Autoimmune Manifestations with Cytokine Administration

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The list of cytokines with possible therapeutic use has been growing. As for any adverse reaction with a new compound, the interpretation of the underlying mechanisms is often difficult. The incidence is obviously related to the properties of the molecule itself, its dose regimen, and mode of administration, but also to the underlying disease as well as to the size of the exposed population. Among the cytokines already in clinical application, IFNa has been the most commonly used, particularly in patients with chronic viral hepatitis. For these reasons, both this cytokine and this disease have been associated with the largest list of side effects. Thus, we review the side effects observed with this cytokine first.

The major indications of INFa are type B and C chronic viral hepatitis, and cancer (mostly renal cell carcinoma and melanoma, and hematological malignancies). The large number of treated patients, the largest for any cytokine, allows a good assessment of its safety (Miossec, 1997).

Induction of autoimmune events appears to be a frequent feature (Fattovich et al., 1996; Wilson et al., 2002). This includes an exhaustive list of manifestations of autoimmunity and associated diseases (Miossec, 1997). This has led to the recommendation to exclude patients with concomitant clinically overt autoimmune disease from the use of IFNa for the treatment of viral hepatitis. The range goes from the mere presence or induction of autoantibodies with no clinical consequence to the most severe autoimmune disease. The pathogenicity of autoanti-bodies is often unclear and far from being always associated with disease manifestations. Their targets include blood cells (red cells, leukocytes, platelets), coagulation factors (factor VIII, lupus anticoagulant), immunoglobulins (rheumatoid factor with or without cryoglobulin activity), intracellular components (nucleus, enzymes), hormones (thyroid hormones, insulin), and the skin (epidermis) (Fattovich et al., 1991). In particular, exacerbation of hepatitis C-related cryoglobulinemia has been described leading to severe clinical consequences, including polyneuritis and even fatal cases (Batisse et al., 2004). This has to be taken into account since an association with hepatitis C is found in almost 50% of all cases of mixed cryoglobulinemia (Agnello et al., 1992), although treatment with IFNa is usually helpful, particularly in combination with ribavirin (Ferri et al., 1993; Mazzaro et al., 2003).

Blood cells and coagulation factors are frequent targets. These manifestations include idiopathic or autoimmune hemolytic anemia and thrombocytopenia (Murakami et al., 1994). Regarding acquired factor VIII inhibitor, some patients with hemophilia A and hepatitis C developed antibodies to factor VIII (Stricker et al., 1994). Induction of lupus anticoagulant has been implicated in the development of thrombotic events.

Regarding the list of organ-specific diseases, thyroid abnormalities appear to be the most common manifestations (Lisker-Melman et al., 1992), but the exact incidence remains unclear. In a survey including 11,241 patients with hepatitis, 71 developed autoimmune thyroid disease during IFNa treatment (Fattovich et al., 1996) and various thyroid abnormalities have been observed. Half of them had hypothyroidism, 30% hyperthyroidism, and 20% a biphasic (hyperthyroidism followed by hypothyroidism) pattern. This includes the two ends of the spectrum, ranging from patients clinically and biochemically hypothy-roid, but negative for thyroid autoantibodies, to patients remaining euthyroid, but with thyroid autoantibodies. Idiopathic thyroiditis is a very common autoimmune disease, often associated with Sjogren's syndrome, resulting in lymphocytic infiltration of the exocrine glands. It is important to keep in mind that such features are commonly found in patients with hepatitis C in the absence of any cytokine treatment (Haddad et al., 1992). Along the same line, induction of insulin antibodies and onset of insulin-dependent diabetes with increased antiglu-tamic acid decarboxylase antibody levels have been observed in 10 out of the 11,241 patients in the survey described above (Fattovich et al., 1996).

Other manifestations include almost the entire list of autoimmune diseases (Miossec, 1997). Regarding arthritis manifestations, IFNa was responsible for the induction or flare of various types of inflammatory arthritis, either associated to RA, psoriasis, lupus, spondyloarthropathy, or as yet unclassified (Conlon et al., 1990; Kiely and Bruckner, 1994). Regarding muscular manifestations, cases of dermatomyositis and polymyositis have been described mostly in patients with chronic hepatitis C (Conlon et al., 1990). Similarly, myasthenia gravis with anti-acetylcholine receptor antibodies and Guillain-Barré syndrome have been observed (Batocchi et al., 1995).

