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AUTOIMMUNE DISEASE

OVERVIEW

Rarely, development or exacerbation of autoimmune (AI) diseases (eg, thyroiditis,

thrombocytopenia, rheumatoid arthritis, interstitial nephritis, myositis, hepatitis, systemic

lupus erythematosus (SLE), idiopathic thrombocytopenic purpura, and psoriasis) has

been observed in patients treated with interferon alfa. In very rare cases, the event

resulted in fatality. The mechanism by which these events develop and their relationship

to interferon alfa therapy is not clear. Any patient developing an AI disorder during

treatment should be monitored closely and, if appropriate, treatment should be

discontinued.

Some immune-mediated diseases strongly associated with HCV infection are sicca

syndrome (similar to Sjögren’s syndrome), membranous glomerulonephritis, mixed

cryoglobulinemia, and AI hepatitis.1 HCV is also associated with AI thyroid disease,

porphyria cutanea tarda, AI thrombocytopenia, diabetes mellitus (DM), neuropathy,

arthritis, lichen planus, idiopathic pulmonary fibrosis, and fibromyalgia.1 There is also a

rare association between HCV and aplastic anemia and lymphoma.1

It has been hypothesized that the presence of auto-antibodies in the HCV positive

individual may be secondary to a nonspecific upregulation of the cellular immune

response.2 A similar effect occurs with interferon, which diffusely activates the cellular

immune system and can initiate new AI diseases in treated patients.2 Data also suggest

that interferon therapy can exacerbate a pre-existing AI process.3

Clifford et al4 conducted a retrospective review of 117 HCV patient records. The charts

were reviewed for results of serum AI markers: antinuclear antibodies (ANAs), (SMAs),

rheumatoid factor (RF), antimitochondrial antibodies, anti-liver-kidney microsomal

(LKM) antibodies, and cryoglobulins. A high prevalence of autoantibody markers was

found, especially SMAs (66%) and RF (76%). Overall, there were no differences

between the groups (presence or absence of antibody markers) regarding age, sex,

severity of HCV, or response to interferon treatment. None of the treated patients

developed clinical signs of AI disease.5

There are no standardized guidelines for treatment of HCV infection in patients with AI

disease. The data suggest that cryoglobulinemia-related symptoms are the only ones

improved by interferon treatment, but patients usually relapse after completion of

therapy.6 Interferon therapy may worsen the outcome of other AI processes.6

Side Effects Management Handbook • III. Contraindications/Cautions • p. 2

AUTOIMMUNE HEPATITIS

Patients with autoimmune hepatitis (AIH) should not be treated with interferon or

ribavirin therapy.

Pathophysiology

AIH is a necro-inflammatory disease, the presentation of which mimics viral

hepatitis—varying from asymptomatic to fulminant hepatitis.5 Left untreated, there is a

50% 3-year mortality rate.5 There is frequent association with other AI disorders, such as

insulin-dependent DM, vitiligo, glomerulonephritis, and AI hemolytic anemia. There are

two types. Type 1 is most common, generally affecting 30- to 60-year-olds, and is less

severe; serum is positive for SMA and/or ANA. Type 2 (rare in the United States)

affects primarily adolescent girls and usually is severe; serum is positive for LKM

type 1 (LKM1) antibody and liver cytosol antibody type 1 (LC1).5 Marked

hypergammaglobulinemia, especially immunoglobulin G (IgG), is present in both types.

The male-female incidence ratio is 1:6. Standard treatment of AIH is prednisone

(Deltasone®), up to 60 mg daily, until the patient is asymptomatic and liver function tests

normalize. Azathioprine (Imuran®) is utilized if the patient is steroid-unresponsive.5

AIH in Hepatitis C

There are reports in the literature of interferon causing an exacerbation of AIH in the

HCV-infected patient. Likewise, steroids cause viral concentrations to increase in the

HCV patient being treated for AIH.2 “…Interferon increases the expression of human

leukocyte antigens (HLA) class I and II antigens on liver cells. This results in an

exaggerated presentation of these antigens to both helper and cytotoxic lymphocytes,

which can lead to an exacerbation of an underlying AI disease process.”2 AIH commonly

caused a false positive enzyme immunoassay (EIA) when the first-generation test was

administered (a nonspecific test). Fortunately, this problem was resolved with use of

EIA-2 and/or recombinant immunoblot assay (RIBA).7 Cassani et al8 found 30% of HCVinfected

patients to have at least one autoantibody, but their subspecificities are different

from those found in the AIH patient (ANA-H, SMA-AA). The HCV-autoantibody

positive patient is predominantly female, with more severe biochemical and histologic

activity.

