Intravenous Immunoglobulin: Revisited - My Experience.

BACKGROUND: Many a times while treating dermatoses conventional therapies are either contraindicated or not effective. Intravenous immunoglobulin (IVIG) is a good alternative available to tide over crises.
METHOD: Over the last 15 years of my practice I have used IVIg in various severe or recalcitrant diseases (including TEN, autoimmune blistering disease,connective tissue disorders , chronic urticaria etc) which were either unresponsive to conventional modality of therapy or primary therapy could not be given because of co-morbidities. RESULT: IVIg a sterile, highly purified preparation containing more than 95% unmodified IgG,was first approved by FDA in 1981 for 6 diseases. As mentioned above in many circumstances we reached a situation when either conventional primary therapy was contraindicated or patients were not responding. IVIg came to our rescue in large number of conditions to tide over the crisis and also created the environment leading to conventional therapy becoming effective. Very few minor side effects like low grade fever and myalgia were observed in very few cases. No serious or severe side effects were seen, however , one has to be prepared for anaphylactic reaction which is a theoretical possibility.
CONCLUSION: It can be said that IVIg though not a magic drug, is a very effective tool available in the armamentarium of Dermatologists to treat plethora of chronic and intractable dermatoses. Copyright:

Introduction

Intravenous immunoglobulin (IVIg) is a sterile, highly purified, unmodified immunoglobulin G (IgG) preparation (95%) with only traces of IgG and IgM. This is made from pooled human plasma of approximately 3–10 thousand individual donors by cold ethanol fractionation.[1]

IVIg was first licensed by FDA in 1981 and approved for use in six conditions: primary immunodeficiencies, Kawasaki syndrome, Immune thrombocytopenic purpura(ITP), recent bone marrow transplantation (in patients 20 years of age or older), chronic B-cell lymphocytic leukemia, and pediatric HIV type 1 infection.

Besides above six conditions, use of IVIg has been well accepted in Graft-versus-host disease and dermatomyositis. Despite of high cost, it has been used in large number of dermatoses. Numerous case reports and series are available in literature of autoimmune blistering mucocutaneous diseases, systemic lupus erythematosus (SLE), atopic dermatitis, chronic autoimmune urticaria, pyoderma gangrenosum, systemic sclerosis, necrotizing fasciitis, polymyositis, vasculitis, psoriasis, and infectious disorders (such as streptococcal toxic shock syndrome), etc.[123456] A consensus statement was published in 2003 on the use of IVIg in patients with autoimmune mucocutaneous blistering diseases.[78]

In the last two decades, use of IVIg in toxic epidermal necrolysis (TEN) has been well accepted; however, no unanimity has been reached due to the lack of randomized clinical trials. Not only the results differ from center to center but also incidence of mortality is different too. Yet, IVIg remains accepted as drug of choice for initial therapy of TEN.[129]

Mechanisms of actions

Multiple mechanisms of actions of IVIg have been postulated based on which its use in various dermatoses can be understood[101112] these are explained briefly in Table 1.

Table 1

Mechanism of action of intravenous immunoglobulin

Mode of action	Effector cell
Functional blockade of Fc receptor (Fc R1)	Macrophages
Elimination of immune complexes
Anti-idiotypic suppression of autoantibodies	B-lymphocytes
Inhibition of complement mediated damage	Complement system
Modulating effects of on production and release of	T-lymphocytes
cytokines/cytokine antagonists
Inhibition of pro inflammatory mediators - IL 1, 4, 6 and TNF α
Up regulation of anti-inflammatory
cytokines -IL1 ra and TNF β
Changes in regulatory T cells and TH17 pathway
Prevents keratinocyte death by blocking Fas (CD95) - Fas (CD95L) interaction	Keratinocyte

TNF: Tumor necrosis factor, IL: Interleukin

Investigations

A complete blood cell count, electrocardiogram, hepatic and renal function tests, rheumatoid factor, and cryoglobulin can be done since patients with cryoglobulin have a higher risk of developing acute renal failure. Tests for antibodies to HIV RNA, HCV RNA, HBV DNA, HAV RNA, and Parvovirus B19 DNA can be done before and after treatment.

Pharmacokinetics

Peak serum concentration reaches immediately after injection and is dose related. Within 24 h, up to 30% of the dose reduces by distribution (intravascular 60% and extravascular 40%) and catabolism. It crosses placenta and may be excreted in milk. Serum half-life is 30 days; hence, a repeat dose if needed may be given after 4–6 weeks.

