Thrombosis-related manifestations

Intra-abdominal thrombotic complications affecting the kidneys, adrenal glands, splenic, intestinal, and mesenteric or pancreatic vasculature were most commonly encountered, and the patients frequently presented with abdominal pain or discomfort. Renal disease was present in 71% of patients. Pulmonary complications were next at a frequency of 64%, with acute respiratory distress syndrome (ARDS) and pulmonary emboli accounting for the majority of these patients, while pulmonary hemorrhage, microthrombi, pulmonary edema, and infiltrates occurred in a minority of patients. The main pathological finding was noninflammatory thrombotic microangiopathy presented in 70% of the patients with lung specimen. Cerebral manifestations (infarcts, encephalopathy, seizures, or cerebral venous occlusions) were also frequent (62%). Microthrombosis was present in 48.9% of those patients who died, as revealed by necropsy. Cardiac problems occurred in 51%, often with valvular defects (mitral or aortic), while myocardial infarctions were a presenting feature in 25% of the patients.

Skin complications such as livedo reticularis , purpura, and skin necrosis, were also reported, occurring in 50% of the patients. In addition, other organs may be occasionally affected, including testicular/ovarian infarction, necrosis of the prostate, acalculous cholecystitis, bone marrow infarction, esophageal rupture, giant gastric ulceration, colonic ulcerations, thrombotic pancreatitis, and adrenal infarction, among other features .

SIRS-related manifestations

Some manifestations of SIRS, particularly ARDS, are frequently encountered in these patients . Although cytokine levels in very ill patients with CAPS have not been measured, it is assumed that SIRS manifestations are due to cytokine activation, which occurs in the acute phase of the illness. This may be superimposed on an underlying infective process, which itself may have been instrumental in “triggering” CAPS.

General measures

General measures should be the backbone in the treatment of these patients because their poor clinical condition frequently warrants vital support to preserve their clinical stability. Aggressive treatment of any identifiable trigger factor should be added to the specific treatment.

Current treatment guidelines for specific CAPS therapy were established >10 years ago on the basis of the analysis of patients with CAPS treated according to their physicians’ criteria . Noteworthy, when each treatment was analyzed individually, only AC had a significant effect in improving the vital prognosis; however, the combination of AC + GC + PE and/or IVIG archived the highest survival rate (70%) .

Data from the first 250 patients included in the “CAPS Registry” permitted the evaluation of the treatments used to date in a large database . Treatment with AC showed a higher recovery rate (63% in patients treated with AC vs. 22% in patients 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 these combinations. Furthermore, 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 patients 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). In addition, a 20% decrease in mortality rate was observed between patients diagnosed before 2001 and those diagnosed between 2001 and February 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 patients 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.

The Task Force on CAPS that met at the 14th International Congress on aPL reviewed current evidence on CAPS treatment. Taking together the evidence summarized above, it recommended the triple therapy (AC + GC + PE and/or IVIG) with a grade of recommendation B. Furthermore, the addition of cyclophosphamide to the triple therapy was suggested for patients with SLE with a grade of recommendation D .

Supportive general measures

According to the patient medical condition, appropriate supportive care should be established, which often includes admission to the ICU . External ventilation support and hemodialysis might be necessary, but mostly only tight control is necessary. Classical thrombotic risk factors should be controlled or avoided when possible. This might include the use of external pneumatic compression devices when immobility is a concern. Any surgery should be postponed when its aim is not to remove necrotic tissue to control the cytokine storm. In addition, CAPS patients may benefit from glycemic control, stress ulcer prophylaxis, and blood pressure control .

Trigger-guided therapy

When an infection is suspected, the infection site (pharmacokinetics) and microorganisms (pharmacodynamics) should be considered to adequately select the antibiotic from the beginning. Also, efforts should be undertaken to isolate the responsible microorganisms. Simultaneously, removing necrotic tissue or limb amputation is advised with the aim of controlling systemic inflammatory response .

The perioperative management of patients with APS or aPL carriers should be handled cautiously with the purpose of decreasing thrombotic recurrence risk or the development of a catastrophic episode. Thus, careful bridging between oral anticoagulant and heparin is required. Probably, a multidisciplinary approach with a hemostasis specialist for each case might be necessary . In addition, puerperium should be adequately covered for a minimum of 6 weeks with parenteral anticoagulants.

