Principles of interferon therapy in liver disease and the induction of autoimmunity

INTRODUCTION — Advances in the understanding of autoimmune liver diseases and those of known etiology, such as chronic viral and drug-induced hepatitis, have underscored the importance of autoimmune reactivity in a variety of hepatocellular diseases. The widespread use of interferon (IFN) therapy in chronic viral hepatitis has revealed diverse biologic activities of administered IFNs and their propensity to induce and/or modify autoimmunity.

IFNs comprise a group of related proteins whose effects include antiviral activity, growth regulatory properties, inhibition of angiogenesis, regulation of cell differentiation, enhancement of major histocompatibility complex antigen expression, and a wide variety of immunomodulatory activities. They were originally classified according to their source and have subsequently been renamed:

●Leukocyte interferon is interferon-alfa (IFNa)

●Fibroblast interferon is interferon-beta (IFNb)

●Immune interferon is interferon-gamma (IFNg)

At least 18 distinct genes for human IFNa (including 4 pseudogenes) are known; in comparison, there is only one IFNb and one IFNg gene [1,2]. A class of cytokines distantly related to IFNa and the interleukin-10 family comprising three genes designated as interleukins 28A, 28B, and 29 has been discovered and termed interferon-lambda [3,4]. These cytokines resemble conventional IFNa because they are induced by viral infection and double-stranded RNA and render cells resistant to viral infections by activation of the same intracellular pathways.

Most cells have receptors and respond to IFNs. IFNa and IFNb (type 1 IFN) bind to the same cell surface receptor, albeit with different affinities, whereas IFNg binds to a distinct receptor for type 2 IFNs. Lambda IFNs bind to a shared own receptor consisting of the interleukin-10 receptor beta and an orphan class II receptor chain designated as IL-28Ra [3]. On average, type 1 IFNs are more than 30 percent homologous and the genes are clustered on the short arm of chromosome 9. None have introns, and all have transcripts with 3' instability sequences. In contrast, the IFNg gene is located on the long arm of chromosome 12 and has four exons [1,2]. Genes of lambda IFNs share 15 to 20 percent sequence homology with IFNa, but are clustered on chromosome 19 and contain multiple exons [3,4].

INTERFERON THERAPY IN LIVER DISEASE — Type 1 interferons (IFNs) were the first therapeutic agents that permitted successful antiviral therapy with acceptable side effects in patients with chronic hepatitis B, D, and C [5,6]. However, in hepatitis C virus (HCV) infection, direct-acting antivirals have become the new paradigm of treatment and have largely replaced IFN-based antiviral therapies worldwide. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Antiviral therapy'.)

Several sources of interferons are available: recombinant alfa IFNs, mixtures containing several type 1 IFNs from natural sources, and IFN-beta. Recombinant IFNs have also been coupled to polyethylene glycol molecules to modify their pharmacokinetic properties and prolong their half-lives. This modification has significantly improved their therapeutic efficacy. In addition, IFNs can be combined with other antiviral drugs such as ribavirin, HCV protease inhibitors, or HBV entry inhibitors [7]. For many years, IFNs were the backbone of antiviral therapy in chronic viral hepatitis. However, owing to the huge progress of IFN-free therapy, manufacturers have discontinued production of IFN-alfa-2a and IFN-alfa-2b. Pegylated IFN-alfa-2a is still available, and pegylated IFN-lambda-1, a synthetic interleukin-29 homolog, is still being studied in clinical trials as potential new therapy of chronic hepatitis D [8]. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection" and "Treatment and prevention of hepatitis D virus infection", section on 'Treatment of chronic hepatitis D' and "Overview of the management of chronic hepatitis C virus infection", section on 'Interferon-containing regimens'.)

