinical trial protocols were reviewed, only 22% of the protocols reported the teratogenic risks and 32% of the protocols reported the gonadotoxic risk. Only 56% of phase 3 protocols had gonadotoxic information and 13% of phase 3 protocols had teratogenic information. Nine percent of the protocols provided fertility preservation recommendations and 4% provided reproductive information in the follow-up and survivorship period. Twenty-six percent had a section in the clinical trials protocol, which identified oncofertility information easily. When gonadotoxic and teratogenic effects of treatment were known, they were not consistently included in the clinical trial protocols and the lack of data for new drugs was not reported. Very few protocols gave recommendations for oncofertility management and follow-up following the completion of cancer treatment. The research team proposes a number of recommendations that should be required for clinicians and pharmaceutical companies developing new trials.
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Monoclonal antibodies that target CD20 expressing B cells represent an important new treatment option for patients with multiple sclerosis (MS). B cell depleting therapy is highly effective against relapsing forms of the disease, and is also the first treatment approach proven to protect against disability worsening in primary progressive MS. Moreover, evolving clinical experience with B cell therapy, combined with a more sophisticated understanding of humoral immunity in preclinical models and in patients with MS, have led to major progress in deciphering the immune pathogenesis of MS. Here, we review the nuanced roles of B cells in MS autoimmunity, the clinical data supporting use of ocrelizumab and other anti-CD20 therapies in the treatment of MS, as well as safety and practical considerations for prescribing. Lastly, we summarize remaining unanswered questions regarding the proper role of anti-CD20 therapy in MS, its limitations, and the future landscape of B cell based approaches to treatment. This article is protected by copyright. All rights reserved.
Article
We report the case of a woman with rheumatoid arthritis (RA) who had two successful pregnancies (at 31 and 35 years old). Her RA was diagnosed when she was 23 years old. The first pregnancy was established while she was taking etanercept (ETN) and prednisolone (PSL) after In Vitro Fertilization - Blastocyst Transfer (IVF-BT). Her RA was controlled well by ETN/PSL during pregnancy and she gave birth to a healthy female infant weighing 2650 g with Apgar scores of 7 and 9. The RA worsened transiently after childbirth and methotrexate (MTX) was administered. Based on her desire to have a second child, MTX was discontinued. Her second pregnancy was established while on PSL/tocilizmab (TCZ) after IVF-BT. The TCZ was halted until gestational week (GW) 8, two doses of TCZ were given at GW 9 and 14 to stabilize RA, TCZ was switched to ETN on and after GW 18, and she gave birth to a healthy male infant weighing 3225 g with Apgar scores of 8 and 9. Counseling was provided several times by a pharmacist to support her RA treatment during her pregnancy.
Article
Introduction: Relapse of Inflammatory Bowel Disease (IBD) during conception and pregnancy has been associated with a negative pregnancy outcome. Therefore, it is advised to maintain drugs in order to prevent relapse. The effect of drugs, which cross the placenta, on children who have been exposed during pregnancy will be discussed in this review. Areas covered: A literature search was performed using the following search terms: inflammatory bowel disease, pregnancy, infant, anti-tumor necrosis factor alpha, infliximab, adalimumab, golimumab, certolizumab, anti-integrins, vedolizumab, anti interleukin 12/23 ustekinumab, placenta, vaccination. Other studies were identified by using references from articles identified through our original literature search. The occurrence of unfavourable pregnancy outcome and congenital malformations does not seem to be increased after exposure to anti-TNFα, but the effects on the developing immune system are largely unknown. For anti-integrins and anti interleukin 12/23, the numbers of exposed pregnancies are to small to draw any conclusions Expert commentary: Follow up of the developing immune system in children exposed to these drugs seems warranted, preferably in a prospective study design.
Article
Background of the article: Biologics are modern immunomodulatory drugs, whose use in the treatment of psoriasis has led to remarkable results in psoriatic patients. The administration of these agents in special population groups, such as patients with chronic infections and renal impairment, as well as perioperative, pregnant or lactating patients, has not been thoroughly addressed, mostly because these patients are excluded from clinical studies. Materials and methods: This report is an updated systematic overview of the use of biologics in the above mentioned types of patients and was conducted according to the PRISMA Guidelines for systematic reviews. Articles derived from the databases PubMed, EMBASE and SCOPUS, published between 1999 and 2018, were analyzed for the study. Results: Research efforts as well as clinical reporting are necessary in order to provide more insight on the management of these therapeutic dilemmas. Conclusion: The aim of this review, other than providing a summarized update on the clinical knowledge on this special topic, is also to raise awareness for the need to conduct larger systematic studies in order to adequately evaluate the use of biologics in these special patient categories and therefore draw definite conclusions on their safety profile.
Article
Background: We evaluated serum anti-Müllerian hormone in women with rheumatoid arthritis newly introduced to tumor necrosis factor-α inhibitor treatment for 54 weeks to investigate the treatment's effect on ovarian reserve. Methods: A total of 12 premenopausal women with rheumatoid arthritis aged 20-50 years were recruited at our division, who had been newly treated with tumor necrosis factor-α inhibitor (infliximab or etanercept) from 1 April 2008 to 31 March 2014. Serial serum anti-Müllerian hormone levels and disease activity scores (DAS28-CRP) were examined at defined periods: start of treatment and 14, 30, and 54 weeks after start of treatment. Results: DAS28-CRP scores in 12 women were significantly decreased from a mean of 4.6 (±SD: 0.4) to 2.3 (±0.4) after 54 weeks of treatment (p < 0.001). Serum anti-Müllerian hormone levels and its z scores did not change significantly. Conclusion: Treatment with a tumor necrosis factor-α inhibitor did not affect serum anti-Müllerian hormone levels in 12 women with rheumatoid arthritis during 54-week treatment.
