For antiphospholipid syndrome, some alternatives to vitamin K antagonists including rituximab and hydroxychloroquine may be suitable, says an international task force. Two clinical trials are recruiting to provide better information.
Erkan D Aguiar CL Andrade D Cohen H. 14th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends. Autoimmunity Reviews (2014) 13: 685–696.
In some cases, rituximab and the lupus drug hydroxychloroquine may prove useful against antiphospholipid syndrome (APS), says the APS Treatment Trends Task Force in newly published recommendations. These are based on discussions during and presentations from the 14th International Congress on aPL (antiphospholipid antibodies) held in 2013.
The committee was tasked with judging new alternatives for APS that might avoid the problems (food and drug interactions, frequent monitoring requirements, and inconsistent test results) that complicate the standard long-term treatment, anticoagulation with vitamin K antagonists (VKA) such as warfarin.
VKA must remain the “mainstay” of anticoagulation, the task force concluded. Its report alerts physicians to two clinical trials now recruiting patients for rigorous assessment of some new alternatives.
The recommendations in brief:
New generation oral anticoagulants
Fixed-dose oral direct inhibitors (ODI) of coagulants -- dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquist), and edoxaban (Lixiana) – have no interactions with food, alcohol, or drugs important to coagulation.
There are no completed studies of ODI in aPL+ patients. RAPS (Ribaroxaban in AntiPhosphlipid Syndrome), an open label non-inferiority randomized trial in patients with thrombotic APS with or without lupus, is currently recruiting (See http://www.controlled-trials.com/ISRCTN68222801)
• Consider ODIs for venous thromboembolism (VTE) only with known allergy or intolerance to VKA or poor anticoagulant control.
• Monitoring remains a challenge: Some reagents show very poor sensitivity, and aPTT may be prolonged because of lupus anticoagulant (LA), and ODI can also cause false-positive LA test results. Better assays exist but are not widely available.
• Non-adherence with VKA is not a good reason to switch. Given the problems with monitoring, patient adherence is even more critical.
• There are no pharmacological reversal agents for ODI. Supportive measures include transfusions with blood components, activated charcoal, and renal replacement therapy for dabigatran.
• The International Society of Thrombosis and Hemostasis offers useful information for ODI use at http://onlinelibrary.wiley.com/doi/10.1111/jth.12038/pdf
Older non-heparin/warfarin anticoagulants
These are the indirect anti-factor Xa inhibitors (fondaparinux, idraparinux, idrabiotaparinux, danaparoid) and the non-oral direct thrombin inhibitors (argatroban, lepirudin, and bivalirudin).
• Consider danaparoid, fondaparinux, and argatroban for heparin-induced thrombocytopenia.
• Fondaparinux may alleviate or may itself induce heparin-induced thrombocytopenia, but the evidence for both is poor.
Many trials of lupus patients show that HCQ reduces thrombosis rates, but the mechanism is not clear.
• HCQ is recommended for all aPL+ lupus patients. There are no good data to recommend it for persistently aPL+ persons without autoimmune disorders, but it may be useful as an adjunct in refractory cases.
• Recruitment is underway for a multicenter prospective, randomized controlled trial of HCQ for primary thrombosis prevention in persistently aPL-positive but thrombosis-free patients without other systemic autoimmune diseases. More information is available at http://www.clinicaltrials.gov/ct2/show/NCT01784523.
• Only about half of lupus patients, at best, are adherent to HCQ.
• Use of HCQ for more than 10 years increases the risk of skin, eye, and muscle toxicity. Retinal screening is recommended at baseline, five years, and annually afterwards.
Besides lowering lipids, statins have anti-inflammatory and anti-thrombotic properties. Fluvastatin, simvstatin, and rosuvastatin reduce aPL-mediated tissue factor and other thrombotic factors in vitro and statins have many profound effects on monocytes, lymphocytes, and endothelial cells in APS.
Human trials have shown noteworthy effects on biomarkers of inflammation and thrombosis in APS patients, but no interventional trials have been published in part because good surrogate markers for patient selection and stratification are lacking.
• Do not use statins for APS in the absence of hyperlipidemia. A subgroup of aPL+ individuals with recurrent thrombosis despite anticoagulation might benefit.
• Consider perioperative statins for APS patients with high thrombosis risk
• Statins are contraindicated in pregnancy
B cell inhibitors
B cells play an important role in APS, and inhibitors prevent APS in mouse models. Limited clinical reports and one open-label Phase II study address rituximab use in APS, with intriguing but inconsistent results. Evidently belimumab has not been clinically tested for APS.
• B-cell inhibition “may have a role in difficult-to-treat APS patients,” possibly those with hematologic and microthrombotic/microangiopathic manifestations.
• The effective dose of rituximab for aPL+ patients is unknown.
• Administer IV methylprenisolone (100 mg) or other gulcocorticoid 30 minutes before each infusion.
• Belimumab has not yet been studied among aPL+ patients with lupus, but further information about this is anticipated.
Complement is implicated in APS via C5a, a potent factor in vascular inflammation. There are only a few case reports of a complement inhibitor (eculizumab) used in APS.
• Complement inhibition may play a role for APS patients refractory to anticoagulation, but more data are needed.
• Meningococcal infections are a risk with eculizumab, and patients should be immunized before taking it.