Facilitated subcutaneous immunoglobulin (fSCIg) therapy--practical considerations.

Clinical and Experimental Immunology

OR I GI NA L ARTI CLE

doi:10.1111/cei.12694

Facilitated subcutaneous immunoglobulin (fSCIg) therapy – practical considerations

M. Ponsford,* E. Carne,* C. Kingdon,* C. Joyce,* C. Price,* C. Williams,† T. El-Shanawany,* P. Williams* and S. Jolles* *Immunodeficiency Centre for Wales, Department of Immunology, and †Department of Radiology, University Hospital of Wales, Cardiff, UK

Accepted for publication 5 August 2015 Correspondence: S. Jolles, Consultant Clinical Immunologist and Honorary Senior Lecturer, Immunodeficiency Centre for Wales,

Summary There is an increasing range of therapeutic options for primary antibodydeficient patients who require replacement immunoglobulin. These include intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), rapid push SCIg and most recently recombinant human hyaluronidasefacilitated SCIg (fSCIg). Advantages of fSCIg include fewer needle punctures, longer infusion intervals and an improved adverse effect profile relative to IVIg. Limited real-life experience exists concerning the practical aspects of switching or starting patients on fSCIg. We describe the first 14 patients who have been treated with fSCIg at the Immunodeficiency Centre for Wales (ICW), representing more than 6 patient-years of experience. The regimen was well tolerated, with high levels of satisfaction and no increase in training requirement, including for a treatment-naive patient. Two patients discontinued fSCIg due to pain and swelling at the infusion site, and one paused therapy following post-infusion migraines. Ultrasound imaging of paired conventional and facilitated SCIg demonstrated clear differences in subcutaneous space distribution associated with a 10-fold increase in rate and volume delivery with fSCIg. Patient profiles for those choosing fSCIg fell into two main categories: those experiencing clinical problems with their current treatment and those seeking greater convenience and flexibility. When introducing fSCIg, consideration of the type and programming of infusion pump, needle gauge and length, infusion site, up-dosing schedule, home training and patient information are important, as these may differ from conventional SCIg. This paper provides guidance on practical aspects of the administration, training and outcomes to help inform decision-making for this new treatment modality.

Department of Immunology, University

Keywords: facilitated subcutaneous immunoglobulin (fSCIg), hyaluroni-

Hospital of Wales, Cardiff CF14 4XW, UK. E-mail: [email protected]

dase, intravenous immunoglobulin (IVIg), primary immunodeficiency (PID), subcutaneous immunoglobulin (SCIg)

Introduction Immunoglobulin (Ig) G replacement therapy is the cornerstone of treatment for primary and most secondary antibody deficiencies and acts to prevent serious infection [1]. Replacement is lifelong, thus acceptability and ease of administration are vital for adherence to treatment. The introduction of Ig replacement therapy for a boy with agammaglobulinaemia by Bruton in 1952 [2] was remarkable for the pioneering use of subcutaneous immunoglobulin (SCIg, 32 g in 20 ml given weekly). A further precedent was set 10 years later with the description of hyaluronidase-facilitated intramuscular immu302

noglobulin, comprising 1 ml of tetracaine hydrochloride with 150 units of hyaluronidase preceding each 30 ml injection of immunoglobulin into the buttocks [3]. Different routes of administration followed these seminal papers by Bruton. Intramuscular immunoglobulin (IMIg) therapy was limited by frequent reactions and painful administration. Improved manufacturing and IgG stabilizing techniques led to the use of intravenous immunoglobulin (IVIg) products, allowing administration of greater volumes and maintenance of physiological immunoglobulin levels at doses of approximately 04 g/kg/month. Following the development of portable

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Facilitated subcutaneous immunoglobulin therapy

syringe drivers and stabilization techniques enabling products to be formulated and administered at higher concentrations, SCIg became increasingly popular using a variety of regimens, including weekly, bi-weekly and rapid push [4]. The introduction of recombinant hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIg) has brought the options in therapy almost full circle. Bruton would not have known that the efficacy of hyaluronidase in reducing resistance to bulk fluid flow would have been even greater if used subcutaneously, where greater amounts of its substrate hyaluronan are found compared to muscle.

