THE LANCET
`
`Volume 345, Number 8946c Founded 1823 • Published weekly • Saturday 11 February 1995 ,/
`
`/
`
`EDITORIAL
`333 Canada's threatened healthcare system
`
`COMMENTARY
`335 World summit on social development
`J Havard
`336 Do cell membrane dynamics participate in insulin resistance?
`M-A Devynck
`337 Temperature and cardiovascular mortality K-T Khaw
`338 Antipyretics in severe sepsis
`
`F Shann
`
`ARTICLES
`339 Public health impact of Rwandan refugee crisis: what happened
`in Goma, Zaire, in July, 1994? Goma Epidemiology Group
`344 Effects of pulsed 13-stimulant therapy on P-adrenoceptors and
`chronotropic responsiveness in chronic heart failure
`S Adamopoulos, M Piepoli, F Qiang, E Pissimissis, M Davies, L Bernardi, C Forfar,
`P Sleight, A Coats
`349 Long-term results of single course of adjuvant intraportal
`chemotherapy for colorectal cancer Swiss Group for Clinical
`Cancer Research (SAKK)
`353 Temperature extremes and mortality from coronary heart
`disease and cerebral infarction in elderly Chinese W-H Pan,
`L-A Li, M-J Tsai
`
`SHORT REPORTS
`355 Hepatitis B virus infection without immunological markers after
`open-heart surgery (cid:9)
`J W F Rasenack, H-J Schlayer, F Hettler, T Peters,
`S Preisler-Adams, W Gerok
`357 Cell membrane dynamics and insulin resistance in non-insulin-
`dependent diabetes mellitus
`P Tong, T Thomas, T Berrish, D Humphriss,
`L Barriocanal, M Stewart, M Walker, R Wilkinson, KGMM Alberti
`
`PUBLIC HEALTH
`359 Why treatment centres failed to prevent cholera deaths among
`Rwandan refugees in Goma, Zaire A K Siddique, A Salam, M S Islam,
`K Akram, R N Majumdar, K Zaman, N Fronczak, S Laston
`
`REVIEW ARTICLE
`362 Hyperlipidaemia, hypertension, and coronary heart disease
`G K Goode, J P Miller, A M Heagerty
`
`************** S -DIGIT 20;40
`LANCE 02(122400 0 01 nO n26 0E12
`
`
`
`GROUP PERIODICAL REGISTRATION
`LIBRARY OF CONGRESS
`WASHINGTON. DC 20E40-0001
`
`CLINICAL PRACTICE
`365 Subcutaneous immunoglobulin
`replacement in patients with
`primary antibody deficiencies:
`safety and costs (cid:9)
`A Gardulf,
`V Andersen, JI3jOrkander,
`D Ericson, S S Froland,
`R Gustafson, L HammarstrOm,
`M B Jacobsen, E Jonsson,
`G Moller, T Nystrom, B Soeberg,
`C I E Smith
`
`VIEWPOINT
`369 Should morbidity replace
`mortality as an endpoint for
`clinical trials in intensive
`care? (cid:9)
`A J Petros,
`J C Marshall, H K F van Saene
`
`Bookshelf
`371 (cid:9) Raising Lazarus
`372 (cid:9) Ethics in clinical practice; Ethics
`and biotechnology
`The pediatric spine
`373 (cid:9) Cystic fibrosis
`Doctors, dilemmas, decisions
`
`376 (cid:9)
`
`News
`375 (cid:9) The new politics of risk
`assessment
`Australian Northern Territories
`to debate euthanasia
`India's kidney transplant racket?
`Anxious times for German
`university hospitals
`France wavering about
`decriminalisation of drugs
`377 (cid:9) Bioethics convention
`endorsed—at a price
`Regulating ICSI in France
`Cautious optimism over new
`anti-HIV agents
`378 (cid:9) UK to study congenital limb-
`reduction defects
`Money for UK medical research
`379 (cid:9) Conflicting views on alleged
`plagiarism
`Sao Paulo's illegal pharmacies
`380 Towards a tighter PHLS
`UK health department urged
`to take the lead
`Russian medical aid
`for Chechnya
`News in brief
`381 Letters to the Editor
`see contents list inside
`
`The Lancet® (ISSN 0099-5355) is published weekly by The Lancet Ltd. The Lancet's agent is located at 655 Avenue of the Americas, New York, NY 10010-5107. Tel: 212-633-3800.
`Fax: 212-633-3850. Second Class Postage paid at New York, NY and at additional mailing offices. POSTMASTER: Send address changes to The Lancet, 655 Avenue of the Americas,
`New York, NY 10010-5107. All literary matter in The Lancet is Copyright. The Lancet Ltd, 1995. The Lancet® is a registered trademark.
