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Hepatitis C Virus and Rheumatoid Arthritis: Further Pieces to the Puzzle

To the Editor:

Hepatitis C virus (HCV) has been considered one of the leading causes of liver disease worldwide, and has also been reported to be a potent inducer of autoimmunity resulting in a broad spectrum of striking extrahepatic syndromes. Serological markers of autoimmunity and clinically apparent immune-mediated nonhepatic syndromes may be present in up to 70% of patients with chronic hepatitis C infection. Although some reports suggest that HCV might induce rheumatoid arthritis (RA) or be involved in its pathogenesis1-8,10-14, the relevant data are difficult to interpret (Table 1).

Table 1. Prevalence of markers of hepatitis C virus infection in patients with RA.

In a recent article, Hsu and colleagues investigated HCV in the pathogenesis of RA, and reported that this virus has probably no role in the etiology of RA in a study based on a US population8. Our findings are in accord with these results.

In a prospective study (1998–2001) we evaluated the prevalence and the clinical significance of chronic HCV infection in patients who met the revised diagnostic criteria for RA of the American College of Rheumatology9. One hundred patients (76 with early onset and 24 with advanced-stage RA; mean duration of disease 7.2 yrs; mean age of patients 54 ± 17 yrs) were prospectively enrolled and screened for anti-HCV antibodies by third-generation ELISA (Abbott Laboratories, Abbott Park, IL, USA). No serum sample was found to be reactive on ELISA.

Our study indicated that HCV infection is an uncommon finding in patients with RA. In Hungary, where the prevalence of anti-HCV positivity in the adult population is less than 1%, HCV does not seem to be a relevant factor in the induction or perpetuation of RA.

It seems worth emphasizing that patients with RA are prone to contract HCV infection because of the natural immunodeficiency as a consequence of the disease, and immunodeficiency caused by longterm immunosuppressive treatment. Furthermore, it may be the consequence of frequent hospitalization including invasive diagnostic and therapeutic measures. Further prospective studies should be done to clarify this picture and to solve this puzzle.

ANTAL CSEPREGI, MD, PhD, Department of Gastroenterology and Medicine, Polyclinic of the Hospitaller Brothers of St. John of God in Budapest, Budapest, Hungary, Department of Gastroenterology, Hepatology, and Infectiology, Otto-von-Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany; GYULA POÓR, MD, PhD, Department of Rheumatology and Metabolic Joint Diseases, National Institute of Rheumatology and Physiotherapy, Budapest, Hungary; ELEMÉR NEMESÁNSZKY, MD, PhD, Department of Gastroenterology and Medicine, Polyclinic of the Hospitaller Brothers of St John of God, Budapest, Hungary. E-mail: csepregia@yahoo.de

REFERENCES

1. Theilmann L, Blazek M, Goeser T, Gmelin K, Kommerell B, Fiehn W. False-positive anti-HCV tests in rheumatoid arthritis [letter]. Lancet 1990;335:1346.

2. Sawada T, Hirohata S, Inoue T, Ito K. Development of rheumatoid arthritis after hepatitis C virus infection. Arthitis Rheum 1991;34:1620-1.

3. Borque L, Elena A, Maside C, Rus A, del Cura J. Rheumatoid arthritis and hepatitis C virus antibodies. Clin Exp Rheumatol 1991;9:617-9.

4. Baffoni L, Frisoni M, Miniero R, Righetti F, Sprovieri G, Ferri S. True positive anti-HCV tests in rheumatoid arthritis. Br J Rheumatol 1993;32:349-50.

5. Rosner I, Rosenbaum M, Zuckermann E, Naschitz Y. Rheumatoid-like arthritis associated with hepatitis C. J Exp Rheumatol 1995;1:182-4.

6. Rivera J, Garcia-Monforte A, Pineda A, Millan Nunez-Cortes J. Arthritis in patients with chronic hepatitis C virus infection. J Rheumatol 1999;26:420-4.

7. Csepregi A, Nemesánszky E, Rojkovich B, Poór G. Rheumatoid arthritis and hepatitis B virus. Evaluating the pathogenic link. J Rheumatol 2001;28:474-7.

8. Hsu FC, Starkebaum G, Boyko EJ, Dominitz JA. Prevalence of rheumatoid arthritis and hepatitis C in those age 60 and older in a US population based study. J Rheumatol 2003;30:455-8.

9. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.

10. Tanaka K, Kobayashi S, Isobe Y, et al. Anti-hepatitis C virus antibody in sera from patients with rheumatic diseases [abstract]. Thirty-fourth Annual Meeting of the Japan Rheumatism Association, Osaka, 1990.

11. Marson P, Vicarioto M, Cavasin F, Volante D, De Silvestro G. Prevalence of antibodies against hepatitis C virus in rheumatoid arthritis. Study using second-generation tests. Recent Prog Med 1991;82:679-81.