Mechanism of action Following a subcutaneous (s.c.) depot injection, a drug must pass through the skin extracellular matrix (ECM) in order to access either capillaries or the lymphatics to enter the vascular space. For small molecules, entry is via the capillaries; larger molecules such as antibodies pass into the lymphatics through their fenestrated endothelium [5]. The ECM contains the structural macromolecules collagen and elastin, which support cellular, vascular and lymphatic components, and all these are embedded in a viscoelastic gel made from glycosaminoglycans and proteoglycans. It is the ability of the complex polysaccharide structure of glycosaminoglycans to retain water which forms the gel-like substance, and this acts to impede the flow of fluids through the ECM. All the glycosaminoglycans except for hyaluronan are bound covalently to core proteins and are termed proteoglycans. The physiological functions of hyaluronan include lubrication (particularly in the synovium), water homeostasis, maintenance of tissue architecture and macromolecular filtering and exclusion [6]. It is estimated that 30% of the body’s hyaluronan is turned over per day and that the dermal barrier following administration of hyaluronidase is reconstituted within 24–48 h [7], in contrast to the 15-year half-life of collagen [8]. It is interesting to note that when hyaluronan is used in the context of cosmetic dermal fillers it needs to be treated chemically to cross-link the molecules in order to avoid rapid degradation [9]. The administration of hyaluronidase to break down hyaluronan temporarily and locally allows increased movement of fluid through the ECM and permits access to a much greater lymphatic surface area, facilitating the absorption of large molecules such as immunoglobulin (150 kDa). Preclinical studies in a swine model confirm this, showing significant reductions in the infusion pressures required (compared to SCIg) and improved subcutaneous perfusion [10]. Animal-derived hyaluronidases have been available for decades, although their use has been generally short term [11]. The use of ovine hyaluronidase-facilitated SCIg in a patient has reduced infusion frequency and needle sites while achieving adequate trough levels [12]. Experience now extends to more than 5 years, demonstrating that

longer-term use is possible [13]. Potential concerns over the purity, immunogenicity and hypersensitivity of animalderived hyaluronidases remain [11,14–16]; however, the advent of recombinant human hyaluronidase PH20 (rHuPH20) promises wider availability with improved safety.

Pharmacokinetics of immunoglobulin replacement Facilitated SCIg has some of the properties of SCIg and IVIg regimens, reflecting its hybrid pharmacokinetics (Fig. 1). The sharp peak in serum IgG level immediately after IVIg infusion is avoided with fSCIg – which is reflected by an adverse event profile closer to conventional SCIg [[18]]. Experience from the Phase III trial of rHuPH20 to facilitate subcutaneous 10% immunoglobulin using 108% of the previous IVIg dose demonstrated this to be generally well tolerated at infusion frequencies and rates similar to IVIg, with a 93% bioavailability at this dosing. Systemic side effects were uncommon (8 versus 25% with IVIg therapy), while six patients (7%) stopped treatment due to mild to moderate side effects. Three severe reactions were documented, including infusion site pain, swelling and genital oedema due to spread from the abdomen. Antibodies to rHuPH20 were detected in 18% of trial patients; these were non-neutralizing and showed no correlation with adverse event risk.

Survey design Following the introduction of facilitated SCIg (HyQviaTM (Baxalta Heathcare, Thetford, Norfolk, UK), we performed a survey to explore patient profiles, practical aspects of

Fig. 1. Immunoglobulin pharmacokinetics. Adapted from Wasserman et al. [17] using facilitated subcutaneous immunoglobulin (fSCIg) at 108% and subcutaneous immunoglobulin (SCIg) at 137% dose-adjustment coefficients relative to intravenous immunoglobulin (IVIg).


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administration and outcomes to help inform decisionmaking for this novel treatment modality. In October 2014 patients in Wales were among the first in the United Kingdom to gain access to fSCIg and we review our experience following 8 months. Patient treatment schedules, training, feedback, adverse events and outcomes were considered. Patient global therapy rating (out of 100) and infusion times (inclusive of travel and set-up) were analysed using paired t-test analysis in GraphPad Prism version 60. Bedside ultrasonography and photography were performed using an Aplio 400 ultrasound unit (Toshiba Medical Systems Europe, Zoetermeer, the Netherlands) and Sony Cybershot DSC-RX100M3 (Sony, 1-7-1 Konan, Minato-ku, Tokyo 108-0075, Japan) at 15-min intervals during the third infusion training visit with patient consent. Subcutaneous tissue depths were calculated using IMPAX client version 64 and ratified by an independent trained radiologist. Ethical approval was deemed unnecessary by the Institution’s Research and Development department. Patients were followed-up for a median of 25 weeks (range 6–36).

