When to use IVIG in Rheumatic Diseases

Evidence based review of IVIg in Rheumatic Diseases.

Fazle Mahmood, MD

Introduction• IVIG is a fraction purified from plasma.

• Principally contains IgG in a form that can be safely administered intravenously.

• Prepared from pooled plasma from 3000-10,000 healthy donors.

• The large number of donors in the pool increases the number of antibody activities in the preparation.

• Products prepared by different manufacturers have differing contents of IgA, traces of other proteins and stabilizers.

• Product to product and lot to lot variation in specific antibody titers is likely.

Safety from blood-borne pathogens

• All products in U.S. are believed to be free from all known pathogens.

• No products produced with the current safety measures have ever been reported to have transmitted a blood borne disease.

• However unknown agents may still be present.

• CDC guidelines;– Caution is still warranted with the use of IVIG.– IVIG should not be considered totally benign.– Patients receiving IVIG should be monitored at regular intervals.

Adverse Reactions

• 5-20% IVIG infusions are associated with adverse reaction.

• Majority are rate-related and mimic one or more features of anaphylactoid reaction.– Chills –Flushing –Tachycardia –Headache– Chest tightness –Shortness of Breath – Nausea/Vomiting.

• Most are non-life threatening; reduce rate or temporarily pause the infusion.

Adverse Reactions

• True anaphylaxis can occur in completely IgA deficient patients.

• Pre-formed IgE or IgG antibodies against IgA are responsible for this reaction.

• Patients with partial IgA deficiency are not at risk.

• Treatement with pre-meds;– Acetaminophen; 30 mins prior to infusion.– Diphenhydramine– Corticosteroids; PO or IV frequently used prophylactically.

Renal complications• >100 cases of acute Kidney injury reported with IVIG infusion.

• >90% cases occurred with sucrose containing products.

• Pathogenesis believed to involve;– Osmotic uptake of sucrose by tubular cells causing swelling and

obstruction of tubules.– Increased blood viscosity and thus reduction in renal flow.– Immune complex deposition.

• Clinical manifestations vary from asymptomatic rise in serum creatinine to anuric renal failure.

• Spontaneous resolution typically occurs within four to eight days.

Renal complications• Risk factors for this adverse reaction include;*

– Renal insufficiency– Diabetes Mellitus.– Dehydration.– Age >65.– Sepsis.– Paraprotienemia.– Concomitant use of nephrotoxic agents.

1. Avoid sucrose containing products in patients with pre-existing renal disease.

2. Patients should be adequately hydrated.

3. Administration of IV fluids before IVIG infusion may be useful in preventing renal complications.

*IVIG adverse effects and safe administartion Orbach et al; Clinical Reviews in Allergy and Immunology, Vol 29, 2005

Thrombotic complications• Multiple cases of serious thromboembolic events following IVIg therapy

have been reported.*

• Majority of cases had risk factors for thromboembolism or received high doses or high infusion rates.

• Precautionary statements have been published and can be found at http://www.fda.gov/medwatch/safety/2002/safety02.htm#igiv.

• High concentrations of IgG can raise the viscosity of serum and whole blood.*

• Local thrombosis at infusion site with extension to larger veins as well as remote thromboembolic events may occur.*

• Transient ischemic attacks, transient angina pectoris, as well as stroke and myocardial infarction have been reported.*

Thrombotic complications

• The use of schemes in which infusion rate is increased “as tolerated” should be avoided.

• Should be used with caution in; – Elderly patients.– Patients with increased risk of hyperviscosity syndromes.– Patients with increased risk of thromboembolic disease.

• When instituted 2g/kg should be given over 5 days (400 mg/kg/d) and not more than 50 mg/kg/hr, in no less than 8 hrs.*

Hematologic complications

• Several cases of Coombs positive hemolytic anemia have been reported after IVIG infusion.

• Episodes are invariably self-limited, although may occasionally be severe.

