Rituximab

What is rituximab?

Rituximab is a biologic medicine used primarily to treat B-cell lymphoma. Recently it is useful in the treatment of several severe skin diseases. In 2018, the FDA also approved its use for moderate to severe pemphigus vulgaris, an immunobullous disease of the skin. Rituximab has some severe side effects. 

Rituximab is a monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Rituximab has human and mouse-derived components. It is given by intravenous injection.

Rituximab is very effective at destroying normal and malignant B lymphocytes that are carrying the CD20 antigen.

Trade names used in New Zealand for rituximab include MabThera (Roche) and Rituximab (Baxter). Rituxan is the name used for the Genentech product available in the USA and elsewhere.

What are B lymphocytes?

B lymphocytes are a type of white blood cell. Their role in immune reactions includes:

• Production of antibodies, including autoantibodies directed against 'self' antigens
• Antigen presentation or identification of a potential protein to attack
• Regulation of T-cell activation — T cells are white blood cells involved in cellular immunity
• Production of proinflammatory cytokines (chemical messenger proteins).

How does rituximab work?

Rituximab is an immunoglobulin G1 (IgG1) kappa monoclonal antibody composed of a murine (mouse) variable region (Fab portion) that is fused onto a human constant region (Fc portion). The Fab portion binds to the CD20 antigen on the surface of pre-B and mature B lymphocytes. The Fc portion then recruits immune cells that destroy these lymphocytes. Mechanisms may include:

• Complement-dependent cytotoxicity (CDC)
• Antibody-dependent cell-mediated cytotoxicity (ADCC)
• Apoptosis (programmed cell death by fragmentation due to intracellular mechanisms).

The exact contribution of each mechanism remains unclear, and different mechanisms may prevail in various diseases.

Rituximab has a limited effect on other immune cells.

• The CD20 antigen is not found on stem cells or early pro-B cells so these can regenerate the B lymphocyte population.
• Plasma cells are B cells that do not usually express the CD20 antigen, so they mostly survive. As these produce antibodies, serum immunoglobulin levels tend not to fall dramatically.
• Rituximab may also act on autoreactive T-effector cells, regulatory T cells, and monocyte-derived macrophages.

What is rituximab used for?

Rituximab is approved by Medsafe in New Zealand for the following conditions:

• CD20 positive B cell non-Hodgkin lymphoma in combination with chemotherapy
• Chronic lymphocytic leukaemia in combination with chemotherapy
• Severe rheumatoid arthritis (RA) in conjunction with methotrexate
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

PHARMAC provides limited funding for rituximab to include some cases with:

• Cold haemagglutinin disease (CHAD)
• Warm autoimmune haemolytic anaemia (warm AIHA)
• Immune thrombocytopenic purpura (ITP)
• Thrombotic thrombocytopenic purpura (TTP)
• Pure red cell aplasia (PRCA)
• ANCA associated vasculitis
• Systemic lupus erythematosus (SLE)
• Rheumatoid arthritis
• Nephrotic syndrome
• Antibody-mediated renal transplant rejection
• ABO-incompatible renal transplant
• Other forms of lymphoma and leukaemia
• Haemophilia with inhibitors.

In the USA, the Food and Drug Administration (FDA) has also approved its use for granulomatosis with polyangiitis and microscopic polyangiitis in adult patients in combination with systemic steroids.

Rituximab has also been found to be useful in a variety of immune-mediated and autoimmune disorders in which traditional therapy has failed or resulted in side effects. However, the efficacy, tolerability and dosing of rituximab in the treatment of dermatological disease are not yet clear.

Off-label indications for rituximab in dermatology

To date, rituximab has been reported to be effective in at least some cases with the following skin conditions:

• Cutaneous B-cell lymphoma
• Primary blistering diseases
• Dermatomyositis
• Graft versus host disease
• Cutaneous vasculitis
• Atopic dermatitis
• Lupus erythematosus
• Eosinophilic fasciitis.

The most suitable dose of rituximab for these disorders has not yet been determined.

Cutaneous B cell lymphoma

Cutaneous B-cell lymphoma includes follicle centre, marginal zone, and diffuse large B-cell lymphoma, which have all been reported to respond to intravenous rituximab. Direct injections into the skin lesions have also been successful, allowing a lower dose to be used. However, after the initial response, the lymphoma may recur within several months. Retreatment may or may not prove successful as lymphomas can lose CD20 expression and, with that, susceptibility to rituximab.

Primary blistering diseases

Primary blistering diseases (also called autoimmune bullous disorders) are associated with autoantibodies directed against various structural support proteins in the epidermis and dermoepidermal junction.