Indication for change and patient profiles The Immunodeficiency Centre for Wales (ICW) service currently cares for 147 adults with primary antibody deficiency who receive immunoglobulin replacement. Roughly half infuse subcutaneous immunoglobulin (SCIG) at home, 20% receive IVIg replacement at home, small numbers currently use rapid push SCIg at home and 25% receive IVIg in hospital. Patients became aware of this new form of therapy through patients’ group meetings (Immune Deficiency Patients Group Wales – IDPGW; idpgwales.org), and some chose to transition to fSCIg following discussion of treatment options at routine outpatient appointments. These patients had a range of immunodeficiency diagnoses and cited a number of different reasons to change therapy (summarized in Table 1). The reasons were varied, and included wear-off effects (defined below), difficult venous access, the number of needle punctures required and adverse effects of IVIg. Lifestyle choice, convenience, flexibility and setting of replacement were also common factors inducing patients to change to fSCIg.

space to increased fluid volumes, an up-dosing schedule is followed (as per product guidance [19]). The majority of patients had prior experience with subcutaneous replacement (69%). Training sessions therefore concentrated on differences between product and infusion techniques and adverse events monitoring. Standard home therapy training documents were adapted to reflect differences in infusion methods (available from the corresponding author). The training period for a treatment-naive patient was the same for facilitated and conventional SCIg (four to six sessions plus a home visit).

Practical aspects of administration A number of practical aspects in the administration of immunoglobulin differ significantly for fSCIg from other currently available delivery options, and merit separate consideration in order to optimize this form of immunoglobulin delivery. These include criteria for choice of pump, fSCIg-specific programming of the pump, needle gauge and length, initial infusion rate, adjustment of the position of the infusion site and patient information about the mechanism of action and management of possible local side effects. Individual centres and patients may vary in their practice and requirements, and the following suggestions based on the experience at ICW are offered as guidance only.

Dosage and frequency of infusions After 6 days the serum–IgG concentration curve for fSCIg approximates that of IVIg replacement, as it tracks downwards until the next infusion cycle (Fig. 1). This raises the possibility of ‘wear off’ – an effect noted by Bruton [3] – associated clinically with an increased fatigue and susceptibility to infection in the fourth week post-IVIg infusion [20]. Accordingly, local centre practice tends towards 3-weekly infusions. Patients transitioning from SCIg or IVIg remained at their original monthly dosage; when the available preparations of 5, 10 or 20 g aliquots could not achieve a straight 1 : 1 conversion, doses were adjusted upwards to avoid wasted product (100–111%). Trough samples are monitored routinely three to four times per year and data are under collection for efficiency calculations.

Training

Infusion pumps

HyQvia is given using a two-step delivery system. The hyaluronidase and immunoglobulin are supplied together as separate bottles containing 5 ml rHuPH20 per 10 g (100 ml) of 10% IVIg. The hyaluronidase is drawn up into a single syringe (combining if more than one set of the hyaluronidase/immunoglobulin is prescribed for injection into a single site). Immunoglobulin administration should commence approximately 10 min following hyaluronidase infusion. To accustomize the patient and subcutaneous

Conventional SCIg is generally administered using a syringe driver such as the Crono PID 20 or 50 (AMT Applied Medical Technology, Cambridge, UK) and the McKinley T34 or Freedom 60 (McKinley Medical UK Ltd, Blackpool, UK). These all require the immunoglobulin to be drawn up into a 20- or 50-ml syringe from one or more vials, and for a typical 300-ml (30 g) fSCIg infusion this would represent a significant number of syringes per infusion. This aspect of setup time is reduced by administration of fSCIg directly from

304


Diagnosis

CVID

CVID

CVID

CVID

CVID

ID

1

2

3

4


5

Seronegative arthritis

Previous thrombocytopaenia

Eczema Previous colitis

Chronic sinusitis Learning difficulties (in-patient therapy preferred)

Chronic sinusitis

Associated medical history

Table 1. Patient outcomes and characteristics

39/M

29.7

26.3

28.2

26/ M

28/ M

32.8

23.5

BMI kg/m2

52/ M

21/F

Age/ sex

11.2 g s.c. Weekly Home

30 g i.v. 3-weekly In-patient



9 g s.c. Weekly Home

Previous therapy, frequency and setting Annoying doing every week although a great treatment. More painful, would last 24 h. Reminded me I was ill. More inconvenient, I had to take it with me when I travelled Rating 5 40/100

Indication for switch and previous regimen rating

35 g 3-weekly (104%)

30 g 3-weekly (100%)

50 g 3 weekly (111%)

