Treatment of Catastrophic Antiphospholipid Syndrome

Chapter 17

Treatment of Catastrophic Antiphospholipid Syndrome Ignasi Rodríguez-Pintó, Gerard Espinosa and Ricard Cervera Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain

17.1 INTRODUCTION Catastrophic antiphospholipid syndrome (CAPS) is the most severe presentation of the antiphospholipid syndrome (APS) that, luckily, affects only a minority of patients with the condition. It is characterized by multiple organ involvement in the setting of high-titre antiphospholipid antibodies (aPL), basically due to multiple-vessel thrombosis all at one time or in a very short time and its resulting inflammatory response syndrome [1]. The optimal management of CAPS has been a challenge since its description. CAPS is a severe clinical condition with a very bad prognosis without treatment [2]. Today, CAPS mortality continues to be extremely high despite therapy [3]. Due to this high mortality rate, early diagnosis, and aggressive treatment are essential clues in its successful management. The evaluation of CAPS treatment in formal prospective randomized studies is very difficult due to its low incidence. Thus, in order to improve our knowledge on this condition, the European Forum on Antiphospholipid Antibodies created the CAPS Registry in 2000. This is an international registry in which all cases from anywhere in the world published or communicated to the coordinators are included. The analysis of hundreds of patients with this condition included in this registry allowed the evaluation of several therapeutic combinations and to propose the current therapeutic approach [4]. These guidelines state that specific therapy together with precipitating factor treatment and supportive treatment should be administered to patients with clinical suspicion of CAPS. Current knowledge supports the treatment with the combination of high doses of glucocorticoids (GC) and anticoagulation (AC) with heparin as first-line treatment. Adding plasma exchange (PE), intravenous immunoglobulins (IVIG), or both should also be considered in cases with Antiphospholipid Syndrome in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63655-3.00017-X © 2016 Elsevier B.V. All rights reserved.

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associated life-threatening situations. Finally, intravenous cyclophosphamide is recommended in patients whose CAPS is associated with systemic lupus erythematosus (SLE) [5] (Fig. 17.1). In addition, rituximab, as an add-on therapy in CAPS patients refractory to conventional treatment or recurrent cases, has shown a benefit [6]. More recently, some authors have reported success in the treatment of CAPS with eculizumab [7,8]. Clinical suspicion of catastrophic APS (ie, 2 classification criteria)*

Treatment of precipitating factors (ie, antibiotics)

Life-threatening condition?

No

Yes

(a) Effective anticoagulation with intravenous heparin + (b) High doses of steroids

Clinical improvement?

Yes

Steroids tapered + Oral anticoagulants

No

(a) Effective anticoagulation with intravenous heparin + (b) High doses of steroids + (c) IVIG and/or plasma exchange**

Clinical improvement?

Yes

No

Add other therapies: Cyclophosphamide (if SLE flare) Rituximab (if severe thrombocytopenia)

or prostacyclin or fibrinolytics or defibrotide

FIGURE 17.1  Treatment algorithm of catastrophic APS. *Consider exclusion of other microangiopathic syndromes (mainly thrombotic thrombocytopenic purpura and heparin-induced thrombosis/ thrombocytopenia). **With fresh frozen plasma, specially indicated if schistocytes are present. IVIG, intravenous immunoglobulins; SLE, systemic lupus erythematosus.

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17.2  CURRENT APPROACH General measures should be the backbone in the treatment of these patients since their bad clinical condition frequently warrants vital support to preserve their clinical stability. Aggressive treatment of any identifiable trigger factor should be attached to the specific therapies. Current treatment guidelines for specific CAPS therapy were established more than 10 years ago based on the analysis of CAPS patients treated according to their physician’s criteria [9]. Of note, when each treatment was analysed individually, only AC had a significant effect in improving the vital prognosis, however, the combination AC + GC + PE and/or IVIG archived the highest survival rate (70%) [10]. In 2006, the data from the first 250 patients included in the CAPS Registry permitted the evaluation of the treatments used up to date in a large database [11]. AC proved to be the treatment associated to a higher recovery rate (63% in episodes treated with AC vs 22% in episodes not treated with AC; p < 0.0001). Considering therapy combinations, the highest survival rate was achieved by the combination of AC + GC + PE (78%) and AC + GC + PE and/or IVIG (69%). However, no statistical difference was found between them. In addition, no difference was found between the recovery rate considering the presence and absence of a specific combination of treatments. However, there was a trend toward a higher rate of recovery for episodes that were treated with AC + GC + PE and/or IVIG and AC + GC + PE (69% vs 54.4% (p = 0.089), and 77.8% vs 55.4% (p = 0.083), respectively). A 20% decrease in mortality rate was also observed between those patients diagnosed before 2001 as opposed to those diagnosed between 2001 and Feb. 2005. The most important difference between these two periods was the higher number of precipitating factors in the second period and the fact that combined therapy of AC + GC + PE and/or IVIG was used most often for CAPS episodes diagnosed in the second period. Despite evident methodological limitations, these data strengthened the initial recommendation of the combined therapy (AC + GC + PE and/or IVIG) as the first line of treatment in patients with CAPS. A task force on CAPS that met at the 14th International Congress on Antiphospholipid Antibodies reviewed current evidence on CAPS treatment. Taking into account the evidence summarized, it recommended the triple therapy (AC + GC + PE and/or IVIG) with a grade of recommendation B [3]. Furthermore, the addition of cyclophosphamide to the triple therapy was suggested for patients with SLE with a grade of recommendation D [12].