An interesting case in point: Bayraktar et al2 studied 162 patients infected with HCV, and

41 patients with AIH. They found that at baseline both groups had similar rates of ANA

(63%) and SMA (65% versus 63%) positivity. Among the 81 HCV-infected patients who

were treated with interferon, there were no differences in response rates between patients

who had autoantibodies present prior to treatment versus patients who did not (very few

patients developed autoantibodies after initiation of treatment). Fifteen interferon-treated

patients developed new onset of an AI disease during the course of treatment; only 6/15

had autoantibodies present prior to treatment. Although most required treatment of their

new AI disease, none required discontinuation of their interferon therapy.2 The study

found an 18.5% incidence of new-onset AI disease (high compared with a literature

review), which was just as likely to occur in individuals without pre-existing

autoantibodies. In conclusion, the presence of autoantibodies in HCV-infected patients

was unrelated to age or sex, nor did it affect the decision to treat the hepatitis in this

study.2

Side Effects Management Handbook • III. Contraindications/Cautions • p. 3

Interferon therapy is specifically contraindicated in the individual with AIH and there are

no approved treatment guidelines. As noted, immunosuppression causes an increase in

viral concentrations, but lowers transaminase levels in the HCV-infected patient. Tran et

al9 recommend that patients affected by both diseases first receive prednisone and

azathioprine, reserving interferon for those who fail to respond.

RHEUMATOID ARTHRITIS

Rare cases of rheumatoid arthritis have been observed in patients treated with alfa

interferons. Any patient developing rheumatoid arthritis should be closely monitored and,

if appropriate, treatment should be discontinued.

Pathophysiology

The association between rheumatoid arthritis and HCV infection has been well

documented.10 HLA-DR4 histocompatibility antigen is elevated significantly in HCVinfected

patients with AI disease, including rheumatoid arthritis. In theory, patients who

are genetically predisposed to autoimmunity and who contract hepatitis C can ultimately

develop polyarthritis consistent with a rheumatoid arthritis diagnosis.10 Kessel et al11 state

that 20% to 30% of HCV positive individuals experience clinical manifestations of

autoimmunity, while up to 70% are positive for autoantibodies (ANA, RF,

anticardiolipin, SMA, and LKM antibodies). Also, 2% to 20% of HCV positive patients

experience arthritis, and as many as 50% experience arthralgia.11

Rheumatoid Arthritis in Hepatitis C

The literature documents case reports of patients referred to rheumatology for workup

of rheumatic manifestations presumably secondary to rheumatoid arthritis,

cryoglobulinemia, or fibromyalgia, only to be subsequently diagnosed with HCV

infection.12 Presentation is often polyarthritis, seropositive for RF. Patients may even

fulfill the criteria for rheumatoid arthritis according to the American College of

Rheumatology.10 The literature also recommends that any patient presenting with new

onset of polyarthritis should be tested for HCV.12

Kessel et al11 conducted a controlled study that determined antikeratin antibody (AKA) to

be a statistically significant test to differentiate between true rheumatoid arthritis and

HCV-related arthralgias. AKA was detected in 60.6% (20/33) of patients diagnosed with

rheumatoid arthritis; AKA was detected in 8% (2/25) of patients with HCV-related

polyarthritis (similar to healthy controls). Prior to this study, AKA was considered a welldocumented

specific marker of rheumatoid arthritis. This article concludes that AKA can

be utilized to distinguish between the different processes, so the disease may be treated

appropriately.11 Case studies showed that individuals treated with interferons for various

diagnoses developed rheumatoid/arthritic symptoms, which resolved after discontinuation

of therapy.3,13

For the patient with an arthritis diagnosis who has subsequently been found to be infected

with HCV, the literature discusses treatment with low-dose steroids or nonsteroidal antiinflammatory

drugs (NSAIDs, eg, aspirin, Vioxx®, Celebrex®, Arthrotec®, Naproxen®,

Motrin®, Relafen®, Tolectin®) (independent of the HCV diagnosis or treatment). Kessel et