Wanted to do infusion at home but not weekly. Large dose requirement with wear-off on 3weekly IVIg Rating 5 20/100 Difficulty self-cannulating, gravity infusion slow, felt very lethargic. Keen to avoid weekly regimen but still remain at home Rating 5 40/100 New epilepsy diagnosis – unable to drive to day unit. Weekly SCIg infusions an increasing strain – keen for alternative Rating 5 90/100

30 g Rate-related side effects with 3-weekly IVIg – felt tired and drained. (100-133*%) Infusions slow, took all day Rating 5 ‘quite bad’

30 g 3-weekly (111%)

HyQvia: frequency and dose equivalence (%)

3

Continuing fSCIg

Still effective, more convenient being 3-weekly Rating: 95/100

Really happy with this. Only painful for a few hours. Only infuse every 3 weeks now, so barely remember I have to do it. No need to take it with me when I travel Rating: 95/100 Able to infuse much quicker: feeling much happier. Some wear off with fSCIg noted *Dose now increased to 40 g every 3 weeks Family now discussing home therapy Rating: ‘very good’ No longer feels unwell next day, or having ‘dip’ before next infusion Rating: 80/100 Discontinued due to swelling Reverted to home IVIg Rating: 30/100

Comments and fSCIg global rating

SCIg: 2 h fSCIg: 15 h

IVIg: 45 h fSCIg: 25 h




Infusion duration per dose (inc. setup, travel)


305

306

Hypogammaglobulinaemia

Hypogammaglobulinaemia

Secondary hypogammaglobulinaemia

SPAD

9

10

11

12

CVID

7

CVID

CVID

8

Diagnosis

ID

6

Table 1. Continued

67/M

53/F

46/F

Age/ sex

Bronchiectasis Migraines Eczema Hypothyroidism

Non-Hodgkin’s Lymphoma (previous rituximab)

35/F

48/M

Bronchiectasis 23/M Chronic sinusitis Previous colon adenocarcinoma Eczema 46/M Benign tremor

Bronchiectasis

Bronchiectasis Chronic norovirus enteropathy

Chronic sinusitis


26.7

34.12

23.0

34.3

26.1

23.9

22.3

BMI kg/m2


16 g SC 2-weekly Home

20 g s.c. 2-weekly Home


30 g s.c. (as 4 doses per week) Home 8 g s.c. Weekly Home

Nil previous

Previous therapy, frequency and setting

25 g 3-weekly (104%)

25 g 3-weekly (104%)

35 g 3-weekly (118%)

30 g 3-weekly (100%)

25 g 3-weekly (104%)

30 g 3-weekly (100%)

15 g 3-weekly (n.a.)


Suffered rate-related side effects with previous home IVIg. Preferred fewer infusions, due to busy lifestyle Did not comment on rating

Busy lifestyle, preferred fewer infusions Rating 5 80/100

Needle phobia – missing infusions when SCIg given weekly. Always thinking about next infusion Rating 5 40/100

New starter. Planning to travel therefore keen for least invasive replacement regimen Rating 5 not applicable Large dose with poor venous access and reactions to multiple i.v. products Rating 5 20/100 Portacath removed, i.v. access very poor, reverted to SCIg but found frequent regimen difficult with tremor Rating 5 60/100 Needle phobia – wanted to switch to reduce number of needles Rating 5 50/100


*

3

Continuing fSCIg

Much better than previous. Tremor still makes siting needle difficult, my wife sometimes helps Rating: 80/100 Better infusing 3-weekly but changing bottles over can be fiddly Rating: 80/100 Fatigue, migraines and vertigo up to 24 h after fSCIg infusions *Has since trialled rapid push but opted to return to fSCIg. Did not comment on rating

Fine, no problems Rating: 90/100

Greater time between treatments a big benefit Rating: 70/100

Would prefer not to have to do any treatment Rating: 50/100 Reverted to SCIg Rating: 10/100


IVIg: 7 h SCIg: 2 h fSCIg: 15 h





SCIg: 4 h per dose fSCIg: 35 h

Nil previousf SCIg: 15 h


M. Ponsford et al.


20 g 3-weekly (99%) 6.75 g s.c. Weekly Home 25.2 56/F Bronchiectasis Eczema Sj€ ogren’s syndrome CVID 14

CVID 5 common variable immunodeficiency; SPAD 5 specific polysaccharide antibody deficiency; fSCIg 5 facilitated subcutaneous immunoglobulin; SCIg 5 subcutaneous immunoglobulin; IVIg 5 intravenous immunoglobulin; BMI 5 body mass index; M 5 male; F 5 female; i.v. 5 intravenous; s.c. 5 subcutaneous.

