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Figure2.Light microscopic and immunofluorescent findings of the kidney biopsy. Periodic acidSchiff (PAS) staining (A, B) shows that most of the glomeruli tend to collapse and exhibit wrinkling changes in the capillary walls and luminal narrowing associated with organized crescents (pseudotubulization) (arrowheads). Periodic acid-methenamine-silver (PAM) staining (C) shows double contouring (arrows) as well as thickening, spike formation, and a bubbly appearance (arrowheads) in the capillary walls. Masson's trichrome staining (D) shows diffuse interstitial fibrosis and tubular atrophy in approximately 50% of the tubulointerstitial areas. Elastica van Gieson (EVG) staining (E, F) shows swelling of the endothelium along with luminal narrowing and obstruction (arrowhead) in the arteriole (E) and small artery (F). Immunofluorescence shows slightly positive staining for IgG in the capillaries and part of the mesangial region of the glomerulus. Original magnification, ×200 (A, E, F, G), ×400 (B, D), and 1,000 (C), respectively.
Source publication
A 31-year-old woman was admitted to our hospital for thrombotic microangiopathy (TMA). She was diagnosed with systemic lupus erythematosus (SLE) and class V lupus nephritis. She had no aggravated SLE activity, Shiga toxin positivity, ADAMTS13 abnormality, or other causes of secondary TMA. Plasma exchange partially improved TMA, and eculizumab was i...
Citations
... A placebo-controlled, double-blind phase I RCT with 24 SLE patients failed to demonstrate the efficacy of eculizumab, according to laboratory and clinical parameters and SLEDAI scores (81). However, case reports described good results with eculizumab in the treatment of refractory LN (82,83). In a review of SLE with renal involvement, irrespective of concomitant LN, all patients (n=6) showed a sustained improvement in renal function and normalization of complement parameters after treatment with eculizumab (median follow-up of 9 months) (80). ...
Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and Sjögren’s syndrome (SS) are heterogeneous autoimmune diseases. Severe manifestations and refractory/intolerance to conventional immunosuppressants demand other options, namely biological drugs, and small molecules. We aimed to define evidence and practice-based guidance for the off-label use of biologics in SLE, APS, and SS. Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice in autoimmune disease management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts’ input until 2021. Preliminary recommendations were drafted by working groups for each disease. A revision meeting with all experts anticipated the consensus meeting held in June 2021. All experts voted (agree, disagree, neither agree nor disagree) during two rounds, and recommendations with at least 75% agreement were approved. A total of 32 final recommendations (20 for SLE treatment, 5 for APS, and 7 for SS) were approved by the experts. These recommendations consider organ involvement, manifestations, severity, and response to previous treatments. In these three autoimmune diseases, most recommendations refer to rituximab, which aligns with the higher number of studies and clinical experience with this biological agent. Belimumab sequential treatment after rituximab may also be used in severe cases of SLE and SS. Second-line therapy with baricitinib, bortezomib, eculizumab, secukinumab, or tocilizumab can be considered in SLE-specific manifestations. These evidence and practice-based recommendations may support treatment decision and, ultimately, improve the outcome of patients living with SLE, APS, or SS.
... Therefore, the diagnosis of aHUS has been performed using the clinical criteria of TMA without STEC, no deficiency of ADAMTS13 activity and no underlying diseases for TMA, resulting in the over-diagnosis of aHUS. In Japan, the clinical characteristics and genetic variations of 34 patients with aHUS were previously reported [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. ...
... TMA screening score À1 was based on the National questionnaire survey of TMA [37,38], and TMA screening score À2 was based on the Clinical Guides of aHUS [39]. Using the TMA screening score system, 34 patients with aHUS were cited in various reports from Japan [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] including 14 cases at Mie University [14,16,17]. The scoring data from aHUS patients were compared with those from 29 patients with TTP and 48 with secondary TMA at Mie Prefectural General Medical Center and Mie University Hospital cited previous reports [40][41][42][43][44][45] as well as 50 anemic patients without TMA (hemoglobin <120 g/L) at Mie Prefectural General Medical Center and Mie University Hospital. ...