Article
Autoimmune inflammatory rheumatic diseases (AIIRD) such as rheumatoid arthritis and spondyloarthritis, including psoriatic arthritis and ankylosing spondylitis are associated with an increased risk of infection due to a combination of the immunosuppressive effect of the AIIRD, comorbidities, and use of corticosteroids and the immunosuppressive effect of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), targeted synthetic (ts-) DMARDs, and biologic (b-) DMARDs. Many infections are preventable with vaccination. However, as the protective immune responses induced by vaccination may be impaired by immunosuppression, vaccination should be considered before the commencement of immunosuppression. Another opportune time to review vaccination status is when planning overseas travel, as destination-specific vaccines are often required. Although limited published data regarding vaccine efficacy in patients with AIIRD make prescriptive guidelines difficult, a vaccination history should be part of the initial workup in all patients with AIIRD. Unfortunately, this is often not done by rheumatologists. This paper encourages those caring for patients with AIIRD to regularly review vaccination status.
Article
Current guidelines advise to maintain immunomodulators and biologicals in pregnant patients because relapse of inflammatory bowel is associated with unfavourable pregnancy outcome. With the exception of Methotrexate, IBD therapy seems not to be related to an increase of congenital malformations or infections requiring hospitalisation of the babies, although the effect the on the developing immune system of the exposed infants remains unknown. In this review we will focus on the effect of IBD drugs on health-related outcomes in children taking into account possible long-term effects of biologicals and immunomodulators, which are transferred across the placenta.
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Background A monovalent, adjuvanted, inactivated H1N1 influenza vaccine (Pandemrix) was reported as highly immunogenic resulting in seroconversion in 77-94% of adults after administration of a single dose (ref). Objectives To investigate impact of different anti-rheumatic treatments on antibody response following H1N1 vaccination in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA). Methods Patients with arthritis (n=333; mean age 58 years, 66% women) participated. Hemagglutination inhibition (HI) assay was performed on blood samples drawn prior to and after mean 8 months following vaccination. A positive immune response was defined as seroconversion i.e. ≥4-fold increase in HI titer or HI ≥40 in case ofa negative pre-vaccination serum. There were 7 treatment groups: RA on MTX; RA on anti-TNF monotherapy; RA on anti-TNF+MTX; RA on other biologics (abatacept, rituximab, tocilizumab); SpA on anti-TNF monotherapy; SpA on anti-TNF+MTX and SpA on NSAIDs/analgesics. Results The figure shows percentages of patients with positive immune responses in different treatment groups. RA patients on rituximab had significantly lower (p<0.001) and SpA on anti-TNF monotherapy significantly better response rates compared to other treatment groups (p 0.001-0.032). No significant differences were found between other groups. Conclusions Rituximab treatment is associated with severely reduced antibody response to the pandemic H1N1 influenza vaccine. Eight months after vaccination, antibody response in SpA patients on anti-TNF monotherapy was still as good as that reported for healthy adults efter 3-4 weeks. All other treatments groups showed lower antibody response. References Broadbent AJ, Subbarao K. Current Opinion in Virology 2011 (1);4:254-262. Disclosure of Interest None Declared
Article
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Background/aims: The Japanese National Hospital Organization evidence-based medicine (EBM) Study group for Adverse effects of Corticosteroid therapy (J-NHOSAC) is a Japanese hospital-based cohort study investigating the safety of the initial use of glucocorticoids (GCs) in patients with newly diagnosed autoimmune diseases. Using the J-NHOSAC registry, the purpose of this observational study is to analyse the rates, characteristics and associated risk factors of intracellular infections in patients with newly diagnosed autoimmune diseases who were initially treated with GCs. Methodology/principal findings: A total 604 patients with newly diagnosed autoimmune diseases treated with GCs were enrolled in this registry between April 2007 and March 2009. Cox proportional-hazards regression was used to determine independent risk factors for serious intracellular infections with covariates including sex, age, co-morbidity, laboratory data, use of immunosuppressants and dose of GCs. Survival was analysed according to the Kaplan-Meier method and was assessed by the log-rank test. There were 127 serious infections, including 43 intracellular infections, during 1105.8 patient-years of follow-up. The 43 serious intracellular infections resulted in 8 deaths. After adjustment for covariates, diabetes (Odds ratio [OR]: 2.5, 95% confidence interval [95% CI] 1.1-5.9), lymphocytopenia (≦1000/μl, OR: 2.5, 95% CI 1.2-5.2) and use of high-dose (≧30 mg/day) GCs (OR: 2.4, 95% CI 1.1-5.3) increased the risk of intracellular infections. Survival curves showed lower intracellular infection-free survival rate in patients with diabetes, lymphocytopaenia and high-dose GCs treatments. Conclusions/significance: Patients with newly diagnosed autoimmune diseases were at high risk of developing intracellular infection during initial treatment with GCs. Our findings provide background data on the risk of intracellular infections of patients with autoimmune diseases. Clinicians showed remain vigilant for intracellular infections in patients with autoimmune diseases who are treated with GCs.
