Intravenous Immunoglobulin Therapy

Kawasaki Disease

Kawasaki disease is an acute febrile multisystem vasculitis syndrome of unknown etiology that occurs in infants and children. The disease primarily involves medium and large arteries, and thus represents one of the leading causes of acquired heart disease in children, because of the risk of coronary artery aneurysms. Clinical and epidemiological data support an infectious cause; many bacterial and viral agents have been implicated. A role of IgA-producing cells within the vascular wall has also been suggested. The acute stage of Kawasaki disease is characterized by fever, conjunctivitis, mucocutaneous inflammation, and cervical lymphadenopathy. Thus, it is associated with an uncontrolled activation of the immune system, including immunocompetent cells, cytokines, autoantibody production, and adhesion molecule expression.

Clinical studies have demonstrated that IVIg together with aspirin (acetylsalicylic acid) given within the first 10 days of illness (as early as possible) leads to a significant reduction in the frequency of coronary artery abnormalities. The current recommendations for the treatment of Kawasaki disease suggest IVIg as a single 2 g/kg infusion over 8 to 12 hours in combination with aspirin (30–100 mg/kg per day) as first-line therapy. IVIg seems to block Fc receptors, neutralize autoantibodies and bacterial superantigens, and modify cytokine production. However, it should be remembered that despite treatment, cardiovascular sequelae and lack of disease responsiveness can occur.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Of note, IVIg might be used as a treatment in other forms of severe vasculitis. In 1995, a small study of 15 patients (poor response to conventional immunosuppressive therapy) with granulomatosis with polyangiitis (GPA, formerly known as Wegener granulomatosis) showed a significant effect in 6 of 15 patients, but none of these patients was in complete remission after IVIg. Recently, other studies were able to demonstrate a clinical benefit of IVIg therapy.

Also, patients with eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg–Strauss syndrome) experienced an improvement after IVIg.

Livedoid Vasculopathy

Livedoid vasculopathy is a chronic, recurrent vasculopathy characterized by thrombotic occlusion of the cutaneous capillaries of the distal lower extremities. Patients report severe pain and often show livedoid skin changes, recurrent superficial leg ulcers, and atrophie blanche. Current treatment strategies involve an effective anticoagulation, with low molecular weight heparin (enoxaparin) or anti-Xa-inhibitors (rivaroxaban, others). Also, IVIg was shown to have a positive effect on the clinical symptoms (ulcers and pain). Thus, IVIg can be considered as a treatment of livedoid vasculitis in refractory cases.

Dermatomyositis

Dermatomyositis is an idiopathic autoimmune myopathy with characteristic cutaneous manifestations, including heliotrope rash, Gottron papules, periungual telangiectasia, scaling scalp with alopecia, and erythema or poikilodermatous skin changes. Muscle weakness is present in >90% of the patients and esophageal involvement with dysphagia or aspiration can also occur. In some patients, dermatomyositis is observed to be associated with malignancy, particularly ovarian and breast cancer in female patients, and colorectal and lung cancer in male patients. A further characteristic feature is the occurrence of myositis-specific Ab as well as elevated serum levels of creatine phosphokinase (CPK).

Q36.2 Treatment of dermatomyositis may be difficult as patients may become resistant or intolerant to standard regimens, including CS in combination with various immunosuppressive agents (azathioprine or methotrexate as first-line options, and rituximab, cyclosporine, mycophenolate mofetil, or cyclophosphamide as second-line options). Dermatomyositis is one of the best-studied indications for IVIg treatment, with published class 1 evidence. Current treatment concepts suggest using IVIg as an effective second-line therapy, particularly for patients with refractory disease incompletely responding to CS and for patients with life-threatening disease (suffering from dysphagia with a risk for aspiration). In a double-blind, placebo-controlled crossover study, a total of 15 patients with therapy-resistant dermatomyositis received either IVIg 2 g/kg per day for 2 days or placebo. Treatment with IVIg resulted in a significant improvement in muscle strength, neuromuscular symptoms, and skin involvement. In addition, there was a decrease in (1) serum CPK levels, (2) muscular intercellular adhesion molecule 1 (ICAM-1), (3) major histocompatibility complex (MHC) class I expression, (4) transforming growth factor (TGF)-β production, and (5) immune complex deposition in the intramuscular capillaries. Numerous trials and case reports indicate a remarkable clinical improvement after monthly IVIg infusions. Concomitant administrations of immunosuppressive agents could be significantly reduced. The successful use of IVIg for pregnant women with dermatomyositis and for children with juvenile dermatomyositis has been reported underlining the safety of the treatment.

Of note, dermatomyositis can also occur without muscle involvement (amyopathic dermatomyositis), which is often difficult to treat. First-line treatments include topical therapy (photoprotection, topical CS, topical calcineurin inhibitors) and systemic treatments (methotrexate, hydroxychloroquine). As a second-line treatment for refractory cutaneous dermatomyositis, IVIg therapies were shown to be effective.