... The aHUS scoring system, which was originally proposed on based several reviews [5][6][7][8][9][10][11][12][13], consists of a past history of TMA, a family history of TMA, age of onset, prodromal symptom and "red or brownish urine", with details shown in Table 2. The aHUS scoring system was evaluated using previously reported 34 Japanese aHUS patients previously reported from 2013 to 2020 [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (Supplementary Table 1). These aHUS patients were evaluated for the PLASMIC score [46]. ...
Objective
Although the definitive diagnosis of atypical hemolytic uremic syndrome (aHUS) depends on a genetic analysis for the complement factors, such a genetic analysis is time-consuming and expensive. We examined the usefulness of a diagnostic scoring system for aHUS.
Methods
The thrombotic microangiopathy (TMA) scoring system consists of hemoglobin, the platelet count, creatinine levels and organ failure, and the aHUS scoring system consists of past history and family history of TMA, age at onset, prodromal symptoms and “red or brownish urine”, and these scoring system were both evaluated in patients with aHUS, thrombotic thrombocytopenic purpura or secondary TMA.
Results
In a receiver operating characteristics analysis, an adequate cut-off value for diagnosing aHUS, TTP, other TMA or all TMA versus patients without TMA was 7 points for both TMA screening scores. The area under the curve was 0.965 for the TMA screening score and 0.966 for the aHUS score. An adequate cut-off value for diagnosing aHUS was 2 points for a positive aHUS score, - 3 points for an exclusion aHUS score and 0 points for the total aHUS score.
Conclusion
The TMA screening and aHUS score systems are useful for making a diagnosis of aHUS without performing specific laboratory tests.
... Охарактеризован субтип ТМА при СКВ и АФС, связанный с аутоантитело-опосредованной активацией системы комплемента [40][41][42][43][44] кислотам и аФЛ, принимающие участие в иммунопатогенезе СКВ и АФС соответственно, напрямую или посредством образования иммунных комплексов (ИК) обладают способностью активировать альтернативный и классический путь системы комплемента с образованием биологически активных фрагментов: анафилотоксины (С3а, C4а, С5а) и мембраноатакующий комплекс -С5b-C9, -вызывающих развитие воспаления и деструкцию клеток-мишеней. Примером антитело-зависимых и ИК-опосредованных заболеваний, патогенетически связанных с активацией системы комплемента, является волчаночный нефрит (ВН) [45], при котором развитие ТМА ассоциируется с неблагоприятным прогнозом и риском развития обострений на фоне терапии [46]. ...
Uncontrolled hypercoagulation and inflammation (“thromboinflammation”), which are both independent and closely related and amplifying each other pathological processes, form the basis for pathogenesis of a wide range of diseases and complications, including immuno-inflammatory (autoimmune) rheumatic diseases, with the development of potentially fatal injuries of internal organs. Thrombotic microangiopathy is one of the most prominent prototypes of “thromboinflammatory” pathological conditions. The close link between environmental factors, hemostasis genetic defects and the complement system, inflammation and autoimmunity as pathogenetic mechanisms of microthrombosis draws particular attention to studying thrombotic microangiopathy in immuno-inflammatory rheumatic diseases, primarily systemic lupus erythematosus, antiphospholipid syndrome and scleroderma renal crisis. In future, these studies may be important for expanding the idea of the role of autoimmune mechanisms in pathogenesis of “critical” hemostasis disorders in human diseases, and for developing new approaches to therapy. Recently, special attention has been paid to the treatment of systemic lupus erythematosus and antiphospholipid syndrome with eculizumab, which is humanized monoclonal IgG2/4k antibody that blocks the complement component C5a and the membrane attack complex (C5b-9) formation, and which is registered for the treatment of atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, as well as severe forms of myasthenia gravis and neuromyelitis optica. Further studies in this direction will create prerequisites for improving the prognosis not only in patients with orphan disorders, but also for widespread human diseases.
... Systemic lupus erythematosus (SLE) is an autoimmune disorder targeting multiple organ systems that results in an increased risk for thrombotic events, including TMA in up to 10% of cases [52,53]. A systematic review and three recent case reports have shown success of anti-complement treatment with eculizumab in cases of SLE with TMA, cases of SLE and lupus nephritis, and cases of SLE and anti-phospholipid syndrome [53][54][55][56][57][58][59]. Mutations in the complement cascade are rare in these conditions, with only two of the cases reported having mutations in FHR3-FHR1 and C3 [53]. ...