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Incremental increase in the risk of serious infections with combinations of tumor necrosis factor-alpha (TNF-α) inhibitors and immunomodulators compared to monotherapy with these agents in inflammatory bowel disease (IBD) is unclear. Our aim was to analyze whether there is such an incremental increase in the odds of serious infections. The FDA Adverse Event Reporting System (2003 - June 2011) was queried for 'Primary Suspect' reports of various infections with TNF-α inhibitors, systemic corticosteroids and immunomodulators with usage indication of IBD. Odds ratios (ORs) were calculated for baseline odds of infections as well as serious infections (requiring hospitalization and/or death) with monotherapy and combination therapy (compared to 5-Aminosalicylates) as well as incremental increase in odds for dual or triple combination therapy (compared to monotherapy or dual combination therapy respectively) using Fisher's exact test with SPSS 20 (IBM Co. Armonk, NY, USA). TNF-α inhibitor (OR 1.95; CI, 1.06-3.59) and immunomodulator (OR 9.99; CI, 1.28-78.16) monotherapy as well as in combination augmented baseline odds of serious infection for IBD patients. No incremental increase in the odds with combination therapy was seen when an immunomodulator was added to a TNF-α inhibitor (OR 0.37; CI, 0.05-2.80) and when both were used with a systemic corticosteroid (OR 0.91; CI, 0.50-1.66). Variations in these were seen for the individual infection subtypes. TNF-α inhibitor and immunomodulator monotherapy increase the baseline odds of acquiring a serious infection. Combination therapy with these drugs does not further increase the odds of serious infections compared to monotherapy.
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The management of RA, SpA, psoriasis and inflammatory bowel disease has significantly improved over the last decade with the addition of tumour necrosis factor inhibitors (anti-TNFs) to the therapeutic armamentarium. Immunogenicity in response to monoclonal antibody therapies (anti-drug antibodies) may give rise to low serum drug levels, loss of therapeutic response, poor drug survival and/or adverse events such as infusion reactions. To combat these, the use of concomitant MTX may attenuate the frequency of anti-drug antibodies in RA, SpA and Crohn’s disease. Although a similar effect to methotrexate has been observed with AZA usage in the management of Crohn’s disease, there is insufficient evidence to suggest that other DMARDs impact immunogenicity. In this article we review the evidence to date on the effect of immunomodulatory therapy when co-administered with anti-TNFs. We also discuss whether such a strategy should be employed in SpA and psoriasis, and if optimization of the MTX dose could improve biologic drug survival and thereby benefit disease management.
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Tumor necrosis factor (TNF)-alpha inhibitors are increasingly being used in inflammatory bowel disease (IBD). Because this chronic intestinal disorder often affects women of fertile age, it is essential to assess the effect of biologics on pregnancy outcome. We performed a systematic review of the English-language literature to investigate if treatment with TNF-alpha blockers during pregnancy in women with IBD increases the risk of spontaneous abortions, preterm delivery, stillbirth, low birth weight, congenital malformations, or risk of infections in the offspring. Of 552 articles and abstracts reviewed, 58 articles or abstracts with unique content were identified and included in this systematic review. However, most presentations were case reports or case series supplied by a limited number of observational studies. No randomized controlled studies were available. TNF-alpha inhibitors do not seem to affect either outcome of pregnancy in mothers with IBD, or the outcome in the offspring (congenital malformations and immunosuppression). Further, recent data have not identified any increased risk of infections in the first year of life in the offspring of mothers who received biologics, even in combination with immunomodulators (thiopurines). From the present systematic review, no association was found between administration of TNF inhibitors for IBD during pregnancy and adverse pregnancy outcome or congenital abnormalities. Further, no increased relative risk of infections has been reported in the first year of life in offspring of mothers who received biologics. Biologics should be discontinued during pregnancy solely if the IBD is in remission using the same stopping criteria as for patients with IBD in general, as uncontrolled activity of IBD may expose the mother and child to a risk greater than those only potentially coming from the use of TNF-alpha inhibitors. In such cases, inoculation of the offspring with live vaccines is contraindicated until the biologic agent is no longer detectable in the child's circulation.
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This study aims to investigate the use of biological disease-modifying antirheumatic drugs (bDMARDs) as monotherapy in patients with rheumatoid arthritis (RA) in "real world" clinical settings and to compare tumor necrosis factor (TNF) inhibitors and tocilizumab monotherapy in terms of efficacy and patient and clinician satisfaction with treatment. This study made use of a retrospective, cohort-19 based study including included data from 254 patients (TNF inhibitors n = 128; tocilizumab n = 126) managed in 30 centers throughout Germany. Efficacy of monotherapy and patient and physician overall satisfaction with treatment were assessed at baseline, 3, and 6 months of monotherapy using a range of measures including Disease Activity Score 28 joint (DAS28), swollen joint count (SJC) and tender joint count (TJC), and visual analogue scales (VAS). Between 18 and 41 % of patients treated with bDMARDs received the agent as monotherapy. Intolerance to DMARDs, contraindications for combination therapy, and comorbidities were the most common reasons for introduction of bDMARD monotherapy. Mean DAS28 (erythrocyte sedimentation rate, ESR) was significantly lower at 3 and 6 months following tocilizumab vs. TNF inhibitors (p ≤ 0.001). Joint counts improved from baseline to month 6 in both groups (SJC -5.1 vs. -3.7 and TJC -5.6 vs. -5.1, for tocilizumab and TNF inhibitors, respectively). Patient as well as physician satisfaction (VAS 100 mm scale) was significantly higher for tocilizumab vs. TNF inhibitors (75.3 vs. 66.8; p = 0.001 and 74.9 vs. 67.1, p = 0.003, respectively). Significantly more patients remained on tocilizumab monotherapy vs. TNF-inhibitor monotherapy (89.7 vs. 75.8 %; p < 0.01). Monotherapy with bDMARDs is common in routine clinical practice. Tocilizumab monotherapy appeared to be superior over TNF-inhibitor monotherapy with respect to DAS28 and drug adherence.
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Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only a few small studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.
