Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them?

To cite this article: Vendramin C, Scully M. Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them? Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.10.006 Presse Med. 2019; //: /// on line on www.em-consulte.com/revue/lpm www.sciencedirect.com

PLASMA EXCHANGES AND OTHER APHERESIS TECHNIQUES IN SYSTEMIC DISEASES

Quarterly Medical Review

Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them? Chiara Vendramin 1,2, Marie Scully 1,2,3

In this issue Editorial Therapeutic plasma exchange in thrombotic thrombocytopenic purpura Adrien Picod et al. (France) Plasma exchange in antiglomerular basement membrane disease Maria Prendecki et al. (United Kingdom) Therapeutic plasma exchange in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy Huy P. Pham et al. (United States) Plasma exchange in catastrophic antiphospholipid syndrome Ignasi Rodrígez-Pintó et al. (Spain) Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them? Chiara Vendramin et al. (United Kingdom)

1. University College London, Haemostasis Research Unit, London, United Kingdom 2. University College London Hospital, Department of Haematology, London, United Kingdom 3. University College London Hospital, UCL Biomedical Research Centre, National Institute for Health Research Cardiometabolic Programme, London, United Kingdom

Correspondence: Marie Scully, University College London Hospital, Department of Haematology, 1st Floor, 51 Chenies Mews, London WC1E 6HX, United Kingdom. [email protected]

Summary Plasma exchange (PEX) is a therapeutic procedure used to treat diseases caused by pathogenic antibodies or immune-complexes through the removal and the replacement of plasma. The frequency of complications and reactions associated with PEX are mild and of limited duration. In systemic autoimmune diseases and in a variety of other conditions, PEX might be use in association with intravenous immunoglobulin (IVIg) or therapeutic monoclonal antibodies for the management of acute or refractory patients to achieve a durable remission.

Plasma exchange therapy Plasmapheresis was initially used for thrombotic thrombocytopenic purpura (TTP) and in hindsight it was applied to other thrombotic microangiopathies (TMAs) and also to severe neonatal hyperbilirubinaemia. However, its utility has expanded into other immune and non-immune conditions. There are 2 processes synonymous with the term plasmapheresis (PEX); filtration, which is the separation of all plasma components, except red blood cells; or centrifugation, which allows for a more selective removal of cell types (e.g. stem cells) [1]. Therapeutic plasma exchange is a treatment option in a variety of systemic diseases. The mechanism of action of plasma exchange (PEX) is based on the removal, for example, of pathogenic antibodies, immune-complexes and cytokines or other macromolecules in the plasma, or less frequently by albumin-bound small molecules (drugs or toxins) that remain predominantly intravascular [2].

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tome xx > n8x > xx 2019 https://doi.org/10.1016/j.lpm.2019.10.006 © 2019 Published by Elsevier Masson SAS.

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To cite this article: Vendramin C, Scully M. Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them? Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.10.006

C. Vendramin, M. Scully

TABLE I Category definitions for therapeutic apheresis Category

Description

Conditions

I

Disorders for which apheresis is accepted as first-line therapy, either as a primary stand-alone treatment or in conjunction with other modes of treatment

Guillain-Barré syndrome Wegener granulomatosis Goodpasture syndrome Paraproteinemic polyneuropathies Haemolyitc uremic syndrome Thrombotic thrombocytopenic purpura Hyperviscosity in monoclonal gammopathies

II

Disorders for which apheresis is accepted as second-line therapy, either as a stand-alone treatment or in conjunction with other modes of treatment

ABO-incompatible haematopoietic stem cell transplantation ABO-incompatible solid organ transplantation Cold agglutinin disease Catastrophic antiphospholipid Ab syndrome Chronic focal encephalitis Multiple sclerosis Systemic lupus erythematosus (severe complications of vasculitis)

III

Optimum role of apheresis therapy is not established. Decision making should be individualized

Aplastic anemia Warm autoimmune haemolytic anemia Hypertriglyceridemic pancreatitis Multiple myeloma Post-transfusion purpura Sepsis with multi-organ failure

IV

Disorders in which published evidence demonstrates or suggests apheresis to be ineffective or harmful. Institutional review board approval is desirable if apheresis treatment is undertaken in these circumstances

Goodpasture syndrome (dialysis dependent) Haemolytic uremic syndrome (diarrea associated) Scleroderma Systemic lupus erythematosus (nephritis)

Adopted from Schwartz et al. J Clin Apheresis 2016;31:149–338.

