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Chapter: Essential Clinical Immunology: Autoimmunity

Treatment of Autoimmune Disease

Treatment for autoimmune disease is diverse, and in recent years, the options have increased rapidly.


Treatment for autoimmune disease is diverse, and in recent years, the options have increased rapidly. Organ-specific autoimmune diseases of endocrine func-tion, such as TID and autoimmune thy-roiditis, may be treated with hormone replacement. In contrast, other forms of organ-specific autoimmune disease such as autoimmune thrombocytopenia, AIHA, and multiple sclerosis are treated with immunosuppressive medications, as are the majority of systemic autoimmune dis-eases. Immunosuppressive medications can be categorized by mode of action.

Anti-inflammatory Agents

Nonsteroidal anti-inflammatory drugs have been used since the 1800s when sali-cin was extracted from willow bark (1828) and sodium salicylate (1875) and aspirin (1899) were synthesized. A large number of these drugs, which either selectively or nonselectively inhibit the enzyme cyclo-oxygenase (a synthetic enzyme for pros-taglandins), are currently in use to treat inflammatory disease. Although most of their anti-inflammatory properties derive from the inhibition of prostaglandin syn-thesis, at high doses, there is inhibition of the transcription factor nuclear factor κB (NFκB), a key mediator of inflammatory cytokine production. Corticosteroids have a more potent effect on NFκB and con-sequently a greater anti-inflammatory effect.

Philip S. Hench discovered the anti-inflammatory properties of cortisone in 1949. Corticosteroids are a mainstay of therapy for many systemic autoimmune diseases, including SLE, RA, and inflam-matory myopathies such as polymyositis. Corticosteroid therapy also is used for the treatment of some of the more seri-ous organ-specific autoimmune diseases, such as AIHA, autoimmune thrombocy-topenia, multiple sclerosis, and Goodpas-ture’s syndrome. Corticosteroids reduce inflammation by multiple mechanisms of action. One major action is enhanced tran-scription of an inhibitor of NFκB called IκB. IκB dimerizes with NFκB, inhibit-ing the production of inflammatory cyto-kines mediated by this transcriptional pathway. In addition, corticosteroids pro-mote the differentiation of a subset of anti-inflammatory macrophages that produce the cytokine IL-10.

Antimalarial Drugs

Antimalarial drugs have been used for the treatment of SLE and RA since the early 1900s. The precise mechanism of action remains uncertain, but they have been shown to inhibit cytokine (IL-1 and IL-6) production in vitro. The antimalari-als pass freely through cell membranes at neutral pH, but in acidic environments, such as endosomes, they become proton-ated and can no longer diffuse freely. This leads to concentration of the drug within endosomes and the collapse of endosomal pH gradients. It has been proposed that the inhibition of endosomal acidifica-tion interferes with antigen processing or, alternatively, that there is an effect on the interaction of microbial substances such as unmethylated CpG DNA or uridine-rich RNA with endosomal toll-like recep-tors (TLR9 and TLR7/TLR8, respectively). In addition to SLE and RA, antimalarials are used in the treatment of juvenile rheu-matoid arthritis, Sjögren’s syndrome, and inflammatory myopathies.

Anticytokine Agents

The development of TNF-α inhibitors in the 1990s ushered in a new era of therapy of autoimmune disease using “biologi-cals” capable of interfering with the interactions between cytokines and their receptors. The initial clinical use of TNF inhibitors such as etanercept (a soluble recombinant TNF receptor II linked to the Fc portion of human IgG1), infliximab (a chimeric human-mouse anti-TNF-α

monoclonal antibody), and adalimumab (a fully humanized monoclonal antibody against TNF-α) in RA demonstrated that although multiple cytokines may be involved in disease pathogenesis (in RA, IL-1, and IL-6 in addition to TNF-α), inhibitors of a single cytokine pathway may show therapeutic efficacy. In addi-tion to RA, TNF-α inhibitors are used for treating inflammatory bowel disease, pso-riasis, and psoriatic arthritis and are being tested in sarcoidosis, Wegener’s granulo-matosis, pyoderma gangrenosum, SLE, and Behcet’s syndrome.

Anti-TNF therapy is only the tip of the “biological iceberg.” Recombinant IL-1 receptor antagonist (anakinra) has been approved for the treatment of RA, and numerous other cytokine antagonists are currently in clinical trials or under develop-ment.


Methotrexate is a folic acid analog used extensively for the treatment of RA. It appears that its ability to inhibit dihydrofo-late reductase is not responsible for its effi-cacy in RA, however. Instead, activity may be related to effects on aminoimidazole-carboxamide ribotide transformylase, leading to the release of adenosine, a potent anti-inflammatory molecule that inhibits neutophil adherence to fibro-blasts and endothelial cells. Methotrexate inhibits IL-1 and increases the expression of TH2 cytokines (e.g., IL-4), leading to decreased production of TH1 cytokines (e.g., IFN-γ).

Anti-T-Lymphocyte Therapy

T cells play a key role in the pathogen-esis of type IV autoimmune reactions and also are critical for generating the T-cell-dependent autoantibodies mediat-ing type II and type III autoimmune dis-eases. Consequently, considerable effort has gone into the development of thera-peutic agents that selectively or nonselec-tively target T lymphocytes. Drugs that target primarily T cells include cyclo-phosphamide, azathioprine, cyclosporin A, tacrolimus, and the biological CTLA4-Ig. Cyclophosphamide is an alkylating agent that substitutes alkyl radicals into DNA and RNA. The drug is inactive by itself but is converted to an active metabo-lite responsible for its immunosuppres-sive effects. It is used for the treatment of lupus nephritis and other life-threatening complications of SLE and other systemic autoimmune diseases.