Side Effects Management Handbook • III. Contraindications/Cautions • p. 4

al11 emphasized that HCV-related arthritis treated with steroids or cytotoxic agents can

exacerbate HCV, and methotrexate (Trexall®, Mexate-AQ®, Folex®) or hepatotoxic drugs

may negatively affect liver function. Therefore, it is important to make an accurate

diagnosis and treat accordingly. Patients who developed arthritis secondary to interferon

treatment required discontinuation of therapy; some were managed with the addition of

NSAIDs.

PSORIASIS

There have been reports of interferons, including peginterferons, exacerbating preexisting

psoriasis; therefore, interferon therapy should be used in these patients only if the

potential benefit justifies the potential risk. In such cases, treatment should be undertaken

in consultation with a dermatologist after the psoriasis is under control.

Pathophysiology

Although the exact etiology of psoriasis is unknown, interferon has been implicated in its

exacerbation.14 It has been proposed that “interferon alfa may act as an inducing factor for

psoriasis due to activation of the dermal dendrocytes, which produce tumor necrosis

factor a. This latter, in turn, induces the expression of adhesion molecules on

keratinocytes and endothelial cells, as well as production of transforming growth

factor a, which triggers the proliferation of keratinocytes. Psoriatic lesions may appear

because the hyperproliferating keratinocytes escape the control mechanisms, due to

genetic mutation….”14 It has been established that psoriasis and psoriatic arthritis are

associated with HLA class I and II.15 In the HCV-infected patient, the virus may act as a

superantigen, inducing self-reactive T cell clones, which promotes the proliferation of

psoriatic lesions.16 Kapp17 acknowledges that psoriasis is probably triggered by more than

one mechanism, including a genetic predisposition and environmental effects on the

immune system.

Psoriasis: an Overview

Psoriasis is a recurrent chronic skin disorder that can be limited to a few areas of the

skin (mild), or it can be widespread (moderate to severe).18 Normal skin cells mature in 28

to 30 days and shed from the skin unnoticed. Psoriatic skin cells mature in only 3 to

4 days.18 They “heap up” and form scaly lesions, which can be painful and pruritic, or can

crack and bleed. Psoriasis is slightly more prevalent in women than in men, and appears

most often between the ages of 15 and 35 years, although it can happen in infancy or old

age. About 2.6% of the US population suffers from psoriasis. Caucasians are at greater

risk than African Americans, and there is an increased risk among those with a family

history of the disease. Approximately 10% of people with psoriasis also have psoriatic

arthritis (PA), which generally affects the hands and feet, but other parts of the body can

be involved as well. PA can affect a few joints, or it can be severe and disabling.

There are several forms of psoriasis18:

· Plaque: Most common; characterized by inflamed skin lesions topped with silvery

white scales

· Guttate: Characterized by small, dot-like lesions

· Pustular: Characterized by pustules and intense scaling

· Inverse: Characterized by its appearance in skin folds

Side Effects Management Handbook • III. Contraindications/Cautions • p. 5

· Erythrodermic: Characterized by intense erythema, swelling, dead skin exfoliation,

and pain

Psoriasis and Interferon

In 1993, Garcia-Lora et al14 presented the first case study of psoriasis occurring in an

HCV-infected patient receiving interferon. Taglione et al19 conducted a study that did not

support the idea that hepatitis C had a role in the genesis of psoriasis. In addition, there

have been interferon-induced cases occurring among the oncologic population, and some

reports correlated interferon dose to severity of psoriasis.3,20,21 In these cases of concurrent

diseases, treatment was generally held, and the psoriasis was treated and resolved. It is

unclear whether interferon, the underlying disease, or both cause the genesis or

exacerbation of psoriasis; large studies need to be conducted to determine the

relationship. Burrows et al22 found that treatment of HCV infection with interferon did

not exacerbate psoriasis.