• More significant hemolysis with reduced haptoglobin, increased serum LDH and transient reticulocytosis may occur following high dose infusions.

• Transient neutropenia have also been reported and is not likely to increase the risk of infection.

IVIG adverse effects and safe administartion Orbach et al; Clinical Reviews in Allergy and Immunology, Vol 29, 2005

Immunoregulatory Effects of Immune Globulin

Fc Receptor- Mediated Effects

Fc Receptor-Mediated Effects of Immune Globulin

Immunoregulatory Effects of Immune Globulin

Immunomodulatory Effects of Immune Globulin on B Cells and T Cells

Indications for use.

• FDA approved for 6 conditions:1. Idiopathic thrombocytopenic purpura.

2. Primary immunodeficiency states.

3. Secondary immunodeficiency in CLL.

4. Pediatric HIV infection.

5. Kawasaki syndrome.

6. Prevention of GVHD and infection in adults.

IVIg in Inflammatory Myopathies.

Dermatomyositis

A controlled trial of high-dose intravenous immunoglobulininfusions as treatment for dermatomyositis.

Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al. NEJM 1993;329:1993–2000.

• A double blind, placebo controlled.

• 15 patients (18-55 years) biopsy-proven, treatment-resistant.

• Randomly assigned to receive IGIV (#8) or placebo (#7) every month for 3 months, with option to cross over to alternative therapy for 3 more months after a wash out period of 1 month.

• Continued to receive prednisone (mean dose 25mg/day), unchanged for 3 months before and after therapy.

• No other immunosuppressants during that time.

• Histological and immunopathological improvement sought in repeated muscle biopsies.

• Clinical response was gauged by assessing changes in:– muscle strength (18 proximal muscle groups), using a modified

Medical Research Council (MRC) scale, a well-validated scale in the treatment of neuromuscular disorders.

– neuromuscular symptom scores that provide a picture of the daily living activities (20 activities).

– the rash, using photography with unchanged lighting conditions.

IVIG in Dermatomyositis

• IVIG is not recommended as monotherapy for dermatomyositis.

• IVIG is recommended as an option, in combination with other agents for treatment resistant (conventional immunosuppressive therapies) patients.

• IVIG is recommended in combination with other agents, as a steroid sparing option.

• IVIG may be considered in conjunction with other agents for treatment of severe, life-threatening dermatomyositis.

Guidelines for use of IVIG for Neurologic conditionsFeasby et al; Transfusion medicine Reviews, Vol 21 No 2, Suppl 1 April 2007: pp S57-S107

Inclusion Body Myositis

IVIg in Inclusion Body Myositis

• The available evidence shows some improvement with IVIG, but no evidence of sustained benefit.

• IVIG is not recommended for treatment of IBM.

Polymyositis

IVIg in Polymyositis.

• IVIG may be considered among the treatment options for polymyositis in patients who fail to respond to first-line therapies.

IVIg in Lupus.

A study of 20 SLE pts with IVIg clinical and serologic responseLevy Y, Sherer Y, Ahmed A, Langevitz P, George J, Schoenfeld Y et al

Lupus 1999;8;705

• 20 SLE patients were treated with high-dose (2 g/kg) IVIg monthly, in a 5-d schedule.

• Each patient received between 1-8 treatment courses. • They were evaluated for;

– Clinical response– Systemic Lupus Activity Measure (SLAM) score before and after

IVIg– levels of antinuclear antibody (ANA)– dsDNA (double-stranded DNA) – SS-A or SS-B, ENA (extractable nuclear antigens) – C3 and C4 levels before and after the treatment, and before and

after each treatment course.

Clinical details of the patients included in the study prior to IVIg treatment

Clinical details of the patients post-IVIg treatment

Lupus 1999;8;705

• There was a tendency towards abnormal levels of complement and Abs before IVIg courses among the treatment responders compared with the non-responders.

