Casey Engel, BA1 and Zachary E. Holcomb, MD2

1Virginia Tech-Carilion School of Medicine, Roanoke, VA, USA
2Dermatology Section, Department of Internal Medicine, Virginia Tech-Carilion School of Medicine, Roanoke, VA, USA

Conflict of interest: Casey Engel has no relevant conflicts of interest. Zachary Holcomb is an investigator for AstraZeneca/Parexel. Funding sources: None.

Abstract:
Intravenous immune globulin (IVIG) is a manufactured blood product commonly used to treat immunodeficiency syndromes, inflammatory disorders, and autoimmune diseases of the skin. The use of IVIG in dermatology has evolved and expanded over time, serving as a useful therapeutic intervention for several inflammatory skin disorders. In addition to demonstrating efficacy in treating several cutaneous pathologies, IVIG also mitigates the need for steroids or other immunosuppressant medications in many dermatologic diseases. This review highlights the evidence for IVIG use across several dermatologic conditions, emphasizing the dosing regimens and safety considerations.

Keywords: intravenous immunoglobulin, IVIG, immunomodulation, autoimmune diseases, bullous dermatoses, dermatomyositis, Stevens-Johnson syndrome

Introduction and Mechanism of Action

Intravenous immune globulin (IVIG) is composed of polyclonal immunoglobulin G (IgG) derived from human plasma and has been used clinically for over 50 years. IVIG has historically been used to treat immunodeficiency syndromes, but more recently it has been employed in treating a wide variety of dermatologic conditions, including autoimmune bullous dermatoses, collagen vascular diseases, inflammatory myositides, systemic vasculitides, severe atopic dermatitis, chronic urticaria, graft-versus-host disease, and more. IVIG exerts its effects through modulation of the immune system and anti-inflammatory actions. Proposed mechanisms of action include Fc receptor blockade, complement inhibition, pathogen neutralization, dendritic cell downregulation, clearance of pathogenic IgG, alterations in regulatory T cells, and enhancement of sensitivity to corticosteroids.1,2 IVIG is typically administered using a dosing regimen of 2 g/kg for most indications, excluding Kawasaki disease and toxic epidermal necrolysis, further detailed below. This dosing regimen is usually distributed evenly over 2-5 days. IVIG undergoes an extensive screening process involving virus inactivation and removal in addition to donor screening.1,2 This review explores the dermatologic conditions where IVIG has demonstrated efficacy (see Table 1).

A Review of the Use of Intravenous Immunoglobulin Therapy in Dermatology - image
Table 1: Common indications and guidelines for IVIG use in dermatology.

Dosing and Administration

There are several different formulations of IVIG available. It is important to be aware of the available formulations as they may vary regarding indication, half-life, storage, contraindications, and administration. If a patient is to receive multiple IVIG treatments, the same previously tolerated formulation should be used when possible to minimize adverse reactions. Immune globulin can also be administered subcutaneously and intramuscularly, though this review will focus on the use of intravenous immune globulin.

The standard dose for IVIG is 2 g/kg divided evenly over 2-5 daily infusions. It is recommended to calculate dosage using actual body weight, unless the patient’s BMI is greater than 30 kg/m2 or if their actual weight is greater than 20% higher than ideal body weight, in which case dosing can be calculated using ideal body weight.1,2

When used to treat immunodeficiencies, trough levels can be obtained to assist in calculating the interval between doses. However, when used for dermatologic conditions, the primary endpoint is often clinical improvement and thus IgG levels are not routinely measured. The half-life of IVIG ranges from 3-5 weeks; accordingly, infusions are typically administered in cycles every 4 weeks until the disease is adequately controlled.

IVIG is generally started at a slow infusion rate, usually 0.01 mL/kg per minute, to reduce the risk of infusion-related adverse effects. This rate may be increased based on patient tolerability and monitoring. The total dose is frequently given over 4-8 hours.

Adverse Effects and Contraindications

Adverse reactions occur in 5-15% of all IVIG infusions and are typically self-limited. They generally occur during or within several hours of the infusion and are often associated with the first infusion or with a new IVIG formulation. Common reactions include headache, chills, flushing, fatigue, abdominal pain, and myalgias. Other adverse effects include urticaria, anaphylactic shock, dyspnea, acute pulmonary edema, aseptic meningitis, hemolysis, transient neutropenia, hyponatremia, and infection. The risk of adverse effects is associated with the dose of IVIG and the rate of infusion. IVIG has a boxed warning for the risks of thrombosis, kidney dysfunction, and acute kidney injury. Subcutaneous immune globulin has a lower rate of adverse effects and may be preferred in patients with contraindications or adverse reactions to IVIG. Risk factors and relative contraindications to IVIG include hyperviscosity states, underlying organ dysfunction, or prothrombotic stimuli. Patients with cardiac or renal disease should be monitored for fluid overload. While most patients with low or absent IgA are able to tolerate IVIG, patients who experience anaphylaxis who have low or undetectable IgA levels and/or IgE anti-IgA antibodies should receive pre-medication and a product with low IgA or subcutaneous immune globulin. Mitigation of adverse effects can be achieved by slowing the infusion rate, providing additional intravenous hydration prior to the infusion, and providing pre-medications as outlined below.