`
`ra
`
`Ex. 1095 - Page 1
`
`(cid:9)
`

`

`For Patients With Chronk Bronchitis,
`Infection May Be Just The Beginning.
`Haemophilus influenzae
`can lead to a vicious circle of
`respiratory decline.
`H influenzae has been shown to persist in
`the sputum of many patients with
`chronic bronchitis, and has been shown
`to slow ciliary beating and increase
`mucus production in vitro.
`Cipro® Tablets give you the power to
`aggressively treat H influenzae and
`resolve infections for many chronic
`bronchitics, before things turn vicious.
`
`Additionally, in two studies that
`included other pathogens, a total of
`95% of bronchitis patients (n=84) had
`, favorable outcomes:
`So the next time bacterial infection
`starts something you'd prefer to avoid,
`trust the power of Cipro® Tablets.
`Cipro® Tablets are indicated for lower
`respiratory infections caused by
`Escherichia coli, Klebsiella pneumoniae,
`Enterobacter cloacae, Proteus mirabilis,
`Pseudomonas aeruginosa, Haemophilus
`influenzae, Haemophilus paraintluenzae,
`Streptococcus pneumoniae.
`
`Power proven against
`H influenzae.
`In three studies of bronchitis patients,
`where pathogens were identified, all
`patients with H influenzae (n=43)
`responded favorably* to Cipro® Tablets.
`
`*Favorable outcome defined as improvement or resolution
`of clinical signs and symptoms.
`t In vitro activity does not necessarily imply a correlation
`with in vivo results.
`
`ra
`
`(ciprofloxacin Ha) Tablets
`500 mg 750 mg
`The most potent fluoroquinolone.t
`
`Most frequently reported adverse events (>1%): nausea; diarrhea; vomiting;
`abdominal pain/discomfort; headache; rash; restlessness.
`
`Please see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections
`of brief summary of prescribing information on following page.
`
`Ex. 1095 - Page 2
`
`

`

`ltrItT opr,
`FEB 1 5
`GROUP
`COPY
`The 0
`
`For Patients With Chronic Bronchitis,
`Infection May Be Just The Beginning.
`Haemophilus influenzae
`can lead to a vicious circle of
`respiratory decline.
`H influenzae has been shown to persist in
`the sputum of many patients with
`chronic bronchitis, and has been shown
`to slow ciliary beating and increase
`mucus production in vitro.
`Cipro® Tablets give you the power to
`aggressively treat H influenzae and
`resolve infections for many chronic
`bronchitics, before things turn vicious.
`
`Additionally, in two studies that
`included other pathogens, a total of
`95% of bronchitis patients (n=84) had
`favorable outcomes.*
`So the next time bacterial infection
`starts something you'd prefer to avoid,
`trust the power of Cipro® Tablets.
`Cipro® Tablets are indicated for lower
`respiratory infections caused by
`Escherichia coli, Klebsiella pneumoniae,
`Enterobacter cloacae, Proteus mirabilis,
`Pseudomonas aeruginosa, Haemophilus
`influenzae, Haemophilus paraintluenzae,
`Streptococcus pneumoniae.
`
`Power proven against
`H influenzae.
`In three studies of bronchitis patients,
`where pathogens were identified, all
`patients with H inlluenzae (n=43)
`responded favorably* to Cipro® Tablets.
`
`*Favorable outcome defined as improvement or resolution
`of clinical signs and symptoms.
`In vitro activity does not necessarily imply a correlation
`with in vivo results.
`
`Pro
`
`(ciprofloxacin HCI) Tablets
`500 mg 750 mg
`The most potent fluoroquinolone.t
`
`Most frequently reported adverse events (>1%): nausea; diarrhea; vomiting;
`abdominal pain/discomfort; headache; rash; restlessness.
`
`Please see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections
`of brief summary of prescribing information on following page.