• Similarly treatment responders tended to have normalization of their abnormal levels more than the non-responders.

• These differences were found statistically significant only with respect to C4 and SS-A or SS-B levels before IVIg courses.

Lupus 1999;8;705

• A beneficial clinical response following IVIg treatment was noted in 17 out of 20 patients (85%).

• Few clinical manifestations responded more to treatment: – arthritis, – fever, – thrombocytopenia, – neuropsychiatric lupus.

• In 9 patients evaluated before and after IVIg, mean SLAM score decreased from 19.3+/-4.7 to 4+/-2.9 (P<0.0001).

Mean dose 29.7 mg/day before IVIgMean dose 13.8 mg/day after IVIg

Mean SLAM 19.3 before IVIgMean SLAM 4 after IVIg.

IVIg Therapy in Various Manifestations of SLE

14 Lupus pts;Proliferative

glomerulonephritis

Cyclophosphamide +

Prednisone

5 pts •IVIg (0.4 g/kg) monthly x 18 mths

9 ptscyclophosphamide every 2 mths x 6 mths

then every 3 mths x 1 yr

Induction therapy

no differences in kidney function, proteinuria, or nephritis between the two treatment groups.

IVIg in Lupus.

• Not recommended as 1st line therapy.

• Can be considered in management of Lupus;– In severe life or organ-threatening

manifestations (cerebritis, nephritis*), when conventional immunosuppression is either unresponsive or contraindicated.

– Life threatening cytopenias such as thrombocytopenia not responsive to steroids.

*Use non sucrose containing formulation

IVIg in APS.

IVIg in APS

• Use of IVIg in APS (mostly hematological manifestations) is found as case reports.*

*Sherer, Y., Levy, Y., and Shoenfeld, Y. (2000), Rheumatology 39, 421–426.

DAH with APA

• Diffuse alveolar hemorrhage (DAH) due to pulmonary capillaritis in the setting of high titer APA.

• No evidence of acute thrombosis as a cause of DAH.

• A case series (4 pts) and literature review (1965-2003) of total 17 pts.

DAH with APA

• All patients had a rapid clinical improvement to high dose corticosteroids.

• Recurrence was noted with subsequent tapering of steroids requiring alternative forms of immunosuppression including; cyclophosphamide, cyclosporine or MMF.

• In case of failure of conventional immunosuppression IVIg was used (3 cases) with stabilization of recurrent disease.

IVIg in CAPS

Catastrophic Antiphospholipid Syndrome: Where Do We Stand?Doruk Erkan, Ricard Cervera, and Ronald A. AshersonARTHRITIS & RHEUMATISMVol. 48, No. 12, December 2003, pp 3320–3327

APA in Pregnancy

• Pregnant women with APS are at increased risk for – Maternal thrombosis– Fetal loss after 10 weeks of gestation – Uteroplacental insufficiency– Intrauterine growth restriction – Preeclampsia

• Most reports about the use of IVIg in APS have focused on the obstetric complications (mainly recurrent abortions).

A multicenter, placebo-controlled pilot study of intravenous immune globulin

treatment of antiphospholipid syndrome* during pregnancy.

The Pregnancy Loss Study Group.

Am J Obstetrics & Gynecology

2000 Jan;182(1 Pt 1):122-7.

* All pts met criteria for APS according to Sapporo criteria.

All patients (n=16)treated withLow dose Aspirin

+Heparin

1g/kg IVIg q month(n=7)

until 36 weeks’ gestation

Placebo(n=9)

until 36 weeks’ gestation

Baseline Characteristics

Results

• No pregnancy losses were observed in the 2 groups.• Some non-significant differences were observed.