Premedication

It is mostly not needed but may be administered to minimize the incidence of infusion-related side effects, such as headaches, myalgia, and rigors. Premedication with analgesics, antihistamines, and even low-dose corticosteroids may be of benefit to a subset of individuals with known history of various allergic reactions.

Precautions

Anaphylaxis is always a potential threat; hence, the treatment room must always have an anti-anaphylaxis tray (containing injections – adrenaline, hydrocortisone, deriphyllin, pheniramine maleate, dopamine, and IV fluids) ready. Therapy with high-dose IVIg can cause fluid overload; hence, it should be used cautiously in patients with renal insufficiency or impaired cardiac function.

Dosage schedule

The standard accepted dosage for IVIg therapy is 2 g/kg given over 5 days (400 mg/kg/day for 5 days). Financial constraints have led to treatment with low-dose IVIg. Few centers have reported satisfactory response with low-dose IVIg in ITP (0.8–1.0 g/kg) and Kawasaki's disease (0.4 mg/kg/day)[1314] In most of the situations, a repeat dose is not needed but can be given after a gap of 4–6 weeks.

My experience

I have been using IVIg for the last 15 years. Out of 30 cases of TEN, 14 were treated with IVIg. Mortality in these cases corresponded well with the SCORTEN on day 1 and day 5 (as reported earlier by me).[9] Outcome in the group without IVIg too corresponded well with SCORTEN prediction. Thus, I did not find any difference in the outcome with or without IVIg in TEN.

Besides TEN, I have used IVIg in few other diseases as well. A brief account of some of these cases is as follows:

Case number 1

A 65-year-old female presented with pemphigus vulgaris of about 5-year-duration [Figure 1]. Since she was diabetic and hypertensive; hence, corticosteroids could not be given for a longer duration. She was given monthly dexamethasone and cyclophosphamide pulse (DCP) therapy with daily cyclophosphamide for 2 years but did not have adequate control. She had frequent exacerbations which could be controlled only with high-dose corticosteroids, aggravating her comorbid conditions. A trial of mycophenolate mofetil and azathioprine also failed. Hence, as a last resort, she was given IVIg 2 g/kg body weight over a period of 5 days. Within 3 weeks, all the lesions of pemphigus vulgaris regressed and she could be maintained well on 50 mg of oral cyclophosphamide for more than a year.

Figure 1

(a) Female with pemphigus vulgaris (before). (b) Female with pemphigus vulgaris (after 14 days)

Case number 2

A 48-year-old female had SLE for 3 years. She had severe photosensitivity, large “lupoid” type of extremely itchy lesions on the body [Figure 2]. Her symptoms could be controlled only with minimum 60 mg of corticosteroids. Steroid-sparing drugs such as azathioprine or cyclophosphamide or chloroquine were either ill tolerated or were ineffective. She put on weight, had Cushingoid features and blood sugar too rose. Hence, a trial of IVIg 2 g/kg was given over 5 days. Her symptoms of severe photosensitivity abated in 7 days and lesions flattened in 2 weeks. Later on her earlier unresponsive cutaneous symptoms could be controlled well with oral hydroxychloroquine, topical photoprotection, and topical steroids for more than a year. Repeat anti-DsDNA after 3 months did show a dip in quantitative analysis; however, this test could not be repeated later.

Figure 2

(a) Female with systemic lupus erythematosus and “lupoid” lesions on the face (before). (b) Female with systemic lupus erythematosus and “lupoid' lesions on the face (after). (c) Female with systemic lupus erythematosus and “lupoid” lesions on back (before). (d) Female with systemic lupus erythematosus and “lupoid” lesions on back (after)

Case number 3

A 35-year-old female had chronic idiopathic urticaria for many years. No precipitating or aggravating factors could be detected after repeated sessions of history and examinations. All possible investigations were within normal limit; since we were in remote Northeast other sophisticated investigations were not available. Response to various antihistamines alone and in combination was at best effective only for few weeks; trial to oral corticosteroids was unsatisfactory. She had been to various doctors at various places without any permanent remedy. It was causing strain on her marital life. In view of above and since IVIg was available with the hospital, this female was given IVIg 1 g/kg over 3 days. Surprisingly, she became asymptomatic in 3 days and remained so with just one tablet of 10 mg of cetirizine for more than a month, hence, that too was stopped by the patient after 2 months. She continues to be asymptomatic and grateful to IVIg since her marriage was saved.