In contrast to type 1 IFNs, IFNg, either alone or in combination with type 1 IFNs, has no apparent therapeutic effect on chronic viral liver disease [5,6]. Lambda IFNs inhibit replication of hepatitis B and C viruses [9,10]. They seem to exert pivotal immunoregulatory effects [11-13], and polymorphisms in the IL28B gene, coding for IFN-lambda-3, have been identified in genome-wide genetic screens to be a prognostic factor for (pegylated) IFN-alfa-induced and spontaneous elimination of HCV.

Mechanism of action in chronic viral hepatitis — It is assumed that increased expression of antiviral genes induced by type 1 IFNs is an important factor in the elimination of hepatitis viruses. These antiviral genes are only partially understood with respect to function; they comprise 2'-5'-oligoadenylate synthetase, a 60 kDa protein kinase, and the Mx protein homolog [14]. Lambda IFNs activate the same set of genes as type 1 IFNs, but induce steady increases in gene activity and can enhance the antiviral effect of subsaturating doses of IFNa [10]. Beyond that, they interact with multiple immunoregulatory pathways [15], and are considered key factors of autoimmunity in rheumatoid arthritis, scleroderma, Sjögren syndrome, and systemic lupus erythematosus [16]. (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)

Control of chronic hepatitis B virus requires a fully functional immune system [17], which is strengthened by the immunostimulatory properties of type 1 IFNs. A variable reduction of HBV-DNA is observed in all patients during IFN treatment; however, a transient flare of aminotransferases followed by their normalization, loss of serum HBV-DNA, and loss of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) is only observed in complete IFN responders. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)

The flare seen in patients with chronic hepatitis B has been attributed to destruction of virus-infected hepatocytes by cytolytic immune effector cells [18]. In comparison, a transient flare of aminotransferases is not usually observed with IFN therapy in patients with chronic HCV infection. Those patients who respond to IFN usually show a gradual decrease in serum aminotransferases shortly after the initiation of IFN therapy.

INTERFERON-INDUCED AUTOIMMUNITY — Because type 1 interferons (IFNs) have such marked immunomodulatory effects, they also have the potential to lead to development of autoimmune phenomena during prolonged courses of treatment [19-28]. IFN therapy may aggravate pre-existing autoimmunity, unmask silent autoimmune processes, or even induce de novo autoimmune diseases. As an example, enhanced humoral immunity with hypergammaglobulinemia, lymphadenopathy, and increased serum concentrations of interleukin (IL)-6 have been reported in a patient treated with both IFN-alfa (IFNa) and IFN-beta (IFNb) for chronic hepatitis B [19].

A predisposition to autoimmunity associated with the presence of baseline autoantibodies has been demonstrated in IFN-mediated autoimmune diseases [29-32]. The association of type 1 IFN-induced autoimmune disease with certain human leukocyte antigen (HLA) phenotypes has also been proposed. No association of autoantibodies with IFN autoantibodies has been detected [33].

The pathogenesis of autoantibody formation in IFN-induced autoimmunity is incompletely understood. A number of factors might alter the balance between self-tolerance and activation of autoreactivity. These include:

●Direct effects of type 1 IFNs on antibody production, inhibition of regulatory T cells, and other cell types with suppressor functions

●Enhanced expression of major histocompatibility complex (MHC) class I antigens

●Aberrant or enhanced MHC class II antigen expression with subsequent activation of T helper lymphocytes by autoantigens

●Enhanced conversion of monocytes to (auto-)antigen-presenting dendritic cells

●Induction of inflammatory cytokines (eg, interleukin-6, tumor necrosis factor, and others)

