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PURPOSE OF REVIEW: To discuss the current understanding regarding the use of biologic therapeutics in pregnancy. RECENT FINDINGS: Our understanding of the mechanisms underlying the potential fetal and infant exposure to biologics as well as a growing body of empirical evidence from real world use of biologics in pregnancy have demonstrated that biologics are generally compatible preconception and during pregnancy. Long-term effects of exposure to biologic agents in utero are not known, but will be uncovered in time. Biosimilars, which are becoming more popular, may not always share the same safety profiles as their originators. SUMMARY: Biologics have revolutionized the management of rheumatologic disease and ushered in a new era of clinical remission among patients. These agents, developed and introduced into clinical use at the beginning of the new millennium, are very potent, yet their efficacy in treating disease often in reproductive aged women, raises questions regarding their safety during pregnancy. These therapeutics can cause immunosuppression and can inhibit immunologic circuits that are not only involved in disease pathophysiology but hypothetically could impact the development of the fetal immune system. Reassuringly, biologics, typically antibodies or antibody-based proteins, are introduced to the fetus via the typical route of transplacental antibody transfer, and thus only begin to be transferred in appreciable amounts in the second trimester (after organogenesis). From theoretic and empirical standpoints, biologic use during pregnancy appears well tolerated for fetal development and to not substantially affect infant immune development.
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Antirreumáticos , Produtos Biológicos , Medicamentos Biossimilares , Doenças Reumáticas , Adulto , Feminino , Humanos , Gravidez , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/induzido quimicamenteRESUMO
PURPOSE OF REVIEW: This article will review the current understanding of the immunologic changes that occur during pregnancy. It will discuss the impact of pregnancy on the disease activity of autoimmune or inflammatory rheumatic diseases (AIRD). Lastly, it will highlight the most recent data on pre-conception and pregnancy management practices that can improve pregnancy outcomes in autoimmune patients. RECENT FINDINGS: Pregnancy is an immunologically complex and dynamic state that may affect the activity of AIRDs, with more patients having active disease during pregnancy than previously thought. Uncontrolled inflammatory diseases are associated with poor pregnancy outcomes such as preeclampsia, small for gestational age infants, and prematurity. Pre-conception counseling and early pregnancy planning discussions can help ensure optimal disease control and medication management prior to attempting conception. Adequate control of AIRDs on pregnancy-compatible medications during the pre-conception, pregnancy, and postpartum periods is required for optimal pregnancy outcomes.
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Doenças Autoimunes , Complicações na Gravidez , Resultado da Gravidez , Humanos , Gravidez , Feminino , Complicações na Gravidez/imunologia , Complicações na Gravidez/terapia , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Doenças Reumáticas/imunologia , Doenças Reumáticas/terapia , Doenças Reumáticas/tratamento farmacológicoRESUMO
The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antibodies directed against phospholipids and phospholipid-binding proteins that are associated with thrombosis and pregnancy-related morbidity. The latter includes fetal deaths, premature birth and maternal complications. In the early 1990s, a distinct set of autoantibodies, termed collectively antiphospholipid antibodies (aPL), were identified as the causative agents of this disorder. Subsequently histological analyses of the placenta from APS pregnancies revealed various abnormalities, including inflammation at maternal-fetal interface and poor placentation manifested by reduced trophoblast invasion and limited uterine spiral artery remodeling. Further preclinical investigations identified the molecular targets of aPL and the downstream intracellular pathways of key placental cell types. While these discoveries suggest potential therapeutics for this disorder, definitive clinical trials have not been completed. This concise review focuses on the recent developments in the field of basic and translational research pursuing novel mechanisms underlying obstetric APS.