`
`Ex. 1095 - Page 3
`
`

`

`Volume 345, Number 8946 • Founded 1823 • Published weekly • Saturday 11 February 1995
`
`EDITORIAL OFFICES
`LONDON
`42 Bedford Square,
`London WC1B 3SL, UK
`
`Telephone 0171 436 4981
`International + 44 171 436 4981
`
`Fax 0171 436 7550
`International + 44 171 436 7550
`
`Editor
`Robin Fox MB FRCPE
`
`Deputy editor
`David Sharp MA
`
`Senior editor
`Imogen Evans MD PhD FRCPC
`
`Staff editors
`John Bignall MB
`Vivien Choo MB
`Stephanie Clark PhD
`Astrid James BSc MB
`John McConnell BSc
`David McNamee MSc PhD
`Rosalind Osmond MSc
`Pia Pini BSc FIBMS
`Sarah Ramsay BA
`Clare Thompson BSc
`
`NEW YORK
`655 Avenue of the Americas,
`New York, NY 10010, USA
`Tel 212 633 3810 (fax 3850)
`
`Assistant editor
`Richard Horton BSc MB
`
`Associate editor
`David H Frankel MD
`
`INTERNATIONAL
`ADVISORY BOARD
`Michael Baum FRCS (London)
`Henri Bismuth MD (Paris)
`lain Chalmers MSc (Oxford)
`A J Dunning MD (Amsterdam)
`Eric Espiner FRACP (Christchurch)
`Robert Fletcher MD (Boston)
`Suzanne Fletcher MD (Boston)
`Karen Gelmon FRCPC (Vancouver)
`Johan Giesecke MD (Stockholm)
`Kelsey Harrison NNmA (Liverpool)
`Jun-ichi Hata MD (Tokyo)
`Sven Hernberg MD (Helsinki)
`Ralph Horwitz MD (New Haven)
`T Jacob John FRCPE (Vellore)
`Yuet Wai Kan FRS (San Francisco)
`Jay A Levy MD (San Francisco)
`Giuseppe Remuzzi MD (Bergamo)
`Juan Rodes MD (Barcelona)
`Frank Sham, FRACP (Melbourne)
`Thomas Sherwood FRCP (Cambridge)
`Michael Steel FRCPE (St Andrews)
`John Swales FRCP (Leicester)
`Jan Vandenbroucke MD (Leiden)
`David Weatherall FRS (Oxford)
`Yoshio Yazaki MD (Tokyo)
`
`Letters to the Editor
`
`381 Travellers' diarrhoea and use of
`single-dose ciprofloxacin
`D C Fiore;
`M J G Farthing;
`M P Connor, A D Green;
`C Hall, J Cornell;
`D Maher, A D Harries
`
`382 Topical treatment for Dupuytren's
`contracture
`A G Freeman
`
`382 Subcutaneous gammaglobulin for
`patients with secondary
`hypogammaglobulinaemia
`L Hammarstrom and others
`
`383 End of New Zealand asthma
`epidemic
`C Schuijt, H Staudinger;
`P Ernst, S Suissa
`
`384 Cardiovascular disease in the
`tropics, ethics, and need for action
`S Lindeberg
`
`385 Dual role for Afipia fells and
`Rochalimaea henselae in cat-
`scratch disease
`S Alkan and others
`
`385 Outcome in offspring of women with
`mild hyperphenylalaninaemia
`I Smith, S Tillotson;
`H L Levy and others;
`D Smithells
`
`386 Sudden infant death syndrome and
`volatile antimony compounds
`P N Gates and others
`
`387 Unnecessary D & Cs
`J G Hooker
`387 Smoking, Alzheimer's disease, and
`confounding with genes
`B L Plassman and others
`
`388 Shifting indications for
`hysterectomy
`J Studd;
`A Saha;
`M Hickey, I S Fraser
`
`389
`
`Is contrast enhancement in cranial
`computed tomography necessary?
`P Demaerel and others
`
`389 Folic acid in prevention of neural
`tube defects
`N J Wald, M P Gilbertson;
`W Doyle
`
`390 HIV testing in prison
`T P Flanigan
`
`390 Nitric oxide production and
`heart failure
`D S Winlaw and others
`
`391 Superoxide dismutase and
`amyotrophic lateral sclerosis
`R J Swingler and others
`
`391 Parental influence on inheritance
`of familial amyotrophic lateral
`sclerosis
`R W Orrell and others
`
`392
`
`Involvement of macrophages in
`lethal forms of graft-versus-host
`disease
`T Facon and others
`
`393 Breastfeeding and neurological
`status
`J F Orlebeke and others;
`C I Lanting and others
`
`393 Migration of Echinococcus
`granulosus via lymphatics
`P J Cant
`
`394 Lack of effect of nedocromil sodium
`in ACE-inhibitor-induced cough
`H Puolijoki, M Rekiaro;
`J G F Cleland
`
`395
`
`When practice makes perfect
`A Karni
`
`395 Hepatitis B vaccine boosting among
`young healthy adults
`M Gesemann, N Scheiermann;
`W R Gilks and others
`
`396 Efficacy of lamivudine on replication
`of hepatitis B virus in HIV-infected
`patients
`Y Benhamou and others
`
`397 Vertical transmission of hepatitis
`A virus
`I Tanaka and others
`
`397 Risk factors in melanoma
`F H J Rampen
`
`398 Delay in onset of malaria with
`mefloquine prophylaxis
`J H Day, R H Behrens
`
`398 Subacute cutaneous lupus
`erythematosus associated with
`cilazapril
`M L Fernandez-Diaz and others
`
`Ex. 1095 - Page 4
`
`

`

`THE LANCET
`
`Subcutaneous immunoglobulin replacement in patients with
`primary antibody deficiencies: safety and costs
`
`Ann Gardulf, Vagn Andersen, Janne Bjorkander, Diddi Ericson, Stig S Froland, Rolf Gustafson, Lennart Hammarstrom,
`Marten B Jacobsen, Egon Jonsson, Gudrun Moller, Tiina Nystrom, Blom Soeberg, C I Edvard Smith
`
`Summary
`Immunoglobulins (IgG) as replacement therapy in primary
`antibody deficiencies can be given as intramuscular
`injections, or as intravenous or subcutaneous infusions. Our
`aims were to obtain information on the frequency of
`adverse systemic reactions during subcutaneous therapy,
`the occurrence and intensity of tissue reactions at the
`infusion sites, and serum IgG changes. Furthermore, we
`compared costs between the different replacement
`regimes.