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Clinical apheresis has always been a challenge for evidencebased medicine [3]. The publication of guidelines by the American Society for Apheresis (ASFA) [4], the American Academy of Neurology (AAN) [5] and 'Kidney Disease: Improving Global Outcomes' group (KDIGO Work Group, 2012) [5] have provided specific indications with broad treatment recommendations for plasma exchange. Therefore, the ASFA Seventh Edition of the Guidelines on the Use of Therapeutic Apheresis is an extensive description on the use of clinical apheresis and categorisation built on evidence for the recommendation [4] (table I). The primary goal of therapeutic PEX is based on the removal of large molecular weight substances in order to reduce further damage and to reverse the pathologic process. It is the main treatment in TTP, aiming to remove anti-ADAMTS13 antibodies and platform to allow large volume replacement of the missing enzyme, A Disintegrin And Metalloproteinase with Thrombospondin type 1 motif, 13 (ADAMTS13), contained in plasma and required for VWF cleavage. Since its role in removing circulating autoantibodies or immunecomplexes, this procedure has been used in a number of other

autoimmune diseases, such as anti-glomerular basement membrane disease (Goodpasture's syndrome) [6], systemic lupus erythematosus [7], antiphospholipid syndrome, Guillain-Barré syndrome [6] or cryoglobulinemia. Different options for replacement fluid are available, but they vary according to national pathways and product availability [8]. In 2015, the British Society for Standards in Haematology published a practice guideline on the clinical use of apheresis procedures recommending solvent-detergent-treated fresh frozen plasma (SD-FFP) as the sole replacement fluid for plasma exchange in TTP and related thrombotic microangiopathies. Instead, 4.5% to 5% human albumin solution (HAS) is the most used replacement fluid for PEX in the UK and worldwide and it is generally the preferred replacement fluid for all other autoimmune conditions [9]. The advantage of HAS is that maintains physiological albumin levels and the patient's whole blood viscosity [9]. The optimum treatment volume for each procedure should be between 1.0 and 1.5 of the patient's plasma volume. Given a blood volume of 5 litres, the plasma volume is 55% of this, so a standard single volume exchange procedure is 40 mLs/kg.

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To cite this article: Vendramin C, Scully M. Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them? Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.10.006 Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them?

PLASMA EXCHANGES AND OTHER APHERESIS TECHNIQUES IN SYSTEMIC DISEASES

TABLE II Ten most frequent conditions and role of plasma exchange therapy, intravenous immunoglobulins and therapeutic monoclonal antibodies Plasma exchange therapy

Intravenous immunoglobulins

Therapeutic monoclonal antibodies

TTP or atypical HUS

H

Myasthenia gravis

H

H

H

Guillain-Barré syndrome

H

H

H

Anti-GBM disease (Goodpasture's syndrome)

H

ANCA-associated vasculitis

H

H

H

ABO-incompatible (ABOi) kidney transplantation

H

H

H

Donor-specific HLA antibodies (DSA) in kidney transplant recipients

H

H

H

Cryoproteinaemias (cryoglobulinaemia or cryofibrinogenaemia)

H

H

H

Waldenström macroglobulinaemia with symptomatic hyperviscosity

H

Chronic inflammatory demyelinating polyneuropathy (CIDP)

H

Intensification in frequency and or volume of PEX procedures should be considered in more resistant cases [9]. The ten most frequent indications for plasma exchange are summarised in table II. In patients with suspected or confirmed aHUS, hemodialysis or veno-venous hemodiafiltration may also be required since the venous access can also be used for administration of plasma exchange [10]. In the acute phase of HUS, renal replacement therapy is necessary in 50%–70% of cases [11]. There is no clear advantage for a specific type of renal replacement therapy; however, in children with diarrhea-associated HUS, peritoneal dialysis has been extensively and successfully performed [12]. As PEX involves the removal of plasma, both normal and pathologic plasma components will be removed since the procedure is non-selective. During PEX using HAS as replacement fluid, coagulation factor activity decreases and coagulation tests may be abnormal, in particular factor V (FV), FVII, FVIII, FIX, FX and VWF activity decline [13–15]. Some of the coagulation factors, such as FVIII, FIX and VWF, return to normal levels 4 hours after completion of the apheresis procedure, but for the other coagulation factors, achievement of normal levels takes a median of 24 hours [13]. Only fibrinogen reaches 66% of pre-PEX levels in 72 hours [14]. In addition to the removal of these normal components of plasma, PEX may remove concomitant medications. Removal of plasma includes removal or elimination of drugs from the plasma compartment, which may have a negative effect, resulting in sub therapeutic doses of therapy or beneficial, for example, drug overdoses.

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H

H

H H

H

Determining the impact of drug removal requires consideration of 2 parameters: volume of distribution and the rate of protein binding. Those drugs with a low volume of distribution and or high protein binding are most likely to be removed during PEX. The effect of PEX on the majority of drugs is unknown due to the very limited availability of pharmacokinetic studies, some medications have been reported to have significant removal [16–18] The most common drugs that have been reported to be removed by PEX are summarised in table III.