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PURPOSE OF REVIEW: Immune check point inhibitors (ICIs) are a unique class of cancer treatments that harness the body's innate antitumor response. Although these medications have transformed oncology care, they also lead to generalized immune activation that can result in toxicities across a spectrum of organ systems called immune-related adverse events. This article reviews the most common rheumatologic immune-related adverse events and their management. RECENT FINDINGS: Inflammatory arthritis, polymyalgia rheumatic, sicca symptoms, systemic sclerosis, myositis, and vasculitis have all been reported as ICI adverse events. Treatment includes nonsteroidal anti-inflammatory drugs, glucocorticoids, traditional DMARDs, and biologics. SUMMARY: Rheumatologists have an important role in the management of patients with rheumatologic immune-related adverse events. Working with our oncology colleagues, we can help manage rheumatologic immune-related adverse events while optimally preserving ICI's antitumor effects.
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Antirreumáticos , Artrite Reumatoide , Miosite , Neoplasias , Vasculite , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Miosite/induzido quimicamente , Miosite/tratamento farmacológico , Antirreumáticos/efeitos adversos , Vasculite/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Neoplasias/tratamento farmacológicoRESUMO
Immune-related adverse events induced by immune checkpoint inhibitor (ICI) therapy may affect diverse organ systems, including skeletal and cardiac muscle. ICI-associated myositis may result in substantial morbidity and occasional mortality. We present a case of a patient with advanced non-small cell lung cancer who developed grade 4 myositis with concurrent myocarditis early after initiation of anti-programmed death ligand 1 therapy (durvalumab). Autoantibody analysis revealed marked increases in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody levels that preceded clinical toxicity, and further increased during toxicity. Notably, the patient had a history of intolerable statin myopathy, which had resolved clinically after statin discontinuation and prior to ICI initiation. This case demonstrates a potential association between statin exposure, autoantibodies, and ICI-associated myositis.
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Carcinoma Pulmonar de Células não Pequenas , Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias Pulmonares , Miosite , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Checkpoint Imunológico , Miosite/induzido quimicamente , Miosite/tratamento farmacológicoRESUMO
Immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAEs) may affect almost any organ system and occur at any point during therapy. Autoantibody analysis may provide insight into the mechanism, nature, and timing of these events. We report a case of ICI-induced late-onset Raynaud's-like phenomenon in a patient receiving combination immunotherapy. A 53-year-old woman with advanced non-small lung cancer received combination anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed death 1 ICI therapy. She developed early (hypophysitis at 4 months) and late (Raynaud's at >20 months) irAEs. Longitudinal assessment of 124 autoantibodies was correlated with toxicity. Although autoantibody levels were generally stable for the first 18 months of therapy, shortly before the development of Raynaud's, a marked increase in multiple autoantibodies was observed. This case highlights the potential for delayed autoimmune toxicities and provides potential biologic insights into the dynamic nature of these events. KEY POINTS: A patient treated with dual anti-PD1 and anti-CTLA4 therapy developed Raynaud's-like signs and symptoms more than 18 months after starting therapy. In this case, autoantibody changes became apparent shortly before onset of clinical toxicity. This case highlights the potential for late-onset immune-related adverse events checkpoint inhibitors, requiring continuous clinical vigilance. The optimal duration of checkpoint inhibitor therapy in patients with profound and prolonged responses remains unclear.
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Imunoterapia , Neoplasias Pulmonares , Autoanticorpos , Feminino , Humanos , Fatores Imunológicos , Imunoterapia/efeitos adversos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The coexistence of inflammatory myositis in systemic lupus erythematosus (SLE) has not been extensively studied. In this study, we describe the incidence, distinct types of inflammatory myositis, and risk factors for this finding in a cohort of pediatric and adult SLE patients. METHODS: We identified SLE patients with coexisting myositis followed between 2010 and 2019 at two pediatric hospitals and one adult hospital. Demographic, clinical, laboratory, and pathological features of myositis were collected, and descriptive statistics were applied. RESULTS: A total of 1718 individuals were identified as having SLE (451 pediatric and 1267 adult patients). Of these, 108 were also diagnosed with inflammatory myositis (6.3%). People of black race had a significantly higher prevalence of inflammatory myositis, as did those with childhood-onset SLE compared to adult-onset disease. In the majority of patients (68%), SLE and inflammatory myositis presented concurrently. Overlapping features of systemic sclerosis occurred in 48%, while dermatomyositis-specific rashes were present in a third. Arthralgias and inflammatory arthritis were seen in >90%. Thrombotic events and significant pregnancy-related morbidity were present in more than a third of patients. Lymphopenia, hypocomplementemia, and a positive RNP were the most common laboratory features noted. Myositis-specific antibodies (MSA) and myositis-associated antibodies (MAA) were present in >40% of patients. A review of 28 muscle biopsy reports revealed a wide array of pathological features, including nonspecific changes, dermatomyositis, polymyositis, and necrotizing auto-immune myopathy. CONCLUSION: In our SLE patient population, 6.3% presented with concurrent inflammatory myositis. Dermatomyositis-specific rashes, clinical features of systemic sclerosis, arthralgias and arthritis, and cytopenias were common coexisting clinical manifestations. A high frequency of RNP, MSA, and MAA were found. People of black race and with childhood-onset disease had a higher prevalence of myositis. Our findings suggest that SLE patients of black race, with childhood-onset SLE, and who possess MSA or MAA should be routinely screened for myositis.