`Our study included 165 patients (69 women, 96 men,
`aged 13-76 years) with primary hypogammaglobulinaemia
`or IgG-subclass deficiencies. Data were compiled from
`questionnaires filled in by the patients and from their
`medical records. 33 168 subcutaneous infusions (27 030
`in home therapy) had been given. 106 (of which 16 were at
`home) adverse systemic reactions (100 mild, 6 moderate)
`were recorded in 28 patients (17%). No severe or
`anaphylactoid reactions occurred. Despite large
`immunoglobulin volumes given during 434 patient years
`(28 480 infusions), no signs have been found that indicate
`the transmission of hepatitis virus. Transient tissue
`reactions occurred at the infusion sites but were not
`troublesome to most patients and we found significant
`increases in mean serum IgG. The use of subcutaneous
`instead of intravenous infusions at home would reduce
`the yearly cost per patient for the health-care sector by
`US $10 100 in Sweden alone.
`We conclude that subcutaneous administration of IgG is
`a safe and convenient method of providing
`immunoglobulins. We were able to reach serum IgG
`concentrations similar to those by the intravenous therapy
`and we found that the method could also be used
`successfully in patients with previous severe or
`anaphylactoid reactions to intramuscular injections.
`Lancet 1995; 345: 365-69
`
`Karolinska Institute at Huddinge University Hospital
`(A Gardulf RN, PhD, L Hammarstrom MD, R Gustafson MD,
`T Nystrom RN, C I Edvard Smith Nit)), Infectious Diseases
`(R Gustafson) and Department of Internal Medicine
`(Prof E Jonsson PhD); Karolinska Institute at Karolinska Hospital
`(A Gardulf); The Swedish Council on Technology Assessment
`in Health Care (Prof E Jonsson, G Mailer RPT, BA);
`Karolinska Institute, Department of Physical Therapy (G Moller);
`Sahlgrenska University Hospital, The Asthma and
`Allergy Research Centre (J Bjorkander MD, D Ericson RN),
`Gothenburg, Sweden; Rigshospitalet, Department of
`Internal Medicine TTA (V Andersen rvio, B Soeberg MD),
`Copenhagen, Denmark; Rikshospitalet, Section of Clinical
`Immunology and Infectious Diseases, Medical Department A
`(Prof S S Froland MD, M B Jacobsen MD), Oslo, Norway
`Correspondence to: Dr Ann Gardulf, Department of Clinical
`Immunology, F71, Huddinge University Hospital,
`S-141 86 Huddinge, Sweden
`
`Vol 345 • February 11, 1995
`
`Introduction
`People with primary hypogammaglobulinaemia, such as
`common variable immunodeficiency (CVID) or X-linked
`agammaglobulinaemia (XLA), need to be given IgG
`replacement therapy.' Patients with selective IgG-subclass
`deficiency, with or without simultaneous IgA deficiency,
`may also benefit.',2 Replacement therapy can be given as
`intramuscular injections or as intravenous or sub-
`cutaneous infusions of immunoglobulin preparations. The
`last two may be administered at home by the patients
`themselves,5-' and subcutaneous administration,' is
`becoming more popular. This change is mainly because of
`reports of low risk of adverse systemic reactions'," and
`normal serum IgG concentrations'""-" being achieved.
`However, reports of the subcutaneous method have so far
`been restricted to patients with CVID or XLA and to
`studies on relatively few patients, although treatment has
`been given to adults,b,','-12 and children.804-16 Furthermore,
`most of the published results have been based on slow
`subcutaneous infusions.'-'2,'4-'5
`We collated our multi-centre study to obtain
`information on: the frequency of adverse systemic
`reactions during hospital and home therapy; the
`occurrence and perceived intensity of tissue reactions at
`the infusion sites; and the serum IgG concentrations. We
`compared the costs of different replacement regimens.