Purpose of Review
This review aims to examine the current definitions of primary and secondary hemolytic uremic syndromes. Specifically, it seeks to determine which external conditions can result in secondary Thrombotic microangiopathy (TMA), which can trigger cases of primary atypical uremic syndromes (aHUS), and the role of complement in the pathogenesis of TMA spectrum disorders.
Recent Findings
Building on the growing insight about the pathogenic role of dysregulation of the alternative complement pathway in primary aHUS, the successful use of complement-blocking treatment in cases of thrombotic microangiopathy with coexisting conditions (secondary TMA), along with the identification of complement mutations in some of these cases, indicates a so far possibly under-appreciated pathogenic role for complement in diagnoses within the TMA spectrum.
Summary
Uncontrolled complement activity and pro-thrombotic environments represent a unifying pathogenic mechanism in aHUS and the TMA spectrum disorders and point towards shared diagnostic and therapeutic pathways.
Systemischer Lupus erythematodes (SLE), das Antiphospholipid-Syndrom (APS) und das Sjögren-Syndrom (SS) sind heterogene Autoimmunerkrankungen. Schwere Ausprägungen sowie Therapieresistenz bzw. -unverträglichkeit gegenüber herkömmlichen Immunsuppressiva erfordern andere Behandlungsoptionen, d.h. biologische Arzneimittel und kleine Moleküle. Unser Ziel war es, evidenz- und praxisbasierte Leitlinien für die zulassungsüberschreitende Anwendung von Biologika bei SLE, APS und SS zu definieren. Die Empfehlungen wurden nach einem umfassenden Literaturreview und 2 Konsensrunden durch ein unabhängiges Expertengremium abgegeben. Das Gremium umfasste 17 Experten für Innere Medizin mit anerkannter Praxis im Bereich der Behandlung von Autoimmunerkrankungen. Die Literaturrecherche erfolgte systematisch für die Jahre von 2014 bis 2019 und wurde später durch Querverweisprüfungen und Experteninformationen bis 2021 aktualisiert. Es wurden vorläufige Empfehlungen von Arbeitsgruppen für jede Krankheit erarbeitet. Ein Revisionsmeeting mit allen Experten fand vor dem Konsensmeeting im Juni 2021 statt. Alle Experten stimmten in 2 Runden ab (stimme zu, stimme nicht zu, stimme weder zu noch widerspreche ich), und Empfehlungen mit mindestens 75% Zustimmung wurden anerkannt. Insgesamt 32 abschließende Empfehlungen (20 für die SLE-, 5 für die APS- und 7 für die SS-Behandlung) wurden von den Experten anerkannt. Diese Empfehlungen berücksichtigen die Organbeteiligung, die Ausprägung, den Schweregrad und das Ansprechen auf frühere Behandlungen. Bei diesen 3 Autoimmunkrankheiten beziehen sich die meisten Empfehlungen auf Rituximab, was auf die höhere Anzahl von Studien und der klinischen Erfahrung mit diesem biologischen Wirkstoff zurückzuführen ist. Eine sequenzielle Behandlung mit Belimumab nach Rituximab kann auch bei schweren Fällen von SLE und SS indiziert sein. Eine Zweitlinientherapie mit Baricitinib, Bortezomib, Eculizumab, Secukinumab oder Tocilizumab kann bei SLE-spezifischen Ausprägungen erwogen werden. Diese evidenz- und praxisbasierten Empfehlungen können die Behandlungsentscheidung unterstützen und letztendlich das Behandlungsergebnis bei Patienten mit SLE, APS oder SS verbessern.