Whatever the mechanism, patients receiving long-term therapy with type 1 IFNs must be carefully monitored for the possible development of autoantibodies and autoimmune disease. This issue is further complicated in patients with chronic liver diseases accompanied by a high spontaneous incidence of autoimmune features (eg, autoimmune hepatitis) or in whom frank autoimmune disease such as vasculitis is present. Of note, coexisting overt autoimmune diseases in patients with viral hepatitis carry a substantial risk to exacerbate with IFN therapy. Thus, IFNs should be avoided in such patients, who should be treated IFN-free with direct-acting antiviral agents instead. Conversely, the presence of nonorgan-specific autoantibodies, although frequently not relevant as a marker of autoimmunity in chronic hepatitis C virus (HCV) infection, seems to reduce the response to IFN/ribavirin combination therapy [34-36]. Although the majority of patients remain autoantibody positive after successful IFN-free anti-HCV therapy, 27 percent of those who were negative before treatment develop autoantibodies even after IFN-free therapy [37]. In addition, a sustained virologic response in HCV does not apparently alter the risk to develop significant autoimmunity later on [38].

Several diseases and syndromes have been reported in patients with malignant and nonmalignant conditions treated with IFN. These include rheumatoid symptoms, a lupus-like disease, rheumatoid factor-positive monoarthritis, the antiphospholipid syndrome, diabetes mellitus, interstitial pneumonitis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, psoriasis, leukocytoclastic vasculitis, thyroid disease, and autoimmune liver disease (table 1) [39]. The major autoimmune disorders encountered during IFN treatment of liver disease involve the thyroid gland and the liver.

Thyroid disease — Thyroid autoantibodies and disorders have been reported in patients with chronic hepatitis both before and after IFN treatment [30,40-45]. The prevalence appears greater in those with chronic HCV infection. The reported frequency of thyroid disorders after type 1 IFNs varies; this may be due to several factors including different diagnostic criteria and study populations, dose and duration of IFN treatment, and concurrent medications. Whether frequencies in developing thyroid autoantibodies differ between treatment with pegylated IFNa and conventional IFN is uncertain since studies have been mixed [46-48].

The most common IFNa-associated thyroid abnormality is the development of antithyroid antibodies without clinical disease (5 to up to 40 percent) [49]. Approximately 5 to 10 percent of patients develop clinical thyroid disease, including painless thyroiditis, Hashimoto thyroiditis, or Graves' disease [40,41,49,50]. In rare instances, Graves' ophthalmopathy has been reported following treatment of HCV with IFNa [51]. Interestingly, some studies have suggested that the development of thyroid disorders during IFN treatment of chronic HCV is associated with an increased likelihood of a sustained virological response [52,53]. (See "Overview of thyroiditis".)

The changes in thyroid function usually appear after three months of therapy, but can occur as long as IFNa is given. Rare patients develop thyroid autoantibodies after IFNa treatment has been completed [54]. The risk of any form of thyroid disease is greater in those patients who have increased serum antithyroid antibody concentrations before initiation of IFNa, a finding which suggests that IFNa in some way exacerbates underlying thyroid autoimmune disease. These relationships and the frequency of thyroid disease can be illustrated by the following observations from several large studies [40,41,55,56]:

●A multicenter survey of 616 patients with chronic HCV treated with IFN-alfa-2a found a 5 percent prevalence of hypothyroidism prior to therapy [40]. An additional 5 percent developed thyroid dysfunction during therapy. Patients in both categories were predominantly female. In those patients who developed thyroid disease during IFN therapy, approximately 25 percent were positive for antithyroid peroxidase antibodies at baseline.

●Another report evaluated 422 patients with chronic viral hepatitis C, B, or D [41]. Increased titers of antithyroid peroxidase antibodies were clustered significantly among women (8.7 versus 3.4 percent), particularly those with chronic HCV (11.2 versus 3.6 percent). Treatment with IFNa significantly increased the prevalence of antithyroid peroxidase antibodies (12.5 to 18.6 percent) and thyroid dysfunction (3.7 to 9.7 percent); euthyroid patients with high baseline antithyroid peroxidase concentration developed thyroid dysfunction during IFNa therapy at an even higher rate (36.4 percent). Hypothyroidism was the most common thyroid abnormality; this occurred early (on treatment) or late (six months after cessation of therapy), and did not necessarily resolve when IFNa was discontinued.