SCIg: 2/3 h fSCIg: 1 h Only one needle every 3 weeks Rating: 95/100

SCIg: 1 h fSCIg: 15 h Not yet rated (only 6 weeks experience)

Lifestyle preference – keen to reduce infusion frequency of weekly SCIg Not yet rated Keen to reduce frequency of needles (2 per week) Rating 5 80/100 30 g 3-weekly (101%) 9.9 g s.c. Weekly Home 34.1 67/F Good’s syndrome 13

Thymectomy Chronic sinusitis

Diagnosis ID

Table 1. Continued


Age/ sex

BMI kg/m2

Previous therapy, frequency and setting



Continuing fSCIg




the bottle via an intravenous (i.v.)-giving set and peristaltic pump. Crono pumps used by home therapy patients also have a maximum speed of 100 ml/h per pump, a third of that recommended for HyQvia (300 ml/h). One patient attempted to use the spring-driven Freedom 60 to infuse fSCIg but abandoned the attempt, as the infusion proved too slow. McKinley T34 pumps are not used routinely by patients with PID in Wales, and were not assessed. To achieve adequate infusion rates, peristaltic infusion pumps were chosen. One difficulty, however, with using a pump designed for i.v. use are the built-in pressure alarms, which activate repeatedly when infusion pressure rises – usually corresponding to intravenous cannula extravasation. The pressure profile of fSCIg is intermediate between intravenous and conventional SCIg [10] and pressures up to 600 mmHg are detected routinely during fSCIg infusions, hence pump reprogramming is mandatory to allow uninterrupted fSCIg infusion. Other qualities of the ideal home infusion pump include minimizing the size of the unit, noise, long battery life and easy programmability. Several pumps which fulfilled these criteria were assessed including: Bodyguard 323 (CME Medical Limited, Blackpool, UK), Q-core Sapphire (Hospira UK Ltd, Maidenhead, UK)and Cadd Solice VIP (Smiths Medical, Ashford, UK). The Bodyguard 323 pumps were selected as already in use locally (Fig. 2).

Infusion needles Needle gauge and length are major influences to infusion rate and resistance [21]. Although smaller needles can reduce pain and increase compliance [22], patients using 27 g Neria needles (used for conventional SCIg; AMT Medical Technology) proved unable to accommodate the high speed of fSCIg: allowing a maximum infusion rate of only 130 ml/h with standard i.v. infusion pumps (Alaris Signature; Alaris Systems, San Diego, CA, USA). Broader-gauge (23 g) needles include the Baxter FlowEase Subcutaneous Infusion set (Baxter Healthcare) and the Butterfly Winged Infusion set (Bound-Tree Medical, Dublin, OH, USA). Length and angle of needle insertion are important considerations, as infusion-site leakage and irritation may be more common if the needle is too short [23]. The Baxter needle is a ‘drawing pin’ (button) style design, which is placed at a 908 angle, whereas the butterfly is longer and placed traditionally at 458: both were well tolerated (Fig. 2).

Infusion site choice The general areas for infusion are similar to conventional SCIg infusion for adults: thighs and abdomen. With the increased infusion volume of fSCIg there is a small risk of genital swelling due to the movement of fluid with gravity following the infusion using abdominal sites. It is important to inform patients of this possibility beforehand, and to minimize this risk further patients using abdominal sites


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to 300 ml/h without pain, thereby speeding and simplifying subsequent infusions. This modified soft start is a faster regimen than that suggested in the product information, but has been tolerated successfully in all patients; however, individualization may still be required to ensure comfort and tolerability.

Patient information

Fig. 2. Needle options and BodyGuard 323 pump. (a) Needle options for subcutaneous (s.c.) therapy: Neria s.c. infusion set (27– 29G, 9 mm length), Blue Butterfly (23G, 19 mm length) and Baxter FlowEase s.d. set (24G, 9 mm length). (b) BodyGuard 323 volumetric infusion pump, CME MedicalTM. (c) Manual infusion of recombinant human hyaluronidase PH20 (rHuPH20) to abdominal infusion site.

were advised to infuse at or slightly above the level of the umbilicus.