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Artrite Reumatoide/complicações , Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/complicações , Miosite/complicações , Escleroderma Sistêmico/complicações , Adolescente , Adulto , Negro ou Afro-Americano , Fatores Etários , Artrite Reumatoide/imunologia , Criança , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Miosite/imunologia , Miosite/patologia , Estudos Retrospectivos , Escleroderma Sistêmico/imunologia , Estados Unidos , Adulto JovemRESUMO
After several decades of deliberation, the US Food and Drug Administration updated the Pregnancy and Lactation Labeling Rule in 2015, eliminating the prior A, B, C, D, X grading system for medication use in pregnancy. Although physicians and patients liked the relative ease of use of this system, it was often misconstrued and not updated to include new data suggesting greater compatibility of medications with pregnancy. The new label is designed to include more clinically relevant data, including data from human studies and registries, and fewer animal data. A key goal of the new label is to assist physicians and patients as they weigh the risks and benefits of medications vs the risks of pregnancy in a woman with a chronic, untreated illness. As such, each label now includes a section outlining the pregnancy risks of the diseases that the medication treats. This review includes a historical perspective on the label change and a guide to the interpretation of the new label. It also includes an assessment of the baseline risk of pregnancy in women with SLE and RA, to help balance the consideration of medication risks and benefits in pregnancy.
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Rotulagem de Medicamentos/legislação & jurisprudência , Exposição Materna/legislação & jurisprudência , Complicações na Gravidez/tratamento farmacológico , Doenças Reumáticas/tratamento farmacológico , United States Food and Drug Administration/legislação & jurisprudência , Antirreumáticos/efeitos adversos , Rotulagem de Medicamentos/métodos , Feminino , Humanos , Gravidez , Medição de Risco/legislação & jurisprudência , Medição de Risco/métodos , Estados UnidosAssuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Miocardite/etiologia , Abatacepte/efeitos adversos , Abatacepte/uso terapêutico , Prática Clínica Baseada em Evidências , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Miocardite/metabolismo , Miocardite/terapia , Neoplasias/tratamento farmacológico , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Índice de Gravidade de Doença , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismoRESUMO
PURPOSE OF REVIEW: To review the recent literature on the safety of nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and traditional disease-modifying antirheumatic drugs before and during pregnancy. RECENT FINDINGS: Recent data suggest that the risk of cleft palate formation after in-utero glucocorticoid exposure is lower than previously reported. Two studies of inadvertent leflunomide exposure during early pregnancy suggest that this medication may be less teratogenic than previously thought. SUMMARY: Although NSAIDs are well tolerated for use during the first two trimesters of pregnancy, they should be avoided during a conception cycle so as not to impede implantation. After gestational week 30, these medications should be discontinued as they may cause premature closure of the ductus arteriosus. The nonfluorinated glucocorticoids, prednisone and prednisolone, can be used throughout pregnancy, although use during the first trimester may increase the risk of cleft palate formation. Protracted glucocorticoids exposure during pregnancy can cause maternal preterm premature rupture of the membranes, gestational hypertension and gestational diabetes. Methotrexate and leflunomide are teratogenic and should be avoided during pregnancy. The immunosuppressive agents, azathioprine, 6-mercaptopurine and cyclosporine A, are compatible with pregnancy.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/uso terapêutico , Complicações na Gravidez/tratamento farmacológico , Anti-Inflamatórios não Esteroides/efeitos adversos , Antirreumáticos/efeitos adversos , Feminino , Fertilidade/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Humanos , Troca Materno-Fetal , Cuidado Pré-Concepcional/métodos , Gravidez , Efeitos Tardios da Exposição Pré-NatalRESUMO