●A study of 625 HCV-infected patients with normal thyroid function at baseline reported the appearance of thyroid abnormalities in 58 patients (9 percent) during IFN treatment [56]. Twenty-six patients had hypothyroidism and nine had hyperthyroidism, with Graves' disease in three patients. Twenty-one patients had biphasic thyroiditis, and in two patients antithyroid-peroxidase antibodies appeared without hypothyroidism. Female sex and pre-existing thyroid-peroxidase antibodies were identified as risk factors for developing thyroiditis.

●A study of 869 patients with chronic HCV genotypes 2 and 3 were randomized to treatment with either pegylated IFN-alfa-2a weekly or albumin-coupled IFN-alfa-2b every two weeks reported at least one abnormal serum thyrotropin (TSH) in 20.8 percent of patients [57]. On multivariate regression analysis, biphasic thyroiditis, which accounted for 58 percent of all thyroid abnormalities, was associated with female sex and high pretreatment TSH, while being Asian or a current smoker decreased the risk of thyroiditis.

●In an analysis of data obtained from the Taiwan National Health Insurance Research Database between 2001 and 2013, which compared 3810 patients with chronic HCV treated with pegylated IFN/ribavirin with 9393 patients with chronic HCV who were untreated, there was a twofold increase in the frequency of thyroid disease in those who received pegylated IFN/ribavirin (4.5 versus 2.6 percent) [48]. The types of thyroid disease included hypothyroidism (42.9 percent), hyperthyroidism (31.3 percent), and thyroiditis.

●In a study of 61 children with chronic HCV aged 3 to 17 years treated with pegylated IFN-alfa-2b and ribavirin, subclinical hypothyroidism and autoimmune thyroiditis developed during treatment in 27.9 and 6.6 percent, respectively [58]. By 24 weeks after treatment, subclinical hypothyroidism was transient in most patients; however, autoimmune thyroiditis persisted in three of the four cases.

These data suggest that the presence of antithyroid peroxidase antibodies before treatment appears to be the most significant risk factor for development of clinical thyroid disease during IFN therapy [30,41,45,56]. Additional risk factors for thyroid disease during IFN treatment may include female sex, older age, and the presence of other autoantibodies [42]. At least one report also found that the presence of liver-kidney microsomal antibodies was associated with an increased risk of development of thyroid disorders during IFN therapy [32]. Some studies suggest a genetic predisposition to develop thyroid disease under IFN therapy putatively linked to genes involved in immune regulation and cell death [59].

Women with chronic HCV and high antithyroid peroxidase antibody titers are at particular risk. The risk of thyroid dysfunction under IFN therapy may also be increased in children with HCV [60]. The addition of ribavirin to IFN therapy does not alter the thyroid autoantibody pattern but increases the risk of developing hypothyroidism [61].

Patients who develop thyroid complications while receiving IFN should be managed in conjunction with an endocrinologist. Most patients with increased thyroid autoantibodies or thyroid dysfunction will recover after completion of antiviral therapy. Thus, interruption of IFN treatment may not always be required but nevertheless should be recommended for patients with severe symptoms. Following IFN withdrawal, spontaneous normalization of thyroid function can be expected in many patients with painless thyroiditis and (biphasic) Hashimoto thyroiditis [62,63], while thyroid abnormalities usually persist in those with Graves' disease [45,64,65]. However, in one case, plasmapheresis was required to control IFNa-induced nonimmune thyrotoxicosis [66]. Persistent thyroglobulin and thyroid peroxidase antibodies after stopping IFN therapy predict the later development of thyroid dysfunction [67]. (See "Painless thyroiditis" and "Disorders that cause hypothyroidism" and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".)

Liver disease — Several different forms of hepatotoxicity have been described with IFN therapy. Some are due to direct effects from IFN or are associated with a response to therapy, whereas others are immune mediated.

