Extracorporeal photopheresis for the treatment of autoimmune diseases

doi:10.1016/j.transci.2015.02.005

Transfusion and Apheresis Science

Volume 52, Issue 2, April 2015, Pages 171-182

https://doi.org/10.1016/j.transci.2015.02.005 Get rights and content

Abstract

The immune system is tasked with the unique challenge of recognizing foreign pathogens and damaged cells while at the same time preserving and protecting the integrity of “self”. When this process fails, severe consequences including cancer and autoimmunity are the end result. Current therapies aimed at treating autoimmune disorders result in generalized immunosuppression and place the patient at increased risk for infection and malignancy. ECP is a potential therapeutic intervention that recapitulates natural physiologic processes of tolerance induction to restore immune homeostasis. Several clinical trials suggest that ECP may be used to treat a broad spectrum of autoimmune diseases.

Introduction

In the past 20 years there has been a significant increase in the global incidence of autoimmune disorders [1]. Over 50 million people in the United States have been diagnosed with an autoimmune disease. Autoimmunity is the second highest cause of chronic illnesses and is one of the leading causes of morbidity and mortality in females [2]. The reason why some individuals develop autoimmune disorders is unknown, although many factors, including genetic susceptibilities, environmental triggers and microbial infections have been implicated.

Autoimmunity occurs when the host's immune system can no longer distinguish between self and non-self antigens. A breakdown in immunologic tolerance allows the host's immune system to mount a response against autoantigens [3]. The manifestations of autoimmune disorders depend on the specific organs or organ systems targeted. Current therapeutic strategies to halt immune responses to self are temporal and systemic. The benefits of most immunosuppressive regimens are only achieved when the patient is actively dosed over long periods of time with pharmacologic agents. These interventions cause generalized immunosuppression, increasing the risk for infection and malignancy [4]. Immunosuppressive drugs may have direct toxic effects on other organ systems (e.g. corticosteroid-induced insulin resistance, renal failure due to calcinurin inhibitors) that contribute to patient morbidity and mortality [4], [5]. The ideal treatment for autoimmune diseases should be selective and targeted at restoration of immune tolerance.

Section snippets

Immune tolerance

Immune tolerance can be divided into two categories, central and peripheral tolerance. Central tolerance refers to the T- and B-lymphocyte maturation and selection process that occurs in the thymus and bone marrow, respectively [6]. Immature T cells first undergo positive selection for those T cells that have the capacity to recognize self-MHC molecules. Negative selection of T cells by intrathymic deletion is triggered when there is high avidity for self-antigens presented in the context of

Immunomodulatory mechanism of ECP

Although ECP has been in use for over 25 years, the mechanisms by which this therapy leads to both immunotherapy against CTCL and immunosuppression in the setting of transplant rejection, GVHD and autoimmunity are not completely elucidated. Recent studies by Edelson et al. support the hypothesis that ECP promotes monocyte differentiation into DC with varying degrees of maturation that is dependent on platelets and on the amount of UVA exposure [13], [14]. In the course of treatment, the plastic

Scleroderma

Scleroderma describes a spectrum of fibrotic autoimmune disorders characterized by thickening of the skin and fibrosis of internal organs (systemic sclerosis) or localized fibrosis of the skin and subcutaneous tissue (morphea). The prognosis of scleroderma depends on the rate of disease progression and the degree of tissue involvement; overall survival at 10 years is a dismal 55% [19].

Skin biopsies from patients with scleroderma show perivascular inflammatory infiltrates consisting of T cells

Barriers to using ECP to treat autoimmunity

Although preliminary studies for many of the autoimmune conditions described earlier suggest that ECP may in fact be a safe, effective means of therapy, there are many barriers to overcome before this intervention can be used routinely in clinical care. The most significant is the relative lack of animal or human studies to support clinical trials. To date, none of the placebo-controlled randomized ECP trials that have been performed show definitive evidence to support the use of this

Conclusion

ECP is an immunomodulatory therapy with an excellent safety profile. Studies suggest that the benefit of therapy in inflammatory conditions is due to recapitulation of normal, physiologic processes to induce and maintain immune tolerance. There is some cumulative evidence to support the use of ECP for treating autoimmune disorders. Unfortunately, the evidence consists mostly of case series/reports because well-designed clinical trials are cost prohibitive in the current funding environment.

