ObjectiveDespite the many years efforts of physicians and scientist to improve the outcome of pregnancies in patients with systemic lupus erythematosus (SLE), a recent publication1 underlines the ...occurrence of many complications for the mother and the child. Aim pf this abstract is to summarize the better strategies to ensure a good maternal and neonatal outcome.MethodsThe physicians’ task should be considered in 3 different scenarios: before, during and after pregnancy. The correct approach and the challenges of these 3 periods will be analyzed.ResultsIdeally, a patient should start the pregnancy when the diseases is in low disease activity or in stable remission under a treatment safe for the fetal health. This is not always the case because sometimes unwanted pregnancies occur or, in other circumstances, desired pregnancies do not come. In both cases the treating physician will be involved in the solution finding process so it could be of help to know in advance what could be done and prepare sound specific protocols. The pre-conceptional counselling also involves the case specific evaluation of potential risk factors for the future pregnancy. These include the evaluation of lupus phenotype, antibody profile and other biomarkers such as the complement system whose levels are important predictors of fetal outcome even if not linked to clinically important disease activity.2 The monitoring of lupus patients during gestation is performed by a multidisciplinary team where gynecologist together with rheumatologists/internists are the main players. It is sometimes difficult to have different specialists at the same time in the same place, so different organizational models of multidisciplinary team have been developed to ensure quick consultation and decision sharing. An early diagnosis of lupus flares and pregnancy complications allow in many cases effective treatments.Puerperium is a difficult time for all the women. But for mothers with systemic lupus it is also combined with doubts on lactation and pharmacological treatment, disease linked fatigue that has to be added to the overworking of the period, and risk of disease flares often occurring. At this time, the patients need to be closely followed by the treating specialists to prevent disease relapses and also to avoid the occurrence of depression, potentially dangerous also for the child growth.ConclusionsSLE is a relatively rare disease, and this do not facilitate physicians to face peculiar aspects of their patients’ life such as reproduction. On the other had the high prevalence of young women in the affected population support the need of detailed protocols to follow them before, during, and after pregnancy. A pre-conceptional counselling with consequent appropriate disease management, a multidisciplinary pregnancy monitoring, and a careful care of puerperium can significantly reduce the problems often reported when data are driven from admirative registries1 and not prospectively followed cohorts.2 AcknowledgementsThe author wants to acknowledge the multidisciplinary team of colleagues working in the Rheumatology Pregnancy Clinic that has allowed a happy family life for many SLE patients.References Mehta B, Jannat-Khah D, Glaser KK, et al. Fetal and maternal morbidity in pregnant patients with Lupus: a 10-year US nationwide analysis. RMD Open 2023;9:e002752. Crisafulli F, Andreoli L, Zucchi D, et al. Variations of C3 and C4 before and during pregnancy in systemic lupus erythematosus: association with disease flares and obstetric outcomes. J Rheumatol. 2023 Oct;50(10):1296–1301.
