Absence Of Antiphospholipid Antibodies Research Articles

Digital Gangrene: A Rare Cutaneous Manifestation of Systemic Lupus Erythematosus in The Absence of Anti-Phospholipid Antibodies

Distal gangrene is a rare and serious manifestation of systemic lupus (LS). Secondary to vasculitis, this complication is most frequently associated with the presence of antipospholipid antibodies. Gangrene affecting all four extremities at the same time is exceptional in addition in the absence of antiphospholide antibodies. We report the observation of a 52-year-old patient with an LS for 16 years, who presented for necrosis of the four extremities of simultaneous installation evolving for 01 month. In addition to the noted dry gangrene, she had peripheral sensorimotor neuropathy in the lower extremities. Despite general corticosteroid therapy, its management required amputation of the fingers and forefeet. We also propose a review of the literature with an analysis of the cases reported to date, i.e. 85 cases including our observation.

Complement Activation on Endothelial Cell-Derived Microparticles-A Key Determinant for Cardiovascular Risk in Patients with Systemic Lupus Erythematosus?

Systemic lupus erythematosus is a classical systemic autoimmune disease that overactivates complement and can affect all organs. Early diagnosis and effective management are important in this immune-complex-mediated chronic inflammatory disease, which has a strong component of vasculitis and carries an increased risk of thrombosis, even in the absence of antiphospholipid antibodies. Development of lupus nephritis can be life limiting but is managed with dialysis and renal transplantation. Therefore, data have become available that cardiovascular risk poses a serious feature of systemic lupus erythematosus that requires monitoring and prospective treatment. Cell-derived microparticles circulate in plasma and thereby intersect the humoral and cellular component of inflammation. They are involved in disease pathophysiology, particularly thrombosis, and represent a known cardiovascular risk. This viewpoint argues that a focus on characteristics of circulating microparticles measured in patients with systemic lupus erythematosus may help to classify certain ethnic groups who are especially at additional risk of experiencing cardiovascular complications.

Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates.

Repurposing of antirheumatic drugs has garnered global attention. The aim of this article is to overview available evidence on the use of widely used antirheumatic drugs hydroxychloroquine, methotrexate and colchicine for additional indications. Hydroxychloroquine has endothelial stabilizing and anti-thrombotic effects. Its use has been explored as an adjunctive therapy in refractory thrombosis in antiphospholipid syndrome. It may also prevent recurrent pregnancy losses in the absence of antiphospholipid antibodies. Hydroxychloroquine favourably modulates atherogenic lipid and glycaemic profiles. Methotrexate has been tried for modulation of cardiovascular events in non-rheumatic clinical conditions, although a large clinical trial failed to demonstrate a benefit. Colchicine has been shown to successfully reduce the risk of recurrent cardiovascular events in a large multicentric trial. Potential antifibrotic effects of colchicine require further exploration. Hydroxychloroquine, methotrexate and colchicine are also being tried at different stages of the ongoing Coronavirus Disease 19 (COVID-19) pandemic for prophylaxis and treatment. While the use of these agents is being diversified, their adverse effects should be timely diagnosed and prevented. Hydroxychloroquine can cause retinopathy and rarely cardiac and auditory toxicity, retinopathy being dose and time dependent. Methotrexate can cause transaminitis, cytopenias and renal failure, particularly in acute overdoses. Colchicine can rarely cause myopathies, cardiomyopathy, cytopenias and transaminitis. Strong evidence is warranted to keep balance between benefits of repurposing these old antirheumatic drugs and risk of their adverse effects.

Strokes in Sneddon syndrome without antiphospholipid antibodies.