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[Eosinophilic fasciitis: From pathophysiology to therapeutics]
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La fasciite à éosinophiles (FE), ou maladie de Shulman, est une pathologie rare du tissu conjonctif caractérisée par un œdème et une induration douloureuse des membres et du tronc, souvent associés à une hyperéosinophilie et une hypergammaglobulinémie. Elle provoque des arthralgies et une limitation des amplitudes articulaires induisant un important retentissement fonctionnel et une altération de la qualité de vie. Depuis sa description par Shulman en 1974, plus de 300 cas ont été rapportés. Nous présentons ici une revue des actualités diagnostiques, physiopathologiques, et thérapeutiques de cette maladie. L’imagerie par résonance magnétique est utile pour orienter le diagnostic et la biopsie. Le diagnostic repose sur la biopsie cutanée profonde comportant le fascia qui met en évidence un œdème, une scléro-fibrose du fascia musculaire et du tissu sous-cutané et un infiltrat inflammatoire parfois composé de polynucléaires éosinophiles. Des formes secondaires à l’utilisation des inhibiteurs de checkpoint ont été décrites et l’apparition d’une sclérose cutanée chez ces patients doit faire évoquer le diagnostic. La physiopathologie reste mal connue et la prise en charge mal codifiée, reposant sur des données issues de cohorte rétrospectives et cas cliniques. Le traitement de première intention consiste en corticothérapie orale, parfois associée à un immunosuppresseur, en premier lieu le méthotrexate. Une meilleure compréhension de la physiopathologie permet d’envisager de nouvelles perspectives thérapeutiques et de préciser la place de thérapies ciblées telles que les inhibiteurs de l’interleukine 5 (IL-5) et de l’IL-6.
Eosinophilic fasciitis (EF) is a rare connective tissue disorder characterized by painful edema and induration of the limbs and trunk, likely associated with hypereosinophilia and hypergammaglobulinemia. EF causes arthralgia and range of motion limitation, leading to significant functional impairment and poor quality of life. Since its description by Shulman in 1974, over 300 cases have been reported. We present here a review of the latest diagnostic, pathophysiological and therapeutic developments in this disease. Magnetic resonance imaging appears useful to guide diagnosis and biopsy. Diagnosis is based on a deep skin biopsy involving the fascia, which will reveal edema, sclerofibrosis of the muscular fascia and subcutaneous tissue, and an inflammatory infiltrate sometimes composed of eosinophilic polynuclear cells. EF may occur in patients treated with immune checkpoint inhibitors and the diagnosis should be raised in case of cutaneous sclerosis in these patients. The pathophysiology of the disease remains poorly understood, and its management lacks randomized, controlled, blinded trials. First-line treatment consists in oral corticosteroid therapy, sometimes combined with an immunosuppressant, mainly methotrexate. A better understanding of the pathophysiology has opened new therapeutic perspectives and clarified the role of targeted therapies in the management of EF, such as interleukin-6 inhibitors, whose efficacy has been reported in several cases.
A case of psoriasis successfully treated by extracorporeal photopheresis during COVID-19 pandemic
2021, Transfusion and Apheresis Science
Citation Excerpt :
Although the mechanism of action is not fully understood, it is thought to provide its effect through lymphocyte apoptosis and normalizing the immune system. Successful outcomes of ECP were investigated in many autoimmune dermatological conditions, such as atopic dermatitis, pemphigus vulgaris, erosive lichen planus, nephrogenic fibrosing dermopathy, cutaneous mucinosis, scleromyxoedema, eosinophilic fasciitis, and psoriasis [5,6]. In this paper, we present a case of psoriasis in which the patient was unresponsive to conventional systemic medications, had a high risk of immunosuppression, which possibly arose from biologics and cyclosporine, and achieved remission following a two and a half month course of ECP.
Psoriasis is a chronic inflammatory skin disease that is characterized by well-demarcated erythematous plaques with a silver scale. Although many new and emerging therapeutic agents are often sufficient to control the disease, there is still a need for alternative treatment options in challenging cases. Extracorporeal photopheresis (ECP) has been applied to many T-cell-mediated diseases to restore immune homeostasis and treat psoriasis effectively. In this paper, we present a psoriasis patient who did not respond to methotrexate, narrowband ultraviolet B, or acitretin. Because of a diagnosis of non-Hodgkin lymphoma, the patient had contraindications for cyclosporine, fumaric acid esters, and biologics but achieved remission with a total of 12 sessions of ECP in two and a half months. Although exacerbation was recorded after polymerase chain reaction (PCR) confirmed coronavirus 2019 (COVID-19) disease infection at the end of the first month, scores from the psoriasis area severity index (PASI) and dermatological life quality index (DLQI) were regressed significantly within two and a half months. ECP seems to provide an effective and rapid response for psoriasis and should be considered for psoriasis patients who fail to respond or have contraindications to existing treatments.
Extracorporeal Photochemotherapy (Photopheresis)
2020, Comprehensive Dermatologic Drug Therapy, Fourth Edition
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that was first approved by the US Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL) in 1988. In addition to CTCL, ECP has been used in the treatment of several immune-mediated skin disorders, most notably chronic graft-versus-host disease (GVHD), scleroderma, oral lichen planus, and pemphigus vulgaris, as well as noncutaneous diseases such as organ transplant allograft rejection (not discussed in this chapter). ECP treatments involve centrifugation leukapheresis, leukocyte passage through a transparent exposure plate, irradiation with ultraviolet A light in the presence 8-methoxypsoralen, followed by reinfusion of both treated and untreated cells. Although the precise mechanism of ECP remains to be fully elucidated, proposed mechanisms against CTCL include monocyte activation and dendritic cell (DC) differentiation, internalization of apoptotic malignant T cells, and presentation of tumor antigens to activate an anti-tumor immune response. In GVHD (and allograft rejection), repetitive reinfusion of apoptotic leukocytes via ECP is believed to facilitate immune tolerance through the induction of regulatory T cells and/or induction of tolerogenic DC. As a monotherapy or as part of a multiagent regimen, ECP is a broadly efficacious and relatively safe therapy for erythrodermic CTCL and a variety of inflammatory skin disorders.
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Apheresis describes a procedure in which whole blood is removed from a subject, separated into components (such as red blood cells, white blood cells, platelets, and plasma), and selective components are removed while the rest is reinfused back to the person with or without the use of replacement fluid(s). Common therapeutic apheresis procedures are therapeutic plasma exchange red blood cell exchange with or without isovolemic hemodilution, leukocytapheresis, thrombocytapheresis, and extracorporeal photopheresis. The common goal of these procedures is to remove the disease mediator(s) and potentially supplement missing component(s) via replacement fluid(s). Many of these procedures are performed for immune-related conditions, which are the primary focus of this chapter.
Ultraviolet Radiation: Both Friend and Foe in Systemic Autoimmune Diseases?
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Ultraviolet radiation (UVR) has been claimed to be one of the environmental factors involved in triggering both the onset and the exacerbations of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), dermatomyositis (DM), and systemic sclerosis (SSc). Therefore, patients affected by these diseases are instructed to avoid sun exposure and to use regularly sunscreens. On the other hand, there is increasing knowledge about the effects of different wavebands of UVR on the cells of the immune system (effector T cells, regulatory T cells, Langerhans cells, monocyte/macrophages). These effects can be exerted both locally in the skin and systemically and have been exploited to treat patients with UVA1 phototherapy and extracorporeal photopheresis. The principles of photobiology will be reviewed and the implications of UVR as “disease trigger” or “therapeutic agent” will be discussed for SLE, DM, and SSc.
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ReviewExtracorporeal photopheresis for the treatment of autoimmune diseases