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During pregnancy, steroids are usually used in maternal diseases such as adrenal failure or other autoimmune diseases, e.g. idiopathic thrombocytopenic purpura (ITP), Crohn’s disease, systemic lupus erythematosus, dermatomyositis, scleroderma, Addison’s disease and hyperemesis gravidarum, HELLP syndrome. Endogenous or exogenous maternal steroids are metabolized by the placental enzyme 11 beta-hydroxy steroid dehydrogenase type 2. Prednisolone and methylprednisolone are highly sensitive to this enzyme, while dexamethasone and betamethasone are less well metabolized. Steroids which can cross the placental barrier are administered in cases like fetal lupus, congenital adrenal hyperplasia and for enhancement of fetal lung maturation, whereas steroids used in maternal diseases are usually the ones with low affinity to the placenta; however, in case of long-term use or in high doses, placental enzyme saturation occurs and thus, resulting in fetal adrenal suppression. Antenatal steroids can lead to low birth weight, as observed in our patient. Here, we report a case with fetal adrenal suppression due to maternal methylprednisolone use presenting with early hypoglycaemia and late hyponatremia in neonatal period and requiring three-month replacement therapy. Conflict of interest:None declared.
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To examine the risk of serious infection conveyed by tumour necrosis factor α (TNFα) inhibitors in the treatment of rheumatoid arthritis (RA). Data from patients with RA enrolled in the German biologics register RABBIT were used for analysis. Baseline patient characteristics, time-varying risk factors (treatment changes, functional capacity) and selection processes caused by dropout, death or switching to non-anti-TNF treatment were taken into account to estimate the adjusted incidence rate ratios (IRR(adj)) of serious infection during treatment with TNF inhibitors compared with non-biological disease-modifying antirheumatic drug treatment. Data were available on 5044 patients, in whom 392 serious infections occurred. The crude rates of serious infections in patients treated with TNF inhibitors declined over the first 3 years of observation (from 4.8 to 2.2/100 patient-years). This decline was driven by (1) treatment termination or loss to follow-up in patients at increased risk and (2) a risk reduction through decreasing glucocorticoid doses and improvement in function. Adjusted for selection processes and time-varying risk factors, the following parameters assessed at baseline (age, chronic diseases) or at follow-up prior to the infection were significantly associated with an increased risk: age >60 years, chronic lung or renal disease, low functional capacity, history of serious infections, treatment with glucocorticoids (7.5-14 mg/day, IRR(adj) 2.1 (95% CI 1.4 to 3.2); ≥ 15 mg/day, IRR(adj) 4.7 (95% CI 2.4 to 9.4)) and treatment with TNFα inhibitors (IRR(adj) 1.8 (95% CI 1.2 to 2.7)). Reasons for the decline in infection rates observed at the group level were identified. The results enable expected infection rates to be calculated in individual patients based on their risk profiles.
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Rituximab is a chimeric anti-CD20 monoclonal B cell-depleting antibody indicated for certain hematologic malignancies and active rheumatoid arthritis with inadequate response to tumor necrosis factor antagonists. Despite counseling to avoid pregnancy, women may inadvertently become pregnant during or after rituximab treatment. Using the rituximab global drug safety database, we identified 231 pregnancies associated with maternal rituximab exposure. Maternal indications included lymphoma, autoimmune cytopenias, and other autoimmune diseases. Most cases were confounded by concomitant use of potentially teratogenic medications and severe underlying disease. Of 153 pregnancies with known outcomes, 90 resulted in live births. Twenty-two infants were born prematurely; with one neonatal death at 6 weeks. Eleven neonates had hematologic abnormalities; none had corresponding infections. Four neonatal infections were reported (fever, bronchiolitis, cytomegalovirus hepatitis, and chorioamnionitis). Two congenital malformations were identified: clubfoot in one twin, and cardiac malformation in a singleton birth. One maternal death from pre-existing autoimmune thrombocytopenia occurred. Although few congenital malformations or neonatal infections were seen among exposed neonates, women should continue to be counseled to avoid pregnancy for ≤ 12 months after rituximab exposure; however, inadvertent pregnancy does occasionally occur. Practitioners are encouraged to report complete information to regulatory authorities for all pregnancies with suspected or known exposure to rituximab.
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Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
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The neonatal FcR (FcRn) binds to the Fc domain of IgG at acidic pH in the endosome and protects IgG from degradation, thereby contributing to the long serum half-life of IgG. To date, more than 20 mAb products and 5 Fc-fusion protein products have received marketing authorization approval in the United States, the European Union, or Japan. Many of these therapeutic proteins have the Fc domain of human IgG1; however, the serum half-lives differ in each protein. To elucidate the role of FcRn in the pharmacokinetics of Fc domain-containing therapeutic proteins, we evaluated the affinity of the clinically used human, humanized, chimeric, or mouse mAbs and Fc-fusion proteins to recombinant human FcRn by surface plasmon resonance analysis. The affinities of these therapeutic proteins to FcRn were found to be closely correlated with the serum half-lives reported from clinical studies, suggesting the important role of FcRn in regulating their serum half-lives. The relatively short serum half-life of Fc-fusion proteins was thought to arise from the low affinity to FcRn. The existence of some mAbs having high affinity to FcRn and a short serum half-life, however, suggested the involvement of other critical factor(s) in determining the serum half-life of such Abs. We further investigated the reason for the relatively low affinity of Fc-fusion proteins to FcRn and suggested the possibility that the receptor domain of Fc-fusion protein influences the structural environment of the FcRn binding region but not of the FcgammaRI binding region of the Fc domain.
Article
Crohn's disease is a relapsing, chronic and inflammatory bowel condition that can involve any part of the gastrointestinal tract from mouth to anus. It was first described in 1932 by Burrill Bernhard Cohen and together with ulcerative colitis it is termed as ‘inflammatory bowel disease’. It is characteristically associated with various extra-intestinal manifestations and increases the lifetime risk of colorectal cancer. The primary care team is important in identifying new cases and in the effective community management of established disease.
