Rheumatology 2005; 1 of 5 Rheumatology Advance Access published April 26, 2005 Rheumatological manifestations of hepatitis C: incidence in a rheumatology and non-rheumatology setting and the effect of methotrexate and interferon M. J. Nissen, E. Fontanges, Y. Allam, F. Zoulim 1, C. Trépo 1 and P. Miossec doi:10.1093/rheumatology/keh668 Objectives. To evaluate hepatitis C virus (HCV)-positive patients followed in a rheumatology department and to compare them with a similar population of HCV-positive patients who had never seen a rheumatologist, in order to describe the rheumatological symptoms present and the effects of methotrexate and interferon-alpha therapy. Methods. We performed a retrospective study of clinical, radiological and biological data on 21 rheumatology patients (Group I) presenting symptoms consistent with a chronic inflammatory arthritis with a known HCV infection and compared them with 41 members of an HCV support association (Group II). Results. Symptoms of myalgia, sicca syndrome, Raynaud s phenomenon or paraesthesias were similarly frequent in the two groups. However, inflammatory joint pain and joint swelling were more common in Group I. In this group rheumatoid factor was positive in 48%, antinuclear antibodies in 26%, cryoglobulin in 44% and a reduced complement level in 63%. The majority of patients from Group I treated with methotrexate demonstrated an amelioration of the rheumatological symptoms with few negative outcomes. Regarding interferon-alpha therapy and rheumatological symptoms in Groups I and II respectively 50 and 66% demonstrated a deterioration, 33 and 30% showed no change and 17 and 4% showed an amelioration. Conclusion. Rheumatological symptoms are common in patients chronically infected with HCV. It is essential to individualize the role of treatment with interferon-alpha and to consider the use of methotrexate for difficult cases. KEY WORDS: Arthritis, Hepatitis C, Methotrexate, Interferon. Hepatitis C virus (HCV) infection is today a major public health concern [1]. The majority of infected individuals are unable to eliminate the virus. Around 20% of them will go on to develop hepatic fibrosis and eventually cirrhosis and there is a 3 5% annual risk of the development of hepatocellular carcinoma. Infection with the HCV has become the principal indication for liver transplantation [1]. In addition to its hepatic effects, chronic infection with the HCV is responsible for numerous extrahepatic manifestations [2, 3], of which the rheumatological manifestations are amongst the most frequent. Recently, there has been a surge of interest in the relationship between chronic HCV infection and systemic autoimmune diseases such as Sjo gren s syndrome (SS), rheumatoid arthritis (RA), polyarteritis nodosa, systemic lupus erythematosus and the antiphospholipid syndrome. However, the bulk of the data are based on small sample groups and case studies, while in the larger multicentre trials of HCV treatment, patients with autoimmune or extrahepatic features were excluded [4]. In this context, the management of severe rheumatological manifestations or a coexisting inflammatory arthritis is difficult. The clinical use of drugs such as methotrexate in this context has only been on a case-by-case basis, due to their well-known hepatic complications. Consequently, there is a paucity of studies demonstrating the hepatic toxicity as well as the actual efficacy of methotrexate. The goal of this study was to investigate an HCV positive population followed in a rheumatology department for a chronic inflammatory arthritis, and to compare it with a similar population of HCV-positive patients not known to a rheumatology department. Our aims were to clarify the different types of inflammatory arthritis amongst random patients infected with HCV, to look for factors predisposing to the development of rheumatological symptoms and to document the beneficial and deleterious effects of methotrexate and interferon therapy with regards to the rheumatological manifestations. Patients and methods Two populations, both with a known chronic HCV infection, were studied. The first group (Group I), from either in-patient or outpatient clinics of two university hospital rheumatology units in Lyon, France (Hoˆ pital