Case 1: A pregnant woman with SLE and APSJB is a Caucasian female (born in 1978), smoker; she consulted us in 2003 (25 years old). She complained frequent episodes of lipothymia and dizziness, ...reported arterial hypertension diagnosed 3 years before that was successfully treated. In the last year, she had been taking oral contraceptive pill. The physical examination was normal, but livedo reticularis was noted. Her blood tests showed: thrombocytopenia 75,500/mm3, prolongation of aPTT, hypergammaglobulinemia (25%); positive ANA, anti Ro/SS-A, low titer anti DNA; mild reduction C3 and C4. She tested positive for lupus anticoagulant, anticardiolipin and anti-beta2-GPI. Renal arteries ultrasound was normal; echocardiogram showed mild mitral insufficiency with thickened leaflets, and ENT consultation was without pathological findings. At brain MRI, multiple hyper-intense foci in white matter compatible with ischemic lesions were present in T2.Her diagnosis was probable antiphospholipid syndrome (APS) with lupus-like disease. She was managed with sun protection 50+, she stopped smoking and oral contraceptive, and started low-dose aspirin (LDA), whilst continuing anti-hypertensive therapy.She returned to clinic in 2005, 12 gestational weeks pregnant, she was already on LDA and folic acid. The treatment was adjusted with the addition of prednisone 5 mg/day and enoxaparin at prophylactic dose. Unfortunately, intrauterine death occurred at 14 gestational weeks; placenta histology showed multiple infarctions. The diagnosis of APS with lupus-like disease was made. She was discharged with hydroxychloroquine (HCQ) 200 mg/day, LDA and prednisone 5 mg/day.One year later, the patient returned to the clinic 6 gestational weeks pregnant. Low molecular weight heparin at prophylactic dose was added to the treatment and prednisone was increased at 10 mg/day.In December 2005 at 30 gestational weeks, urgent caesarean section was performed for pre-eclampsia (proteinuria 5310 mg/24 h) evolved in HELLP syndrome.In the following years she was treated with HCQ, low dose prednisone (5 mg/day), LDA, anti-hypertensive therapy and supplementation with vitamin D, folic acid and iron. Proteinuria progressively decreased (<500 mg/24 hours) and GFR reduced to 55 ml/min. She was persistently anemic (Hb 10 g) due to metrorrhagia and remained thrombocytopenic (60,000/mm3). The baby was healthy and grew regularly.In 2013 (aged 35-years-old) she was doing well, and she returned to the pregnancy clinic because she wanted another baby. After a joint consultation with the gynecologist and rheumatologist, she was discouraged to start a new pregnancy because of her history. In 2015 malar rash was observed together with evolution of her serology. The diagnosis of SLE with APS was made and she was started on belimumab. Case 2: A 31-year-old womanRI is a Caucasian female, that consulted us in 1995 at 31 years old.She reported a pregnancy complicated by preeclampsia at 28 gestational weeks, 6 months before; a female baby of 850 g was born and, unfortunately, died after one day. Subsequent investigations revealed the presence of IgG anticardiolipin antibodies at high titre and lupus anticoagulant. At the time of our consultation, she reported frequent vision changes in the days before her monthly periods. She also reported photosensitivity since her 20s. Physical examination was normal with a normal blood pressure. Blood tests revealed low titre ANA and triple antiphospholipid antibody positivity. Treatment with low dose aspirin (LDA) was started.In 1996 she came to see us at 6 weeks of gestation, she was already on LDA and folic acid. Prednisone 5 mg was added. The pregnancy was carried on without complications. At 38 gestational weeks. Caesarean section was performed, because of PROM, and a female baby was born with a birthweight of 3100 g.The patient, living in another town, came for a follow-up visit in 1998. She reported some episodes of dizziness and diplopia. Physical examination and blood pressure were normal. The serology was repeated and resulted unchanged. Hydroxychloroquine and LDA were prescribed.One year later (1999), the patient presented at the beginning of a second pregnancy. The clinical situation was substantially unchanged, we decided to continue HCQ and LDA with the addition of 5 mg prednisone and folic acid. At 17 gestational weeks, HCQ was withdrawn because of an itching diffuse rush. At 35.3 gestational weeks, blood pressure started to rise, and a Caesarean section was performed at 36 gestational weeks. A healthy female baby was born, with a birthweight of 2510 g.Five days after delivery, the mother developed slurred speech and right hemiplegia suddenly occurred while she was taking unfractionated heparin 0.2 ml twice a day. Brain CT scan revealed and ischemic area in lentiform nucleus, caudate nucleus and left posterior limb of the internal capsule.Learning ObjectivesExplain the importance of counselling in order to improve the pregnancy outcomeDescribe risk factors for recurrence in patient with obstetric APS, including triple antibody positivity as an important risk factor driving treatment adjustmentsDiscuss why it could be necessary discourage a patient to start a new pregnancyDescribe the possible effective treatments of obstetric APSExplain the importance of focusing on the post-partum period and to the possible occurrence of serious complications linked to the presence of antiphospholipid antibodies
Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review ...(01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.
The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, ...overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.
A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a ...systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.