12. Perrot S, Job-Deslandre C, Puechal X, Menkes C. Hepatitis C virus related polyarthritis: 11 cases [abstract]. Arthritis Rheum 1994;37 Suppl:S234.

13. D'Amico E, Palazzi C, Fratelli V, et al. High prevalence of hepatitis C virus infection in patients with rheumatoid arthritis. J Clin Rheumatol 1996;2:233-4.

14. Lovy M, Starkebaum G, Uberoi S. Hepatitis C infection presenting with rheumatic manifestations: a mimic of rheumatoid arthritis. J Rheumatol 1996;23:979-83.


Etanercept in Breast Milk

To the Editor:

Etanercept (Enbrel®) is a soluble tumor necrosis factor (TNF) receptor fusion protein that binds and inactivates TNF. Its metabolites are excreted in bile and urine and are not bioactive. Clinical studies have shown that etanercept effectively suppresses arthritis not only in patients with rheumatoid arthritis (RA), but also in juvenile idiopathic arthritis, ankylosing spondylitis, and psoriatic arthritis1. The main side effect of etanercept in children and adults is infections, particularly upper respiratory tract infections. However, serious events like sepsis or aseptic meningitis occur in less than 1% of treated patients1. In women with child-bearing potential, treatment with etanercept can interfere with pregnancy or lactation. It is not known whether etanercept is secreted into human breast milk. We measured etanercept in breast milk of a patient with RA.

A 30-year-old woman with rheumatoid factor positive RA had active disease throughout pregnancy. Four weeks after delivery, treatment with etanercept injections 25 mg twice weekly was started because of acute flares of arthritis. She did not breastfeed her child, but had milk flow throughout the duration of the study. The first injection of 25 mg etanercept was given 30 days after delivery, and thereafter twice weekly subcutaneously. A blood sample of the mother was taken one day after the fifth etanercept injection, and thereafter milk samples were collected. The maternal plasma and milk samples were kept frozen at –80°C until analyzed by an ELISA test selective for etanercept3.

The results are summarized in Table 1. The measured concentrations of etanercept in maternal serum corresponds to 2 mg/ml levels reported previously2. The maximal etanercept level measured in breast milk was 75 ng/ml on the day after injection and decreasing during the following days (Figure 1). The lack of an increase of etanercept after the second injection was presumably due to the spontaneous cessation of milk secretion in this lactating, but not nursing mother.

Table 1. Excretion of etanercept in human breast milk.

2003-500.fig.1
Figure 1. Etanercept in breast milk.

To our knowledge this is the first report showing that etanercept is secreted in human breast milk. It is not known whether etanercept can be absorbed orally. Since it is a large protein, bioavailability by oral ingestion can be assumed to be small. However, the nursing infant absorbs immunoglobulins and thus the possibility exists for a fusion protein3. The amount of a drug secreted into breast milk varies depending on the frequency of nursing and the composition of milk proteins and lipids. Thus no precise calculation of the amount ingested by a nursing infant can be made in this lactating mother who was not nursing her child. Further, the volume of milk secreted during the day was not recorded. If one assumes that a nursing infant is breastfed 6 times a day with about 200 ml of milk at each feeding, the amount of etanercept ingested by the child is 50 to 90 µg per day. Therefore, the maximum exposure by oral ingestion can be calculated to be 0.1 to 0.05 mg/kg body weight. In comparison, the recommended dose of etanercept for the treatment of children aged 4 years or older is 0.4 mg/kg subcutaneously twice a week. At present, any risk possibly exerted by these small amounts of etanercept, which theoretically could be ingested by a nursing infant, remains speculative and not very likely. Should the necessity arise to treat a nursing patient who wants to continue breast-feeding during treatment with etanercept, measurement of serum concentrations in the suckling child could solve the question whether orally ingested etanercept is absorbed.

MONIKA OSTENSEN, MD, Department of Rheumatology and Clinical Immunology and Allergy, University Hospital, CH-3010 Bern; GABRIELLA OBRIST EIGENMANN, DrPharm, Wyeth–AHP (Schweiz) AG, Zug, Switzerland. E-mail: monika.oestensen@insel.ch

REFERENCES

1. Culy CR, Keating GM. Etanercept: An updated review of its use in rheumatoid arthritis, psoriatic arthritis and juvenile rheumatoid arthritis. Drugs 2002;62:2493-537.

2. Korth-Bradley JM, Rubin AS, Hanna RK, Simcoe DK, Lebsack ME. The pharmacokinetics of etanercept in healthy volunteers. Ann Pharmacother 2000;34:161–4.