PURPOSE OF REVIEW: In contrast to the disease remission enjoyed by a majority of rheumatoid arthritis (RA) patients during pregnancy, the immediate postpartum period is generally characterized by flare. Managing symptoms during this time is challenging because the potential transfer of medication into the breast milk of nursing mothers may limit which antirheumatic drugs can be safely used. The benefits of breastfeeding are significant, however, so an understanding of how to adjust medications to permit lactation and nursing is important for rheumatologists. RECENT FINDINGS: Although nonsteroidal antiinflammatory drugs (NSAIDs) in general are passed into milk in low doses, shorter acting NSAIDs are preferred, with caution for premature infants. Prednisone can be taken by nursing mothers, although when used at doses higher than 20âmg/day an interval of 4âh after dosing and prior to breastfeeding is recommended. Hydroxychloroquine and sulfasalazine are compatible with nursing. Cyclosporine is generally allowed in lactating women, although a single infant was reported to develop therapeutic drug levels. Azathioprine (AZA) and tissue necrosis factor-α-inhibitors have little to no transfer into breast milk, with negligible levels measured in infant sera, and thus may be considered for use in lactating mothers. Methotrexate and leflunomide should not be used. Other biological RA medications have not been evaluated, and are, therefore, best avoided by breastfeeding patients. SUMMARY: Many but not all RA medications may be used during lactation with low risk to the nursing infant; this review summarizes the available data for commonly used medications in order to help guide therapy during the postpartum period.
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Anti-Inflamatórios não Esteroides/farmacocinética , Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Lactação/efeitos dos fármacos , Leite Humano/metabolismo , Transtornos Puerperais/tratamento farmacológico , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/metabolismo , Aleitamento Materno , Feminino , Humanos , Transtornos Puerperais/metabolismo , Medição de Risco/métodosRESUMO
Systemic lupus erythematosus (SLE), a multiorgan systemic inflammatory disorder, predominantly affects women during their reproductive years. In this review, we summarize the state of knowledge about preconception planning and management of SLE during pregnancy. Achieving remission or low disease activity for several months on medications compatible with pregnancy prior to conception is essential to decreasing the risk of disease flare and improving pregnancy outcomes, including pre-eclampsia, preterm birth, and intrauterine growth restriction. With close management and well-controlled disease before and during pregnancy, <10% of patients flare. All patients with SLE should remain on hydroxychloroquine unless contraindicated. Expectant mothers with a history of antiphospholipid syndrome should be treated with anticoagulant therapy during pregnancy. Women with anti-Ro/SSA or anti-La/SSB antibodies require additional monitoring because their offspring are at increased risk for congenital heart block. Patients with SLE should be offered low-dose aspirin starting at the end of the first trimester to reduce the risk of pre-eclampsia. Flares of SLE during pregnancy require escalation of therapy. The immunosuppressives azathioprine, tacrolimus, and cyclosporine are compatible with pregnancy, and biologic agents can also be considered. Glucocorticoid use in pregnancy should be limited to the lowest effective dose. Mycophenolate mofetil/mycophenolic acid, methotrexate, leflunomide, and cyclophosphamide are known to be teratogenic and are contraindicated in pregnancy. Distinguishing a flare of lupus nephritis during pregnancy from pre-eclampsia can be particularly challenging. Overall, outcomes in pregnancy for women with lupus are improving, but gaps in knowledge about optimal management strategies persist.