●Nonimmune causes of transaminitis – Direct IFN-associated liver toxicity that is not immune mediated can occur, but is rare during IFN treatment of viral hepatitis. By contrast, an asymptomatic rise in serum aminotransferases has been noted in up to 25 percent of patients treated by type 1 IFNs for malignancies and in as many as 80 percent of patients who were treated with doses greater than 100 million units per week. Abnormalities were usually seen at the onset of IFN therapy, and the elevation in serum aminotransferases resolved with continued therapy or after dose reduction [68,69].

In patients being treated for chronic hepatitis B, a flare of aminotransferases during therapy can herald seroconversion, and in this setting, it is not regarded as evidence of toxicity or autoimmunity. However, fatal hepatic decompensation with ascites, jaundice, and hepatic encephalopathy can occur occasionally during such flares. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)

●Autoimmune hepatitis – Autoimmune hepatitis can develop during treatment of chronic hepatitis B and C with IFN. In one report of 144 patients with HCV, deterioration in liver function and the development of autoantibodies occurred in seven patients (5 percent) during IFN therapy, all of whom were women [70]. On rare occasion, autoimmune hepatitis has developed up to 10 years after IFN therapy of chronic HCV was completed [71]. There are also cases of autoimmune hepatitis developing in patients without pre-existing liver disease who were treated with IFN, as was described in a patient with chronic myeloid leukemia [72].

In most reports, autoimmune hepatitis has developed during treatment with standard IFN. Whether the risk differs between pegylated and standard IFNs is unclear. Only a few case reports have been published on autoimmune hepatitis developing during treatment with peginterferon [73-76]. In one case, a plasma cell-rich autoimmune-type hepatitis was observed when recurrent HCV was treated with peginterferon after liver transplantation in a patient without prior evidence for autoimmune hepatitis [76].

IFN-induced autoimmune hepatitis can occur suddenly and may progress to fulminant hepatic failure [75].Thus, when autoimmune hepatitis occurs during IFN therapy, IFN must be withdrawn. Additional treatment considerations include:

•Patients with HCV can be transitioned to an IFN-free regimen using direct-acting antivirals, if possible, since such regimens can be safely administered to patients with overt clinical features of autoimmunity [77-79]. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Interferon-free regimens'.)

•Patients with autoimmune hepatitis benefit from immunosuppressive therapy; however, if an IFN-free regimen cannot be used for treatment of HBV or HCV, the benefit of introducing immunosuppression therapy must be balanced against the associated risks of increased viral replication. (See "Autoimmune hepatitis: Treatment".)

In patients with chronic HCV, screening for autoantibodies such as antinuclear antibodies, smooth muscle antibodies, or liver-kidney microsomal antibodies before the start of IFN therapy has not proven useful in predicting who will develop autoimmune hepatitis [80]. Although some patients who develop autoimmune hepatitis while receiving IFN have pre-existing autoantibodies, detection of autoantibodies does not correlate with the development of autoimmune hepatitis [81-83], and autoimmune hepatitis can occur in individuals without pre-existing features of autoimmunity [80,83].

On rare occasion, autoimmune hepatitis may be seen in the setting of chronic HCV infection, but is not related to IFN therapy. The appropriate management of these patients must be individualized since the treatment of autoimmune hepatitis involves immunosuppressive therapy, while HCV infection is treated with antiviral agents. As an example, the treatment for HCV infection does not need to be delayed if patients can receive an IFN-free regimen using direct-acting antivirals. However, in clinical situations in which interferon is required, treatment is often first directed toward autoimmune hepatitis, given the danger of exacerbating autoimmune hepatitis with IFN-based treatment. More detailed discussion of autoimmune hepatitis is presented elsewhere. (See "Overview of autoimmune hepatitis" and "Autoimmune hepatitis: Treatment".)