3. Lohse AW, Gerken G, Altes U, Mayet WJ, Meyer zum Büschenfelde KH. Transmission of maternal IgG autoantibodies via cord blood and breastmilk without transmission of hepatitis. Lancet 1993;341:1216-7.


Severe Recurrent Neurological Disease in the MAGIC Syndrome

To the Editor:

Patients with features of Behçet's disease and relapsing polychondritis have been described as having the MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome. It has been suggested that there may be a particularly close relationship between these 2 diseases, resulting in overlap. This report documents severe recurrent neurological involvement that was clinically, radiologically, and pathologically consistent with neuro-Behçet's even while cartilage inflammation was taking place. Thus, even though there may be common pathways leading to disease expression in the MAGIC syndrome, each manifestation should be evaluated individually to determine if it is primarily related to Behçet's disease or relapsing polychondritis so that appropriate therapy may be given.

A 38-year-old Caucasian man presented with increasing confusion, papulopustular skin lesions on his chest, and scrotal ulcerations. Over the preceding 10 years he had recurrent oral ulcerations 3–6 times per year as well as scrotal ulcers. Two years prior to admission he presented to another institution with oral ulcerations, right-side weakness, and diplopia. A left third nerve palsy was confirmed. There was decreased muscle strength on the right side, with hyperreflexia and clonus at the ankle. Magnetic resonance images (MRI) of the brain revealed a mass-like lesion deep in the left side of the brain. The epicenter was in the left cerebral peduncle with cephalad extension into the basal ganglia and the frontal corona radiata, anterior extension into the left optic tract, and caudal extension into the midbrain and left pons as far as the left inferior cerebellar peduncle. There was also extension into the left cerebellar hemispheric white matter about the left lateral margin of the fourth ventricle. Heterogenous enhancement was noted after intravenous gadolinium injection. Venous sinuses were patent, as were the internal cerebral veins.

A stereotactic brain biopsy was performed. The tissue had patchy inflammatory infiltrates composed primarily of mononuclear lymphocytic cells and microglial rod cells. In a number of foci there were accumulations of foamy macrophages, some of which retained rod-like nuclei. The inflammation was present in both grey matter and striate white matter bundles, and was dispersed throughout the tissue with some accentuation around vascular profiles, often involving small venous channels. Even in the perivascular regions, the majority of the reactive cells appeared to be microglial cells and foamy macrophages. This was felt to be highly consistent with neuro-Behçet's.

He improved with corticosteroid therapy but failed followup appointments and received no further therapy for 2 years. In the month before admission at our institution, he became more confused and developed papulopustular skin lesions and oral and scrotal ulcers. He also gave a one-year history of intermittent redness, swelling, and tenderness of the ears with decreased hearing. The inflammation would persist from several days to several weeks. He had no joint pains or tenderness over the thyroid or the anterior tracheal cartilage.

Pertinent findings on physical examination revealed conjunctival injection of the left eye and a third-nerve palsy, but no evidence of vasculitis on funduscopic examination. There were soft floppy deformities of both ears ("cauliflower ears") with sparing of the noncartilaginous portion of the ear. There was no evidence of a saddle-nose deformity. There were oral ulcerations, but the epiglottis and the vocal cords revealed no abnormality. Skin examination revealed papular lesions on his nose and papulopustular lesions on the thorax and back. He had numerous scrotal ulcerations.

Liver function tests, electrolytes, urinalysis, and rheumatoid factor were all negative or within normal limits. Antinuclear antibody was 1:40 in a speckled pattern with negative anti-Sm, anti-RNP, anti-Ro, anti-La, anti-Scl70, anticentromere, antidouble stranded DNA, anticardiolipin, antichromatin, and antineutrophil cytoplasmic antibodies. Erythrocyte sedimentation rate was 112 mm/h.

MRI of the brain continued to reveal increased T2-weighted signal within the left frontal lobe, the left corona radiata, putamen, internal capsule, thalamus, and left mid-brain, although this was markedly improved in size and intensity compared to the previous MRI. There was also an interval increase in signal intensity on FLAIR (fluid attenuated inversion-recovery), T2, and proton density-weighted images within the right thalamus, right cerebral peduncle, the medulla, and the pons, which was not present previously.

He was treated with prednisone orally 1 mg/kg/day and started azathioprine. His confusion improved and his oral and genital ulcers cleared. He was subsequently lost to followup.