`
`Patients and methods
`Patients
`165 patients (69 women, 96 men, mean age 43, range 13-76
`years) with ongoing or previous subcutaneous replacement
`therapy were included from 4 centres in 3 Scandinavian
`countries: Stockholm and Gothenburg in Sweden; Copenhagen
`in Denmark; and Oslo in Norway. The sample included patients
`with CVID (n 101), XLA (n 7) and IgG-subclass deficiencies
`with (n 5) or without (n 52) simultaneous IgA deficiency. Before
`initiation of subcutaneous therapy, most ptients (n 126, 76%)
`were treated by intramuscular injections (n 69), intravenous
`infusions (n 13), or alternate intramuscular injections and
`intravenous infusions (n 44).
`From 165 patients, subjects 18 years or older who received
`ongoing subcutaneous therapy and were able to read and write,
`were asked to report their opinions of the subcutaneous method.
`158 patients fulfilled the criteria and 152, 89 women and 63 men
`(96%), answered the questionnaire.
`
`Clinical details
`Data of previous and ongoing immunoglobulin therapy, adverse
`systemic reactions, liver function tests, and serum IgG
`concentrations were compiled from medical records. Blood
`samples for IgG and IgG subclasses were always collected as
`preinfusion samples during hospital treatment. In home therapy,
`blood collection varied with respect to IgG administration. Blood
`samples from the patients on intramuscular or intravenous
`treatment before subcutaneous therapy were collected as
`preinfusion samples. The reported systemic reactions were
`classified in one of the following four groups: mild, moderate,
`
`365
`
`Ex. 1095 - Page 5
`
`

`

`THE LANCET
`
`Number of
`patients
`
`Immunoglobulin preparations
`
`mg/kg month
`mean (min-max)
`
`Infusion rate (mL/h/
`syringe driver)
`
`mL/infusion
`site (max)
`
`Infusion Interval
`
`400* (210-730)
`
`20t
`
`10 (18)
`
`Once per week
`
`Gammaglobulin Kabi, Pharmacia,
`Sweden 165 mg/mL or
`Gammabulin, Immuno, Austria
`160 mg/mL
`Gammaglobulin Kabi, Pharmacia,
`Sweden 165 mg/mL
`Nordimmun, Novo Nordisk, Denmark
`150 mg/mL
`Gammaglobulin Kabi, Pharmacia,
`Sweden, 165 mg/mL
`*A dose of 400 mg/kg/month was given to the majority of the patients (54/59, 92%). tTwo syringe-drivers were used simultaneously during hospital practice (=40 mL/h). tFaur
`syringe-drivers were used simultaneously during hospital practice (=80 mL/h).
`Table 1: Patients and data about immunoglobulin preparations and the subcutaneous therapy
`
`Stockholm, Sweden
`
`59
`
`Gothenberg, Sweden
`
`Copenhagen, Denmark
`
`Oslo, Norway
`
`40
`
`20
`
`46
`
`325 (80-800)
`
`465(310-765)
`
`220 (140-480)
`
`214
`
`4-8
`
`5
`
`10
`
`20
`
`Once per week or once
`every two weeks
`1-4 times per week
`
`20 (40)
`
`1-3 times per week
`
`severe, or anaphylactoid reactions. We classified symptoms such
`as headache, dizziness, cold sweats, nausea, fatigue, and myalgias
`as mild reactions. Moderate and severe reactions included
`wheezing, dyspnoea, chest pain, flushing, tachycardia,
`abdominal, and/or back pain, diarrhoea, and chills. If these
`reactions required treatment (adrenaline, hydrocortisone, etc),
`they were classified as severe, otherwise as moderate. Mental
`confusion and clouding of consciousness were also classified as
`severe reactions. Table 1 shows the routes and immunoglobulin
`preparations employed.
`All the infusions were given in the abdominal wall, thigh
`and/or buttocks (the latter used only in Gothenburg) by using
`portable syringe drivers (MS16A, Graseby Medical, UK)
`combined with infusion sets with 0.3-0-6 mm butterfly needles.
`All patients in Stockholm, Copenhagen, Oslo, and 1 patient in
`Gothenburg self infused the immunoglobulin at home (n=125).
`The remaining patients in Gothenburg received their infusions in
`the hospital's out-patient clinic.