TRIGGERS OF PSORIASIS23

· Genetic predisposition · Interferon-induced AI modification

· Stress or nervous tension · Illness or injury

· Bacterial or viral infection · Poison ivy or sunburn

· Lithium (EskalithTM, LithobidTM) · Overuse of drugs or alcohol

· Chloroquine (AralenTM) · Use of NSAIDs in those with pre-existing psoriasis

· Beta blockers (eg, Calan®, Inderal®,

Isoptin®, Verelan®)

· HIV/AIDS patients often have severe psoriasis

Management23

1. Diagnosis via skin exam. Occasionally a skin biopsy is done. No specific test is used

to diagnose psoriasis.

2. Nails sometimes show signs of psoriasis: may be pitted, discolored, thickened, and

crumbly.

3. Affected skin may be reddened and hot to the touch with characteristic lesions.

4. Rule out other causes of a psoriatic flare—even in patients without an apparent family

history.

5. Assess patient for pre-existing history of psoriasis; treat carefully.

6. Examine the scalp, knees, elbows, back, buttocks, hands, and feet. Nails, eyebrows,

axilla, and anal and genital regions may also be affected. Rarely affects the face,

although no area of the skin is exempt.

7. Exacerbation of psoriasis may best be treated with ultraviolet light (UVL)—psoralen

(methoxsalen, Oxsoralen®) and ultraviolet light A (PUVA) or ultraviolet B therapy.

8. The literature cites case studies with conflicting recommendations to either

discontinue interferon or treat psoriasis with supportive therapy while the patient

completes interferon therapy.

9. Refer patient to National Psoriasis Foundation for patient education information,

newsletter, and “buddy” support network: 800-723-9166 or www.psoriasis.org.

Side Effects Management Handbook • III. Contraindications/Cautions • p. 6

PHARMACOLOGIC AND OTHER AGENTS

1. PABA (para-aminobenzoic acid) for sunscreening properties; treats underlying

reaction

2. Topical corticosteroids are used to discourage skin cells from multiplying and control

inflammation; short-term use only

3. Keratolytics used in lotion, cream, or ointment (anthralin [Drithocreme®]) to soften

scales and skin debris and facilitate removal

4. Keratolytics in shampoo form (anthralin [Dritho-Scalp®]) to treat lesions as above

5. Actiderm skin patch: sometimes applied over psoriasis medications, especially

cortisone (Cortone) ointments, to increase efficacy

6. Activated vitamin D3 ointment (calcipotriene [Donovex]); available by prescription for

severe forms

7. Methoxsalen (psoralen), a liquid drug, is also widely used

8. Liquid nitrogen for freezing of moderately sized psoriatic lesions

9. Antineoplastic agent used for severe recalcitrant disease

10. Hydroxyurea (Zerit®), cyclosporine (Sandimmune®, Neoral®, Restasis®), and calcitriol

(Rocaltrol®) may produce improvement and are under study; all have potentially severe

side effects

GENERAL SUPPORTIVE MEASURES

1. PUVA or ultraviolet B therapy to retard the production of new skin cells; anthralin

(Drithocreme or Dritho-Scalp) may be used in tandem with UVL (see Pharmacologics

table)

2. Lubricants to soften skin (dermatologist will determine/prescribe)

3. Exposure to sunlight; 15 to 30 minutes, but strict avoidance of sunburn, may reduce

scaling and erythema

4. Stress-reduction programs

5. Prevention of mechanical injury to skin

6. Instruction to family and significant others that lesions are not communicable

7. Counseling if body image is affected and to help patient adapt to chronic nature of

disease

8. Close dermatologic follow-up for complications such as PA or exfoliative psoriatic

dermatitis, which can lead to severe disability

Side Effects Management Handbook • III. Contraindications/Cautions • p. 7

SYSTEMIC LUPUS ERYTHEMATOSUS

Rare cases of SLE have been observed in patients treated with alfa interferons. Any

patient developing SLE during treatment should be monitored closely and, if appropriate,

treatment should be discontinued. SLE itself is a contraindication to interferon therapy.