Sneddon syndrome (SS) is characterized by the association of a livedo reticularis with stroke. Clinicoradiological features of its neurological manifestations, its prognosis, and the frequency of associated cardiac valvulopathy remain poorly known, particularly in the absence of antiphospholipid antibodies (APL). The objectives were to assess the clinicoradiological pattern of SS without APL (SSAPL- ) and its midterm prognosis. Clinical data, transthoracic echocardiograms, and brain imaging of 53 consecutive patients (83% women) with SSAPL- , followed up at our institution between 1991 and 2011, were reviewed. Seventy-four strokes were reported; 76% were ischemic strokes (IS), 15% transient ischemic attacks, and 9% hemorrhagic strokes. Heart valve lesions were found in 50% of the cases. Brain imaging showed 177 IS of 3 different types: large territorial (43%), small distal corticosubcortical (14%), and small deep (23%) IS. No significant association was found between the valve involvement and the presence of territorial IS. After a mean follow-up of 7.4 years, 82% of patients had a modified Rankin Scale score ≤ 2. The ischemic event recurrence rate was 20%, with a similar annual rate in the antiplatelet group (3%) compared to the anticoagulation group (2.7%). SSAPL- is not only a neurocutaneous disorder, but is frequently associated with heart valve involvement. The latter does not influence the IS type, which suggests that strokes are caused by vasculopathy of the small and medium-size cerebral arteries. Our results show no progression toward a serious disability in the majority of the cases and a moderate recurrence rate under antiplatelet therapy.

Reply to comments and questions of Dr. Correale et al. about our review concerning CTEPH.

We would like to thank Dr. Correale et al. for their interest and valuable comments on our review regarding the diagnostic approach to chronic thromboembolic pulmonary hypertension (CTEPH) and the available surgical and medical therapeutic options [1]. They ask for further comments on congenital abnormalities causing hypercoagulability in these patients. The prevalence of CTEPH after acute pulmonary embolism is estimated at 0.1–4.0 % after 2 years [2−5]. It is still not known why some patients develop CTEPH after acute pulmonary embolism and others do not. The risk of developing CTEPH is increased in patients who have recurrent venous thromboembolism, large perfusion defects and echocardiographic signs of pulmonary hypertension at the initial presentation [6]. Interestingly, the development of CTEPH is not associated with common risk factors for venous thromboembolism, such as factor V Leiden, factor II mutation, deficiency of antithrombin, protein C and protein S or a prothrombin G20210A gene mutation [7]. The prevalence of these factors is low in CTEPH and some of them seem to occur with similar frequency among patients with CTEPH and the general population. There are two exceptions. The presence of antiphospholipid antibodies and Lupus anticoagulant is found in 10–20 % of the CTEPH patients and antiphospholipid antibodies predispose to acute venous thromboembolism and in some cases even recurrent pulmonary embolism [6,8−10].The study of D’Armini et al. compared 28 patients with high levels of antiphospholipid antibodies with 156 patients with low level or absence of antiphospholipid antibodies who all underwent pulmonary endarterectomy. There was no difference between the two groups after surgery in terms of mortality and major complications. However, the patients with high levels of antiphospholipid antibodies had significantly more transient neurological complications postoperatively [11]. Several studies demonstrated increased levels of FVIII in CTEPH patients [12−14]. One study investigated the effect of pulmonary endarterectomy on FVIII levels, and found no change after surgery. Interestingly, the level of FVIII decreases after medical treatment of pulmonary arterial hypertension (PAH) [15]. However, the exact mechanism of how these factors contribute to CTEPH remains unknown. To our knowledge, there are no studies comparing methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism between CTEPH patients and healthy controls. Furthermore, MTHFR polymorphism is not associated with PAH [16]. Routine screening for thrombophilia seems only reasonable when it has an impact on the prognosis, treatment or outcome of CTEPH. We must keep in mind that all patients receive life-long anticoagulant treatment. In the literature, only high levels of antiphospholipid antibodies were demonstrated to influence postoperative outcome after pulmonary endarterectomy. Therefore, according to the guideline, we think that screening for the antiphospholipid syndrome is reasonable [17].

Acute Unilateral Blindness from Superior Ophthalmic Vein Thrombosis: A Rare Presentation of Nephrotic Syndrome from Class IV Lupus Nephritis in the Absence of Antiphospholipid or Anticardiolipin Syndrome.

Patients with systemic lupus erythematosus (SLE) are at high risk of arterial and venous thrombosis secondary to anti-phospholipid antibodies. Herein, we are presenting an interesting case of venous thrombosis in a patient with SLE in the absence of anti-phospholipid antibodies.