Edouard Herriot and Centre Hospitalier Lyon-Sud) between 1996 and 2001, presented symptoms consistent with a chronic inflammatory arthritis. Patients of Group II consisted of members of an HCV support association with chronic HCV infection, but not followed by a rheumatology unit. The study was approved by the ethical committee and all patients gave written informed consent. Both groups were studied with the same specifically designed questionnaire, with the answers recorded anonymously. Details are given in the supplementary data available at Rheumatology Online. The questionnaire, distributed to Group I patients during their hospital examination and to Group II patients by mail, collected information on patient demographics, the history of the hepatitis Departments of Immunology and Rheumatology, Hôpital Edouard Herriot and 1 Department of Hepatology, Hoˆtel Dieu, Lyon, France. Submitted 25 October 2004; revised version accepted 29 March 2005. Correspondence to: P. Miossec, Clinical Immunology Unit, Departments of Immunology and Rheumatology, Hoˆ pital Edouard Herriot, 69437 Lyon Cedex 03, France. E-mail: miossec@univ-lyon1.fr 1of5 ß The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
2of5 M. J. Nissen et al. and treatments received, the rheumatological manifestations (arthralgia, arthritis, myalgia, SS, peripheral neuropathy) and the effects of treatments on these manifestations. The questions were precise enough to distinguish between inflammatory and mechanical joint disease. In addition, patients from Group I on methotrexate were submitted to the same questions on the efficacy and tolerance of the drug. Biological and liver biopsy details were not available for Group II patients because of the anonymous nature of the survey. Immunological parameters such as rheumatoid factor (RF), antinuclear antibodies (ANA) (specifically anti-ssa/ssb), cryoglobulin and complement levels were collected for nearly all patients, as well as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. The viral activity of the hepatitis was assessed by the transaminase level, the viral load measured by polymerase chain reaction, and for a proportion of patients a liver biopsy was performed with an evaluation of the degree of histological activity and fibrosis with the Metavir score [5], which measures the activity score (A) from 0 3 and the fibrosis score (F) from 0 4. Statistical analysis Statistical analysis of the qualitative data was performed with the use of the 2 test or the Fisher test. For the quantitative data, a Student s t-test was used. The difference was considered to be significant for a P score of <0.05. Results Definition of the Group I patient population A total of 62 HCV-positive patients were included: in Group I there were 21 patients followed by a rheumatological service and in Group II 41 members of an HCV support organization (Table 1). Group I was made up of 17 females and 4 males, with a mean age of 58.1±10.7 yr (range 34 80 yr) and mean duration of hepatitis of 14.6±10.3 yr (range 0 42 yr). Post-transfusional contamination was the most common mode of HCV acquisition in 11 patients (52.4%), iatrogenic contamination in three (14.3%), intravenous drug use in two (9.5%) and unknown for five (23.8%). Fourteen of the 21 patients were taking, or had previously used antiviral therapy (66.6%), eight interferon-alpha and ribavirin, five interferon-alpha monotherapy and one ribavirin monotherapy. In Group I, 19/21 patients (90.5%) presented joint manifestations, of which 77.7% described inflammatory arthritis, nine with joint swelling (42.8%). The other manifestations most commonly reported were: marked fatigue (85.7%), sicca syndrome, with xerostomia and xerophthalmia (57.1%), myalgia (28.6%), paraesthesias (14.3%), Raynaud s phenomenon (14.3%), purpura (9.5%) and pruritus (9.5%). Out of a radiological analysis performed in 14/21 patients, none showed destructive changes. Regarding biological manifestations, an elevation of the transaminases was observed in 14 patients (66.7%). A viraemia was present in 14 of 18 patients (77.7%), indicating that four patients, previously positive for HCV, had become negative. The mean ESR value was 18.7±8.4 mm/h (range 6 40) and CRP 9.2±11.1 mg/l (range 3 41). Rheumatoid factor