Pathophysiology

Many patients afflicted with SLE have measurable serum levels of interferon alfa

correlating with the amount of disease present, suggesting pathogenesis.24

SLE and Interferon

SLE has been correlated with interferon treatment. Review of the literature revealed

many case studies of individuals who were diagnosed with SLE after long-term cancer

treatment with interferon (diagnoses varied). The majority of patients had a history of

SLE syndrome. Features included myalgia, migratory arthralgia, malar rash, elevated

levels of ANA and/or antinative DNA antibodies, hypocomplementemia, lymphopenia,

and proteinuria.

Ronnblom et al24 reported a case in which a patient developed SLE during interferon

therapy. The patient’s symptoms resolved upon discontinuing interferon, then she

relapsed when rechallenged with interferon. Incidentally, tumor regression continued

after discontinuation of interferon.25

Another study by Ronnblom et al25 followed 135 patients who were being treated with

interferon for malignant carcinoid tumors to assess the development of autoantibodies

and/or AI diseases. Only one of the 25 patients who developed an AI disease had SLE.

Roughly half of the patients who developed autoantibodies did so after initiation of

interferon therapy. Autoimmunity did not affect tumor responses.25

Treatment of the patient who develops SLE while on interferon-based therapy is not

specifically addressed in the literature. In the documented case studies, interferon was

discontinued to allow the SLE to improve or resolve. However, AI disease is clearly

listed as a warning in interferon package inserts. Thus, these patients should be monitored

closely.

REFERENCES

1. Manns MP, Rambusch EG. Autoimmunity and extrahepatic manifestations in hepatitis C

infection. J Hepatol. 1999;31:39-42.

2. Bayraktar Y, Bayraktar M, Gurakar A, Hassanein TI, Van Thiel DH. A comparison of the

prevalence of autoantibodies in individuals with chronic hepatitis C and those with

autoimmune hepatitis: the role of interferon in the development of autoimmune diseases.

Hepatogastroenterology. 1997;44:417-425.

3. Conlon KC, Urba WJ, Smith JW 2nd, Steis RG, Longo DL, Clark JW. Exacerbation of

symptoms of autoimmune disease in patients receiving alpha-interferon therapy. Cancer.

1990;65:2237-2242.

4. Clifford BD, Donahue D, Smith L, et al. High prevalence of serological markers of

autoimmunity in patients with chronic hepatitis C. Hepatology. 1995;21:613-619.

5. Ellett ML. Autoimmune hepatitis. Gastroenterol Nurs. 2000;23:157-159.

Side Effects Management Handbook • III. Contraindications/Cautions • p. 8

6. Lunel F, Cacoub P. Treatment of autoimmune extrahepatic manifestations of hepatitis C virus

infection. J Hepatol. 1999;31:210-216.

7. Czaja AJ. Autoimmune hepatitis and viral infection. Gastroenterol Clin North Am.

1994;23:547-561.

8. Cassani F, Cataleta M, Valentini P, et al. Serum autoantibodies in chronic hepatitis C:

comparison with autoimmune hepatitis and impact on the disease profile. Hepatology.

1997;26:561-566.

9. Tran A, Benzaken S, Yang G, et al. Chronic hepatitis C and autoimmunity: good response to

immunosuppressive treatment. Dig Dis Sci. 1997;42:778-780.

10. Rivera J, García-Monforte A. Hepatitis C virus infection presenting as rheumatoid arthritis:

why not? J Rheumatol. 1997;26:2062-2063.

11. Kessel A, Rosner I, Zuckerman E, Golan TD, Toubi E. Use of antikeratin antibodies to

distinguish between rheumatoid arthritis and polyarthritis associated with hepatitis C infection.

J Rheumatol. 2000;27:610-612.

12. Barkhuizen A, Bennett RM. Hepatitis C infection presenting with rheumatic manifestations. J

Rheumatol. 1997;24:1238-1239.