Aspirin and Heparin Effect on Basal and Antiphospholipid Antibody Modulation of Trophoblast Function

Low molecular weight (LMW) heparin, with or without aspirin (acetylsalicylic acid [ASA]), is used to prevent complications in antiphospholipid syndrome in pregnancy. Our objective was to elucidate the actions of low-dose LMW heparin and ASA on basal and antiphospholipid antibody-induced modulation of trophoblast function. The human first-trimester trophoblast cell line (HTR-8) was treated with or without antiphospholipid antibody in the presence of no medication, low-dose LMW heparin, low-dose ASA, or combination therapy. Interleukin (IL)-6, IL-8, IL-1β, growth-regulated oncogene-α, vascular endothelial growth factor (VEGF), placental growth factor, soluble FMS-like tyrosine kinase-1, and soluble endoglin were measured in the supernatant. Cell migration was performed using a two-chamber assay. Low molecular weight heparin improved basal trophoblast migration and induced potent increases in growth-regulated oncogene-α and soluble FMS-like tyrosine kinase-1. Aspirin did not affect basal function. Combined therapy promoted migration but did not reverse the LMW heparin-induced soluble FMS-like tyrosine kinase-1 effect. Antiphospholipid antibody increased IL-8, IL-1β, growth-regulated oncogene-alpha, VEGF, placental growth factor, and soluble endoglin secretion, while decreasing cell migration and IL-6 and soluble FMS-like tyrosine kinase-1 secretion. The antiphospholipid antibody-induced cytokine changes were best reversed with LMW heparin, with partial reversal of IL-8 and IL-1β upregulation. The antiphospholipid antibody-induced angiogenic changes were worsened by LMW heparin, with increased soluble FMS-like tyrosine kinase-1 secretion. The therapies did not reverse antiphospholipid antibody-induced decrease in migration. In the absence of antiphospholipid antibodies, LMW heparin induces potentially detrimental proinflammatory and antiangiogenic profile in the trophoblast. In the presence of antiphospholipid antibodies, single-agent LMW heparin may be the optimal therapy to counter trophoblast inflammation, but also induces an antiangiogenic response. These findings may explain the inability of current therapies to consistently prevent adverse outcomes.

The PTPN22*R620W polymorphism does not confer genetic susceptibility to antiphospholipid syndrome in the Spanish population

In this work, we proposed to determine the association of the PTPN22*R620W SNP with primary antiphospholipid syndrome (PAPS) in a case-control association study of Spanish Caucasian individuals. A total of 81 PAPS patients were compared with 81 blood-donor healthy control subjects. PTPN22 SNP (R620W) genotyping was performed by using a polymerase chain reaction-restricted fragment length polymorphism assay. No statistically significant differences were found between control subjects and PAPS patients for the PTPN22*R620W genotypes (P = 0.214). No statistically significant differences were found according to either the presence or absence of antiphospholipid antibodies or the clinical manifestations associated to PAPS. Our results indicate that this functional PTPN22*R620W polymorphism is not associated to PAPS; it seems not to be a risk factor in our Spanish population. The effect of the PTPN22 SNP on clinical manifestations and presence of antiphospholipid antibodies in APS warrants further investigations.

Retinitis preceding systemic lupus erythematosus in absence of anti-phospholipid antibodies

Retinitis preceding systemic lupus erythematosus in absence of anti-phospholipid antibodies

Improvement of neurological symptoms and memory and emotional status in a case of seronegative Sneddon syndrome with cyclophosphamide

Sneddon syndrome (SS) is characterized by livedo racemosa, recurrent ischemic strokes, and often progressive vascular dementia. Treatment options for SS center on either anticoagulation or immunosuppression to prevent strokes and to dissipate the skin findings, with these modalities based historically on the presence or absence of antiphospholipid antibodies (APA) respectively. However, few effective treatments have been reported to reverse the cognitive decline in SS. We report a case of a woman with seronegative SS (absence of APA) with cognitive decline who demonstrated objective and subjective improvements in her memory and emotional functioning after treatment with cyclophosphamide.

Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review.