Infusion rate HyQvia (Baxalta Heathcare) should be allowed to equilibrate to room temperature before infusion, which may take up to 60 min. The product manufacturer advises four sequential infusion rate increases over the first 20–60 min, until maximal infusion rate is achieved [19]. All patients achieved 300 ml/h by the end of the third infusion. Furthermore, we found that once established (by the fourth infusion), patients were able to commence infusions at a rate of 50 ml/h for a total of 2 ml before increasing directly

Patients received the same initial information concerning risk of infection or reaction with any immunoglobulin replacement product. Additional information was given regarding the unknown long-term effects on skin, pregnancy [reflecting current European (EU) licensing which may be subject to change] and risk of gravitational spread.

Patient outcomes We reviewed data on 14 patients who have been commenced on HyQvia, including three patients who chose alternative treatments and their reasons for doing so. Feedback has generally been positive, for instance: ‘doing it less often gives me more freedom. There’s less interference, fewer reminders, less organisation involved’. All patients experienced transient swelling and warmth at site of infusion during infusion, but this was usually well tolerated: ‘before [using conventional SCIg] I would have a swollen and fat stomach for 3–4 days after each infusion, and then I’d have to inject again at the end of week. Now [using fSCIg] the swelling only lasts a day and I can feel normal for longer’. There was a significant reduction in needlestick burden: prior to conversion, patients using conventional SCIg Fig. 3. Comparison of patient global therapy rating and total treatment durations. Global therapy rating provided by patients following completion of training and independent administration. Note that four patients were excluded from analysis, as they were unable to comment on both treatment modalities: patient 2 (mild learning difficulties, provided positive response), patient 6 (previously treatment-naive), patient 13 (therapy duration with facilitated subcutaneous immunoglobulin (fSCIg) only 6 weeks) and patient 12 (did not comment on this aspect within the survey). Bars represent mean and standard deviation. Therapy duration includes travel and setup. Note that patient 6 was a new starter and patient 7 was administering high-dose subcutaneous immunoglobulin (SCIg) four times a week and therefore excluded from analysis. Times were available for intravenous immunoglobulin (IVIg), SCIg and fSCIg for patient 12.

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Fig. 4. Comparison of subcutaneous fluid accumulation with subcutaneous immunoglobulin (SCIg) and facilitated subcutaneous immunoglobulin (fSCIg). C 2015 British Society for Immunology, Clinical and Experimental Immunology, 182: 302–313 V

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required up to 32 needlesticks per month (mean 5 11; range 5 8–32). Using fSCIg this was reduced to one needle every 3 weeks, an equivalent infusion frequency to IVIg (13 per month), although this does not take into account additional needlesticks due to failed i.v. cannulation attempts. Ten patients (71%) used abdominal infusion sites, three (21%) used upper thigh and one patient (patient 4) tried both. Total infusion times (including setup and travel) reported by patients were significantly lower with fSCIg therapy from both SCIg and IVIg, and global therapy ratings were also consistently higher for fSCIg than SCIg (P 5 0048), Fig. 3.

Adverse events Adverse effects were reported by five patients (33%), with three opting to change therapy. Patient 5 reported local bruising at the infusion site associated with transient abdominal rash lasting < 48 h. Despite this, he was delighted with the new regimen overall and continues under monitoring with no subsequent rashes. Patient 12 experienced migraines up to 24 h following fSCIg infusion. This was on a background history of migraines for which the patient had undergone closure of a patent foramen ovale. There had also been a history of adverse events on IVIG, although the patient had not been troubled with migraines when using weekly SCIg. They have since trialled daily rapid push SC replacement and elected to return to fSCIg. Two patients (patients 4 and 7) reported discomfort lasting over 24 h post-infusion and opted to return to original regimens. Patient 4 considered self-cannulation for IVIg preferable to the swelling she experienced with both facilitated and conventional subcutaneous (s.c.) infusion, while patient 7 required high immunoglobulin doses (2 g/ kg/month) due to chronic norovirus infection and found it difficult to infuse the high volumes required to maintain adequate trough levels. She noted right-hand swelling ipsilateral to the central line used for total parenteral nutrition (TPN), and subsequently returned to conventional SCIg, using a 16% product given four times weekly to minimize infusion volumes. One patient (patient 2) experienced profound fatigue in the third week following fSCIg requiring dosage increase; conversely, patient 3, experiencing wearoff with IVIg, has not experienced this on 3-weekly fSCIg now more than 5 months since transition. Although all subjects had a body mass index within the normal or obese range (185–249 kg/m2, 25–30 kg/m2, respectively), patients discontinuing fSCIg tended to have lower body mass index (BMI) than those able to tolerate fSCIg (mean 256 versus 285 kg/m2), although this was non-significant (unpaired t-test, P 5 0339) in this small cohort. To define more clearly the distribution of the infused fluid an ultrasound scan was performed for a patient (patient 1) with normal BMI (235 kg/m2) following conversion to fSCIg, comparing subcutaneous space 310