`
`Questionnaire
`23 questions (out of 38) in the questionnaire concerned patients'
`perceptions of tissue reactions at the infusion sites. The patient
`answered yes or no to questions about occurrence of tissue
`reactions and also visual analogue scales about intensity, 1 local
`reaction is not troublesome, 100 local reaction is very
`troublesome.
`
`Cost
`The cost of the replacement therapy to the Swedish health-care
`system included: immunoglobulin preparations, materials,
`personnel, rooms, and administrative overheads. We used the
`data to compare the costs of five available, alternative-therapy
`regimens: hospital treatment with intramuscular injections;
`intravenous or subcutaneous infusions; and home therapy with
`intravenous or subcutaneous infusions. A WHO-suggested
`monthly immunoglobulin dose of 400 mg per kilogram was used
`in the costing. We compared the costs by calculating them in US
`dollars at 1993 prices (7.80 Swedish kronor to 1 US dollar).
`
`Statistical analysis
`We used non-parametric and parametric statistical methods. The
`differences between two groups were tested by the Mann-
`
`Whitney U-test or by Student's t-test. The differences between
`several groups were tested by the Kruskal—Wallis, one-way
`analysis of variance or by ANOVA (with a 95% CI). The
`relations between variables were expressed by Spearman rank-
`order-correlation coefficients or Pearson's product-moment-
`correlation coefficients. Nominal data were treated by the x' test.
`Statistical significance was accepted if p<0•05.
`
`Ethics
`The study was approved by the local ethics committee at each
`participating hospital and, in Stockholm, also by the ethics
`committee at the Karolinska Institute. Informed consent was
`obtained from the patients or from their parents.
`
`Results
`Duration of subcutaneous IgG-replacement therapy
`ranged from 5 months to 9 years 8 months (median 3
`years). 33 168 infusions, of which 27 030 at home, were
`administered (table 2). 106 adverse systemic reactions
`were reported in 28 patients (17%). 100 were mild and
`the remaining 6 moderate. There were no severe or
`anaphylactoid reactions. 16 of the 106 reported mild or
`moderate reactions occurred at home. Table 2 shows that
`a low total frequency of reactions were reported from
`Copenhagen and Oslo; this was because if mild reactions
`occurred, they were not recorded at these two centres.
`There was no difference in the reported frequency of
`adverse systemic reactions between the patients with
`CVID or XLA compared with patients with IgG-subclass
`deficiencies, or between men and women.
`Of the 126 patients who previously had intramuscular
`injections and/or intravenous infusions, 48 had
`experienced 678 adverse systemic reactions. In the years
`before subcutanous therapy, 9554 intramuscular
`injections had been given to the patients of which 486
`(5%) resulted in an adverse reaction. These reactions
`consisted of 430 mild, 25 moderate, 16 severe, and 15
`anaphylactoid reactions. During 1416 intravenous
`infusions, 192 (14%) reactions (146 mild, 46 moderate)
`were reported. Of the 48 patients with adverse reactions
`
`Hospital-based therapy and home therapy
`
`Number of
`infusions
`
`Number and types of
`reactions (patients)
`
`During home therapy
`
`Total number of
`reactions (%) (patients)
`
`Number of
`infusions
`
`Number and types of
`reactions (patients)
`
`Total number of
`reactions (%) (patients)
`
`Stockholm
`Gothenburg
`Copenhagent
`Oslot
`
`Total
`
`8836
`4353
`8619
`11 360
`
`33 168
`
`Mild
`
`57 (n=17)
`43 (n=7)
`
`Moderate*
`
`3 (n=3)
`2 (n=2)
`1 (n=1)
`0
`
`100 (n=24)
`
`6 (n=6)
`
`60 (0.7) (n=20)
`45 (1.0) (n=7)
`1 (n=1)
`0
`
`106 $ (n=28)
`
`7674
`370
`8534
`10 452
`
`27 030
`
`Mild
`
`Moderate*
`
`14 (n=3)
`0
`
`1 (n=1)
`0
`1. (n=1)
`0
`
`14 (n=3)
`
`2 (n=2)
`
`15 (n=4)
`0
`1 (n=1)
`0
`
`16 (n=5)
`
`*No severe or anaphylctoid reactions occurred during the subcutaneous infusions. 1-At these two centres, mild reactions were not recorded. $The prevalence of systemic adverse
`reactions was estimated as 0.8% (Stockholm, Gothenburg).
`Table 2: Frequency and types of adverse systemic reactions during subcutaneous Immunoglobulin replacement therapy
`
`366
`
`Vol 345 • February 11, 1995
`
`Ex. 1095 - Page 6
`
`

`

`Symptom
`
`Score intervals"
`
`Median
`
`1-25
`Grade I
`
`26-50
`Grade II
`
`51-75
`Grade III
`
`76-100
`Grade IV
`
`Swelling (n=123)
`Soreness (n=106)
`Redness (n=81)
`Induration (n=77)
`
`70 (57%)
`44 (42%)
`67 (83%)
`45 (58%)
`
`26 (21%)
`28 (26%)
`4 (5%)
`16 (21%)
`
`19
`29
`5
`15
`*VAS score 1=local reaction not troublesome, 100=local reaction very troublesome.