Azathioprine is a purine analog that inhibits the synthesis of adenosine and guanine. Like cyclophosphamide, it is converted to an active metabolite (6-mer-captopurine), which inhibits the division of activated B and T cells. Azathioprine is used in the treatment of RA, SLE, auto-immune hepatitis, inflammatory myopa-thy, vasculitis, and other autoimmune disorders.

Unlike cyclophosphamide and aza-thioprine, cyclosporine and tacrolimus (FK506) have immunosuppressive prop-erties that are highly selective for T cells. Both agents interfere with the phosphatase calcineurin, ultimately leading to an inhi-bition of the activation of the transcription factor NFAT (nuclear factor of activated T cells). Cyclosporine binds to the intracel-lular protein cyclophilin and tacrolimus to a protein called FK binding protein. The cyclosporine-cyclophilin and tacroli-mus-FK binding protein complexes bind to calcineurin, preventing its activation by intracellular calcium, and the activation of NFAT. Although used most frequently to prevent transplant rejection, these agents have been shown to have activity in the treatment of RA, SLE, and certain forms of vasculitis.

The CTLA4 (CD152) molecule is an inhibitory receptor expressed by acti-vated T cells that block the co-stimulatory interaction between CD80 or CD86 on the surface of antigen-presenting cells and CD28 on T cells. It acts by binding CD80/ CD86 with greater affinity than CD28. CTLA4 is expressed late in T-cell activation and serves to turn off the activated state. CTLA4-Ig (abatacept) is a recombinant chimera of CTLA4 and the Fc fragment of IgG1. CTLA4-Ig/abatacept is used for the treatment of RA and is active in mouse models of lupus. Clinical trials in SLE patients are in progress.

Anti-B-Lymphocyte Therapy

Rituximab is a cytotoxic chimeric human-mouse monoclonal antibody with a high affinity for CD20, a pan-B-cell surface anti-gen. It was developed originally for the treatment of B-cell lymphomas. The kill-ing of B cells by rituximab is thought to depend on both the specific recognition of B cells by this monoclonal antibody and natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of those cells. There is considerable evi-dence that the interaction of B-cell-bound monoclonal antibodies with NK cell CD16 (FcγRIIIA) is a critical event leading to ADCC following treatment with rituximab. Rituximab appears to have activity in a variety of autoimmune diseases associated with autoantibody production, including RA, SLE, polymyositis/dermatomyositis, Sjögren’s syndrome, and cryoglobulinemic vasculitis.

Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIG) is a preparation of human immunoglobulin pooled from thousands of healthy indi-viduals. It was originally developed for replacement therapy in humoral immu-nodeficiency syndromes but has more recently become an important therapeutic modality in severe autoimmune disor-ders, such as thrombocytopenic purpura, AIHA, neuroimmunological diseases such as Guillain-Barré syndrome, SLE, certain forms of vasculitis, and polymyositis/ dermatomyositis. The mechanism of action remains unclear, but IVIG may block the function of Fc receptors expressed by phagocytes of the reticuloendothelial sys-tem and also induces FcγRIIB (inhibitory Fc receptor) expression on infiltrating mac-rophages in the K/BxN model of RA. An additional mode of action may involve the presence of anti-idiotypic antibodies that block the antigen combining sites of patho-genic antibodies. The duration of action is limited by the metabolism of serum immu-noglobulin, and generally, IVIG is regarded as a temporary measure that is followed by more definitive therapy.


Autologous Hematopoietic Stem Cell Transplantation (HSCT)

The ability to adoptively transfer autoim-mune diseases with bone marrow trans-plantation in a variety of animal models provides strong evidence that these dis-orders are mediated by cells derived from hematopoietic cells. There is compelling evidence that autoimmune disease results from a loss of B- or T-cell tolerance to cer-tain self-antigens. Hematopoietic stem cells are the earliest progenitor cells of the immune system and give rise to B and T lymphocytes as well as antigen-present-ing cells (monocytes, macrophages, and dendritic cells). The rationale for HSCT as a therapy for autoimmune disease is based on the concept that the peripheral expan-sion of autoreactive T- and B-cell clones is central to the pathogenesis of autoim-munity. If these autoantigen-specific cells can be deleted and the immune system regenerated with “normal” hematopoietic stem cells, there is the potential to effect a “cure” of autoimmune disease. Therapy is based on the mobilization of hematopoi-etic stem cells using C-CSF or G-CSF plus cyclophosphamide. There is the risk dur-ing mobilization of flares caused by G-CSF treatment. The stem cells are depleted of lymphocytes and enriched for CD34+ cells followed by expansion and reinfusion into the same donor after “conditioning.” The conditioning regimen involves cyclophos-phamide treatment or other immunosup-pressive treatments aimed at depleting mature lymphocytes. Phase III clinical tri-als of the efficacy of autologous HSCT in MS, SLE, RA, and scleroderma are ongoing or planned. Promising preliminary results have been obtained with all of these condi-tions, but further study is needed.

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