Randomized Study of SubcutaneousLow Molecular Weight Heparin Plus AspirinVersus Intravenous Immunoglobulin in the

Treatment of Recurrent Fetal LossAssociated With Antiphospholipid Antibodies

Giovanni Triolo, Angelo Ferrante, Francesco Ciccia, Antonina Accardo-Palumbo, Antonino Perino, Antonio Castelli,

Antonio Giarratano, and Giuseppe Licata

ARTHRITIS & RHEUMATISMVol. 48, No. 3, March 2003, pp 728–731

40 pregnant pts with recurrent abortion (at least 3 occurrences)

and repeatedly positive tests for aCL or LA

IVIg Group(n=21)

LMWH + Low dose ASA

Group(n=19)

ASA stopped at34 week,

LMWH stopped at37 week

Stopped at 31week

gestation

Major outcomes of pregnancy in the study groups

Treatment with LMW heparin plus low-dose aspirin should be considered as the standard therapy for recurrent pregnancy loss due to aPL.

IVIg in APS

• Not recommended as a standard therapy.

• No role for IVIg in obstetric complications of APS found in randomized controlled trials.

• IVIg can be considered in special circumstances in APS;– Marked APS-associated thrombocytopenia (similar to ITP)– 2nd line therapy in life threatening cases of CAPS– Subset of pts with Pulmonary capillaritis leading to DAH and

unresponsive to conventional immunosuppressive agents.

IVIg in Vasculitis

IVIg for the treatment of Kawasaki disease in children Oates-Whitehead, R. M., Baumer, J. H., Haines, L.,et al. (2003),

Cochrane Database Syst Rev 4, CD004000

• Meta-analysis of 16 randomized controlled trials of IVIg in Kawasaki disease.

• Showed a significant decrease in new coronary artery abnormalities (CAAs) in favor of IVIG, at 30 days [RR = 0.74, 95% CI 0.61 to 0.90].

• 400 mg/kg/day x 5 days vs. 2 gm/kg in a single dose showed statistically significant reduction in CAAs at 30 days [RR = 4.47, 95% CI 1.55 to 12.86].

• Significant reduction in duration of fever with the higher dose

Children fulfilling the diagnostic criteria for Kawasaki disease should be treated with IVIG (2 gm/kg single dose) within 10 days of onset of symptoms.

Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependant on gamma globulin dose but independent of salicylate dose.

Terai,M, Shulman,STJournal of Pediatrics 1997; 131:888

• Meta-analysis of 6 randomized controlled studies.(1629 pts)

Treatment

Modality

CA abnormalities

30 days

CA abnormalities

> 60 days

Aspirin alone 26 % 18 %IVIg(<1g/kg)+ ASA 18% 14%IVIg(1-1.2g/kg)+ ASA 16% 10%IVIg(1.6g/kg)+ ASA 9% 6%IVIg(2g/kg)+ ASA 4% 4%

2 gm/kg IVGG combined with at least 30 to 50 mg/kg per day aspirin provides maximum protection against development of coronary abnormalities after KD.

IVIg for relapses of systemic vasculitides associated with ANCA: Results of a multicenter, prospective, open-label study of twenty-two patients

Martinez V, Chen P, Pagnoux C.; French Vasculitis Study GroupArthritis Rheum. 2008;58(1):308-17

• 19 WG and 3 MPA pts who had relapsed after their initial treatment were enrolled.

• Pts were maintained on same regimen with which they had relapsed and IVIg was added.

• Pts received 0.5mg/kg/day x 4 days of IVIg (total 2gm) every month for total 6 months.

• Pts followed for 24 months.

By month 9Complete remission in 13 of the 22 patients (59.1% [95% confidence interval 0.39-0.79]) Partial remission in 1 patient (4.5%)

IVIg for relapses of systemic vasculitides associated with ANCA: Results of a multicenter, prospective, open-label study of twenty-two patients

Martinez V, Chen P, Pagnoux C.; French Vasculitis Study GroupArthritis Rheum. 2008;58(1):308-17

• 8 pts were still in remission at 24 months.

• Median oral prednisone dosage at study inclusion was 20 mg/day (range 5-500).