`Table 3: The four commonly reported, transient, local tissue
`reactions reported
`
`20 (16%)
`20 (19%)
`8 (10%)
`9 (12%)
`
`7 (6%)
`14 (13%)
`2 (2%)
`7 (9%)
`
`during intramuscular and/or intravenous therapy, 35 did
`not have any reactions when they used the subcutaneous
`route and the 13 others had only mild reactions.
`18 patients had acquired chronic hepatitis C from
`contaminated batches of intravenous gammaglobulin
`products before subcutaneous therapy and one patient
`had hepatitis B from intravenous drug abuse. The
`remaining 146 patients (28 480 infusions, 434 patient
`years) were followed-up for signs of hepatitis virus
`transmission during subcutaneous therapy. The
`investigations included tests for AST, ALT, alkaline
`phosphatase and total bilirubin every 3-6 months. In spite
`of large doses IgG, no signs indicated the transmission
`of hepatitis virus by intramuscular products given
`subcutaneously.
`
`Local tissue reactions
`The responSes to the questionnaire in 152 patients,
`revealed that 87% of the patients had experienced some
`form of tissue reaction in the infusion sites at least once.
`The number of patients reporting local reactions were for
`swelling 123, soreness 106, redness 81, induration 77,
`local heat 56, itching 34, bruising 24, and rash 8. These
`tissues reactions were reported to occur sporadically and
`to be transient. Most patients did not perceive them to be
`troublesome (table 3). There were no skin infections or
`abscesses.
`The perception of inconvenience caused by local
`reactions such as swelling (p<0.05), soreness (p<0.05),
`and induration (p<0.05) were inversely correlated with
`their body mass index (BMI),2 thus the lower the BMI,
`the more pronounced the perception of symptoms. When
`comparing patients who received slow (Copenhagen and
`Oslo) versus rapid (Stockholm and Gothenburg)
`infusions, there were no differences between the two with
`the exception of itching (p<0.05); the patients on rapid
`infusion thought this symptom was more pronounced.
`
`Patients ending the therapy
`After six years, 1 female patient in Copenhagen stopped
`having the subcutaneous infusions when she refused any
`form of replacement treatment. In Gothenburg,
`subcutaneous therapy was stopped because of local tissue
`reactions which gave pronounced erythema, itching, and
`soreness in two female patients after 95 and 173
`infusions, respectively.
`
`Serum IgG and IgG-subclasses
`Table 4 shows that in individuals with CVID or XLA who
`had not previously received immunoglobulins, mean
`serum IgG levels increased.
`In subjects who were treated with intramuscular
`injections immediately before subcutaneous therapy,
`mean IgG concentration increased from 3.0 to 6.2 g/L
`(p<0.001, paired Student's t-test) after 6 months of
`
`Vol 345 • February 11, 1995
`
`THE LANCET
`
`IgG concentration
`(g/L)
`
`Stockholm*
`
`Copenhagen*
`
`Oslo*
`
`Total
`
`0
`
`6
`
`12
`
`24
`
`36 months
`
`2.1
`8.2
`0.4-4.2) 6.0-11-0
`(n=8)
`(n=8)
`0.5
`5.9
`0-1.6
`2.3-9.2
`(n=8)
`(n=6)
`2.5
`5.0
`0-1-4.7
`2-5-7.8
`(n=8)
`(n=8)
`1.7
`6.4
`0-4.7
`2-3-11.0
`(n=24)
`(n=22)
`
`10.1
`7-9-14.7
`(n=8)
`4.9
`2.3-8.7
`(n=5)
`5.9
`
`(n=5)
`7.5
`2.3-14.7
`(n=18)
`
`10.9
`7.5-14.0
`(n=8)
`5.6
`
`(n=5)
`6.4
`4.5-8.3
`(n=4)
`8.3
`3.8-14.0
`(n=17)
`
`9.9
`6.9-12-7
`(n=7)
`6.7
`5-3-8.9
`(n=6)
`
`8.4
`5.3-12-7
`(n=13)
`
`Data are given as mean, range, and number of patients. Normal range for IgG (adults):
`7-15 g/L. *Gothenburg excluded as they had no unsubstituted CVID/XLA subjects.