17.2.1  Supportive General Measures According to the patient medical condition, appropriate supportive care should be established. Often it includes intensive care unit (ICU) admission [13]. External ventilation support and haemodialysis might be necessary, but mostly only tight control is necessary. Classical thrombotic risk factors should be controlled or avoided when possible. It might include the use of external pneumatic compression devices when immobility is a concern. Any surgery not removing necrotic tissue to control the cytokine storm should be postponed. In addition,

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CAPS patients may benefit from glycaemic control, stress ulcer prophylaxis, and blood pressure control [14].

17.2.2  Trigger-Guided Therapy A precipitating factor is reported in more than half of patients with CAPS [11]. Infections are the most common precipitating condition in patients with CAPS. They are present as a precipitating factor in 22% of patients. Thus, early identification and treatment of any possible infection is mandatory. They are followed by surgical procedures (10%), anticoagulation withdrawal or low international normalized ratio (INR) (8%), medications (7%), obstetric complications (7%), neoplasia (5%), and SLE flares (3%) as precipitating factors [2]. Therefore, whenever possible, known CAPS triggers should be avoided in patients with APS. Accordingly, when an infection is suspected, the infection site pharmacokinetics and microorganisms pharmacodynamics should be taken into consideration in order to adequately select the antibiotic from the beginning. Thus, any effort should be undertaken in order to recover the responsible microorganism. At the same time, removing necrotic tissue or limb amputation is advised with the aim of controlling systemic inflammatory response [14–16]. The perioperative management of patients with APS or aPL carriers should be very cautious with the purpose of decreasing thrombotic recurrence risk or the development of a catastrophic episode. Thus, careful bridging between oral anticoagulant to heparin is required. A multidisciplinary approach to each case with an haemostasis specialist may likely be necessary [17]. In addition, puerperium should be adequately covered for a minimum of 6 weeks with parenteral anticoagulants.

17.2.3  Specific Therapies Specific therapeutic approach to CAPS is based on the rationale of the physiopathologic events thought to take place during the catastrophic episode and the evidence accumulated by the empirical approach of the physicians over time. From a rational point of view, CAPS could be understood as a ‘thrombotic storm’, where multiple thrombotic events affecting several vascular territories take place over a brief period of time. It is similar to other clinical conditions such as purpura fulminans or haemolysis, elevated liver enzymes, and low platelets (HELLP) [18]. Kitchens et al. hypothesized that newly formed clots in patients with preexisting hypercoagulability would promote thrombin generation, driving to a prothrombotic storm. In addition, fibrinolysis would not be able to prevent this process due to an increase in plasminogen activation inhibitors [19]. However, some of the clinical manifestations of CAPS seem not to be caused by vascular thrombosis, but by systemic inflammatory response syndrome due

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to the high level of inflammatory reactants [20]. Indeed, most patients with CAPS exhibit an increase of acute phase reactants, such as erythrocyte sedimentation rate, C-reactive protein, ferritin, fibrinogen, and/or factor VIII levels, thus revealing an inflammatory milieu [21]. Altogether, an inflammatory storm attached to multiple sites thrombosis seems to take place in patients with CAPS. Thus, concomitant treatment with AC associated with immunomodulatory therapies seem to be the more attractive approach for patients with CAPS.