Pretreatment Testing, Pre-medication and Monitoring

To rule out infection and risk for complications, it is recommended to obtain a complete blood count, hepatic function panel, metabolic panel, and urinalysis prior to initiating IVIG. This pretreatment testing can be repeated at 6-month or yearly intervals on a case-by-case basis. Some clinicians may also choose to assess coagulation parameters, viral serologies, cryoglobulins, immunoglobulin levels (including screening for IgA deficiency), and rheumatoid factor prior to initiation of IVIG, although this testing is not routinely performed.

Some patients do not require pre-medication for IVIG, but a standard pre-medication protocol includes acetaminophen or a nonsteroidal anti-inflammatory drug to prevent inflammatory and anaphylactoid symptoms. H1-antihistamines (such as diphenhydramine) are also frequently administered at the beginning of the infusion. Finally, glucocorticoids can be given to patients who experience an adverse reaction, such as headache, with their first infusion. Patients should be well-hydrated before and during their IVIG infusion, particularly those with risk factors for thrombosis or renal complications. This can be accomplished through oral fluid intake and/or administration of intravenous fluids with the infusion. Throughout the infusion, patients should be monitored for symptoms or alterations in vital signs.3

Autoimmune Bullous Dermatoses

IVIG has emerged as a valuable second-line or adjunctive treatment in pemphigus vulgaris, pemphigus foliaceus, epidermolysis bullosa acquisita, and bullous pemphigoid. Two randomized controlled trials demonstrated efficacy in treating pemphigus and bullous pemphigoid with IVIG at 4-week intervals in combination with conventional therapies of systemic steroids and immunosuppressants.4,5 IVIG causes a selective and rapid decline in autoantibodies implicated in the bullous dermatoses, with the proposed mechanism of increasing the catabolism of abnormal serum IgG antibodies.6 A consensus statement on the use of IVIG in patients with autoimmune mucocutaneous blistering diseases reinforces its use in cases of treatment failure, significant adverse effects from conventional therapy, contraindications to systemic therapy (such as aseptic bone necrosis, diabetes mellitus, severe osteoporosis), progressive disease despite conventional therapy, uncontrolled and debilitating disease, and rapidly progressive epidermolysis bullosa acquisita with generalized cutaneous involvement.7 IVIG can be used as monotherapy or in combination with rituximab or corticosteroids in patients with recalcitrant disease, and a multidrug approach may confer a lower relapse rate.8 IVIG has also demonstrated utility in treating mucous membrane pemphigoid, linear IgA dermatosis, IgA pemphigus, paraneoplastic pemphigus, and pemphigoid gestationis. Administered at the standard dosage of 2 g/kg over 2-5 consecutive days every 4 weeks for a duration of 3-6 months, IVIG has been used to treat severe, treatment-resistant bullous dermatoses for decades. Treatment response is assessed by monitoring for the absence of new lesions, epithelialization of existing lesions, and a decrease in autoantibody titers (autoantibody titers typically decrease over 6 or more months of therapy). Once disease control is achieved, the interval between IVIG infusions may be progressively increased until discontinuation (once the interval is >2 months in between infusions cycles). This approach underlines the evolving and nuanced role of IVIG in the management of autoimmune bullous dermatoses, providing an effective alternative for patients with specific clinical considerations and treatment challenges. Of note, IVIG is typically used as adjunctive therapy in these bullous disease processes due to the possibility of symptom rebound upon weaning or discontinuation (in the absence of another concomitant immunomodulatory therapy).

Dermatomyositis

Several clinical trials have demonstrated the efficacy and tolerability of IVIG in treating dermatomyositis, resulting in US FDA approval for this indication in 2021.9 IVIG has been identified as a first-line treatment in patients with dermatomyositis exhibiting severe muscular involvement, those with malignancy, and cases where nutritional intake is compromised due to pharyngeal muscle involvement. It serves as a valuable second-line and adjunctive option in juvenile dermatomyositis and paraneoplastic dermatomyositis. Notably, controlled studies have demonstrated favorable outcomes with the use of IVIG in dermatomyositis including improvement of refractory cutaneous dermatomyositis as well as decrease or discontinuation of immunosuppressive medications in the majority of patients.10 A recent meta-analysis demonstrated that in patients with refractory dermatomyositis, IVIG significantly improved muscle strength and decreased serum creatine kinase level in addition to improving cutaneous manifestations.11 For this indication, IVIG is administered at the standard dose of 2 g/kg body weight given in divided doses over 2-5 consecutive days. The maximal response to IVIG treatment typically occurs at around 4 months, necessitating ongoing therapy for at least 3-6 months in conjunction with conventional treatments at lower doses for sustained benefits in most patients.12 These developments underscore the growing importance of IVIG in the comprehensive management of dermatomyositis, as it provides an efficacious and non-immunosuppressive treatment option for this patient population.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