• Median oral prednisone dosage at follow-up;– 15 mg/day (range 0-30) by week 4.– 8 mg/day (range 0-12) by month 9. – 3.25mg/day (range 0-10) by month 24.

IVIg for ANCA-associated systemic vasculitis (AAV) with persistent disease activity

Jayne, D.R.W., Chapel,H., Adu,D., et al. QJ Med 2000; 93:433-439.

• Randomized, placebo controlled trial.

• 34 pts with persistent active AAV despite previous immunosuppression therapy.

• 17 pts randomized to receive 0.4mg/kg/day x 5 days IVIg (single course) and 17 to receive placebo.

• Intention was to keep current immunosuppressive drugs unchanged.

• Pts were followed for 12 months.

• Vasculitic activity was monitored by Birmingham vasculitis activity score (BVAS), CRP and ANCA levels.

• Reduction in BVAS >50% after 3 months was defined as treatment response.

IVIg in Vasculitis.

• IVIg is 1st line therapy in management of acute Kawasaki disease (single dose 2g/kg over 8-12 hrs). [Grade 1A*]

• IVIg may be used in pts with ANCA-associated vasculitis; [Grade 1B/2B*]– refractory (not responsive sufficiently to pred/cyclophosphamide)

disease.– Pts with leukopenia or opportunistic infection and persistent

disease activity to bridge time until further immunosuppression is reintroduced.

• Little or no evidence for IVIg use in other vasculitides. [Grade 4C*]*Intravenous Immunoglobulin Therapy in Vasculitis; Aries PM, Hellmich B, Gross WL Clinical Reviews in Allergy & Immunology Volume 29, 2005

Thank You.

Introduction• Passive immunization with immunoglobulin fraction of pooled

normal human sera used in the 1950s had a dramatic impact on the frequency of sepsis in patients lacking immune globulins.

• Doses were limited by IM route of administration.

• Intravenous preparations of immune globulin became available in 1960s.

• These preparations contained protein aggregates that caused anaphylactoid reactions.

• Today, large scale production of IVIG is carried out using pooled plasma from thousands of donors.

Introduction

• Different manufacturers use various combinations of precipitation, chromatography and/or purification steps to obtain a final preparation that consists of >95% IgG.

WHO minimum standards for IVIG manufacturing

• Should be extracted from a pool of at least 1000 individual donors.

• Should contain as little IgA as possible.

• Should be modified biochemically as little as possible and possess opsonizing and complement-fixing activities.

• Should be free from accumulating preservative or stabilizers.

Safety from blood-borne pathogens

• Meticulous donor screening and selection is done.

• The individual blood units are tested for known viruses by antigen and nucleic acid testing.

• Also tested for elevated liver enzymes (window period)

• Donated units that pass the tests are held back (quarantine) until subsequent donation from same donor is obtained and tests negative.

• The previous donation can then be pooled after nucleic acid testing is repeated and is negative.

Headache

• Headache is most common adverse event reported with IVIG infusion.

• Most resolve within 24 hrs .

• Some can be delayed in onset by 24-48 hrs.

• Induction of Migraine more likely in patients with prior history.

• Severe headache with other features of meningeal irritation/inflammation can be seen with high doses of IVIG.

Hematologic complications

• Incidents far less frequent in the last decade since efforts have been made to lower the titers of RBC antibodies in IVIG preparations.

IVIG adverse effects and safe administartion Orbach et al; Clinical Reviews in Allergy and Immunology, Vol 29, 2005

Mechanisms of Action

• Most “natural antibodies” in healthy people and hence in the immune globulin pool are autoantibodies.

• Autoantigens stimulate autoreactive B cells to produce natural autoantibodies (mostly IgG class).

• Natural autoantibodies are more polyreactive than immune antibodies (can bind to various antigens).

Immune regulation.

• Natural antibodies of immune globulin are capable of interacting with idiotypes.