17.2.3.1 Anticoagulation AC with heparin is the mainstay CAPS treatment. The main reason for its use is the inhibition of ongoing clotting and its ability to break up existing clots that may contribute to ongoing thrombosis [1,3,14,22–24]. Moreover, although its pharmacodynamic mechanisms are not completely understood, the antiinflammatory activity of heparin seems to account for its extraordinary usefulness in CAPS [25] and, in addition, heparin seem to inhibit aPL binding to their target on the cell surface [26]. Most CAPS patients are initially treated with unfractionated heparin because nonfractionated heparin enables throwing back its effect if necessary. This is often a need during ICU period to perform invasive procedures either electively or because of bleeding. Later, nonfractionated heparin can be switched to low molecular weight heparin (LMWH) and finally to oral anticoagulation. However, physicians should not rush to change heparin to other anticoagulants because a long period under heparin treatment favours clot fibrinolysis. A 7- to 10-day course under heparin treatment is recommended. Still, heparin should not be withdrawn before achieving a correct INR between 2 and 3 with oral anticoagulant treatment. 17.2.3.2 Steroids GC are the most commonly used antiinflammatory drugs in the treatment of autoimmune diseases. GC bind to a cytoplasmic receptor that, subsequently, binds to the chromosomic material and modulates gene expression. In this sense, GC are used to overcome the excessive inflammatory response triggered by multiple blood flow occlusions and resultant ischaemic necrotic tissue. In addition, beneficial effects of GC treatment have been invocated because steroids inhibit nuclear translocation and function of proinflammatory transcription factors such as activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) that are in the core of the intracellular signal elicited by aPL binding to endothelial cells. Moreover, due to their antiinflammatory effects, GC decrease antibody production and therefore, aPL production. Although no direct evidence supports GC use in patients with severe infections or in CAPS unless patients develop adrenal insufficiency [11,27], strong rational arguments drive investigators to think that this lack of evidence is attributable to underpowered studies. Thus, GC are recommended in patients with

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CAPS, although the best initial dose, the route of administration, and the tapering strategies are still an area of investigation. Data from the CAPS Registry showed that GC are given as intravenous pulses of 500–1000 mg/day for 1–3 days in a third of episodes and as oral or intravenous dosages of 1–2 mg/kg per day in another third. Nevertheless, most physicians continue GC treatment until the patient is discharged in a daily oral dose, and then taper the dose until it is administered in a low dose.

17.2.3.3  Plasma Exchange PE is a technique designed to remove high-molecular-weight molecules from plasma. It removes large quantities of plasma (usually 2–5 L) and replaces it with either fresh-frozen or stored plasma. Plasmapheresis should be kept to refer to the extraction of a smaller quantity of plasma (approximately 600 mL) without reposition [28]. Thus, its use in CAPS relies on the rationale that PE removes aPL and cytokines from the patient while volume replacement with fresh-frozen plasma would restore natural anticoagulants, such as antithrombin-III. Its use comes from analogy to the management of classical microangiopathic conditions where this treatment has shown beneficial effects in randomized controlled trials [29]. Therefore, PE is especially suitable in those patients with CAPS who present serological features of microangiopathy (schistocytes) [30]. The use of therapeutic PE in CAPS is recommended with a grade of evidence of 2C by the American Society for Apheresis (ASA) [31]. It is indicated when a patient with CAPS evolves to a life-threatening situation as an add-on therapy to effective anticoagulation with intravenous heparin and high-dose steroids [32]. There is no consensus on the replacement fluid of choice for therapeutic PE in CAPS, and fresh-frozen plasma, human albumin, and solvent/detergent plasma have been used [11]. Following ASA recommendations, a combination of plasma and albumin would provide the necessary benefit of therapeutic PE and minimize potentially serious and undesirable side effects from excessive exposure to plasma. Finally, there is no recommendation about the duration of this procedure. In general, it is continued for a minimum of 3–5 days; however, clinical response is the main parameter that should dictate discontinuation of the therapy. 17.2.3.4  Intravenous Immunoglobulins Intravenous immunoglobu­lins (IVIG) are used in a wide variety of autoimmune and inflammatory conditions, although the mechanisms of action by which IVIG exert its immunomodulatory and antiinflammatory effects remain unclear [33]. High intravenous antibody concentration most likely leads to Fc-receptor overload, thus inhibiting pathologic autoantibody to develop their detrimental effects and increasing their clearance. At the same time, it might increase regulatory T cells (Tregs) downregulating cytokine storm [33].