Case number 4

A 10-year-old boy born out of consanguineous marriage reported with vesiculobullous lesions all over body [Figure 3] of 5-year-duration. He did not have mucosal or any other ectodermal involvement. Skin biopsy and direct immunofluorescence (DIF) studies confirmed the diagnosis of Chronic Bullous Disease of Childhood (CBDC). He was treated with dapsone, oral corticosteroids alone and with cytotoxic drugs such as cyclophosphamide without any significant or long-standing response. He continued to develop crops of new lesions all over body making his day-to-day life miserable; he was not allowed to attend school by school administration. At last IVIg 1 g/kg was administered over 4 days. Within 2 weeks, older lesions healed and severity and periodicity of new crops reduced significantly. He has now been maintained on intermittent low-dose steroids and topical therapy. He remains functional, has gained height, and has started attending school.

Figure 3

(a) 10-year-old child with Chronic Bullous Disease of Childhood (before). (b) 10-year-old child with chronic bullous disease of childhood (after)

Case number 5

A 27 years pregnant female in the 2nd trimester reported with sudden onset of tense vesicobullous lesions all over body [Figure 4] without any oral involvement. Diagnosis of Herpes Gestationis was confirmed by skin biopsy and DIF. Since high dose of corticosteroids and cytotoxic drugs could not be given, she was treated with IVIg 2 g/kg over 5 days. Within 8–10 days > 95% lesions regressed. Few new vesicles appeared for the next 2 months; hence, she was maintained on plasmapheresis, done every 6 weeks till delivery.

Figure 4

(a) Female with herpes gestationis (before). (b) Female with herpes gestationis (after)

Case number 6

A 65-year-old female, being treated for Ca esophagus (surgery followed by medical oncotherapy) for more than 3 years; she reported with sudden onset of flaccid vesicobullous lesions all over the body and ulcerations of lips and oral mucosa [Figure 5]. Diagnosis of paraneoplastic pemphigus was confirmed by skin biopsy and DIF studies. Since she was symptomatic, had dysphagia, was on palliative therapy including pulses of oncotherapy drugs, prolonged DCP or corticosteroid therapy was not indicated. Hence, she was treated with IVIg – 2 g/kg over 5 days. There was excellent response, all cutaneous lesions regressed in 2 weeks' time and had more than 75% relief in oral lesions. She developed relapse after 7 months, which was controlled with repeat dose of IVIg. After that she did not develop vesicobullous lesions for the next 18 months.

Figure 5

(a) Female with paraneoplastic pemphigus (before). (b) Female with paraneoplastic pemphigus (after). (c) Female with paraneoplastic pemphigus on the face (before)

Case number 7

A 6-year-old girl had high-grade fever of 1-week duration associated with cervical lymphadenopathy, purpuric lesions on legs, and leukocytosis presented to the pediatrician. She was treated with antibiotics and antipyretics, without response. After 3 days, she developed mucocutaneous lesions in the form of “strawberry” tongue, fissured lips, and bulbar conjunctivitis. Erythema of limbs increased with induration. There were no vesicular lesions. Thus, with above signs and symptoms, clinical diagnosis of Kawasaki syndrome was reached. She was treated with IVIg 2 g/kg body weight. Being 12 kg of weight, she was given 25 g of IVIg over 5 days. Her fever settled in 3 days, all mucocutaneous lesions regressed in 2 weeks' time with desquamation of skin. ECHO-cardiology studies ruled out any cardiac involvement at the time of treatment as well as 6 months later.

It will be apparent from the description of above cases that IVIg was used not to achieve cure but for following reasons:

First case of pemphigus vulgaris did not respond to DCP and her comorbid conditions aggravated

Second case of SLE did not respond to 1st line therapies and had severe side effects

Third case of urticaria did not respond completely to multiple therapies and had marital stress

Fourth case, a child with CBDC was not able to continue schooling because of lack of response and frequent recurrences even after conventional therapy

Fifth case, a pregnant female with herpes gestationis could not be given immunosupressants

Sixth case – In paraneoplastic pemphigus, conventional modalities of treatment were contraindicated

Seventh case of Kawasaki's disease – IVIg was given as first-line therapy.