imaging with conventional SCIg at separate sites on the same day (Fig. 4). This confirmed the ability of rHuPH20 to allow volume and infusion rate 10 times that of conventional SCIg with less local site tenderness. Self-injection of rHuPH20 was painless, with accumulation within a fascial plane visible subcutaneously. Following 15 min of IgG infusion (approximately 65 versus 15 ml administered), both sites felt tense with a similar ‘peau d’orange’ appearance superficially (Supporting information, Fig. S1). Ultrasound showed local, tiny fluid collections within the subcutaneous fat at the site of infusion. Warmth and erythema were maximal around 30 min for both infusion methods, accompanied by mild discomfort to touch at both sites. The distribution of erythema appeared significantly different, with the conventional infusion creating an elliptical pattern on the upper thigh, compared to circumferential spread more laterally on the thigh, approximating the infusion diameter of fSCIg defined by ultrasound. Ultrasound demonstrated lower echogenicity within the subcutaneous tissue, consistent with fluid dispersion within the fat (oedema). On the fSCIg site these changes were more diffuse, extending over a greater range (maximal distance 28 versus 18 cm) and depth (maximal increase in s.c. tissue depth 175 versus 114% from baseline) compared to conventional SCIg (Supporting information, Fig. S2). Settling of erythema and tenderness after the initial 30 min of infusion was reproduced across fSCIg patients, occurring faster than at the conventional site. The patient was able to drive immediately after the infusion, although commented she would not wish to drive for more than an hour the same day after a thigh infusion.

Discussion This survey represents the largest current real-life singlecentre experience within Europe or the United States outside a trial setting with a cumulative exposure of 6 patient years (representing more than 100 infusions), describing in particular the practical aspects of switching patients to this new form of therapy. To our knowledge, this is the first use of ultrasound to chart the subcutaneous changes accompanying fSCIg in humans. Together, this work highlights a range of clinical, convenience, flexibility and practical factors which contribute to treatment success and patient satisfaction with fSCIg. The impact of infusion and needle frequency and homebased care were major indications to switch. Studies demonstrating significant quality-of-life benefits for patients converting from in-patient IVIg to weekly home SCIg therapy suggests that the care setting is the major factor [24]. In contrast, the majority of patients transitioning to fSCIg within our cohort already benefited from home therapy; however, satisfaction levels still improved, with a significant increase in patient-reported global therapy rating for previous SCIg users. This is in line with the major reduction in



total therapy time with both SCIg and IVIg. Our survey is limited by sample size and lack of participant randomization, reflecting instead the importance of patient choice regarding frequency of infusion, number of needle sites and clinical problems with previous regimens. Across the European Immunodeficiency Community, net use of SCIg is only 27% [25], IVIg remains prevalent in the United States [26] and there exist large populations worldwide with secondary antibody deficiency: all groups where access to a greater range of treatment options would allow individualization and may improve therapy. The pharmacoeconomic accessibility of fSCIg will vary across health-care settings, and represents a balance between the increased up-front product costs of this therapy against the potential savings achievable by reduced inpatient expenses. While demonstrable savings have been achieved on switching from hospital IVIg to home SCIg therapy [27,28], the degree to which this remains the case for fSCIg, given that many patients may switch from SCIg, requires further assessment. More information is also needed on the possible impact of differences in bioavailability derived using area under the curve (AUC) analysis between SCIg (67%) and fSCIg and IgG trough levels and clinical outcomes [18,29]. The pivotal fSCIg study, following area AUC analysis, used a dose increase of 108% from IVIg to fSCIg on transition [18] to achieve a bioavailability of 93%: within the tolerance of 80–125% permitted by the Food and Drug Administration (FDA) for bioequivalence. This compares to a suggested dose adjustment in the United States of 137% from IVIg to conventional SCIg [30]. However, it is usual clinical practice in the EU (and indeed for the majority of immunologists in the United States) to switch from IVIg to SCIg at 1 : 1, using trough IgG as a surrogate marker of replacement and making further adjustments based on clinical response. Indeed, a 1 : 1 switch from IVIg to SCIg has been shown to lead to a 17% rise in trough IgG level [31], highlighting the difficulty in comparing between use of bioavailability by AUC and the IgG trough measurement used in clinical practice. More information is needed from both additional studies and real-life experience to understand more clearly the effect of fSCIg on bioavailability for differing cycle durations as determined by trough and, ultimately, clinical outcomes. With close financial scrutiny in National Health Service (NHS)-England on immunoglobulin demand management and commissioning [32], keeping the cost of fSCIg as close as possible to parity with existing immunoglobulin products will result in this new form of therapy being available as an option to those patients who would benefit most. A number of practical considerations for doctors, nurses and patients in which fSCIg differs from the other existing immunoglobulin delivery options were highlighted by this review. These include the possible switch to peristaltic pumps, given the volume and rate of infusions, circum-