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The beneficial effects of IVIG in primary APS have been proved only recently by decreasing aPL titres and, therefore, reducing the thrombotic risk of these patients [34,35]. Thus, rationally IVIG may be effective to achieve a prompt reduction of aPL titres and downregulate proinflammatory levels in patients with CAPS. There is no established recommendation on the dose that might be beneficial in patients with CAPS. Although, by analogy to other autoimmune diseases, they have been used following two different schemes: 400 mg/kg daily for 5 days and a total dose of 2 g/kg of body weight infused over a period of 2–5 days. However, when PE is performed, IVIG are administered after PE session and often an extra IVIG dose is administered after PE in order to replace IVIG removed by it. IVIG are usually well tolerated, but there are some reports of thromboembolic events and acute renal failure after IVIG, especially in those patients with CAPS in whom AC must be stopped because of bleeding. Thus, IVIG should be administered slowly, especially in elderly patients with high blood pressure, diabetes, or hypercholesterolaemia. In any case, attention should be maintained for early detection of any complication.

17.2.3.5 Cyclophosphamide Cyclophosphamide is a nitrogen mustard-alkylating agent that binds to deoxyribonucleic acid in immune cells leading to their death. At the same time, cyclophosphamide enhances T effector cells proliferation while suppressing Th1 helper activity and upregulating Th2 response and abrogates the function of Tregs [36]. In CAPS, lymphoid tissue suppression leads to aPL and cytokines level reduction, thus downregulating the elicited storm. According to the CAPS Registry, cyclophosphamide was prescribed in a third of episodes of CAPS, mostly as an intravenous pulse but also as an oral dose. However, different dosages and routes of administration did not lead to a statistically relevant difference between patients who died and those who survived, nor did the addition of cyclophosphamide to combined therapy [11]. However, Bayraktar et  al. [5] performed a multivariate analysis of the data included in the CAPS Registry that showed cyclophosphamide to be associated with a decrease in mortality rate in those patients with CAPS associated with SLE. Thus, cyclophosphamide is recommended in cases of severe CAPS in patients with SLE. Although no data is available in CAPS, similarity to other autoimmune conditions, a recommended regimen of 750 mg/m2 monthly or 500 mg biweekly during 6 or 3 months has been proposed [37].

17.3  NEW APPROACHES Despite adequate treatment, mortality rate in patients with CAPS continues to be too high. Recent advances on pathogenic mechanism understanding together

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with the development of new biologic-based immunotherapies led to new treatments that have transformed the current therapeutic approach of systemic autoimmune diseases. Simultaneously, biologic science knowledge increase raised the possibility of new therapeutic approaches. In this sense, rituximab and eculizumab have been proposed in refractory cases of CAPS.

17.3.1 Rituximab Rituximab is a chimeric monoclonal antibody against CD20, a surface protein expressed on B cells membrane. Although rituximab seems not to have any effect on memory B and plasma cells (because they discontinue CD20 expressing when they mature) some regulatory effects of B cells independent of antibody production have been claimed to explain rituximab effect in acute disease. Rituximab is approved by the regulatory agencies for the treatment of chronic lymphocytic leukaemia, diffuse large B-cell, advanced follicular lymphoma, refractory rheumatoid arthritis, and severe vasculitis remission induction [38]. However, rituximab is often used off-label for the treatment of several autoimmune diseases [6,39–41]. Indeed, an open-label trial showed rituximab to be safe and useful in controlling noncriteria manifestations of APS, such as thrombocytopenia, skin ulcers, nephropathy, and cognitive dysfunction [42]. Furthermore, rituximab was able to decrease recurrence rates in patients with recurrent thrombosis or refractory thrombocytopenia [43]. In this regard, rituximab has been used as an alternative second-line therapy when facing refractory or recurrent cases of CAPS. Although no randomized trial can be driven in patients with CAPS due to its rarity, the analysis of 20 cases treated with rituximab included in the CAPS Registry showed that 80% recovered from the CAPS episode and did not present new episodes of thrombosis [3,6]. Although no comparison group was included in this study, a clear decrease in mortality rate published to date (50%) is recognizable. Indeed, based on these observations, rituximab is now considered safe in APS patients, although with an uncertain effect on the aPL profile. Furthermore, rituximab is recommended in refractory cases of CAPS and has even been proposed as first-line therapy in patients with CAPS [6]. Current guidelines recommend rituximab in the treatment of patients with a refractory and relapsing course of CAPS [3].