Article
Background RA is one of the autoimmune disease, often generated in a middle-aged woman and the patient of reproductive age is not few either. We set up the registry of RA patients treated using biologics named Tsurumai Biologics Communication Registry (TBCR) and collected 2072 cases until now. Objectives The evidence of treatment with Disease Modifying Anti Rheumatic Drugs (DMARDs) for the pregnant RA patient is limited. It is very difficult to give what kind of medication for them because of a possibility of the pregnancy. The aim of this study is to investigate how the pregnant patients in TBC registry were treated with biologics. Methods The usage of biological agents including tumor necrosis factor inhibitors and interleukin-6 inhibitors before or during pregnancy and the outcome of pregnancy in patients with rheumatoid arthritis (RA) were investigated using TBCR until December, 2011. Results 30 pregnancies in 26 female patients with RA were identified among 2072 patients during 8-year registry periods (22 with ETN exposure, 2 with INF exposure and 6 with TCZ exposure). Biological agents were prescribed at conception in 19 pregnancies (63.3%) among which etanercept and tocilizumab were used in 15and 4, respectively. Although biological agents were prescribed during pregnancy after conception in no case, oral prednisolone was prescribed more frequently during pregnancy (70.0%) than before planning pregnancy (36.0%). Although 3 premature deliveries and 4 spontaneous abortions occurred, no anomalies of infants were observed. Conclusions In this study, we reported how the biologic agents used in young female RA patients and how many pregnancies were occurred in TBC registry. It is difficult to do clinical research about safety of drug for the pregnancy. Although the usage of biological agents, especially etanercept, is one of the choices in the strategy of pregnancy in patients with active RA, firm conclusion on safety of etanercept use during pregnancy is difficult to describe from the results of this retrospective study without control. More information on association between biological agents and pregnancy in RA patients should be collected in the future. Disclosure of Interest None Declared
Conference Paper
Background Certolizumab pegol (CZP) is a PEGylated, Fc-free anti-TNF approved in several countries for the treatment of rheumatoid arthritis (RA) and Crohn’s disease (CD). Pre-clinical and clinical data suggest a lack of active neonatal Fc receptor-dependent placental transfer of CZP.1,2 Objectives To provide additional information on the primary pregnancy outcomes for women exposed to CZP through a retrospective safety database analysis. Methods The UCB Pharma global safety database was searched for all medically confirmed cases of pregnancy, including both clinical trial and post-marketing reports, through March 6, 2012. The proportion of live births, miscarriages and elective terminations for women directly exposed to CZP (maternal exposure) before and during pregnancy was examined. Exposure to concomitant medications (pooled across indications) and disease activity prior to conception was reviewed for pregnancies that occurred in clinical trial subjects (N=57). Results Of 294 reported pregnancies, 152 had known outcomes; of which 139 occurred following maternal exposure to CZP. For these pregnancies, the underlying conditions for the pregnant mothers were CD (109/139), RA (17/139) and healthy subjects (2/139); indication was unknown/unavailable for the remaining pregnancies. 91/139 (66%) pregnancies were from the US. 103/139 (74%) pregnancies resulted in live births and the median gestational age was 38 weeks (data available for 40 births). 21/139 (15%) pregnancies ended in miscarriage and 15/139 (11%) women had an elective termination. In the 103 live births there were 2 (1.4%) cases of congenital disorder (US general population rate is 3%3). A single neonatal death was reported, however medical review showed no evidence of correlation with CZP exposure. Where data was available from clinical trial subjects, corticosteroids (7/29 live births, 2/10 miscarriages, 3/13 elective terminations) and methotrexate (2/29 live births, 2/10 miscarriages, 1/13 elective terminations) were the most common relevant concomitant medications reported during pregnancy. However, exposure to concomitant medication was either brief (<3 weeks) or unknown (medication end date unknown) therefore conclusions are limited. Most clinical trial subjects had low to moderate disease activity at conception (median CDAI 184.9 for 22 CD subjects, DAS28(ESR) range 1.1-6.1 for 7 RA subjects); however, as subjects exited clinical trial at conception further data are unavailable. Miscarriages were not associated with high disease activity at conception. Conclusions regarding concomitant medications and disease activity are limited due to low numbers. Conclusions Currently available data from pregnant women exposed to CZP reported outcomes similar to what is expected in the general population (US General Population4: 64% live births, 17% miscarriages and 19% elective terminations; data from 6,390,000 pregnancies). However, additional data from large numbers of pregnant women exposed to CZP are required to fully evaluate the safety and tolerability of CZP in pregnancy. References Acknowledgements The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma. Disclosure of Interest M. Clowse Consultant for: UCB Pharma, D. Wolf Grant/research support from: Abbott, BMS, Genetech, GIVEN Imaging, Janssen, Millennium, Prometheus, UCB Pharma, Consultant for: Abbott, Genetech, GIVEN Imaging, Janssen, Millennium, Prometheus, Salix, UCB Pharma, Speakers bureau: Abbott, Janssen, Prometheus, Salix, UCB Pharma, Warner Chilcott, F. Förger Consultant for: Roche, UCB Pharma, Speakers bureau: Roche, UCB Pharma, C. Stach Shareholder of: UCB Pharma, Employee of: UCB Pharma, G. Kosutic Shareholder of: UCB Pharma, Employee of: UCB Pharma, S. Williams Shareholder of: UCB Pharma, Employee of: UCB Pharma, I. Terpstra Employee of: UCB Pharma, U. Mahadevan Grant/research support from: Prometheus, Millenium, GSK, Consultant for: Abbott, Janssen, Elan, Genetech, Shire, UCB Pharma
Article
Biologic therapies have revolutionized treatment outcomes for patients with inflammatory arthritis. However, there remains a concern regarding their safety during conception, pregnancy and breastfeeding. Data on the safety of these treatments are largely limited to uncontrolled case reports. Collective evidence from many hundreds of pregnancies in inflammatory arthritis and IBD have suggested that exposure to anti-TNF therapies at the time of conception or during the first trimester does not result in an increased risk of adverse pregnancy and fetal outcomes. Monoclonal antibodies, and to a lesser extent recombinant fusion proteins, do cross the placenta during the second and third trimester and are functional in the fetus, as evidence by lymphopaenia reported at birth in children exposed to rituximab in utero. In addition, live vaccines should be avoided in children with in utero exposure to biologics for at least the first 6 months of life. The longer-term effects of in utero exposure remain unknown. Studies suggest that many of these drugs do enter breast milk in small amounts, but the extent to which they are absorbed by the infant is less clear. Limited reports have not suggested adverse pregnancy outcomes in women whose partners were exposed to anti-TNF therapies or rituximab at the time of conception. Data on other biologic therapies, including anakinra, abatacept and tocilizumab, in both men and women remain extremely limited.