Therapeutic monoclonal antibodies Monoclonal antibodies such as rituximab, basiliximab and natalizumab [19] tend to have long half-lives, high leukocyte specificity, intravascular protein binding and low volume of distribution, thus allowing for significant removal via PEX. Rituximab may be removed by PEX, preventing its full effect. Darabi and Berg reported 2 cases of refractory TTP in which the combined use of daily PEX and rituximab was associated with clinical resolution of TTP. They discussed the benefits and possible timing of combined therapy and concluded that delays in PEX during concomitant rituximab therapy are unnecessary [20]. Instead, some authors suggested postponing PEX as long as clinically possible after rituximab administration [21]. Rituximab is usually administered in weekly doses and the mean half-life of the first dose is 76.3 hours [20]. Based on this information, it is rational to expect that resumption of daily PEX shortly after rituximab infusion might remove a considerable amount of it from the circulation and impede its clinical effect. However, a study in human patients with lymphoproliferative disorders

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Conditions

To cite this article: Vendramin C, Scully M. Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them? Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.10.006

C. Vendramin, M. Scully

TABLE III The most common drugs that have been reported to be removed by PEX Chemotherapeutic agents Rituximab Cisplatin Vincristine Palivizumab Immunosuppressants Basiliximab Interpheron alpha Cardiovascular agents Propranolol Calcium channel blockers (diltiazem, verapamil) Omeostatic agents Immunoglobulins Antiinfective agents Cephalosporins (ceftriaxone, ceftazidime) Chloramphenicol Amynoglycosides (tobramicyn) Miscellaneous agents Propoxiphene

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showed that rituximab therapy depleted more than 50% of the circulating B cells during and immediately after administration [22]. Therefore, it might be useful delay PEX treatment at least up to 24 hours after rituximab infusion. Afterwards, a prospective study on the pharmacokinetic and pharmacodynamic behaviour of rituximab, during the management of patients admitted with acute idiopathic TTP undergoing daily PEX [23], showed that rituximab was removed by PEX when the monoclonal antibody was initiated almost 24 hours from the procedure [23]. Rituximab has a long half-life divided in to a 1.5–3 days distribution phase and an approximately 20 days elimination phase [24,25]. Patients receiving PEX concurrently with rituximab therapy achieved lower peak and trough serum rituximab concentrations than those not receiving PEX on a weekly infusion regime. Therefore, to maintain a trough level, monoclonal therapy was given every 3–4 days during PEX. Removal of 65% of the dose of rituximab was detected during PEX procedure. Pharmacokinetics in patients not receiving PEX was similar to other disease groups such as lymphoma or autoimmune disease with an increase in peak levels with each dose [24,25]. Therefore, it is advised that rituximab is given immediately after a PEX procedure and to wait 24 hours after PEX before undertaking a further one. This is obviously dependent on the patients' clinical condition and a minimum of 4 hours is suggested between end of rituximab infusion and further PEX.

More recently, a single study, with the aim of comparing rituximab pharmacokinetics between kidney patients with antibodymediated disease requiring plasmapheresis and others without plasmapheresis, measured the amount of rituximab in the removed plasma and found that between 47% and 54% of the drug was removed when PEX was performed between 25 and 66 hours after infusion [26]. Basiliximab is a chimeric mouse/human monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor on activated T-cell lymphocytes. It has a low volume of distribution (approximate to plasma volume). A study on removal of basiliximab by plasmapheresis reported a decrease in basiliximab blood concentrations to about 65% removal of the circulating drug by plasma exchange after a 20 mg dose. As a result, supplemental basiliximab should be administered after plasmapheresis to maintain the desired duration of IL-2R saturation [27]. Eculizumab is a humanised monoclonal antibody that inhibits complement function by binding with high affinity to human C5 complement protein and blocks the formation of proinflammatory and prothrombotic molecules C5a and C5b-9 [28,29]. It prevents terminal complement pathway activation and protects from microvascular thrombosis and has radically improved the outcome of patients with atypical hemolytic uremic syndrome (aHUS) [28]. The aim of therapy is to improve the thrombotic microangiopathy and renal function, so as patients are able to come off dialysis. Therefore, therapy may be given during renal replacement therapy. In a recent report, the effect of intradialytic administration of eculizumab and pharmacokinetic studies of an infant with end-stage renal disease due to aHUS were described [30]. Their data suggested that hemodialysis does not significantly affect eculizumab pharmacokinetics. In addition, since eculizumab has an estimated molecular weight of 148,000 Da, a minimal removal of the drug by hemodialysis is expected [30]. Therefore, they concluded that intradialytic administration during the last hour of dialysis is a feasible alternative dosing strategy to achieve therapeutic concentrations [30].