The efficacy of inpatient treatment with corticosteroids and immunosuppressive agents in SJS/TEN continues to be controversial. While supportive care and causative drug discontinuation remain the mainstay of treatment, the high mortality of this severe drug reaction merits continued exploration of other treatment options. The administration of IVIG at doses exceeding 2-3 g/kg, initiated promptly upon diagnosis, has been shown to arrest disease progression, reduce mortality, and improve overall outcomes in some patients.13-15 For TEN, higher doses of 3 g/kg distributed over 3 consecutive days are recommended. Assessment of treatment response is typically based on the absence of epidermal detachment and re-epithelization of affected areas. It is worth noting that while some studies have reported improvement in TEN with the use of IVIG, other studies have found that IVIG does not yield survival benefits in TEN and SJS/TEN overlap, necessitating further exploration through randomized controlled trials.16,17

Scleromyxedema

While scleromyxedema remains a challenging cutaneous mucinosis that does not always respond well to immunosuppressive agents, several case reports and case series have demonstrated encouraging outcomes with the use of IVIG. More recently, the first prospective trial exploring the use of IVIG for scleromyxedema reported a significant objective clinical improvement with IVIG, further demonstrating its utility as a first-line treatment.18 IVIG can be used alone or in combination with corticosteroids or other therapies.19,20 Treatment is administered at the standard dose of 2 g/kg over 2-5 days every 4 weeks for 6 months or longer for maintenance. If patients have not achieved an adequate response after six cycles of IVIG, it is recommended to transition them to another therapy.

Kawasaki Disease

In conjunction with acetylsalicylic acid, IVIG is the gold standard FDA-approved treatment for Kawasaki disease, a vasculitis that most frequently affects pediatric patients. In this context, IVIG should be administered within 10 days of symptom onset at a dose of 2 g/kg as a single infusion given over 10-12 hours, alongside acetylsalicylic acid 50 mg/kg.21 If this standard treatment fails, a second dose of IVIG can be administered. Appropriate treatment is instrumental in reducing the risk of severe disease sequelae such as myocardial, coronary, and neurologic abnormalities, and meta-analyses have shown that the use of IVIG is associated with a significant decrease in new coronary artery abnormalities with a dose-dependent effect.21 The use of IVIG in Kawasaki disease exemplifies the vital role of immunoglobulin therapy in modulating inflammatory responses and preventing long-term complications, particularly in the pediatric population.

Systemic Lupus Erythematosus (SLE)

While not a conventional therapy for SLE, IVIG has demonstrated efficacy in severe forms of SLE such as refractory lupus nephritis and SLE-associated immune thrombocytopenia.22 IVIG has shown some response in cutaneous lupus erythematosus resistant to conventional therapies. A meta-analysis found that IVIG led to a significant reduction in SLE disease activity as well as improvement in complement levels.23 There is also a role for IVIG in the treatment of pregnant patients with SLE due to its safety profile, where it has been shown to reduce lupus activity scores and pregnancy loss.24 Other SLE variants in which IVIG treatment should be considered include neuropsychiatric lupus, Guillan-Barré syndrome associated with SLE, refractory lupus nephritis, and lupus-associated immune thrombocytopenia.22 For SLE, IVIG is typically administered at the standard dose of 2 g/kg over 2-5 days every 4 weeks. Given the recent advances and emerging therapeutic options for cutaneous lupus erythematosus, IVIG is generally reserved for patients who need to avoid immunosuppression.

Other Uses

Several case studies have explored the use of IVIG in antineutrophilic cytoplasmic antibody (ANCA)-associated small vessel vasculitides, Behcet disease, pretibial myxedema, systemic sclerosis, livedoid vasculopathy, pyoderma gangrenosum, severe atopic dermatitis, chronic urticaria, graft-versus-host disease, herpes gestationis, erythema multiforme, and Kaposi sarcoma. Further trials are needed to explore the overall efficacy and tolerability of IVIG in these conditions.

Conclusion

In conclusion, this review explores the multifaceted use and significance of IVIG in dermatology. From more common autoimmune bullous dermatoses to relatively rare conditions such as scleromyxedema, IVIG is a versatile, effective, and generally safe therapeutic option. Though often used off-label, the list of indications for IVIG in dermatology continues to grow, reflecting the dynamic landscape of dermatologic treatments. While further randomized controlled trials are needed to fully understand the efficacy of IVIG in treating many dermatologic conditions, this review aims to enhance patient care and promote evidence-based decision-making based on available data.

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