For polymyositis, controlled clinical trials for IVIg are still lacking, although open studies demonstrated a benefit for patients.

Scleroderma

Scleroderma is a chronic autoimmune disease affecting the microvasculature and connective tissue of multiple organ sites, and is characterized by fibrosis and obliteration of blood vessels in the skin. It may occur in a localized form (morphea, linear scleroderma) or as a systemic sclerosis (diffuse cutaneous, limited cutaneous) with multiple organ involvement. In systemic sclerosis, different autoantibodies can be found (antitopoisomerase I [Scl 70], anticentromere [ACA], or anti-RNA-polymerase I, II, or III).

Treatment with immunosuppressive agents is difficult and the disease often shows a progressive course. According to open-label studies and case reports, treatment with 2 g/kg of IVIg on a monthly basis in patients with scleroderma resulted in an improvement in joint and muscle involvement, skin scores, and gastrointestinal symptoms.

Scleromyxedema

Scleromyxedema is a severe connective tissue disease, characterized by a generalized skin thickening caused by fibrosis and mucinosis, and is associated with monoclonal gammopathy in more than 90% of sufferers. A cutaneous finding in addition to the skin thickening is lichenoid papules, especially in the face, neck, hands, forearms, trunk, and thighs. The glabella shows typically deep longitudinal furrows. As it is a systemic disease, sclerosis of kidney and coronary arteries, lung fibrosis, polyneuropathies, arthralgias, and gastrointestinal motility dysfunctions can occur.

Treatment of this rare, chronic disease is difficult and CS, cyclophosphamide, plasmapheresis, melphalan, and thalidomide are suggested.

According to current guidelines, IVIg can be used to treat severe cases of scleromyxedema. Although no randomized trials have been performed, some small case studies showed a significant clinical improvement and even a complete remission after therapy with IVIg. Of note, continued IVIg therapy seems to be necessary to remain in remission.

Pemphigus Vulgaris and Pemphigus Foliaceus

Pemphigus vulgaris (PV) is a potentially fatal mucocutaneous autoimmune disease. It is characterized by an eruption of flaccid blisters that rupture easily, resulting in painful erosions. Involvement of the mucous membranes is very common. Autoantibodies in patients with PV target desmosomal cadherins, especially desmoglein 3 and, less commonly, desmoglein 1. Sera of patients contain circulating Ab to one or more keratinocyte cell surface antigens, and frequently the Ab titer correlates with disease activity. Patients with pemphigus foliaceus (PF) develop superficial blisters. The target antigen for PF is desmoglein 1, which is predominantly expressed in the upper layers of the epidermis of the skin, but not in the mucous membranes, thus only a cutaneous involvement is typically seen.

Q36.3 Treatment strategies include CS, usually in combination with other immunosuppressive agents. Recently, a randomized double-blind trial for IVIg in pemphigus showed significantly reduced disease activity in the treatment group treated with 400 mg/kg per cycle. Other reports suggest that the use of IVIg (1–2 g/kg per cycle) for the treatment of PV has been promising. In the majority of patients, a favorable response has been reported, allowing for a reduction or withdrawal of the concomitant immunosuppressive therapy. This ultimately resulted in a decreased rate of immunosuppressive drug-related adverse effects (AE). However, a recent study reported that the best results in lowering pemphigus Ab are obtained by combining IVIg and immunosuppressive drugs. In an open-label study, 9 of 11 patients with refractory PV treated with both IVIg and rituximab showed rapid resolution of lesions. Further studies are required to better define dosage, duration, and mechanism of action of IVIg in pemphigus treatment.

Bullous Pemphigoid

Bullous pemphigoid (BP) is characterized by large tense blisters that frequently occur on flexural surfaces of the extremities, axillae, groin, and abdomen. Mucosal lesions are found in 10% to 30% of the patients. The disease usually develops in the elderly; the patients often report an intense pruritus and occasionally BP occurs in association with malignancy. Subepidermal blister formation is caused by autoantibodies directed against two hemidesmosomal antigens, BP antigen 1 (BPAg1, also known as BP230 or dystonin) and BP antigen 2 (BPAg2, also known as BP180 or type XVII collagen).

Conventional treatment consists of CS (topical or systemic) in combination with immunomodulative (tetracyclines and dapsone) or immunosuppressive drugs such as azathioprine, cyclophosphamide, methotrexate, chlorambucil, cyclosporine, and mycophenolate mofetil. In severe cases, rituximab is appropriate. Controlled trials for the efficacy of IVIg in BP are still lacking, but several clinical studies and case reports including pediatric patients have been published. IVIg treatment in case reports was given every 4 weeks at a dose of 2 g/kg per cycle, with a significant reduction in the number of relapses and recurrences observed. Moreover, a significant decrease in autoantibody titers to both BPAg1 and BPAg2 resulted during treatment with IVIg. Overall, IVIg seems to be a promising approach for the treatment of BP, especially in patients not responding to conventional therapy.