Rituximab has been successfully used for pemphigus vulgaris and treatment-resistant cases of:

• Pemphigus foliaceus
• Paraneoplastic pemphigus associated with CD20+ lymphoma
• Bullous pemphigoid
• Epidermolysis bullosa acquisita
• Mucous membrane pemphigoid.

Dermatomyositis

Dermatomyositis is an autoimmune disease characterised by inflamed, weakened muscles associated with a characteristic rash. How this occurs is unknown, but it involves T cells, B cells and antibodies directed against the endothelial cells lining blood vessels in the muscles.

Treatment of treatment-resistant dermatomyositis with rituximab has led to the improvement of muscle and skin disease in several patients. Clinical trials have been set up to determine the role of rituximab in dermatomyositis.

Graft-versus-host disease

Chronic graft versus host disease (GVHD) affects 60–70% of long-term survivors after bone marrow transplantation. It results in lichenoid and sclerodermatous skin changes as well as disease of internal organs. GVHD often fails to respond to conventional treatment, and a quarter of the patients die from it.

Chronic GVHD has been thought to be due to donor T cells, but drugs targeting T cells have not proved very useful. There is now mounting evidence that B cells are responsible. There have been reports of improvement with rituximab in some patients with GVHD.

Cutaneous vasculitis

Vasculitis is classified as a type-III hypersensitivity reaction involving immune complexes, that is, antibodies bound to antigens in the affected blood vessels. Exactly how rituximab works in vasculitis is unknown.

In April 2011, the US FDA approved rituximab for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis). Case reports suggest rituximab is also efficacious in cutaneous vasculitis due to cryoglobulinaemia.

Atopic dermatitis

Atopic dermatitis (eczema) results from a complex interaction between various immune cells and proteins and in many patients is characterised by high levels of serum IgE. B cells and plasma cells produce IgE, so theoretically, B-cell depletion could help treat the disease.

Rituximab has resulted in an impressive improvement of atopic dermatitis in some patients with severe disease. However, although researchers confirmed a reduction in circulating B cells in their patients, they found little change in IgE levels.

Cutaneous lupus erythematosus

Rituximab has been successfully used to treat refractory cutaneous lupus erythematosus.

Adverse events due to rituximab

Most patients experience mild-to-moderate side effects from their first infusion of rituximab. The most common symptoms are:

• Fever (48%)
• Chills (32%)
• Weakness (18%)
• Nausea (17%)
• Headache (13%)
• Itch (12%)
• Rash (11%).

The symptoms usually settle if the infusion is stopped temporarily and tend to be less severe with subsequent infusions. Pretreatment with paracetamol and antihistamines is recommended. A corticosteroid may also be used.

Although infections are rare, some patients have died from infection after rituximab infusions due to:

• Bacterial sepsis
• Reactivation of hepatitis B with fulminant hepatitis
• Progressive multifocal leukoencephalopathy — a viral infection affecting the central nervous system.

Patients should be urged to seek prompt medical attention if they develop new neurological symptoms such as changes in vision, balance or thought processes.

Other deaths from rituximab have been due to:

• Tumour lysis syndrome
• Infusion reactions
• Stevens-Johnson syndrome and toxic epidermal necrolysis.

Many other less severe adverse reactions have been reported, including a variety of rashes and:

• Stomatitis
• Alopecia (hair loss)
• Urticaria
• Flushing 
• Hyperhidrosis.

The use of rituximab in children and patients with kidney or liver failure has not been studied extensively. Rituximab should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus (Pregnancy Risk Category C). Breastfeeding mothers should be advised to discontinue nursing until circulating blood levels are no longer detectable.

Current safety information is based on treatment for non-Hodgkin lymphoma and rheumatoid arthritis and may not be applicable when rituximab is used for other disorders.

Dosage and administration of rituximab

Prior to treatment, check immunoglobulin levels as well as routine haematology and biochemistry. Screen for infections such as hepatitis B and treat these prior to treating with rituximab. Pretreatment immunisation should be considered especially pneumococcus, influenza and hepatitis B.

The usual dose of rituximab is 375 mg for every square metre of body surface area is given intravenously over several hours, once weekly for several weeks. Regimes have varied for the skin diseases described above. Infusions are accompanied by antihistamine to reduce urticarial reactions.

The blood count should be monitored monthly for several months then every three months, as neutropenia may occur.

What are the contraindications to rituximab?

Rituximab is not recommended for treatment of patients with severe active infections.

What are the drug interactions with rituximab?

Though there have been no formal drug interaction studies performed with rituximab, the concomitant use of rituximab and cisplatin should be avoided as this combination has been associated with renal failure.