was present in 10/21 (47.6%), cryoglobulin in 8/18 (44.4%) and a reduced complement level (CH50) in 12/19 (63.2%). Antinuclear antibodies were detected by immunofluorescence in 5/19 (26.3%), one positive for anti-ssa/ssb, one for anti-ribonucleoprotein (anti-rnp). In 13 patients a hepatic biopsy was performed, with an average Metavir activity score of 1.18±0.98 and a fibrosis score of 2.3±1.16. One patient had cirrhosis, two a pre-cirrhotic state and three patients widespread fibrosis. TABLE 1. Comparison of the two patient populations and the clinical manifestations Group I (rheumatology) n ¼ 21 Group II (non-rheumatology) n ¼ 41 P value Age (yr) 58±10.7 56±12.5 NS Sex-ratio (M/F) 4/17 19/22 Duration of hepatitis (yr) 14.6±10.3 10.3±8.6 0.015 Joint manifestations 90.5% 65.8% 0.06 Inflammatory arthralgias 77.7% 34.1% 0.001 Joint swelling 42.8% 12.2% 0.01 Myalgias 28.7% 26.8% NS Sicca syndrome 57.1% 43.9% NS Raynaud s phenomenon 14.3% 9.8% NS Paraesthesias 14.3% 22.0% NS NS ¼ non-significant. Amongst 10 of these patients, the rheumatological manifestations had been severe enough to require treatment by diseasemodifying anti-rheumatic drugs (DMARDs), the most commonly prescribed agents being methotrexate (seven cases) and corticosteroids (five cases). Definition of the Group II patient population The 41 patients in Group II consisted of 22 females and 19 males with a mean age of 56.1±12.6 yr (range 34 78 yr) and mean duration of HCV 10.3±8.7 yr (range 3 45 yr), which was significantly less than Group I (P ¼ 0.015). Thirty-two patients had received interferon-alpha therapy (78%). Twenty-seven patients (65.8%) reported articular pains. In 14/27 patients, arthralgias were inflammatory (34.1%) with frank joint swelling in five (12.2%), sicca syndrome in 18 (43.9%), myalgias in 11 (26.8%), paraesthesias of the lower limbs in nine (22.0%) and Raynaud s phenomenon in four (9.8%). A comparison of the two patient populations is given in Table 1, with no difference for myalgia, sicca syndrome, Raynaud s phenomenon or paraesthesias. Inflammatory joint pain and joint swelling were significantly more common in Group I. However, it is critical to note the high frequency of rheumatological complaints in the HCV population not directly seen in a rheumatology unit. Effect of methotrexate treatment on the rheumatological manifestations Seven patients in Group I (and none in Group II) had been treated with methotrexate because of the articular manifestations (Table 2). All seven were women with a mean age of 54.8±6.8 yr and a mean duration of HCV infection of 17.4±9.3 yr. Two had a clinical picture consistent with SS (according to the American European Consensus Group criteria, with characteristic salivary gland biopsies), three patients had an RA-like symmetrical, inflammatory arthritis [all three patients satisfied the American College of Rheumatology (ACR) criteria of RA] and the final patient an oligoarthritis with recurrent episodes of episcleritis. Methotrexate (mean dose 12.5±3.0 mg/week, range 7.5 15 mg/ week) had been used for an average duration of 15.2±9.9 months (range 5 28 months). In six of seven patients treated with methotrexate, there were no negative HCV-related outcomes, either in terms of a modification of the viraemia or an alteration of the liver function tests. After 2 months of treatment with methotrexate, one patient demonstrated a viral reactivation,
Arthritis and hepatitis C 3of5 TABLE 2. Clinical characteristics and response of patients treated with methotrexate (Group I) Patient number which was subsequently controlled with ribavirin. In terms of response, five of seven patients expressed a reduction in joint pains, five of seven a decrease in joint swelling and five of seven an amelioration in the symptoms of the sicca syndrome. Two of the three patients who satisfied the ACR criteria for RA showed an improvement in arthralgias and arthritis. It is interesting to note that such treatment was also effective in three of the four non-ra patients in terms of joint pain, and in all four patients in terms of joint swelling. Effect of interferon-alpha treatment on the disease manifestations In Group I, 13/21 patients (61.9%), 10 women and 3 men, mean age 57.5±9.3 yr, mean duration of HCV hepatitis 13.6±7.4 