Behçet's disease is a multisystem inflammatory disorder classified among the vasculitides1. Chronic progressive central nervous system (CNS) involvement occurs in up to 20% of patients and is characterized by exacerbations and remissions2. Neuro-Behçet's disease may present with parenchymal or nonparenchymal involvement. Parenchymal involvement often involves the brain stem, basal ganglia, internal capsules, and peduncles. Low grade inflammation may be present throughout the CNS, and multiple high intensity focal lesions in the brain stem, basal ganglia, and cerebral white matter are seen on T2-weighted MRI. FLAIR sequences detect even more lesions, particularly in the juxtacortical white matter, suggesting subclinical abnormalities are present3. Clinically, aseptic meningitis, meningoencephalitis, cranial nerve palsies, brain stem and cerebellar syndromes, as well as nonspecific psychiatric disturbances may be seen1,2.

Relapsing polychondritis is an episodic inflammatory disease of the cartilaginous structures including the ear, nose, peripheral joints, trachea, and bronchial tree. Other proteoglycan-rich structures such as the eyes, heart, blood vessels, and inner ear may be affected. Patients present with redness, swelling, and tenderness of the cartilaginous portion of the ear, which becomes damaged and deformed after repeat attacks. The external auditory meatus and eustachian tube may become narrowed by edema or collapse4. Relapsing polychondritis may rarely present with multifocal neurological abnormalities4-6, although this may be a result of a concomitant systemic vasculitis.

Firestein, et al described 5 patients with features of coexistent Behçet's and relapsing polychondritis and proposed the MAGIC syndrome as the name for this entity7. Since 1985 there have been a few case reports of the syndrome8-10 and other descriptions of patients with symptoms suggestive of overlap. Most patients had disease presentations and courses in which symptoms and signs most consistent with Behçet's developed earlier in the course and were more prominent. A few had prominent symptoms of polychondritis early in their course, which persisted.

Firestein, et al suggested that the similarities between the clinical manifestations of the 2 diseases may imply a common cause or pathogenesis, possibly related to autoimmunity to components of cartilage. Whether there is a particularly close relationship between Behçet's disease and relapsing polychondritis, or the MAGIC syndrome merely represents the overlap of 2 rheumatological diseases, the clinical experience reported suggests that the course and prognosis of each organ involved reflects that of the individual disease most likely responsible for the particular manifestation -- either Behçet's disease or relapsing polychondritis. Thus, our patient had neurological involvement clinically, radiologically, and pathologically in a manner classic for neuro-Behçet's disease. This recurred after 2 years, again in a manner classic for Behçet's (along with other symptoms of oral and genital ulcers), even while he had several attacks of polychondritis. Each manifestation should therefore be evaluated to determine whether this is primarily related to Behçet's disease or relapsing polychondritis so that appropriate therapy can be given. This is particularly useful when lesions relatively specific for each process are present7. Treatment with immunosuppressive agents such as azathioprine or methotrexate would be reasonable, and preliminary data suggest that there may be a role for anti-tumor necrosis factor-a agents as well.

ELIE GERTNER, MD, FRCPC, FACP, University of Minnesota Medical School and Section of Rheumatology, Regions Hospital, 640 Jackson Street, St. Paul, Minnesota 55101, USA

REFERENCES

1. Andrews J, Haskard DO. Current management options in Behçet's disease. Minerva Medica 2002;93:335-45.

2. Serdaroglu P. Behçet's disease and the nervous system. J Neurol 1998;245:197-205.

3. Jager HR, Albrecht T, Curati-Alasonatti WL, Williams EJ, Haskard DO. MRI in neuro-Behçet's syndrome: comparison of conventional spin-echo and FLAIR pulse sequences. Neuroradiol 1999;41:750-8.

4. Letko E, Zafirakis P, Baltatzis S, Voudouri A, Livir-Rallatos C, Foster CS. Relapsing polychondritis: A clinical review. Semin Arthritis Rheum 2002;31:384-95.

5. Willis J, Atack EA, Kraag G. Relapsing polychondritis with multifocal neurological abnormalities. Can J Neurol Sci 1984;11:402-4.

6. Sundaram MB, Rajput AH. Nervous system complications of relapsing polychondritis. Neurology 1983;33:513-5.

7. Firestein GS, Gruber HE, Weisman MH, Zvaifler NJ, Barber J, O'Duffy JD. Mouth and genital ulcers with inflamed cartilage: MAGIC syndrome: Five patients with features of relapsing polychondritis and Behçet's disease. Am J Med 1985;79:65-72.

8. Orme RL, Nordlund JJ, Barich L, Brown T. The MAGIC syndrome (mouth and genital ulcers with inflamed cartilage). Arch Dermatol 1990;126:940-4.

9. Le Thi Huong D, Wechsler B, Piette JC, et al. Aortic insufficiency and recurrent valve prosthesis dehiscence in MAGIC syndrome. J Rheumatol 1993;20:397-8.

10. Imai H, Motegi M, Mizuki N, et al. Mouth and general ulcers with inflamed cartilage (MAGIC syndrome): a case report and literature review. Am J Med Sci 1997;314:330-2.



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