Article
Pregnant women suffering from autoimmune disease use glucocorticoids. Glucocorticoids can partly diffuse to the fetus, and may influence the development of the fetal hypothalamic-pituitary-adrenal axis, especially in early stage of pregnancy. The objective was to investigate whether prednisone-exposure in utero influences the cortisol levels of the prepubertal children. Mothers participated in a prospective cohort study on rheumatoid arthritis (RA) and pregnancy. Children were exposed (n=44) or non-exposed (n=65) to prednisone in utero. Salivary cortisol levels were taken from all children during one day: at awakening, 30 minutes after awakening, 1pm and, bedtime. Cortisol levels between groups were also analyzed using area under the curve (AUC), cortisol awakening response (CAR), and slope. The mean age (SD) of the children was 6.98 (1.23). The difference in mean (SD) cortisol level at '1pm' was 5.42 nmol/L (4.08) in the prednisone-exposed and 3.97 nmol/L (4.00) in the non-exposed (p=0.03). Prednisone-exposed children had a higher AUC (β=13.28; p=0.02), even after correction for RA disease activity. No differences were found on CAR, slope or blood pressure. The cortisol levels of the non-exposed were more similar to the age-specific references than the prednisone-exposed. Prednisone use during pregnancy is associated with a higher daytime cortisol level, in the prepubertal offspring, not yet accompanied with clinical outcomes. This conclusion will have no consequences at this moment, but is does raise questions concerning prednisone-exposure in utero and the long-term consequences for the offspring, This article is protected by copyright. All rights reserved.
Article
In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.
Article
To evaluate pregnancy safety of anti-TNF-α medications. Prospective, comparative, observational study done at the Israeli Teratology Information Service between 2002 and 2011. 83 anti-TNF-α-exposed-pregnancies (97.6% in the first trimester, T1) were followed-up and compared with 86 disease-matched (DM) and 341 non-teratogenic-exposed (NTE) pregnancies. The anti-TNF-α group consisted of 35 infliximab-, 25 etanercept-, and 23 adalimumab-exposed pregnancies. The rate of major congenital anomalies did not significantly differ between the three groups [3/65 (4.6%) (anti-TNF-α, T1), 5/79 (6.3%) (DM), 8/336 (2.4%) (NTE)], even after excluding genetic or cytogenetic anomalies [3/65 (4.6%) (anti-TNF-α, T1), 4/79 (5.1%) (DM), 6/336 (1.8%) (NTE)]. There were no cases of VATER/VACTERL association. The present study suggests that anti-TNF-α treatment does not pose a major teratogenic risk in humans. This conclusion is based on relatively small numbers of exposed pregnancies and should be interpreted with caution. Larger studies are needed to establish anti-TNF-α pregnancy safety.
Article
Psoriasis is a systemic disease that affects approximately 2% of the US population. Traditional treatment modalities include phototherapy, topical therapy, methotrexate, cyclosporine, and retinoids. Three tumor necrosis factor (TNF) inhibitors have been approved by the US Food and Drug Administration for the treatment of plaque psoriasis: etanercept, infliximab, and adalimumab. The combination of TNF inhibitors with phototherapy and topical and systemic agents may be effective in treating patients who are recalcitrant to monotherapy. We examine clinical trials that evaluated the efficacy and safety of combination treatments with TNF inhibitors. This review elucidates that combination therapy is both effective and well tolerated among patients with refractory psoriasis. Furthermore, combination therapy may allow for reduction of required treatment doses, thereby decreasing the potential for toxicity. It is important to note, however, that the studies reviewed here are limited in the long-term follow-up of patients. We conclude that dermatologists can safely and effectively incorporate combination therapy with TNF inhibitors in the treatment of patients with recalcitrant psoriasis.
Article
Infection is one of the leading causes of morbidity and mortality in systemic lupus erythematosus (SLE). Bacterial infections are most frequent, followed by viral and fungal infections. The impaired cellular and humoral immune functions seen in patients with SLE are predisposing conditions, whilst disease activity, prednisone doses over 7.5-10 mg/day, high doses of methylprednisolone or cyclophosphamide are well-recognised risk factors for infection. The first six months after rituximab treatment and the use of more than three courses are also associated with an increased susceptibility for infection. It has not been established whether belimumab, azathioprine and mycophenolate mofetil increase the risk of serious infections. Most vaccines are effective and safe in SLE patients, although vaccination should be avoided during periods of active disease. Live virus vaccines are contraindicated for immunosuppressed patients. Influenza and pneumococcal vaccines are universally recommended. Tuberculosis prophylaxis should be considered in selected cases. Therefore, it is advisable not to exceed doses of 5 mg/day of prednisone in chronic treatment. Methylprednisolone and cyclophosphamide should be used in low-dose regimens. Antimalarials have a well-known protective role against infection, in addition to other beneficial properties, thus, hydroxychloroquine is recommended for all SLE patients where no contraindication exists.