Anticoagulation

AC with heparin is the mainstay of CAPS treatment. The main reason for its use is the inhibition of ongoing clotting and its ability to degrade existing clots that may contribute to the ongoing thrombosis . Moreover, although its pharmacodynamic mechanisms are not completely understood, anti-inflammatory activity of heparin seems to account for its extraordinary usefulness in CAPS , and in addition, heparin seems to inhibit aPL binding to their target on the cell surface . Most of the patients with CAPs are initially treated with unfractionated heparin because it enables repeating its effect in case of requirement. This is often a need during the ICU period either to perform invasive procedures electively or to control bleeding. Later, the unfractionated heparin can be switched to low-molecular-weight heparin (LMWH) and finally to oral anticoagulants. However, physicians should not rush to change heparin to other anticoagulants because a longer period of heparin treatment favors clot fibrinolysis. A 7–10 day course of heparin treatment is recommended. However, heparin should not be withdrawn before achieving a correct INR between “2” and “3” with oral anticoagulant treatment.

Steroids

GCs are the most commonly used anti-inflammatory drugs in the treatment of autoimmune diseases. GCs bind to a cytoplasmic receptor that in turn binds to the chromosomal material and modulates gene expression. In this sense, GCs are used to overcome the excessive inflammatory response triggered by multiple blood flow occlusions and resultant ischemic necrotic tissue.

In addition, the 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 intracellular signal elicited by aPL binding to endothelial cells. Moreover, because of their anti-inflammatory effects, GCs decrease antibody production and therefore aPL production.

There is no direct evidence to support the use of GCs in patients with severe infections or with CAPS, unless patients develop adrenal insufficiency ; this lack of evidence is probably attributable to underpowered studies. Thus, GCs are recommended in patients with CAPS, although the best initial dose, the route of administration and the tapering strategies are still under investigation. Data from the “CAPS Registry” showed that GCs are administered as intravenous pulses of 500–1000 mg/day for 1–3 days in one-third of the patients and as oral or intravenous dosages of 1–2 mg/kg/day in another one-third. Nevertheless, most physicians continue GC treatment until the patient is discharged on a daily oral dose and then taper the dose until it is being administered at low doses.

Plasma exchange

PE is a technique designed to remove large molecular weight molecules from the plasma. It includes removing large quantities of plasma (usually 2–5 L) and replacement by either fresh-frozen or stored plasma. The term plasmapheresis should be restricted to refer to the extraction of a smaller quantity of plasma (∼600 ml) without reposition . Thus, its use in CAPS rely on the rational 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 follows the analogy to the management of classical microangiopathic conditions where this treatment has shown its beneficial effects in randomized controlled trials . Therefore, PE is especially suitable in those patients with CAPS who present with serological features of microangiopathy (schistocytes) .

The use of therapeutic PE in CAPS is recommended with a grade of evidence of 2C by the American Society for Apheresis (ASFA) . It is indicated when a patient with CAPS developed a life-threatening condition as an add-on therapy to effective AC with intravenous heparin and high-dose steroids .

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. Following ASFA recommendations, a combination of plasma and albumin would provide the necessary benefits of therapeutic PE and minimize potentially serious and undesirable side effects from excessive exposure to plasma.

Recommendation has not been given about the duration of this procedure. It is generally continued for a minimum of 3–5 days; however, clinical response is the main parameter that should dictate discontinuation of the therapy.

Intravenous immunoglobulins

IVIGs are used in a wide variety of autoimmune and inflammatory conditions although the mechanisms of action by which IVIGs exert its immunomodulatory and anti-inflammatory effects remain unclear. Probably, high-antibody concentration leads to Fc-receptor overload, thus inhibiting pathologic autoantibody to develop their detrimental effects and increasing their clearance. Simultaneously, it might increase Tregs downregulating cytokine storm . Only recently, the beneficial effects of IVIGs in primary APS have been proved by decreasing aPL titers and, therefore, reducing the thrombotic risk of these patients . Thus, rationally IVIGs may be effective to achieve a prompt reduction of aPL titers and downregulate proinflammatory levels in patients with CAPS.

Recommendations have not been established on the dose that might be beneficial in patients with CAPS. Although, by analogy to other autoimmune diseases, IVIGs 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 for a period of 2–5 days. However, when PE is performed, IVIGs are administered after the PE session, and in addition, often an extra IVIG dose is administered after PE to replace the IVIG removed by it.

IVIGs are usually well tolerated, but there are some reports of thromboembolic events and acute renal failure after administering IVIGs, especially in those patients with CAPS in whom AC has to be stopped because of bleeding. Thus, IVIG should be administered slowly, especially in elderly patients with high blood pressure, diabetes, or hypercholesterolemia. In any case, monitoring should be done for early detection of any complication.

Cyclophosphamide

Cyclophosphamide is a nitrogen mustard-alkylating agent that binds to deoxyribonucleic acid in immune cells leading to their death. Simultaneously, cyclophosphamide enhances T-effector cell proliferation while suppressing Th1 helper activity and upregulating Th2 response and abrogates the function of regulatory T cells (Tregs) . In CAPS, lymphoid tissue suppression leads to the reduction of aPL and cytokine levels, thus downregulating the elicited storm.