Systemic lupus erythematosus (SLE) can present with a diverse array of hematologic manifestations, among which atypical hemolytic uremic syndrome (aHUS) is a rare entity. SLE-triggered aHUS has significant morbidity and mortality without timely intervention, yet its frequency remains uncertain and optimal strategies for complement-directed therapies are largely expert-driven. We performed a comprehensive literature review and present a case of a 23-year-old female newly diagnosed with SLE/class IV lupus nephritis who developed aHUS that rapidly responded to the C5 antagonist, eculizumab. Review of the current literature identified forty-nine published cases of SLE with concurrent aHUS and revealed a predilection for aHUS in younger SLE patients, concurrent presentation with lupus nephritis, anti-dsDNA positivity, and complement system abnormalities. Over seventy percent of cases used eculizumab as complement-directed therapy with a trend towards faster time to improvement in laboratory parameters, though reported outcomes were highly variable. Early recognition of aHUS in SLE is pivotal in guiding appropriate therapeutic interventions, and prompt initiation of eculizumab may reduce the potential morbidity associated with plasmapheresis and additional immunosuppression. While eculizumab showcases promising results, its optimal timing and duration remain elusive. An understanding of a patients' complement genetics could aid management strategies, and ongoing research into complement-targeted therapies offers promising avenues for both SLE and aHUS treatment.
Background:
Thrombotic microangiopathy (TMA) syndromes are potentially life-threatening complications and are defined as integrated syndromes of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ injury. Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect various organs, including the hematopoietic system. SLE can complicate with TMA and can be categorized into two distinct groups by chronological association: TMA occurring as the initial presentation and leading to a diagnosis of SLE concurrently (TMA-cSLE) or TMA developing in patients previously diagnosed as having SLE (TMA-pSLE). We examined the differences in clinical characteristics, treatment responses, and clinical outcomes between these groups.
Methods:
We reviewed data of patients diagnosed as having TMA and SLE at Taipei Veterans General Hospital between 2002 and 2013. We included 29 patients: 8 and 21 in TMA-cSLE and TMA-pSLE groups, respectively. All underwent plasma exchange. Patients' demographic and clinical characteristics, disease activity, and treatment modality were summarized.
Results:
Overall survival (OS) from SLE or TMA diagnosis was poor for the TMA-cSLE group. Median OS from SLE diagnosis was 2.9 months in the TMA-cSLE group and 103.5 months in the TMA-pSLE group (p < 0.001). Median OS from TMA diagnosis was 2.9 months in the TMA-cSLE group and 10.7 months in the TMA-pSLE group (p = 0.58). Time to TMA remission after treatment appeared longer in the TMA-cSLE group (38.00 vs 10.76 days). Multivariate Cox analysis revealed TMA-cSLE and anti-RNP positivity were independent risk factors for mortality in SLE patients with TMA.
Conclusion:
The occurrence of TMA with SLE is rare, and its vigorous course results in high mortality and morbidity rates. In patients without a history of autoimmune disease, early suspicion of TMA and working-up for SLE under this condition are vital. Early recognition of TMA-cSLE and prompt plasma exchange with upfront immunosuppressive therapies for TMA-cSLE patients or anti-RNP-positive patients may improve their prognosis.
According to modern concepts, for the development of atypical hemolytic uremic syndrome (aHUS) in predisposed individuals, additional factors are necessary, which today are considered as complement-activating states. The most common of them are infections, pregnancy and childbirth, autoimmune diseases, transplantation of bone marrow and solid organs, some medications. Less commonly, aHUS is preceded by malignant arterial hypertension and glomerular kidney disease. Clinical observation of a patient suffering from a steroid-sensitive relapsing nephrotic syndrome (NS) for 10 years, in which after a viral infection first increased blood pressure, developed impaired renal function and hematological manifestations of thrombotic microangiopathy (ТМА), is given. In the presented observation, aHUS developed as a “second disease” in a patient with previously diagnosed glomerular kidney disease, which led to the rapid progression of chronic kidney disease with the development of terminal renal failure. This is evidenced by the nature of the course of the disease – NS recurring after acute respiratory viral infections, not accompanied by changes in urine sediment, arterial hypertension, impaired renal function and easily stopped by corticosteroids with rapid disappearance of proteinuria and normalization of protein blood counts. The change in the clinical picture of nephritis after a herpes zoster infection made us think about the development of a second renal disease of a different nature, other than glomerulonephritis. Undoubted AKI, combined with severe anemia and thrombocytopenia, was the basis for the exclusion of primarily TMA. The exclusion of TTP, STEC-HUS and the most common causes of secondary TMA made it possible to diagnose atypical HUS. The role of NS in the development of TMA is discussed. Blood coagulation disorders and VEGF-dependent mechanisms are considered as possible mechanisms.