13. D’Hondt L, Delannoy A, Docquier C. Hypothyroidism and arthritis during interferon therapy.

Clin Rheumatol. 1993;12:415-417.

14. Garcia-Lora E, Tercedor J, Massare E, López-Nevot MA, Skiljo M, Garcia-Mellado V.

Interferon-induced psoriasis in a patient with chronic hepatitis C. Dermatology. 1993;187:280.

15. Makino Y, Tanaka H, Nakamura K, Fujita M, Akiyama K, Makino I. Arthritis in a patient with

psoriasis after interferon-a therapy for chronic hepatitis C. J Rheumatol. 1994;21:1771-1772.

16. Georgetson MJ, Yarze JC, Lalos AT, Webster GF, Martin P. Exacerbation of psoriasis due to

interferon-alpha treatment of chronic active hepatitis. Am J Gastroenterol. 1993;88:1756-

1758.

17. Kapp A. The role of cytokines in the psoriatic inflammation. J Dermatol Sci. 1993;5:133-142.

18. National Psoriasis Foundation web site. www.psoriasis.org. Accessed February 24, 2003.

19. Taglione E, Vatteroni ML, Martini P, et al. Hepatitis C virus infection: prevalence in psoriasis

and psoriatic arthritis. J Rheumatol. 1999;26:370-372.

20. Quesada JR, Gutterman JU. Psoriasis and alpha-interferon. Lancet. 1986;1:1466-1468.

21. Wolfe JT, Singh A, Lessin SR, Jaworsky C, Rook AH. De novo development of psoriatic

plaques in patients receiving interferon alfa for treatment of erythrodermic cutaneous T-cell

lymphoma. J Am Acad Dermatol. 1995;32:887-893.

22. Burrows NP, Norris PG, Aleaxander G, Wreghitt T. Chronic hepatitis C infection and

psoriasis. Dermatology. 1995;190:173.

23. Psoriasis. In: Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy.

Whitehouse Station, NJ: Merck Research Laboratories; 1999:816-818.

24. Ronnblom LE, Alm GV, Oberg KE. Possible induction of systemic lupus erythematosus by

interferon-alpha treatment in a patient with a malignant carcinoid tumour. J Intern Med.

1990;227:207-210.

25. Ronnblom LE, Alm GV, Oberg KE. Autoimmunity after alpha-interferon therapy for

malignant carcinoid tumors. Ann Intern Med. 1991;115:178-183.

Side Effects Management Handbook • III. Contraindications/Cautions • p. 9

Interferon Induced ANAs Don't Affect Treatment Hepatitis Weekly via Individual Inc.

The administration of interferon to patients with chronic hepatitis C virus frequently produces antinuclear antibody, but this does not appear to affect treatment efficacy, according to a report from Japan. An autoimmune mechanism has been reported to be involved in the pathogenesis of type-C viral hepatitis.

It has been suggested that hepatitis C virus (HCV) may affect the immunologic functions of hosts during long persistent infection and may induce aberrant tissue autoantibodies, similar to those seen in autoimmune hepatitis (AIH). In contrast to AIH patients, the autoantibodies found in viral hepatitis patients are usually of low titers. "Although the presence of autoantibodies is considered to be an epiphenomenon without any pathogenic significance in viral hepatitis, this finding produces a problem when these patients are to be treated with interferon," researcher K. Noda and colleagues wrote ("Induction of Antinuclear Antibody after Interferon Therapy in Patients with Type-C Chronic Hepatitis: Its Relation to the Efficacy of Therapy," Scandinavian Journal of Gastroenterology, July 1996;31(7):716-722).