Immune-mediated skin diseases — Cutaneous reactions to IFN therapy, both local and distant from the injection sites, are common. Eczematous and lichenoid reactions are most frequently observed, but the spectrum of skin reactions ranges from self-resolving pruritus and erythematous papules and lupus-like reactions at injection sites to multiple fixed-drug eruptions [84-86]. There are also isolated reports of the development or exacerbation of lichen planus and psoriasis during IFN treatment for chronic HCV; in these cases, skin lesions improve when IFN is stopped [87-89]. In addition, repeated local panniculitis following injection of pegylated interferon has been reported in a patient with hepatitis [90].

Pulmonary toxicity — Interstitial pneumonitis [91,92], pleural effusion [93], bronchiolitis obliterans-organizing pneumonia [94,95] as well as exacerbation of sarcoidosis [96] and asthma [97] have been observed during IFN therapy. Pulmonary complications of IFN therapy appear to be rare. However, prompt investigation and discontinuation of medication is warranted if any signs of significant pulmonary involvement develop, because pulmonary dysfunction can become severe, and the outcome is variable. Pneumonitis can present with any combination of fever, dyspnea, and cough; affects males and females equally; and has been described with both standard and peginterferon. In a comprehensive review of the literature and drug toxicity databases, a mortality rate of 7 percent was observed in patients who developed pneumonitis during treatment with peginterferon-alfa-2b [98]. Pneumonitis has also been reported with peginterferon-alfa-2a [99].

There is no consensus concerning treatment of interstitial pneumonitis induced by IFN. In most reports, pneumonitis improved after IFN withdrawal alone or with corticosteroids. The relatively high mortality rate suggests favoring an aggressive approach, particularly in patients treated with peginterferon who probably should be treated with corticosteroids early after the diagnosis of pneumonitis has been established.

In some clinical trials for HCV [100-102] the reported incidence of dyspnea and cough were higher in patients on peginterferon combination therapy with ribavirin than in patients with IFN monotherapy. However, it remains unclear whether this observation reflects increased pulmonary toxicity of peginterferons or immune-modulating effects of ribavirin. De novo induction and exacerbation of sarcoidosis [93] have been observed during IFN therapy. Although these complications appear to be rare, they can be severe, and the outcome is variable.

Systemic lupus erythematosus — Systemic lupus erythematosus (SLE) develops in <1 percent of patients treated with IFNa [103,104]. Many more IFNa-treated patients develop a lupus-like syndrome with only some SLE symptoms, which are insufficient to formally fulfill diagnostic criteria [103]. SLE and lupus-like syndrome have reportedly occurred after a wide range of exposure times, including as early as one month and as late as seven years after drug initiation. Typical manifestations of SLE such as malar rash, oral ulcers, photosensitivity, renal disease, and typical autoantibodies (eg, anti-Sm or anti-dsDNA) have been observed, suggesting that these cases were not "drug-induced" SLE but instead resembled idiopathic SLE [105].

As observed in other cases of drug-induced lupus, SLE due to IFNa affects males and females equally. Patients typically develop high titers of antinuclear antibodies, including antibodies to dsDNA. Antibody titers diminish and symptoms clear with IFNa discontinuation (see "Drug-induced lupus"). IFN-induced SLE can occasionally be severe; life-threatening multiorgan involvement comprising glomerulonephritis, serositis, discoid rash, myopericarditis, and vasculitis have been reported [106]. Cardiac disease with pericarditis has been observed in patients receiving IFN therapy, both as a sequela of SLE and due to direct cardiotoxicity of IFNs [107].

Type 1 diabetes mellitus — Type I IFN therapy appears to be linked with an up to 18-fold increased risk of type 1 diabetes mellitus [108,109]. Studies of type 1 diabetes in animals and humans suggest a pathogenic role for type I interferon signaling [110-112].