Article
Infectious eccrine hidradenitis (IEH), which usually manifests as singular or multiple erythematous papules or plaques, is a rare dermatosis involving an infectious agent and histologic findings identical to that of neutrophilic eccrine hidradenitis (NEH). We report a case of IEH in a 24-year-old woman who developed a pruritic, erythematous, papular rash after a sunburn. A culture of a pustule revealed methicillin-sensitive Staphylococcus aureus. Our patient had complete resolution of her rash within 2 weeks of starting amoxicillin and clavulanate. This case of IEH and NEH related to both intense sun exposure and infection supports the hypothesis that NEH is a response to nonspecific stimuli and may occur in many different clinical settings.
Article
Rheumatoid arthritis (RA) is a chronic inflammatory immune-mediated systemic disease which primarily affects the joints. Leflunomide (LFN) is a disease modifying anti-rheumatic drugs (DMARDs) which acts by inhibiting the synthesis of pyrimidines. Several trials have demonstrated the efficacy and safety of LFN alone or in combination with biological agents such as tumor necrosis factor-α (TNF-α) inhibitors in the treatment of RA patients. TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of RA. TNF-α inhibitors have demonstrated efficacy as monotherapy or in combination with other anti-inflammatory or DMARDs in the treatment of RA. Five TNF-α inhibitors are available for clinical use and include infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. In this editorial, we briefly discuss the efficacy and safety of LFN and TNF-α inhibitors in the treatment of RA, and the potential beneficial effect of both LFN and TNF-α inhibitors in improving the endothelial dysfunction and in reducing the risk of acute cardiovascular and/or cerebrovascular events.
Article
Objective: To study the pregnancy outcome following Rituximab treatment before conception in patients with refractory autoimmune rheumatic diseases. Methodology: Five women with systemic lupus erythematosus (SLE) and 1 woman with ANCA positive vasculitis fulfilling the respective ACR classification criteria were studied retrospectively when they became pregnant following rituximab treatment for refractory disease. Rituximab was given as a 1 g infusion together with 500 mg Methylprednisolone, on day 1 and day 15 after written informed consent. Results: The median age was 34 (range 32-39) years and median disease duration was 10 (range 5-16) years. All the patients achieved complete B-cell depletion < 1 cell/μL at 1 month and <5 cells/μL at 6 months with prolonged B-cell depletion. Four women had successful pregnancies with median gestational age of 38 (range 31-40) weeks; median weight of the new born was 3.25 (range1.17-3.3) kg with no documented adverse neonatal events. One patient with lupus nephritis (LN) had a premature delivery and increasing proteinuria in the third trimester. One other patient with LN had a premature delivery and the new born had oesophageal atresia. Conclusion: We report a child with oesophageal atresia born to a mother with lupus nephritis who had received Rituximab 12 months prior to conception, while four other pregnancies in women with SLE resulted in morphologically normal children. We also describe the first report, to our knowledge, of a successful pregnancy outcome in a woman with granulomatosis with polyangiitis treated with rituximab.
Article
Rheumatic diseases may be active during pregnancy necessitating drug treatment in order to control maternal disease activity and ensure a successful pregnancy outcome. The present literature survey of the last 2 years does not profoundly change the recommendations given in recent reviews: the teratogenic drugs cyclophosphamide, methotrexate, mycophenolate mofetil, and biologics without or with few pregnancy data must be withdrawn before a planned pregnancy. Leflunomide has up to date not shown to be a human teratogen. Drugs that can be used throughout pregnancy include corticosteroids, sulfasalazine, antimalarials, cyclosporine, tacrolimus and azathioprine. Among biological drugs extended pregnancy experience exists only for TNF-inhibitors. The effect of immunosuppressive drugs and biologics on male reproductive function is only partly known.
Article
Fetal growth restriction (FGR) is a serious pregnancy complication, resulting in significant perinatal morbidity and mortality. Increased vascular resistance in the fetoplacental circulation is a hallmark of FGR and is associated with enhanced vasoconstriction of the resistance arteries in the placenta, the chorionic plate arteries (CPAs). Although the cause is unknown, FGR is associated with excess exposure to glucocorticoids (GCs), key mediators of vascular resistance in the systemic circulation. We hypothesized that GCs alter CPA reactivity, thereby contributing to the altered blood flow dynamics seen in FGR. We aimed to examine the acute and chronic effects of GCs on CPA reactivity and the operational mechanisms. Glucocorticoid receptors were highly expressed by CPA. 11β-Hydroxysteroid isoenzyme type 2 was detected within the endothelium, whereas 11β-hydroxysteroid isoenzyme type 1 was absent. Acute GC treatment significantly attenuated U46619-induced constriction. This effect was reversed by cotreatment with mifepristone or an endothelial NOS inhibitor. In contrast, chronic GC treatment potentiated U46619 constriction in a dose-dependent manner, which was partially abolished by mifepristone cotreatment. Similar effects were observed using a novel nonsteroidal glucocorticoid receptor-specific agonist. Chronic treatment with GCs altered the expression of several vasoactive factors, including thromboxane and bradykinin receptors, prokineticin-1, cyclooxygenase-2, and endothelial NOS. In summary, acute and chronic GC treatment exerts contrasting effects on CPA vasoreactivity. These opposing effects are consistent with temporal actions in other vascular beds and reflect activation of distinct nongenomic and genomic pathways. Chronic exposure to elevated GCs may contribute to the raised vascular resistance observed in the fetoplacental circulation in FGR.