yr, had been treated with interferon-alpha. Eight patients had been treated with interferon-alpha and ribavirin and five with interferon-alpha monotherapy (Table 3). Between the different 2 4 6 7 12 14 19 Sex F F F F F F F Age (yr) 65 60 47 51 55 47 59 Arthralgia Yes Yes Yes Yes Yes Yes Yes Arthritis Yes Yes Yes Yes Yes Yes Yes Sicca syndrome Yes Yes Yes Yes Yes Yes Yes Fatigue Yes Yes No No Yes Yes Yes Other signs No No Episcleritis Paraesthesias Raynaud s No No ESR/CRP 12/5.0 12/5.0 15/5.0 25/3.0 20/4.0 18/31 RF Yes No No No Yes Yes Yes ANA Yes No No No No No No SSA/SSB Yes No No No No No No Cryoglobulinaemia Yes Yes No No No No CH50 Decreased Normal Normal Normal Decreased Normal Viraemia a Yes Yes No No Yes No Yes Elevated transaminases Yes Yes No No Yes No No Metavir score A3, F4 A2, F2 A0, F0 A1, F2 A1, F1 Salivary gland biopsy Positive Positive Normal Normal Mean dose of methotrexate (mg/week) 12.5 10 7.5 12.5 15 10 15 Effect on arthralgias A B A A B A A Effect on arthritis A A A A B B A Effect on sicca syndrome A A A A B A B Effect on viraemia B C B B B B B Effect on transaminases B C B B B B B Changes following methotrexate treatment are indicated as A ¼ amelioration, B ¼ no effect, C ¼ aggravation. a These results apply to samples obtained when methotrexate was started. All patients demonstrated positive HCV testing at the time of diagnosis of HCV hepatitis. TABLE 3. Effect of interferon treatment on the clinical manifestations and hepatic parameters of Group I patients Patient 2 3 4 7 8 9 11 13 14 15 16 17 18 þribavirin Yes No No No No Yes Yes Yes Yes No Yes Yes Yes Arthralgias C A C B C A B C C C B B Arthritis C B C B C Sicca syndrome C B B C B B Fatigue C A C A C C B Myalgias A B C B Paraesthesias B B Viraemia B B A B A B B A B Transaminases B A A A B A A A A B Changes are indicated as A ¼ amelioration, B ¼ no effect, C ¼ aggravation. patients treated or not with interferon-alpha in Group I there were no significant differences with regards to the presence of antinuclear antibodies, cryoglobulin or a positive rheumatoid factor or the degree of hepatic fibrosis. Summarizing the outcomes of 12/13 patients following treatment with interferon-alpha: four (33.3%) had no clinical effect on the rheumatological manifestations, six (50%) a negative effect (three with an aggravation of symptoms and three with the development of a chronic inflammatory arthritis with therapy) and only the final two patients (16.7%) reported an amelioration. In Group II, 32/41 patients received interferon-alpha (17 women and 15 men, average age 55.6±11.5 years, P ¼ 0.66 vs Group I), 25 with combination therapy and seven with interferon-alpha monotherapy. The clinical effects of interferon-alpha therapy were available for 27 patients: 11 (40.7%) reported an aggravation of symptoms, eight (29.6%) no clinical difference and six (22.2%) the appearance of rheumatological manifestations ( joint pain, sicca syndrome and myalgia), which disappeared with the cessation
4of5 M. J. Nissen et al. of therapy. Only a single patient reported a clinical improvement with the disappearance of the inflammatory joint pains after the completion of treatment. Discussion To better evaluate the incidence and severity of the rheumatological manifestations in HCV patients and their response to therapy, we compared a group of patients followed by a rheumatology department (Group I) with a group from a hepatitis support association who had never seen a rheumatologist (Group II). Only the inflammatory joint pains and joint swelling had a significantly greater occurrence in Group I. Although there is no specific pattern to HCV-related arthritis, two subsets have been described: an RA-like symmetrical, inflammatory polyarthritis involving mainly small joints, but without destruction, and a mono- or oligo-arthritis involving medium-sized and large joints, which often displays an intermittent course and is associated with the presence of cryoglobulins [2, 3]. Anti-citrullinated peptide antibodies (CCP) are absent in these patients, but present in 60% of patients with established RA associated with HCV positive serology [6]. If we divide the rheumatology group into two subgroups, the first consisting of all the patients who had received diseasemodifying treatment (and thus we can assume the more severe cases) and the second subgroup with less severe symptomatology, we found no difference regarding the state of hepatic fibrosis, the levels of ESR and CRP, rheumatoid factor, antinuclear antibodies, reduced complement levels or the presence of a cryoglobulin. In a study of 28 HCV-infected patients with arthritis, 43% had detectable cryoglobulin, which was remarkably similar to the 44% (8/18) of patients in the rheumatology group of our study [7]. One of the interesting trends from this study was the apparent dissociation between the frank inflammatory nature of the rheumatological manifestations and the relative normality of ESR and CRP, as described previously [8]. It is important that these aspects are well understood. Otherwise HCV-positive patients with vague symptoms of fatigue, arthralgia and myalgia (with the typical age/sex distribution) in the absence of a biological inflammatory syndrome could well be considered to have primary fibromyalgia, if the positive hepatitis serology is unknown. Turning to the therapeutic aspects of our study, seven patients were treated with methotrexate without deleterious effects on hepatic function or the course of the HCV infection. In a study on 600 RA patients tested for HCV [9], the two patients who had been treated with methotrexate (both for a period of greater than 6 months) showed no modifications of the transaminase level. Long-term studies are required to indicate whether chronic administration of methotrexate leads to an increased risk of hepatic fibrosis. Methotrexate, with not only its well-described anti-inflammatory actions at the hepatic level [10, 11] but in addition its immunosuppressive properties, may play an important role in the treatment of the rheumatological symptoms of HCV [12]. The discussion regarding the treatment options of these manifestations will become even more complex with the novel agents such as the tumour necrosis factor (TNF) inhibitors. Indeed, a small recent study found no significant variations in transaminases or HCV viraemia in RA patients with HCV treated with TNF antagonists [13]. The efficacy of interferon-alpha in the treatment of chronic HCV infection is well known, in particular in association with ribavirin. Another beneficial role of interferon-alpha treatment in HCV infection relates to the treatment of the clinical manifestations of cryoglobulinaemia [14]. However, there is a paucity of literature on the efficacy of interferon-alpha on the other rheumatological manifestations associated with HCV. In a study of 21 HCV-positive patients presenting symptoms consistent with a diagnosis of RA, a beneficial therapeutic response to interferon-alpha therapy was demonstrated in 76% of cases [7]. However, as 43% of patients had detectable cryoglobulin many of these cases could equally be classified as mixed cryoglobulinaemia. On the other hand, interferon-alpha therapy has also been implicated in the development of autoimmune dysfunction [15]. Out of our 62 patients, 45 (72.5%) had received interferonalpha and 29 responded to the question on its clinical effects. Only three (7.7%) reported an amelioration, 12 (30.8%) no change, 14 (35.9%) an aggravation and the final 10 (25.6%) the development of new inflammatory rheumatological symptoms. For the majority of these latter patients, these symptoms disappeared with the cessation of interferon-alpha therapy. Conclusion Patients seen in a rheumatology setting differ only by the objective manifestation of joint swelling and, on average, such arthritis is not associated with an inflammatory syndrome or radiological destruction. Treatment with methotrexate was usually effective and well tolerated. The clinical effect of interferon-alpha was, however, markedly more variable, with manifestations aggravated or induced in a high proportion. Thus, in order to most effectively treat these patients it is essential to individualize the effect of treatment with agents such as interferon-alpha, and in certain cases methotrexate could be added to the therapeutic armamentarium. The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology Online. References 1. Lauer GM, Walker BD. Hepatitis C virus infection. 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