In one study, IFN-induced type 1 diabetes mostly occurred three to six months after initiation of IFN therapy, but in some patients it also occurred after cessation of IFN therapy [109]. The typical presentation of IFN-induced diabetes mellitus was fulminant with severe hyperglycemia, marked insulin deficiency, and excessively high titers of glutamic acid decarboxylase autoantibodies. Most patients developed ketoacidosis between one week and three months after onset of hyperglycemic symptoms. Virtually all patients remained long-term insulin-dependent. Prior to therapy, risk factors for an increased predisposition towards type 1 diabetes mellitus could not be identified, although 25 to 30 percent of patients also had autoimmune thyroid abnormalities.

Others — IFN therapy may cause and/or exacerbate glomerular disease, and rarely rheumatoid arthritis [103,113]. (See "Overview of kidney disease associated with hepatitis C virus infection".)

IFN-induced arthritis can mimic rheumatoid arthritis because of the frequent detection of rheumatoid factor [114]. Antibodies to cyclic citrullinated peptides are usually not present, potentially helping to differentiate the two conditions. Management of arthritis is mainly empirical.

Finally, there is accumulating evidence that IFN treatment of chronic viral hepatitis can induce or exacerbate a variety of immune-mediated neuropathy syndromes, neuromuscular junction disorders, and myopathies [115]. In isolated case reports of patients with HBV or HCV, IFN therapy and mixed cryoglobulinemia treatment triggered or exacerbated peripheral neuropathy [115]. Patients suffered from sensory or sensorimotor polyneuropathy or mononeuritis multiplex. Furthermore, a variety of demyelinating syndromes, axonal neuropathy, and myasthenia gravis were also encountered in rare instances. Management comprised prompt cessation of IFN treatment in combination with supportive, immunomodulatory, and symptomatic measures as clinically indicated.

SUMMARY AND RECOMMENDATIONS

●Type 1 interferons (IFNs) have marked immunomodulatory effects and thus have the potential to lead to the development of autoimmune phenomena during prolonged courses of treatment. (See 'Interferon-induced autoimmunity' above.)

●Patients receiving long-term therapy with type 1 IFNs must be carefully monitored for the possible development of autoantibodies and autoimmune disease. Patients with viral hepatitis and coexisting autoimmune diseases should not be treated with IFN therapy. A careful history concerning autoimmunity should be taken before the start of therapy, and thyroid-stimulating hormone (TSH) should be checked at baseline. Organ-independent autoantibodies are optional but should also be determined at baseline if the patient has a history suggesting an enhanced risk of autoimmunity. TSH and relevant autoantibodies should be reevaluated every three months during treatment or earlier if symptoms arise. (See 'Interferon-induced autoimmunity' above.)

●Thyroid autoantibodies and disorders have been reported in patients with chronic hepatitis both before and after IFN treatment. The most common IFN-alfa-associated thyroid abnormality is the development of antithyroid antibodies without clinical disease (5 to up to 40 percent). Approximately 5 to 10 percent of patients develop clinical thyroid disease, including painless thyroiditis, Hashimoto thyroiditis, or Graves' disease. (See 'Thyroid disease' above.)

●Several different forms of hepatotoxicity have been described with IFN therapy when given in high doses. Direct IFN-associated liver toxicity is rare during IFN treatment of viral hepatitis. (See 'Liver disease' above.)

●Cutaneous reactions to IFN therapy, both local and distant from the injection sites, are common. Eczematous and lichenoid reactions are most frequently observed, but the spectrum of skin reactions ranges from self-resolving pruritus and erythematous papules and lupus-like reactions at injection sites to multiple fixed-drug eruptions. (See 'Immune-mediated skin diseases' above.)

●Interstitial pneumonitis, pleural effusion, bronchiolitis obliterans-organizing pneumonia, exacerbation of sarcoidosis, and asthma have been observed during IFN therapy but appear to be rare. (See 'Pulmonary toxicity' above.)

●Case reports have described several other autoimmune disorders in association with IFN treatment, including systemic lupus erythematosus, glomerular disease, immune-mediated neuropathy, and myopathy syndromes. (See 'Others' above.)