The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late non-recurrent pregnancy loss, which has prompted investigators to evaluate the benefit of low molecular weight heparin (LWMH) to achieve live birth. A similar benefit for LMWH has also been proposed independent of thrombophilia status. We conducted a systematic review of randomized controlled trials to assess the benefit of LMWH in achieving live birth for women with a history of recurrent or late non-recurrent pregnancy loss in the absence of antiphospholipid antibodies. For the five studies that satisfied the eligibility criteria, the risk ratio of live birth for women with a history of pregnancy loss treated with LWMH compared with control ranged from 0.95 to 3.00. There was considerable heterogeneity among studies in terms of treatment effect (Q-value was 41.7, P=0.000, and I2=90.4%) independent of thrombophilia status. There was also a wide variation among all studies in terms of definition of early or late pregnancy loss, thrombophilic risk factors, and number of prior pregnancy losses. There is a trend for increased live births when using LWMH for the prevention of recurrent pregnancy loss. Currently, there is insufficient evidence to support the routine use of LWMH to improve pregnancy outcomes in women with a history of pregnancy loss. Not only are additional studies necessary but standardized criteria for trials evaluating the benefit of an intervention in recurrent pregnancy loss should be established.

Anti‐C1q Autoantibodies in Lupus Nephritis

Anti-C1q antibodies are found in a variety of diseases, in addition to systemic lupus erythematosus (SLE), and in 3-5% of normal individuals. In particular, anti-C1q antibodies are detected at a high titer in 100% of patients with hypocomplementemic urticarial vasculitis and in 30-48% of SLE patients. Their titer correlates with active renal disease with a sensitivity of 44-100% and a specificity of 70-92%. An increase in anti-C1q antibody titer has been suggested to be able to predict renal flares in lupus nephritis so that monitoring anti-C1q might be valuable for the clinical management of SLE patients as a noninvasive biological marker. Recently our group studied 228 patients affected by lupus nephritis and found that the association of anti-C1q, C3, and C4, in a multivariate analysis, provided the best prediction of renal flares, particularly in patients with focal and diffuse proliferative lupus nephritis and in the absence of antiphospholipid antibodies.

Livedo racemosa as a marker of increased risk of recurrent thrombosis in patients with negative anti-phospholipid antibodies

Background and objective Livedo reticularis racemosa and cerebrovascular lesions characterize Sneddon's syndrome. We report 23 patients with livedo racemosa and describe the association with thrombotic events. Our objective was to determine whether livedo racemosa may be an independent clinical marker for the development of thrombotic events in patients who test negative for anti-phospholipid antibodies. Methods Twenty-three patients with widespread livedo racemosa were studied. None of the patients were positive for anti-phospholipid antibodies. The clinical protocol included a register of thrombotic events, fetal death or miscarriages, hypertension, and valvular heart disease. Cerebral MRI and echocardiography were systematically performed in all patients. Results Nineteen patients (82.60%) had thrombotic events. Fifteen (65.21%) had arterial thrombosis and eleven (47.82%) presented venous occlusions. Seven patients (30.43%) had both arterial and venous thrombosis. Fetal losses were recorded in seven cases (30.43%), with a total number of 33; five patients had 3 or more fetal losses. Eleven out of 23 patients (47.82%) had valvular heart disease. Arterial hypertension was detected in 16 (69.56%) patients. Four patients did not have thrombotic events but had other clinical manifestations. After anti-coagulation therapy was withdrawn, a new thrombotic event was observed in 9 out of the 14 treated patients (64.28%). Conclusions Livedo racemosa seems to be a good clinical marker for the detection of hypercoagulable states even in the absence of anti-phospholipid antibodies or other known biologic markers of thrombosis. Long-term anti-coagulation is probably warranted in patients with livedo racemosa and a previous thrombotic event.