"The specific therapy differs between AIH and chronic hepatitis C - that is, prednisolone therapy for AIH and interferon therapy for chronic hepatitis C - thus differentiation of these two diseases is of great importance. The most effective antiviral drug available today, interferon, has immunomodulatory properties as well, and the administration of interferon to these patients with autoimmune diseases may exacerbate these diseases, as reported recently." The prevalence of antinuclear antibody (ANA) and interferon-induced ANA has been documented in patients with chronic hepatitis C. In this study Noda et al. evaluated whether the induction pattern of ANA after interferon therapy is related to the efficacy of interferon therapy. Forty-four patients with chronic hepatitis C were enrolled. Autoimmune hepatitis was excluded in all. ANA was measured every month before, during and six months after interferon therapy (total dose, 336 to 480 M units). Eight of the 44 (18 percent) patients were positive for ANA before interferon therapy (group I). In group I six of the eight ANA-positive patients showed an increase in ANA titers during the therapy. Twenty-two of 36 (61 percent) ANA-negative patients turned positive for ANA, with titers of 1:80 or less during interferon therapy (group II). Another 14 patients (39 percent) remained negative for ANA throughout therapy with interferon (group III). "The rates of sustained responders with a negativity of serum hepatitis C virus RNA and with normal alanine aminotransferase levels for at least six months after the cessation of therapy in groups I, II, and III were 25 percent, 23 percent, and 21 percent, respectively, giving no significant difference in the efficacy of therapy," Noda et al. wrote. None of the patients showed any serious side effects related to autoantibody formation throughout the interferon therapy. In most patients who developed ANA during therapy (group II) the antibody disappeared within six months after cessation of treatment.

"Recent reports and our present study showed that the occurrence of clinical autoimmunity is very rare in patients with chronic hepatitis who developed autoantibodies, before, and/or during the interferon therapy, suggesting that ANA positivity is presumably an epiphenomenon without a pathogenic significance in viral hepatitis," Noda et al. wrote. "However, some possibilities remain that the positivity of autoantibody before and/or during the interferon therapy might be associated with an exacerbation of underlying subclinical autoimmune disorders. There have been many reports concerning an intimate relationship between the administration of interferon and the development of exacerbation of autoimmune disease, such as thyroid disease, autoimmune thrombocytopenia, and anemia (Colon et al, Cancer 1990;65:2237-2247 and Marcellin et al., Gut 1992;33:855-856). Thus, the presence of ANA before and/or during interferon therapy should not be a contraindication for interferon therapy in patients with chronic hepatitis C; however, careful monitoring of autoantibody induction and of signs of autoimmunity should be required during and after the therapy." The corresponding author for this study is Harumasa Yoshihara, Department of Gastroenterology, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Sakai Osaka 591, Japan.