Side effects

IVIg was very well tolerated by all patients. Few minor side effects such as low-grade fever and/or body ache for few hours were experienced by many patients. No serious side effects were noticed. However, one has to be aware of anaphylaxis all the time. Various side effects reported in literature are as follows: vasomotoric symptoms, cardiovascular and thromboembolic complications, renal failure (“osmotic nephrosis”), hematologic complications (hemolysis), and aseptic meningitis. Reactions such as headache, back pain, chills, flushing, fever, hypertension, myalgia, nausea, vomiting, etc., appear to be related to rate of infusion and may disappear if infusion is temporarily discontinued.[21516] These minor side effects only need treatment with analgesics and antihistamines.

Current Indications for the use of IVIg[17]

Indications for use of intravenous immunoglobulin

Severe forms of dermatomyositis, inclusion body myositis, polymyositis

Toxic epidermal necrolysis

Severe forms of autoimmune blistering diseases

Severe systemic vasculitic syndromes

Severe forms of lupus erythematosus

Scleromyxedema.

Less obvious indications

Atopic dermatitis

Autoimmune urticaria

Severe forms of collagen vascular diseases

Livedoid vasculopathy.

My recommendations for Indian scenario

In India, due to monetary constraints, IVIg is not given as a drug of choice in most dermatologic conditions. As per consensus statement on the use of IVIg in patients with autoimmune mucocutaneous blistering diseases published in Archieves[8] as reported by various dermatologists all over and European Guidelines 2017 [Table 2][17] and based on my experience, following guidelines can be recommended for the use of IVIg in dermatology in India:

Table 2

Guidelines for use of intravenous immunoglobulin in dermatology

Disease	Indication	Duration	Interval	Evaluation of efficacy
Dermatomyositis	1st line for severe myolysis or arthralgia/conventional Rx* contraindicated	6 months	4-6 weeks Dose: 2 g/kg	1. Normalization of muscle strength 2. Fading of erythema
Lupus erythematosus	Given in combination with CS/IS/ Conventional Rx *contraindicated	6 months	4-6 weeks Dose: 2 g/kg	1. ↓Protein excretion in↓urine 2. DsDNA
Autoimmune blistering diseases	Either as combination with oral CS/IS/conventional Rx contraindicated/not adequately controlled with Rituximab	6 months	4-6 weeks Dose: 2 g/kg	1. Stoppage of new lesions and healing of existing lesions 2. Ig G autoantibody titers by ELISA of IIF
Vasculitis	1st line in Kawasaki, others along with other IS or CS/conventional Rx* contraindicated	3-6 months	4 weeks Dose: 2 g/kg	1. Improvement in clinical response 2. Organ specific lab tests showing reduction in titre
TEN	Early administration Can be used as monotherapy +/-CS	1 cycle	Dose: 2 g/kg	Survival and cessation of ongoing epidermal detachment
Scleromyxedema	All cases 1st line since Rx* with other IS is refractory	6 months	4 weeks Dose: 2 g/kg	↓Dermatological response, in CNS symptoms or internal organ involvement

*Rx: Treatment. TEN: Toxic epidermal necrolysis, CS: Corticosteroids, IS: Immunosupressants, ELISA: Enzyme-linked immunosorbent assay, IIF: Indirect immunofluorescence, CNS: Central nervous system

Contraindications (relative or absolute), to the use of high-dose and long-term systemic therapy with corticosteroids/cytotoxic drugs, due to presence of comorbid conditions such as diabetes, pregnancy, hepatic/renal disease, and malignancy

Failure of conventional therapy

In case of significant adverse effects due to conventional therapy

Uncontrolled or rapidly progressing debilitating disease despite of conventional therapy

As an augmentation modality to reduce dose and in turn side effects of conventional therapy.

I have used four brands of IVIg available in India; however, I did not find any difference in their effectivity or incidence of side effects. Most of the pharmaceutical companies in India import it from Korea or China.

Big disadvantage or hindrance in the treatment is the exorbitant cost which ranges from Rs. 2 to 3 lakhs for each patient. With passage of time and improvement in the technology, cost of IVIg may reduce.

Conclusion

It can be said that IVIg though not a magic drug, is a very effective tool available in the armamentarium of dermatologists to treat plethora of chronic and intractable dermatoses (Autoimmune blistering disorders, connective tissue disorders, vasculitic syndromes, chronic Urticaria, atopic dermatitis, etc.) It is not a “;cure” but a very effective handy “weapon” to control various crisis situations as described above.

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.