According to the “CAPS Registry,” cyclophosphamide was prescribed in one-third of patients with CAPS, mostly as an intravenous pulse but also as an oral dose. However, different dosages and routes of administration did not lead to statistically relevant difference between patients who died and those who survived nor did the addition of cyclophosphamide to the combined therapy .

However, Bayraktar et al. 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 patients with severe CAPS with SLE. Although data are not available on CAPS compared with other autoimmune conditions, a recommended regimen of 750 mg/m ² monthly or 500 mg fortnightly for 3–6 months has been proposed .

Rituximab

Rituximab is a chimeric monoclonal antibody against CD20, a surface protein expressed on the membrane of B cells. Although rituximab does not seem to have any effect on memory B and plasma cells, because they discontinue CD20 expression when they mature, some regulatory effects of B cells independent of antibody production have been claimed to explain the effect of rituximab on acute disease.

Rituximab is approved by the regulatory agencies for treating chronic lymphocytic leukemia, diffuse large B-cell lymphoma, advanced follicular lymphoma, refractory rheumatoid arthritis, and severe vasculitis remission induction . However, rituximab is often used off-label for the treatment of several autoimmune diseases . Indeed, a small open-label trial suggested rituximab is safe and useful to control noncriteria manifestations of APS, such as thrombocytopenia, skin ulcers, nephropathy, and cognitive dysfunction . Furthermore, rituximab could decrease the recurrence rate in patients with recurrent thrombosis or refractory thrombocytopenia . In this regard, rituximab has been used as an alternative second-line therapy for refractory or recurrent cases of CAPS.

The evidence for the use of rituximab in patients with CAPS comes from the recent review performed by our group . In this review, we identified 20 of 441 (4.6%) patients included in the “CAPS Registry” as of May 2013 who were treated with rituximab.

Regarding treatment, AC was the most frequent treatment being used in all patients followed by GCs in 17 (85%) patients, IVIGs in 16 (80%), PE in 13 (65%), and cyclophosphamide in 4 (20%). Overall, 16 (80%) patients were initially treated with the complete combination of AC + GC + PE and/or IVIG.

Rituximab was the first-line treatment associated with combined therapy of CAPS in 8 (40%) patients. In six of them, the reason was the initial severity of clinical picture, and in the remaining two, rituximab was administered as a treatment of lymphoma. In 12 (60%) patients with poor response to initial treatment or recurrent episodes of CAPS, worsening of thrombocytopenia or development of new thrombosis, rituximab was the second-line therapy. Rituximab was used in different regimens: the most frequent was two fortnight doses of 1000 mg (8 patients), followed by four weekly doses of 375 mg/m ² (6 patients).

Considering the outcome, 16 (80%) patients recovered from the acute CAPS episode and 4 (20%) died at the time of the event. The two patients died had received rituximab as the first-line therapy. The median follow-up time was 9.5 (interquartile range 17.25) months (range 1–36 months). A recurrent episode of thrombocytopenia 24 months after the episode of CAPS developed in a patient requiring an increase in prednisone dose and a second course of rituximab. Another patient presented with cutaneous necrosis 9 months after the CAPS event, and he required high dose of intravenous methylprednisolone and a second 4-week course of rituximab (375 mg/m ² /week) with complete resolution. Interestingly, no further episodes of thrombosis developed in the remaining patients.

Regarding the effect of rituximab in aPL profile, these data were available in only 8 patients. Overall, half of the patients remained with persistent aPL during the follow-up with positive lupus anticoagulant (LA) at 11 weeks and LA plus anticardiolipin (aCL) antibodies at 2, 3, and 5 months of follow-up, respectively. In the remaining 4 patients (50%), aPL became negative. Briefly, in one patient, LA became negative 7 months after the infusion without information on the status of aCL and anti-β2-glycoprotein I (aβ2GPI) antibodies after and before rituximab administration. In the second patient, LA became negative several weeks after discharge from the hospital. Unfortunately, no information about the status of aCL and aβ2GPI after rituximab was available. In the third patient, triple aPL negativity was reported after 1 month of follow-up. Finally, the fourth patient became negative for aβ2GPI. Information on LA and aCL was not available.

Despite the scientific value of this review, it has several limitations such as the low number of patients with CAPS treated with rituximab and the difficulty of analyzing the isolated effect of rituximab given the fact that all these patients received a combined therapy including AC, GC, PE, and/or IVIG. Thus, although rituximab can be considered in selected patients with CAPS, especially in those with prominent hematologic and/or microthrombotic manifestations, further studies are needed to determine the true effectiveness of rituximab in CAPS.