`Table 4: Serum IgG levels (g/L) before and during 36 months of
`subcutaneous gammaglobulin therapy in previously
`unsubstituted CVID/XLA subjects
`
`Yearly cost*
`
`Percent of cost related to IgG
`preparations
`
`Hospital•based therapy
`Intramuscular injections
`Intravenous infusions
`Subcutaneous infusions
`
`Home therapy
`Intramuscular injections
`Subcutaneous infusions
`
`3204
`14 124
`4656
`
`13 224
`3096
`
`75%
`93%
`51%
`
`99%
`78%
`
`*Cost per year in $US at 1993 prices, and as the percentage of the cost that relates
`to the immunoglobulin preparations.
`The calculations are based on an immunoglobulin dose of 400 mg/kg/month. The less
`costly products registered in Sweden have been used in the calculations.
`Table 5: The yearly costs of five alternative strategies of IgG
`replacement therapy
`
`subcutaneous therapy (46). In subjects treated with
`intravenous infusions before subcutaneous therapy, mean
`IgG concentration increased from 4.9 to 7.3 g/L
`(p<0.001, paired Student's t-test) after 6 months (27). In
`all patients with CVID or XLA, a significant correlation
`was found between the monthly immunoglobulin doses
`given and serum IgG concentrations reached (p<0.001)
`after 6 months on the subcutaneous therapy.
`In patients with IgG subclass deficiencies not previously
`treated the mean subclass concentrations increased during
`the first 6 months: with IgG1 deficiency the mean IgG1
`concentration increased from 31 to 5.5 g/L; in patients
`with IgG2 deficiency, the mean IgG2 concentration
`increased from 0.6 to 44 g/L, and in patients with IgG3-
`deficiency, the mean IgG3 concentration increased from
`0.13 to 0.22 g/L.
`
`Cost of replacement therapy
`The total, yearly costs for the hospital-based
`intramuscular and subcutaneous treatments were
`approximately comparable, while the cost of the
`intravenous treatment was 3-4 times higher. Comparison
`between the two home-therapy alternatives showed that
`the total, yearly cost of the subcutaneous therapy was
`approximately $3100 compared with $13 200 for the
`intravenous therapy (table 5). The costs for the
`immunoglobulin preparations represented most of the
`total yearly costs: intramuscular therapy 75%, intravenous
`therapy 93-99%, and subcutaneous therapy 51-78%.
`
`Discussion
`The main purpose of IgG replacement therapy is to
`reduce the frequency and severity of infections. The
`development of immunoglobulins which have a low risk of
`
`367
`
`Ex. 1095 - Page 7
`
`(cid:9)
`

`

`THE LANCET
`
`virus transmission and cause as few adverse systemic
`reactions as possible is important. Likewise, the
`administration should have a minimal, negative impact on
`patients' daily lives. Home therapy has been shown to be
`convenient for the patients, as it is time-saving, reduces
`the time lost from work or school and increases
`independence.'-6,8,1708 The use of the subcutaneous
`administration route has been reported from several
`countries.6-12, 14-16,19,20
`In our study, there were only 106 adverse systemic
`reactions with more than 33 000 subcutaneous IgG
`infusions. The prevalence of undesired reactions was less
`than 1%. Most reactions (100/106) were mild, the
`remainder were classified as moderate. For comparison,
`126 of the same patients had had a total of 678 reactions
`during intramuscular or intravenous treatment. The
`prevalence of adverse reactions in connection with
`intravenous infusions was calculated as 14% and for the
`intramuscular injections as 5%. However, severe and
`anaphylactoid reactions occurred only during
`intramuscular therapy not during intravenous therapy.
`Subcutaneous therapy was in our study safely used at
`home, and used on patients who had previously
`experienced severe or even anaphylactoid reactions during
`intramuscular treatment.
`16 of the 106 reactions in our study occurred at home.
`The low number of reactions reported during home
`therapy may be explained in two ways: more reactions
`might occur during the initial, hospital-based phase of the
`therapy, when the patients still have a higher frequency of
`infections leading to the formation of antigen-antibody
`complexes;" or the patients may be less inclined to report
`mild reactions when they have home therapy. However,
`we believe that moderate or severe reactions will be
`reported by patients.
`The most common transient local tissue reactions at
`the infusion sites were swelling, soreness, redness,
`induration, local heat, and itching. Less subcutaneous
`tissue seems to increase the inconvenience of these local
`reactions. The difference between the intensity of itching
`and the infusion rate (slow vs rapid) may be due to
`mechanical and/or chemical local mechanisms afflicting
`superficial, dermal sensory nerve fibres.22
`Unfortunately, mild adverse systemic reactions were
`not routinely recorded at the two clinics where slow
`infusions were practised. It was therefore not possible to
`investigate whether rapid infusions