Hepatitis C-Associated Autoimmunity Although initial results indicated chronic HCV infection in a vast majority of autoimmune diseases, and the refinement of HCV detection systems has modified these findings, the diversity of HCV-associated hepatic and extrahepatic autoimmunity remains striking. A recent prospective study by Pawlotsky et al. has shown a prevalence of cryoglobulinemia in 36%[others recently showed higher than 50%] , rheumatoid factor in 70%, anti-tissue antibodies (ANA, SMA, LKM, anti-thyroid) in 41%, salivary gland lesions in 49% and lichen planus in 5% of patients with chronic HCV hepatitis. Control subjects and HBV patients displayed less associated autoimmunity. Mixed cryoglobulinemia (MC) is an immune complex mediated disease associated with cold precipitable immunoglobulins that usually consist of polyclonal IgG and monoclonal IgM (usually exhibiting rheumatoid factor activity). Serum complement factors (C3, C4) are depressed. Pathophysiologically, MC leads to multiple organic manifestations through the deposition of immune complexes. The association with HCV has been found in up to 90%, and HCV-RNA has been detected as an important component of cryoprecipitates. Interestingly, more of these patients are HCV-RNA positive than have anti-HCV antibodies detectable by commonly used tests (antigens commonly used [antibodies to different parts of the core of the HCV virus] C2-3, C33, C-100, C5-1-1). Patients with cryoglobulinemia usually profit from interferon treatment [as regarding their cryoglobulinemia], implicating an etiological role of the hepatitis C virus. Regarding hepatic involvement of mixed cryoglobulinemia, it has been suggested that mixed cryoglobulinemia and autoimmune hepatitis may be identical disorders, but it still remains unclear whether the hepatitis C virus, the circulating immunocomplexes or other associated autoimmunity causes hepatic injury. Recently, membranoproliferative glomerulonephritis was found to be associated with chronic HCV infection in eight patients. All were HCV RNA positive and had characteristic IgG, IgM and C3 deposits in their glomeruli upon biopsy. Most of these patients also had detectable cryoglobulins in their sera, which again contained HCV-RNA, anti-HCV antibodies, and HCV antigen. As in mixed cryoglobulinemia, interferon treatment proved effective, underlining a causative role of the hepatitis C virus. ...The issue whether GOR is a true auto-antigen and not a cross-reaction with HCV, with which it shares some homology, has still to be determined. ...The association of Sjogren's disease and chronic HCV infection was described by Haddad et al. in 16 of 28 HCV positive patients in a prospective study ...Sporadic porphyria cutanea tarda has been linked to chronic HCV infection ....The significance of these observations, the role of the HCV virus and the immune system will have to be further investigated. Vasculitis is frequently observed in patients with cryoglobulinemia. Chronic HCV infection may also be associated with and presumably represents an etiological factor for some cases of polyarteriitis nodosa and lichen planus. Autoimmune thyroid disease associated with chronic HCV infection has been well studied. ....The identification of serological markers of autoimmune thyroid disease is particularly important for the initiation and conduct of interferon therapy for chronic hepatitis C, since interferon is known to induce and/or aggravate autoimmune thyroid disease. Reports have indicated that dysthyroidism can be reversible after the cessation of interferon treatment and temporary thyroid therapy. Conversely, a delayed initiation of adequate thyroid therapy can lead to permanent thyroid dysfunction. These considerations show that precise pre-treatment diagnostic measures to determine serological markers of thyroid autoimmunity are essential for safe interferon treatment in HCV infection. ... Conclusions There is mounting evidence that the hepatitis C virus is the trigger and perhaps the causative agent of a multitude of autoimmune phenomena and serological markers of autoimmunity. Recent data have indicated that this may be paralleled by another hepatotropic RNA virus, the hepatitis D agent, which has been found to be associated with LKM-3 autoantibodies directed against family 1 UDP-glucuronosyl transferases. The examples of autoimmunity and autoimmune disease that have been found in chronic HCV infection, as reviewed above, raise two important questions:

 1) How can criteria for well-tolerated treatment with interferon be established in patients displaying markers of autoimmunity? and 2) can these examples serve as models for the study of etiologic and pathophysiologic implications of autoimmune disease? ...... ...More insight into the association of virus and autoimmunity will be provided by the evaluation of immunogenetics, the role of T-cells and of cytokines. The role of cytokines is stressed by the well-known phenomenon of exacerbation of autoimmune hepatitis through interferon alpha treatment, in the course of which not only does the activity of liver function tests increase but the titer of LKM-1 autoantibodies also rises. In-Vivo investigations have shown that acute phase mediators IL1, IL6 and TNF alpha are able to downregulate cytochrome P450 2D6, thereby illustrating direct regulation of an autoantigen through cytokines.

DEVELOPMENT OF ARTHRITIS AND HYPOTHYROIDISM DURING ALPHA-INTERFERON THERAPY FOR CHRONIC HEPATITIS-C

Alpha-interferon (alpha-IFN) therapy may induce, reveal or exacerbate various autoimmune-related disorders. The most common is the development of autoantibodies, while clinically overt autoimmune diseases are rare. We describe a 49-year-old woman who developed seronegative rheumatoid-like arthritis and autoimmune hypothyroidism after 7 months of human lymphoblastoid alpha-IFN therapy given for hepatitis C virus-related chronic active hepatitis (CAH-HCV). There tvas no family or personal history of autoimmune, thyroid or articular diseases. Our patient required continuous therapy for arthritis and hypothyroidism despite discontinuation of alpha-IFN. This suggests that alpha-IFN therapy may induce the contemporary appearance of two different persistent autoimmune-related diseases in the same patient. However chronic HCV infection may play an important adjuvant role in the development of these diseases.

Author: A BOGLIOLO, IST CLIN MED, CATTEDRA REUMATOL 1, VIA S GIORGIO NO 12
I-09124 CAGLIARI, ITALY
Source: CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 1997 JUL-AUG;15(4):415-419
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