• The formation of idiotype-idiotype dimers may account for some clinical effects of immune globulin.

Six-Month IVIG Utilization by Indication

Indication Total = 243

Category I 13 (5.3%)

Neonatal alloimmune thrombocytopenia (NAIT) 0

X-linked agammaglobulinemia (XLA) 0

Parvovirus infection with blast crisis 3

Other primary immune deficiency disorders presenting with a life-threatening infection, subject to the approval of either Dr. Gilsdorf or Dr. McMorris

Severe combined immunodeficiency syndrome (SCID) 3

Kawasaki Disease 7

Category II 102 (42.0%)

Guillain Barre Syndrome (acute) 5

Chronic inflammatory demyelinating polyneuropathy (CIDP) 9

Multifocal motor neuropathy (MMN) 1

Myasthenia Gravis 4

BMT with prolonged hypogammaglobulinemia 83

Post-plasmaphoresis in pediatric patients due to IgG deficiency 0

Category III 60 (24.7%)

Common variable immune deficiency (CVID) 14

Immune thrombocytopenia 29a

CLL with hypogammaglobulinemia 3

Polymyositis and Dermatomyositis 12

Primary immunodeficiency diseases (other than SCID) 2b

Category IV 1 (0.4%)

Vasculitides 1

Others 61 (25.1%)

Acquired vWD (control of vWf inhibitor-mediated clearance) 1

Antiphospholipid syndrome 1

Autoimmune hemolytic anemia 2

BK viremia 5

CMV viremia 1

Demyelinating disease (other than GBS, CIDP) 2

Hyperacute rejection post-renal transplant 2

Hypoalbuminemia post-BMT 1

Hypogammaglobulinemia in patient with relapsing polychondritis, macrocytosis 1

Infection prophylaxis post-BMT 29

Intestinal lymphangiectasia 1

Macrophage activating syndrome (hemophagocytic syndrome) 2

Monoclonal gammopathy of undetermined significance (MGUS) 1

Opsoclonus-myoclonus-ataxia 1

Parainfluenza 2

Red cell apalsia 1

Rejection post-LVAD 1

Renal transplant in B-cell crossmatch-positive patient 1

Rotavirus 1

Seizures 2

Steven’s Johnson Syndrome 2

X-linked lymphoprofilerative syndrome 1

$20,000

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Service

UMHS IVIG USE 2004-2005 - BY TOTAL DRUG COSTS

Service codes: MBM = Adult BMT; MCM = Critical Care; MHE = Medicine Hematology MDD = Medicine Dock (IM); MFH = Medicine Faculty Hospitalists; MH = Medicine Hewlett (IM); MN = Medicine Newburg; MP = Pulmonary Medicine; MS = Medicine Sturgis (IM); NG = Neurology; NNM = Neurology Neuromuscular; NON = Neurooncology; PB = Peds Blue (General); PBM = Peds BMT; PH = Peds Heme/Onc; PIC = PICU; PRH = Peds Rheumatology; PY = Peds Gold (General); STC = Cardiothoracic Surgery; STX = Surgery Transplant; TBE = Trauma/Burn

1714 13

1211 12

110120

Service

UMHS IVIG USE 2004-2005 - BY NO. OF PATIENTS

Service codes: MBM = Adult BMT; MCM = Critical Care; MHE = Medicine Hematology MDD = Medicine Dock (IM); MFH = Medicine Faculty Hospitalists; MH = Medicine Hewlett (IM); MN = Medicine Newburg; MP = Pulmonary Medicine; MS = Medicine Sturgis (IM); NG = Neurology; NNM = Neurology Neuromuscular; NON = Neurooncology; PB = Peds Blue (General); PBM = Peds BMT; PH = Peds Heme/Onc; PIC = PICU; PRH = Peds Rheumatology; PY = Peds Gold (General); STC = Cardiothoracic Surgery; STX = Surgery Transplant; TBE = Trauma/Burn

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