Abstract

Introduction

Section snippets

Immune tolerance

Immunomodulatory mechanism of ECP

Scleroderma

Barriers to using ECP to treat autoimmunity

Conclusion

Transfus Apher Sci

Transfus Apher Sci

Transfus Apher Sci

Clin Immunol

Cell Immunol

J Am Acad Dermatol

J Am Acad Dermatol

Lancet

Ann Dermatol Venereol

J Am Acad Dermatol

J Eur Acad Dermatol Venereol

Lancet

Lancet

J Am Acad Dermatol

J Am Acad Dermatol

Clin Dermatol

Transfus Apher Sci

Lancet

Ann Dermatol Venereol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Autoimmun

Semin Arthritis Rheum

Autoimmun Rev

Best Pract Res Clin Rheumatol

J Autoimmun

Clin Dermatol

Clin Ther

A potential link between environmental triggers and autoimmunity

Autoimmune Dis

The Cost Burden of Autoimmune Disease: The Latest Front in the War on Healthcare Spending

Autoimmunity in 2012

Clin Rev Allergy Immunol

Side effects of corticosteroid therapy

J Clin Gastroenterol

Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence

Am J Nephrol

Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance

Science

Mechanisms maintaining peripheral tolerance

Nat Immunol

Dendritic cells: cellular mediators for immunological tolerance

Clin Dev Immunol

Identification of a dendritic cell receptor that couples sensing of necrosis to immunity

Nature

Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells

J Exp Med

Apoptotic cell-based therapies against transplant rejection: role of recipient's dendritic cells

Apoptosis

Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation

Immunol Rev

Transimmunization for cutaneous T cell lymphoma: a phase I study

Leuk Lymphoma

Leucocyte scintigraphy with 111In-oxine for assessment of cell trafficking after extracorporeal photopheresis

Exp Dermatol

The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo

Transplantation

Criteria for the classification of early systemic sclerosis

J Rheumatol

T cells in systemic sclerosis: a reappraisal

Rheumatology (Oxford)

The effects of extracorporeal photochemotherapy on T cell activation and regulatory mechanisms in patients with systemic sclerosis

Clin Rheumatol

Reduction of regulatory T cells in skin lesions but not in peripheral blood of patients with systemic scleroderma

Ann Rheum Dis

Treatment of autoimmune disease with extracorporeal photochemotherapy: progressive systemic sclerosis

Yale J Biol Med

Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial

Arch Dermatol

Review
Extracorporeal photopheresis for the treatment of autoimmune diseases