Features of systemic lupus erythematosus including severe cases with nephropathy, cerebral vasculitis, and chorea have been reported (Wilson et al., 2002). More recently, the role of IFNa in the pathogenesis of lupus has been demonstrated, suggesting that IFNa may represent a target for treatment (Pascual et al., 2003; Schmidt and Ouyang, 2004). However, induction of lupus remains a rare event in patients treated with IFNa.

Interference with graft survival also has been a major consequence of such treatment, including graft versus host disease following therapy for relapsed leukemia after allogeneic bone marrow transplantation, as well as allograft rejection following treatment of hepatitis C after liver and renal transplantation (Saab et al., 2004). Treated recipients may also develop progressive cirrhosis despite achieving a sustained virological response.

Other cytokine side effects also are of interest. IL-2 was the first cytokine used as a recombinant product. In early studies, it was used for the ex vivo culture of autologous peripheral blood lymphocytes before reinjection and production of lymphokine-activated killer (LAK) cells. Similarly tumor-infiltrating lymphocytes (TILs) have been cultured the same way. Reduction of metastases was observed in patients with extensive melanoma and renal cell carcinoma (Rosenberg et al., 1988). Most recent studies have used IL-2 either alone or in combination with other cytokines, mainly IFNa. One of the major adverse reactions with IL-2 was the acute accumulation of body fluid related to a capillary leak syndrome (Ballmer-Weber et al., 1995). In vivo studies have shown the activation of vascular endothelial cells by proinflammatory cytokines, the production of which was stimulated by IL-2. When used on a more chronic basis, such effect may contribute to the migration of inflammatory cells, mostly lymphocytes, to the perivascular site. A number of side effects observed with IFNa have been described with IL-2 (Gaspari, 1994), including the induction of chronic arthritis, myositis, and thyroid manifestations.

Interferon P (IFNP) is currently used for the treatment of multiple sclerosis (Francis, 2004). Although the clinical experience is not as large as with IFNa, autoimmune manifestations do not appear to be a frequent concern, although thy-roiditis is also the most common autoimmune reported event.

Interferon y (IFNy) is a NK/Thl-derived cytokine and some of the comments regarding IFNa apply to IFNy. The experience with the latter cytokine, although limited, indicates its autoimmune potential. In patients with hepatitis C, thyroid dysfunction was uncommon in contrast to the induction of antinuclear antibodies. In patients with psoriasis arthritis or spondyloarthropathy, increased arthritis activity was observed. In patients with RA, no benefit was demonstrated, but in some cases, induction of antinuclear antibodies was observed (Cannon et al, 1993). In some patients with multiple sclerosis, treatment with IFNy led to increased disease activity (Panitch et al, 1987). More recently, however, autoimmune manifestations were not observed in patients with cancer or opportunistic infections related to HIV infection (Riddell et al, 2001; Stuart et al., 2004).

Interleukin 12 (IL-12) is a cytokine produced by monocytes and antigen-presenting cells with a major effect on cell-mediated immunity in part through the production of IFNy. IL-12 has been recently used as protein and through gene therapy for cancer treatment (Cebon et al., 2003; Sangro et al., 2004). Autoimmune manifestations have not been observed but further data with prolonged exposure are needed.

The family of colony-stimulating factors (CSFs) includes IL-3 or multi-CSF, granulocyte-CSF (G-CSF), and granulocyte-monocyte-CSF (GM-CSF). Such cytokines are used for the stimulation of bone marrow precursors after spontaneous or postchemotherapy bone marrow depression. Most autoimmune manifestations have been observed with G-CSF or GM-CSF. They have been used in patients with RA, particularly those with Felty's syndrome, defined as the combination of rheumatoid factor-positive destructive RA, severe neutropenia, and splenomegaly. Improvement of the neutropenia has been observed, sometimes with increased thrombocytopenia and anemia (Hoshina et al., 1994). Some patients also showed increased arthritis activity (Yasuda et al., 1994). However, such flare-up was not a constant observation.

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