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 as the membrane attack complex assembly. It is approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria and for atypical hemolytic uremic syndrome . A complement inhibitory property of heparin has been claimed to explain its effects in obstetric APS. Furthermore, basic research has shown that sublytic concentration of the membrane attack complex stimulates endothelial cell adhesion molecule expression and tissue-factor synthesis, and induces apoptosis leading to endothelial cell detachment, basement membrane collagen exposure, and subsequent indirect clotting pathway activation. Because 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 agent and immune complex opsonization and thus immune-mediated mechanisms to control infections.

Moreover, although renal transplant is classically contraindicated in patients with CAPS with end-stage renal diseases based on the risk of CAPS recurrence, Lonze et al. reported a successful renal transplant in a patient with a history of CAPS prophylactically treated with eculizumab together with AC and standard immunosuppression . In this regard, a phase 2, open-label clinical trial ( NCT01029587 ) was conducted to prove the efficacy and safety of eculizumab to prevent recurrence in patients with a history of CAPS who undergo renal transplant. However, the low incidence of this condition precluded enrolment of enough patients to conduct any trial, and this study had to be completed prematurely.

Recently, some authors reported success with eculizumab use in patients with refractory episodes of CAPS . Dosage was taken from previous experience on other thrombotic microangiopathies. Weekly doses of 900–1200 mg of eculizumab have been used in the acute phase, with a decrease in its frequency after effervescence to 900 mg administered every 2 weeks. However, the optimal duration of the treatment is unknown.

Although eculizumab seems to be an attractive promising treatment for patients with CAPS or at least to prevent its recurrence in high-risk situations, a larger study is needed to define the role of eculizumab in CAPS treatment. The high cost hinders many initiatives to use it. Probably, the expected drop in its cost in the future will increase its use in CAPS, thereby providing the required experience.

New oral anticoagulants

Vitamin K antagonists have a slow onset of action, a narrow therapeutic window, and numerous interactions, and thus, regular INR monitoring is required. These limitations have driven a search for new alternative AC drugs. Recently, new oral anticoagulants have appeared in the hemostasis therapy armamentarium. They are administered in a fixed dose with predictable effect and do not require regular AC monitoring because its 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 been started to prove its efficacy in patients with classical APS. However, they have never been used during the acute phase of CAPS and until a larger study with the use of new anticoagulants is available on APS, heparin is the recommended anticoagulant for CAPS.

Intracellular signal modulation

Recently, the mammalian target of rapamycin (mTOR) pathway has been proposed to be a key step in the vascular stenosis that results from mechanical endothelial injury of patients with CAPS . mTOR is a large protein kinase ubiquitously and constitutively expressed . It associates with various proteins to generate two structurally and functionally distinct complexes termed mTOR complex 1 (mTORC1) and mTORC2 . Under high nutrient supply, mTORC1 promotes protein synthesis, lipogenesis, and energy metabolism . Endothelial intimal hyperplasia in kidney biopsies from patients with APS nephropathy was associated with mTOR pathway activation despite adequate AC . Furthermore, mTOR pathway activation and endothelial cell proliferation was proved in both carotid and left anterior descending arteries of patients with CAPS . Hence, mTOR pathway activation by aPL seems to induce part of the vascular injury noted in patients with CAPS although the mechanism through which aPL leads to cell activation remains unknown.

Sirolimus is a macrolide antibiotic produced by Streptomyces hygroscopicus . Initially, it was evaluated as an antifungal, but later, it was proved to be a potent immunosuppressant. In 1999, sirolimus was approved by the regulatory agencies as a treatment to prevent acute renal transplant rejection. Later, sirolimus has shown to avoid restenosis in patients undergoing percutaneous coronary intervention when eluted from a stent. Indeed, sirolimus-eluting stents are currently in use as a potent antiproliferative drug in patients to avoid arterial restenosis. However, some evidence point to a prothrombogenic effect of mTOR inhibitors, and thus, its potential benefits in patients with CAPS remain debatable .

Simultaneously, some new pathways are being traced that point to possible new therapeutic targets. Bacterial infection and lipopolysaccharides released are known to induce intracellular signaling through Toll-like receptor 4. It leads to the upregulation of tissue factor and adhesion molecules, which probably accounts for some of the clinical manifestations seen in DIC and probably in CAPS triggered by infections. GCs are known to block nuclear translocation of NF-κB and, although they seem to show little benefits in sepsis , they improved patient outcome when used in patients with CAPS. In this sense, a specific proteasome inhibitor (MG-132) has been shown to inhibit the thrombogenic properties of aPL antibodies in mice . However, its usefulness in patients with APS has not yet been proved.