Extracorporeal photopheresis (ECP) is a form of apheresis and photodynamic therapy in which blood is treated ex vivo with a photoactivable drug (ie, one that is activated with ultraviolet light). The whole process takes approximately 3 to 4 hours to complete and involves leukapheresis, separation of the buffy coat, photoactivation, and finally reinfusion. ECP has been approved by the FDA for cutaneous T-cell lymphoma (CTCL) since 1988.
The history of the photoactivable drug methoxsalen (8-methoxypsoralen) dates to ancient Egypt. Medicinal properties were observed in Ammi majus
, a plant commonly known as Bishop’s weed, which was found next to the Nile River. The injudicious use of the weed, which the Egyptians used to treat skin ailments, caused skin damage. This damage is now understood to be activated by ultraviolet radiation (UVA) and is the result of phototoxic mechanisms that are dependent on the psoralen content of Bishop’s weed. The results are clinical changes such as erythema, bullae in the skin 24 to 72 hours later, and hyperpigmentation. Methoxsalen’s exact mechanism of action is not known, but in the presence of UVA methoxsalen intercalates with the patient’s DNA and produces adducts, thereby deranging DNA synthesis in those cells. A second mechanism, which is being recognized more often and is the subject of ongoing research, is the immune effects on macrophages, dendritic cells, and helper T cells. This second mechanism is thought to be more likely contributing to the benefits seen with ECP in graft-versus-host disease (GVHD).
Oral methoxsalen provides clinical benefit to patients with psoriasis, vitiligo, and CTCL. In CTCL, ECP is approved for the palliative treatment of the skin manifestations of CTCL that are unresponsive to other forms of treatment. Additional disease areas in which ECP has been shown to provide benefit are GVHD and autoimmune diseases such as multiple sclerosis.
Causes of GVHD
GVHD occurs when immune cells transplanted from a nonidentical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. The leading cause of GVHD is allogeneic hematopoietic cell transplantation (HCT), though solid organ transplants, blood transfusions, and maternal-fetal transfusions also reportedly cause GVHD.
GVHD has been classically divided into acute and chronic subtypes based on the time of onset from the HCT. Acute GVHD occurs when the disease presents within the first 100 days of HCT and chronic GVHD refers to the disease having onset after the first 100 days. However, this division at day 100 post-HCT is artificial, and there has been a shift toward defining acute and chronic GVHD based on the clinical manifestations, rather than the arbitrary cutoff of a particular date posttransplantation.
Clinically significant acute GVHD occurs in 9% to 50% of patients who receive an allogeneic HCT from a genotypically HLA-identical sibling, despite intensive prophylaxis with immunosuppressive agents such as methotrexate, cyclosporine, tacrolimus, corticosteroids, or antithymocyte globulin. Patients with acute GVHD commonly demonstrate a classic maculopapular rash, liver toxicity, diarrhea, and affects on the hematopoietic system.
Chronic GVHD occurs in more than 50% of long-term survivors of HLA-identical sibling transplants and can occur after previous or ongoing acute GVHD. It may also appear in patients without a history of acute GVHD (ie, de novo chronic GVHD). The target organs affected by chronic GVHD differ from those observed with acute disease. The skin involvement with chronic GVHD resembles lichen planus or the cutaneous manifestations of scleroderma. Patients may also have dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract, and a rising serum bilirubin concentration. Lung involvement also commonly occurs with chronic GVHD. With chronic GVHD, there is a marked immunodeficiency due to direct immunosuppressive effects and the consequences of the agents administered to treat the disease. Since chronic GVHD also causes a delay in the recovery of immune function, patients remain immunodeficient as long as the disease is active. In chronic GVHD, helper T cells react against major histocompatibility complex and generate excessive help. This enhanced help activates a subpopulation of selfreactive (possibly host) B cells, thereby causing autoantibody formation. Autoantibodies found in patients with chronic GVHD are similar to those observed in systemic lupus erythematosus and other rheumatologic disorders, implicating autoimmunity and autoimmune disease-related gene polymorphisms as important components of chronic GVHD.