Article
BACKGROUND & AIMS: We assessed the course of inflammatory bowel disease (IBD) among pregnant women who stopped taking anti-tumor necrosis factor (TNF) agents. We also analyzed levels of anti-TNF agents in cord blood samples. METHODS: We followed 31 pregnancies in 28 women with IBD, between April 2006 and April 2011, who were treated with anti-TNF agents (18 received infliximab, 13 received adalimumab) during pregnancy. We used ELISAs to measure levels of anti-TNF agents in cord blood collected from 18 newborns (12 whose mothers took infliximab and 6 whose mothers took adalimumab). RESULTS: Among the patients taking infliximab, 12 (71%) discontinued treatment before gestational week 30; all patients remained in remission. All the patients taking adalimumab discontinued treatment before gestational week 30; 2 patients had relapses of IBD. There were 28 live births, 1 miscarriage among patients taking infliximab (at gestational week 6), and 2 miscarriages among patients taking adalimumab (at weeks 6 and 8); there were no congenital malformations. The mean cord blood level of infliximab was 6.4±1.6 μg/mL; it was significantly lower among women who received the drug 10 weeks or less before delivery (2.8±1.1 μg/mL) than those who received infliximab closer to delivery (10±2.3 μg/mL; P=.02). Adalimumab was detected in 5 samples of cord blood (mean concentration, 1.7±0.4 μg/ml); 1 cord blood sample, from a woman who discontinued the treatment at gestational week 22, had an undetectable level of the drug. CONCLUSION: Discontinuation of anti-TNF therapy appears to be safe for pregnant women with quiescent IBD. However, these drugs are still detected in cord blood samples.
Article
The efficacy of influenza vaccination in patients treated with rituximab is a clinically important question. Rheumatology clinics are populated with patients receiving rituximab for a broad array of disorders. Although several studies have explored the efficacy of other vaccines in rituximab-treated populations, results have been conflicting. We wished to define influenza vaccine efficacy in a rituximab-treated cohort. We examined 17 evaluable subjects treated with rituximab for rheumatologic conditions. T cell subsets, B cells subsets, T cell function, and B cell function were evaluated at specific time points along with hemagglutinination inhibition titers after receiving the standard inactivated influenza vaccine. T cell subset counts were significantly different than controls but did not change with rituximab. B cells depleted in all patients but were in various stages of recovery at the time of vaccination. Influenza vaccine responsiveness was poor overall, with only 16 % of subjects having a four-fold increase in titer. Pre-existing titers were retained throughout the study, however. The ability to respond to the influenza vaccine appeared to be related to the degree of B cell recovery at the time of vaccination. This study emphasizes that antibody responses to vaccine are impaired in subjects treated with rituximab and supports the concept that B cell recovery influences influenza vaccine responsiveness.
Article
Corticosteroids are commonly used to treat inflammatory diseases. There is conflicting evidence regarding the association of corticosteroid use in pregnancy and congenital malformations in offspring. We conducted a prevalence study of 83,043 primiparous women who gave birth to a live-born singleton in northern Denmark, in 1999-2009. Through medical registries, we identified prescriptions for corticosteroids, congenital malformations, and covariates. Furthermore, we summarized the literature on this topic. Overall, 1449 women (1.7%) used inhaled or oral corticosteroids from 30 days before conception throughout the first trimester. Oral cleft in the offspring was recorded for 1 of the users (0.08%) and 145 of the nonusers (0.2%), prevalence odds ratio (OR) 0.47 [95% confidence interval (CI), 0.07-3.34]. The prevalence OR for congenital malformations overall was 1.02 (95% CI, 0.79-1.32). According to published studies, the use of corticosteroids in early pregnancy was associated with congenital malformations overall with relative estimates ranging from 0.8 (95% CI, 0.4-1.7) to 2.1 (95% CI, 0.5-9.6). For oral clefts, the ORs ranged from 0.6 (95% CI, 0.2-1.7) to 5.2 (95% CI, 1.5-17.1). We found no evidence of an association between use of corticosteroids in early pregnancy and risk of congenital malformations in offspring.
Article
Background Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age. Information regarding human pregnancy outcome with corticosteroids is limited.Methods We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure. The primary outcome was the rate of major birth defects. A meta-analysis of all epidemiological studies was conducted. The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals. A cumulative summary odds ratio was also calculated by combining studies in chronological order. Chi-squared for homogeneity was determined to establish the comparability of the studies.ResultsIn our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups. In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI 0.80, 2.60] and 3.03 [95% CI 1.08, 8.54] when Heinonen et al. ('77) was removed. This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids. In addition, summary odds ratio for case-control studies examining oral clefts was significant (3.35 [95% CI 1.97, 5.69]).Conclusions Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft, which is consistent with the existing animal studies. Teratology 62:385–392, 2000. © 2000 Wiley-Liss, Inc.
Article
Background: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy. Methods: This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti-TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women. Results: Thirty-two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37-39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti-TNF treatment were not different from those in pregnancies before anti-TNF treatment or with indirect exposure to anti-TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis. Conclusions: Direct exposure to anti-TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall.
Article
Adult onset Still's disease (AOSD) is an uncommon, systemic, inflammatory disorder of unknown etiology, characterised by spiking fevers, skin rash, and arthritis. Treatment consists of glucocorticosteroids and immunosuppressive drugs. Over the last few years it has become increasingly evident that treatment with the IL-1 receptor antagonist (IL-1RA) anakinra is highly effective even in patients with intractable disease. So far, there are scant data available on the effects of anakinra in pregnancy. We report two patients with AOSD who successfully gave birth while treated with anakinra during pregnancy.