To analyze the performance of a line blot assay for the identification of autoantibodies in sera of patients affected by myositis, compared with immunoprecipitation (IP) as gold standard.
66 sera of ...patients with myositis (23 polymyositis, 8 anti-synthetase syndromes, 29 dermatomyositis and 6 overlap syndromes) were tested by commercial LB (Euroimmun, Lubeck, Germany); 57 sera were analyzed also by IP of K562 cell extract radiolabeled with 35S-methionine. Inter-rater agreement was calculated with Cohen's k coefficient.
Myositis-specific antibodies (MSA) were detected in 36/57 sera (63%) by IP and in 39/66 sera (59%) by LB. The most frequent MSA found by LB were anti-Jo1 and anti-Mi2 found in 15% (10/66) of sera, followed by anti-NXP2 and anti-SRP detected in 106% (7/66) of sera. Anti-TIF1gamma and anti-MDA5 were found in 6 (9%) and 5 sera (7.6%), respectively.
A good agreement between methods was found only for anti-TIF1γ, anti-MDA5 and anti-NXP-2 antibodies, while a moderate agreement was estimated for anti-Mi2 and anti-EJ. By contrast, a high discordance rate for the detection of anti-Jo1 antibodies was evident (k: 0.3).
Multiple positivity for MSA were found in 11/66 (17%) by LB and 0/57 by IP (p: 0001). Comparing the clinical features of these 11 sera, we found total discrepancies between assays in 3 sera (27.3%), a relative discrepancy due to the occurrence of one discordant autoantibody (not confirmed by IP) in 5 cases (45.5%) and a total discrepancy between LB and IP results, but with a relative concordance with clinical features were found in other 3 sera (27.3%). The semiquantitative results do not support the interpretation of the data.
The use of LB assay allowed the detection of new MSA, such as anti-MDA5, anti-MJ and anti-TIF1gamma antibodies, previously not found with routine methods. However, the high prevalence of multiple positivities and the high discondant rate of anti-Jo1 antibodies could create some misinterpretation of the results from the clinical point of view. These data should be confirmed by enlarging the number of myositis cases.
New 2016 ACR/EULAR classification criteria for primary Sjogren's syndrome (SS) have been developed and endorsed by the ACR. The newly proposed criteria include simple-to-perform items.Two important ...points of the new criteria should be considered. Firstly, they indicate that either salivary gland biopsy or anti-Ro must be positive in order to corroborate the inflammatory and autoimmune nature of the disease. Secondly, the criteria recognize the systemic nature of SS, namely that patients without salivary or ocular glandular symptoms, but with extraglandular manifestations and B cell activation markers were also included in the SS classification. Additionally, the new criteria modified some technical points. The ocular staining score threshold was increased to 5 due to the higher specificity. The immunological profile includes only anti-Ro antibodies, while positivity for antinuclear antibodies and rheumatoid factor or isolated anti-La was excluded due to a lack of specificity.The 2016 ACR/EULAR criteria are suitable for early identification of SS, providing patients with the opportunity of enrollment in clinical trials for new specific treatment. Although validation has been successful, the real life application of these criteria will test their performance.
Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we ...initiated a process to achieve consensus on potential definitions for remission in SLE.
An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%.
The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows:
…………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy:
requires the patient to be on no other treatment for SLE than maintenance antimalarials; and
allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life.
The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.
Critically ill patients with coronavirus disease 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy which leads to organ failure and death. Because of a prolonged ...activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies (aPLs) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-β
GPI), and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies was not investigated systematically. Epitope specificity of anti-β
GPI antibodies was not reported.
To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-β
GPI antibodies.
ELISA and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic events.
Anti-β
GPI IgG/IgA/IgM was the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM was detected in 5.7/6.6% by ELISA. Comparable values were found by chemiluminescence. aPS/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA. No association between thrombosis and aPL was found. Reactivity against domain 1 and 4-5 of β
GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-β
GPI nor with thrombosis.
aPL show a low prevalence in COVID-19 patients and are not associated with major thrombotic events. aPL in COVID-19 patients are mainly directed against β
GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome.
Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing ...increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.
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