17.3.2 Eculizumab Eculizumab is a monoclonal antibody that binds with high affinity to complement protein C5, inhibiting its cleavage and, thus, preventing C5a formation and its chemoattractant function so as the membrane attack complex assembly. It is approved by the US Food and Drug Administration (FDA) for the treatment

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of paroxysmal nocturnal haemoglobinuria and for atypical haemolytic uraemic syndrome [44]. A complement inhibitory property of heparin have been claimed to explain its effects in obstetric APS. Furthermore, basic research has shown that sublytic concentration of membrane attack complex stimulates endothelial cells adhesion molecules expression, tissue-factor synthesis and induce apoptosis leading to endothelial cells detachment, basement membrane collagen exposure and subsequent indirect clotting pathway activation. Since CAPS is often triggered by a concurrent infection, a targeted therapy against C5 offers an attractive therapeutic approach to CAPS because its capacity to inhibit complement cascade at the level of C5 preserves C3b-mediated infectious agents and immune complexes opsonisation and thus, immune mediated mechanisms to control infections. Moreover, although renal transplant is classically contraindicated in CAPS patients with end-stage renal diseases based on the risk CAPS recurrence, Lonze et al. reported a successful renal transplant in a patient with a previous history of CAPS prophylactically treated with eculizumab together with anticoagulation and standard immunosuppression [45]. In this regard, a phase 2 open-label clinical trial (NCT01029587) was launched in order to prove the efficacy and safety of eculizumab to prevent recurrence in patients with previous history of CAPS who undergo a renal transplant. However, the low incidence of this condition precluded enrolment of enough patients to conduct any trial, and this study had to be finished prematurely. Recently, some authors reported success with eculizumab use in patients with refractory episodes of CAPS [7,8,45,46]. Dosage has been taken over from the experience on other thrombotic microangiopathies. Weekly doses of 900–1200 mg of eculizumab have been used in the acute phase, decreasing its frequency after effervescence to 900 mg administered every 2 weeks. However, there is no known clue to decide the duration of the treatment and, then, often not only effectivity has to be taken into consideration but also efficiency. In conclusion, eculizumab seems to be an attractive, promising treatment for patients with CAPS or at least to prevent its recurrence in high-risk situations, although a larger study is needed to define eculizumab’s place in CAPS treatment. However, its high cost makes it difficult for many initiatives to use it. Expected future economic cost drop will probably increase its use in CAPS, providing the required experience.

17.3.3  New Oral Anticoagulants Anticoagulation with heparin, followed by long-term anticoagulation with a vitamin K antagonist, constitute the mainstay of therapy for thrombotic APS and CAPS. However, vitamin K antagonists have a slow onset of action, a narrow therapeutic window, numerous interactions and, thus, regular INR monitoring

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is required. These limitations have driven a search for new alternative anticoagulant drugs. Recently, new oral AC have appeared in the haemostasis therapy armamentarium. They are administered in a fixed dose with predictable effect and do not require regular anticoagulant monitoring because their effect is not influenced by diet and drug interaction. Pivotal phase III randomized controlled trials have established its comparable efficacy and safety to vitamin K antagonists in patients with deep vein thrombosis. Moreover, recently a phase II/III randomized controlled clinical trial has begun in order to prove its efficacy in patients with classical APS. However, they have never been used during the acute phase of CAPS. Before they can be used in the acute phase of CAPS, some problems might need to be overcome because undoing their effect is not possible and is frequently required in patients admitted in the ICU where invasive procedures often need to be undertaken. In addition, unlike the treatment with heparin, no effects are known from the new anticoagulants on complement system. Thus, until a larger experience with the use of new anticoagulants is available, heparin continues to be the recommended anticoagulant drug for CAPS. However, new anticoagulants may have a role in the future, at least as a prophylaxis for those cases that develop CAPS while under treatment with vitamin K antagonists.

17.4 CONCLUSIONS In summary, the treatment of CAPS is based on three base pillars: supportive care, precipitating factor identification and treatment, and specific therapy. However, the most important point should be to suspect the condition in patients in a critical clinical situation due to multiorgan involvement. Supportive care should be assured, along with intensive care support colleagues. Simultaneously, a workup should be undertaken in order to identify and treat any precipitating factor. AC together with corticosteroids remains the basic treatment in patients with CAPS because it is clearly associated with a higher survival rate. When CAPS patients evolve to a life-threatening situation involving cerebral or cardiac manifestations or signs of microangiopathic haemolytic anaemia are detected, triple therapy should be the treatment of choice. However, in those cases without these severity parameters, AC + GC might be sufficient. In addition, cyclophosphamide might be added in patients with associated SLE. Unfortunately, despite the current approach, CAPS mortality remains unacceptably high and optimizing current available therapy is necessary. In those cases with a severe presentation, the addition of rituximab has shown to be of great value. However, eculizumab might be a better option in patients with microangiopathic anaemia features. Regardless of these promising results with these new therapies, more experience is required.

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