Intravenous immunoglobulins Intravenous immunoglobulin (IVIg) is the treatment of choice for patients with antibody deficiency. For this purpose, IVIg is used at a 'replacement dose' of 200–400 mg/kg/3-weekly. In contrast, 'high-dose' IVIg at 1–2 g/kg is used as an 'immunomodulatory' agent in an increasing number of immune and inflammatory disorders. IgG is the major component of IVIg and is responsible for most of the immune-modulating effects [31]. Pharmacokinetic studies on serum IgG levels after IVIg therapy have been conducted in patients with immune deficiencies. These studies suggested that IgG levels reach a peak at 3 days and have a half-life of 18 to 32 days after IVIg treatment [32]. However, patients presented a variability in pharmacokinetics

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To cite this article: Vendramin C, Scully M. Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them? Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.10.006 Indications of plasma exchanges in combination with intravenous immunoglobulins or therapeutic monoclonal antibodies. How to combine them?

PLASMA EXCHANGES AND OTHER APHERESIS TECHNIQUES IN SYSTEMIC DISEASES

after treatment, which may affect the efficacy of IVIg [33]. Also, the variability in pharmacokinetics in patients with normal immunoglobulin levels has been less clear and the therapeutic target concentration of serum IgG is unknown [34]. Thus, the pharmacokinetics might partly explain the diversity in clinical course and outcome of immune systemic diseases, such as Guillain-Barré syndrome. Intravenous immunoglobulin is the first choice therapy for Guillain-Barré syndrome [35]. Regarding the use of IVIg in GuillainBarré syndrome, all patients initially received a comparable dose of IVIg at 2 g/kg, however not all patients showed a comparable recovery after this standard dose. They hypothesised IVIg clearance may depend on disease severity and vary between individuals, suggesting that this dose might be suboptimal for some patients [35]. They also determined whether the pharmacokinetics of IVIg might be related to outcome in Guillain-Barré syndrome. After a standard dose of IVIg, Guillain-Barré syndrome patients showed a large variation in pharmacokinetics, which is related to clinical outcome. This may suggest that patients with a small increase in serum IgG level may benefit from a higher dose or second cycle of IVIg [35]. A previous systematic review identified that the pharmacokinetics of IVIg showed considerable intra- and inter-population variability among different categories of patients receiving IVIg treatment. Despite the large number of studies, major literature gaps included lack of information on IVIg clearance and target serum IgG concentrations [33]. In a study on the pharmacokinetics of IVIg in patients with multifocal motor neuropathy, it was hypothesised that IgG concentration after IVIg infusion may represent a potentially useful biomarker to optimise IVIg dosing. The authors concluded that IVIg pharmacokinetics may vary in patients with multifocal motor neuropathy and may be associated with clinical response [36].

Other therapies used in autoimmune diseases and the effect of plasmapheresis Prednisolone is 90–95% bound to proteins and has a moderate volume of distribution (0.6–0.7 L/kg) [17]. Therefore, further

steroid may need to be given following PEX or, alternatively, hold steroid therapy until after PEX is completed. Cyclosporin has a large volume of distribution (13 L/kg) and a 90–98% binding to plasma proteins. Plasma protein binding is primarily to high-density lipoproteins [6]. Therefore, patients receiving oral therapy had between 1–10% removal following PEX [37]. However, cyclosporin given over 4 hours has not been associated with any appreciable change in levels following PEX, due to the large intracellular distribution accounting for approximately 50% in erythrocytes. Therefore, the amount of drug available for removal in plasma appears limited [38]. Cyclophosphamide and azathioprine are unlikely to be removed during PEX given their low protein binding rates of 23% and 30% and their volume of distribution values of 0.8 L/kg and 0.6 L/kg, respectively [39]. These agents may be used in severe systemic lupus erythematous, myasthenia gravis or autoimmune-associated pulmonary hemorrhage in conjunction with PEX.

Conclusions Plasma exchange is a treatment option applied in a wide range of autoimmune diseases through the removal of plasma. The procedure has its challenges but is undertaken typically within the capacity of life-threatening diseases. Advances in the understanding of disease pathogenesis have benefit of the introduction of monoclonal antibodies, which can be used as strategy therapy in a wide range of systemic autoimmune diseases. Intravenous immunoglobulin has a major impact in neurology, haematology, immunology, rheumatology and dermatology. Prospective studies are required to determine if monitoring of serum IgG levels can be used as a tool to evaluate the response to IVIg treatment. In conclusion, monoclonal antibodies or intravenous immunoglobulin may be used in association to plasma exchange procedure in order to achieve a more efficacious response to treatment. Disclosure of interest: MS has received speakers fees and attended advisory boards for Ablynx, alexion, shire, octapharma and novartis. CV declares that he has no competing interest.

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