Predicting thrombosis in systemic lupus erythematosus

Biomarkers that reliably identify or even predict disease manifestations in systemic lupus erythematosus (SLE) are needed. In a recent issue of the Clinical Journal of the American Society of Nephrology, Wu and colleagues reported on the predictive value of routine D-dimer measurements for future thromboembolic events in patients enrolled in the Ohio SLE study, a unique prospective, longitudinal evaluation of individuals with recurrently active SLE. As in other disease settings, low D-dimer levels (<0.5 microg/ml) excluded clotting at a given time point and identified a zero risk of future clotting events. Conversely, 42% of patients with a high D-dimer level (>2.0 microg/ml) subsequently experienced a clinically relevant clotting event, in some cases in the absence of antiphospholipid antibodies or lupus anticoagulant. This Practice Point commentary considers whether the D-dimer assay will remain simply a tool to rule out thrombosis in symptomatic patients with SLE or whether it could eventually be used to initiate preventive anticoagulation in asymptomatic patients.

The point prevalence of an abnormal ankle-brachial index in antiphospholipid antibody negative patients with livedo reticularis: a controlled study

Livedo reticularis (livedo) is characterised by reticular cyanotic cutaneous discolouration surrounding a pale central area. Physiological livedo, also known as cutis marmorata, is common in young women on exposure to...

Longitudinal myelitis in patient with systemic lupus erythematosus, homozygous prothrombin G20210A and heterozygous MTHFR 677T

Longitudinal myelitis is an uncommon complication of systemic lupus erythematosus (SLE). We describe an unusual case of longitudinal myelitis and ischemic stroke in the presence of homozygous prothrombin G20210A, heterozygous MTHFR 677T mutations and the absence of antiphospholipid antibodies in a young woman with SLE.

Does the anti-prothrombin antibodies measurement provide additional information in patients with thrombosis?

The aim of this study is to get new insight into the relevance of IgG anti-prothrombin antibodies in patients with thrombosis and to determine whether human prothrombin alone (aPT) or complexed to phosphatidylserine (aPS/PT) should be preferentially used for measuring these antibodies by enzyme-linked immunosorbent assay (ELISA). To this end, prevalence of anti-prothrombin antibodies, their characteristics in terms of avidity and heterogeneity, and their relationship with anti- β2 glycoprotein I antibodies (a β 2GPI) were studied in 152 patients with thrombosis. Patients were divided into two groups according to the presence or absence of antiphospholipid antibodies (aPL), called aPL+ or aPL−, respectively. In the aPL− group ( n=90), the prevalence of anti-prothrombin antibodies was substantial (10%) but not significantly different from that of control (5%). In the aPL+ group ( n=62), lupus anticoagulant (LA) or anticardiolipin antibodies (aCL) positive, 61% were positive for anti-prothrombin antibodies with no statistical difference between aPT and aPS/PT prevalence (42% vs. 55%, respectively). In the whole thrombotic population, 19% were only aPT and 34% only aPS/PT suggesting the presence of different antibodies. Absorption experiments confirmed the heterogeneity of aPT and aPS/PT. No difference in their avidity was demonstrated. From the aPL+ group, 60 were LA positive. Among them, 18% were negative for a β 2GPI and anti-prothrombin antibodies showing that the detection of these antibodies could not substitute for LA determination. In conclusion, our data show that the screening of the different anti-prothrombin antibodies is not warranted in the aPL+ group since these antibodies do not provide additional information compared to aCL, LA and/or a β2GPI measurement. Nevertheless, the substantial prevalence of anti-prothrombin antibodies in the aPL− group should be further explored in a large prospective study.