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Lúpus Eritematoso Sistêmico , Pré-Eclâmpsia , Complicações na Gravidez , Nascimento Prematuro , Gravidez , Humanos , Recém-Nascido , Feminino , Resultado da Gravidez , Anticorpos AntinuclearesRESUMO
Immune checkpoint inhibitors (ICIs) have revolutionized oncology treatment. However, their success is mitigated by the recognition that ICI-induced immune-related adverse events (irAEs) pose considerable challenges to patients and clinicians. These autoimmune toxicities are heterogeneous, unpredictable, and reflect a disease state resulting from a change in the immune system of patients. This contrasts with the typical acute nature of toxicities from chemotherapy and molecularly targeted oncology therapies. Management is further complicated by the extended bioavailability of these agents in patients as well as the persistence of autoimmune pathology. Currently, irAE treatment remains suboptimal in many areas, as many expert guidelines remain vague on the optimal selection, dosing, and duration of steroids and the use of other immunosuppressive agents. This coupled with delays in diagnosis and difficulties for patients accessing effective irAE treatment results in barriers to effective irAE care. The latter is complicated by the lack of US Food and Drug Administration-approved irAE treatments that lead to insurance denials, as well as the high cost of biological immunosuppressant therapies. Fortunately, rheumatologists and other subspecialists with expertize in the management of chronic autoimmune conditions have become more involved in irAE diagnosis and management and may help navigate treatment. In this commentary, we discuss these issues and propose potential solutions to advance the field.
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Inibidores de Checkpoint Imunológico , Humanos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/imunologiaRESUMO
Women of childbearing age are at risk for developing systemic rheumatic diseases. Pregnancy can be challenging to manage in patients with rheumatic diseases for a variety of reasons including the impact of physiological and immunological changes of pregnancy on underlying disease activity, the varied presentation of rheumatic disease during pregnancy, and the limited treatment options. Previously, patients with rheumatic disease were often advised against pregnancy due to concerns of increased maternal and fetal morbidity and mortality. However, recent advancements in the understanding of the interaction between pregnancy and rheumatic disease have changed how we counsel patients. Patients with rheumatic disease can have successful pregnancy outcomes, particularly when a collaborative approach between the rheumatologist and obstetrician is applied. This review aims to discuss the effect of pregnancy on patients with the most common rheumatic diseases, the effect of these diseases on the pregnancy itself, and the management of these patients during pregnancy.
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Artrite Reumatoide/complicações , Lúpus Eritematoso Sistêmico/complicações , Complicações na Gravidez/terapia , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , GravidezRESUMO
Family planning in women with vasculitis requires an interdisciplinary approach. This article summarizes recommendations and guidance for each phase of family planning in persons with vasculitis including preconception counseling, birth control, pregnancy, and breastfeeding. Pregnancy complications are presented by category of vasculitis with accompanying diagnostic and therapeutic recommendations. Birth control and assisted reproductive technology options are reviewed with special considerations for women who are high risk or have a history of blood clots. This article can be used as a clinical reference for reproductive discussions in all patients with vasculitis.
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Aconselhamento , Vasculite , Gravidez , Humanos , Feminino , Vasculite/diagnóstico , Vasculite/terapia , Cuidado Pré-ConcepcionalAssuntos
Artrite Reumatoide/diagnóstico , Autoavaliação Diagnóstica , Complicações na Gravidez/diagnóstico , Índice de Gravidade de Doença , Avaliação de Sintomas/métodos , Adulto , Feminino , Humanos , Medidas de Resultados Relatados pelo Paciente , Gravidez , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
Management of women with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and obstetric antiphospholipid syndrome (APS) during pregnancy presents unique clinical challenges. Women with both RA and SLE can have disease flares during pregnancy, leading to pregnancy complications, such as preeclampsia, small-for-gestational-age infants, and preterm delivery. Disease should be under control prior to conception. Women with obstetric APS need to be anticoagulated during pregnancy. Many but not all antirheumatic medications can be used during pregnancy and lactation.