venting the more limited syringe volumes and lower infusion rates of pumps used normally for SCIg. Although local circumstances will impact upon pump choice, they need to be easily programmable to avoid infusion pressure alarms (for peristaltic pumps) and allow rate titration. The ‘soft start’ rate (50 ml/h for at least the first 2 ml) before rate increase to the tolerated maximum established during training and ramp-up helps to ensure comfort as the rHuPH20 begins to take effect, while also dramatically simplifying the infusion protocol and shortening overall infusion time. Despite these changes, training requirements for home therapy were achieved in an equivalent or lower number of sessions to conventional SCIg therapy used in our centre with potentially less training needed if patients were already experienced with home SCIg. A further way to manage the rare development of genital oedema was by a dose reduction in rHuPH20 (personal communication, Martin van Hagen). We have modified the patient information to include the possible occurrence of transient gravitational genital oedema and have adjusted the abdominal infusion sites to a slightly higher position around the level of the umbilicus to mitigate this risk. Although we observed a trend towards discontinuation of fSCIg in patients with lower BMI, this association was not evident in the Phase III trial. Future developments for fSCIg may include reduction in the volume of the rhuPH20 (by increasing the concentration), as the volume currently increases linearly with dose increases. This need not be the case, as the rhuPH20 is advanced by the immunoglobulin which is being infused following the initial injection. In the reported patient receiving ovine hyaluronidase [12], this is reconstituted from a lyophilized powder to 07 ml for a 130-ml (208 g Subcuvia; Baxalta Heathcare) infusion, the equivalent volume of rhuPH20 used in 20 g (200 ml) of HyQvia is 20 ml. It is also likely that the development of higher concentrations of SCIg products could be utilized for fSCIg, further reducing the volume and potentially infusion time. This potentially opens the door to treatment with fSCIg of other patient groups requiring high-dose immunoglobulin; for instance, immunomodulation of neurological disease [33]. Ongoing studies charting real-life experience and longterm safety with fSCIg remain limited, and will add important information to guide optimal patient care. Among these are the HyQvia post-authorization safety study (PASS), a pregnancy registry, a Phase IV quality-of-life study and a burden of treatment study. As 21st-century drug delivery comes full circle to Ogden Bruton’s pioneering insight, the arrival of facilitated subcutaneous immunoglobulin therapy adds another option for physicians and patients to individualize and optimize care.

Acknowledgement S. J. is supported by a NISCHR Fellowship.


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Disclosures M. P. has received support for conference and training day attendance from Shire Pharmaceuticals and Biotest. T. E. S has received support to attend conferences and/or advisory board fees from Biotest, CSL Behring and Octapharma. E. C. has received support for consulting and conferences from CSL Behring, Baxalta, BPL, Biotest, Octapharma and Shire. C. J. and C. K. have received conference support from CSL Behring. S. J. has received support for consulting, conferences and/or research from CSL Behring, Baxalta, BPL, Biotest, Octapharma, Shire, UCB Pharma, SOBI and NISCHR. P. E. W., C. P. and C. W. have nothing to declare.

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Supporting information Additional Supporting information may be found in the online version of this article at the publisher’s web site: Fig. S1. Facilitated (upper) and conventional (lower) subcutaneous immunoglobulin (SCIg) infusions at 30 min,

demonstrating erythema and peau d’orange distension of skin. Fig. S2. Maximal subcutaneous tissue depth assessed by ultrasound. Dotted lines denote infusion completion. Facilitated subcutaneous immunoglobulin (fSCIg) is associated with greater subcutaneous distension consistent with greater fluid volume infused. Maximal subcutaneous depth increases rapidly during first 15 min of infusion before reaching plateau phase.


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Overview of recombinant human hyaluronidase-facilitated subcutaneous infusion of IgG in primary immunodeficiencies.

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Subcutaneous immunoglobulin in CIDP and MMN: a different long-term clinical response?

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