Necrotizing Livedo Related to Neoplastic Microvascular Embolism

Sir, A 64-year-old woman was admitted for evaluation of a necrotic livedo of the perineal area. She had developed fluctuating erosive lesions of the buttocks within the past 3 months, initially considered as sacral herpes zoster and treated with oral aciclovir without significant results. Her medical history included multi-complicated type 2 diabetes mellitus, elevated blood pressure, atrial flutter, inter-atrial communication, and chronic exposure to tobacco (40 packs (7300 cigarettes) per year). At initial evaluation, she displayed erythematous, exquisitely painful, necrotic and livedoid lesions of the buttocks, lumbar areas, vulva and perineum. No other skin lesions were noticed, especially on the extremities. Physical examination also showed a reduction in intensity of pulses on lower limbs, effort-related claudication, a mitral heart murmur and a mild alteration of the intellectual capabilities. Biological explorations disclosed increased inflammatory parameters but no significant abnormality regarding standard and coagulation tests (absence of anti-phospholipid antibodies or cryoglobulinaemia; serum levels of protein C and S, anti-thrombin III and homocysteine within normal limits; no resistance to activated C protein). Echocardiography was normal except for the inter-atrial communication already known. Skin biopsies revealed obstructions of the dermal vessels by clusters of neoplastic cells further identified by immuno-histological methods as adenocarcinoma cells with positive results for cytokeratins AE1-AE3 and 7 and no staining with cytokeratin 20 and CA-125. However, renal, abdominal and pelvic ultrasound, endoscopic exploration of upper and lower digestive tract, total-body scan and mammography failed to identify any primary neoplastic lesion. Instead, the scanner disclosed an aortic sub-renal thrombosis with complete luminal occlusion along with a highly reduced perfusion in the hypogastric and iliac territories contrasting with the development of a collateral circulation directed to the lower limbs. Anticoagulant therapy was then introduced without any significant clinical improvement and the livedo slowly spread during the following month, resulting in severe necrotic lesions while small, painful ulcerations of the legs and weakness of the lower limbs appeared as well. In the meantime, intellectual alterations quickly worsened with increasing negligence without any evidence of brain metastasis, cerebral infarct, neoplastic, viral or bacterial meningitis or meningo-encephalitis according to comprehensive investigations including cerebrospinal fluid analysis and brain magnetic resonance imaging (MRI). Two courses of gemcitabine were eventually performed due to the undetermined origin of the causal neoplasia, but the patient died 2 months after admission and 5 months after the occurrence of the first cutaneous signs. No post-mortem examination was performed.

Cognitive dysfunction in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune-mediated collagen disease that results in multiorgan failure. It is the collagen disease most frequently associated with neuropsychiatric symptoms, which have been hypothesized to stem from certain types of cognitive dysfunction. Subjects were 21 patients with SLE (one man, 20 women; aged 16-55 years; mean age, 35.1+/-10.7 years) who were undergoing treatment in the rheumatology unit of a general hospital, and 17 healthy control subjects matched to the patient group with respect to age and gender (two men, 15 women; mean age, 35.9+/-6.3 years). They were administered various tests of cognitive function including verbal reasoning, non-verbal reasoning, verbal memory, non-verbal memory, attention and mental flexibility, psychomotor speed and frontal lobe function. In addition, the SLE patients were tested for antiphospholipid antibodies. The SLE patients performed worse than the control group on immediate, delayed and interference of the Rey verbal test and paired associate tests of Wechsler Memory Scale, and their reaction time was slower in Trail A and Trail B tests. Moreover, these findings were more pronounced in the group with major neuropsychiatric symptoms. However, no relationship was apparent between these deficits in cognitive function and the presence or absence of antiphospholipid antibodies. The results suggest that verbal memory and psychomotor speed underlie the neuropsychiatric symptoms seen in SLE patients.

Prevalence and biological effects of anti-trophoblast and anti-endothelial cell antibodies in patients with recurrent spontaneous abortions.

Trophoblasts and endothelial cells represent a potential target for antibodies in women with recurrent spontaneous abortions. These antibodies have been shown to be associated with anti-phospholipid antibodies. Are they also present in women with unexplained pregnancy losses in the absence of anti-phospholipid antibodies? The anti-trophoblast antibodies were tested by an immunofluorescence assay on cells purified from pooled first-trimester placentae, whereas the anti-endothelial cell antibodies were measured by enzyme-linked immunoadsorbent assay (ELISA) on cells isolated from the umbilical vein and were cultured to confluence. The cytotoxicity of trophoblasts was evaluated in a homologous system. The expression of adhesion molecules on endothelial cells was quantitated by ELISA using specific monoclonal antibodies, and the expression of tissue factor was quantitated by a chromogenic assay measuring the formation of factor Xa. Complement-fixing antibodies to trophoblast represent a better marker to discriminate patients with recurrent spontaneous abortions from controls and are cytotoxic for the target cells. Anti-endothelial antibodies are also present in these patients and exhibit pro-inflammatory and pro-coagulant activities.