Rheumatology

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (35) Request Permissions Disclaimer Google Scholar Articles by Fujii, T. Articles by Mimori, T. Search for Related Content PubMed Articles by Fujii, T. Articles by Mimori, T. Related Collections Immunogenetics Systemic Lupus Erythematosus and Autoimmunity Social Bookmarking          What's this?

Rheumatology 2001; 40: 1398-1404
© 2001 British Society for Rheumatology

Original Papers

Cytokine and immunogenetic profiles in Japanese patients with adult Still's disease. Association with chronic articular disease

T. Fujii, T. Nojima, H. Yasuoka, S. Satoh, K. Nakamura, M. Kuwana, A. Suwa, M. Hirakata and T. Mimori

Section of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objective. To determine cytokines and MHC class II alleles in Japanese patients with adult Still's disease (ASD) and clarify the association between those profiles and chronic articular disease.

Methods. Of 35 patients with ASD (13 men, 22 women, mean age at onset 34.0 yr), 17 (49%) had chronic arthritis (>6 months, chronic articular ASD) and 18 (51%) lacked chronic arthritis (systemic ASD). Cytokines and cytokine receptors in sera were measured by ELISA. Correlations of each cytokine with disease activity or C-reactive protein (CRP) were determined. MHC class II alleles were examined by polymerase chain reaction methods.

Results. In chronic articular ASD, female gender was more frequent and liver dysfunction and myalgia were rarer than in systemic ASD. In active disease, the white blood cell count was lower, but total IgG was greater in patients with chronic articular ASD than in those with systemic ASD. Tumour necrosis factor (TNF) , soluble TNF receptor 2 and interleukin (IL)-18 were increased in both types of ASD, even in remission. Soluble IL-2 receptors, IL-4 and IL-18 levels were correlated with disease activity or CRP value only in chronic articular ASD. Interferon and IL-8 remained increased only in chronic articular ASD, even when disease activity, including IL-6 and CRP, was low. DRB1*1501 (DR2) and DRB1*1201 (DR5) alleles were more frequent in chronic articular than in systemic ASD, whereas DQB1*0602 (DQ1) was frequently observed in both types of ASD.

Conclusion. The present study suggests that ASD with chronic articular disease has distinct clinical, cytokine and immunogenetic profiles.

KEY WORDS: Adult Still's disease, Cytokines, MHC class II alleles, Chronic arthritis.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Adult Still's disease (ASD) is a systemic disorder of unknown origin characterized by high spiking fever, rash, polyarthralgia, leucocytosis and increased concentrations of acute-phase reactants. Following the initial description by Bywaters [1], increasing numbers of patients with ASD were reported throughout the world [2–7]. ASD is unlike other rheumatic diseases, in that antinuclear antibodies and rheumatoid factors are not demonstrable; its immunopathogenesis remains unknown, even though patients with ASD often have chronic arthritis similar to rheumatoid arthritis (RA). While the articular damage in patients with ASD is distinct from that in RA, the long-term prognosis of patients with ASD appears to depend on the sequelae of chronic arthritis [8]. A previous report indicated that serious bilateral hip destruction sometimes occurred [9]. To improve the treatment of ASD patients with chronic arthritis, therefore, a useful immunological marker of ASD is needed.

Recently, increased interleukin (IL)-6 or T-cell activation has been reported in the acute phase of ASD [10–12]. Not all patients with ASD, however, have a similar disease course; four different disease patterns (monocyclic systemic, monocyclic chronic articular, polycyclic systemic and polycyclic chronic articular) have been described [13]. In this study we sought to identify cytokine profiles and immunogenetic patterns specific for the chronic articular subset of ASD.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Patient selection and evaluation of their clinical findings
We studied 35 Japanese patients (13 men and 22 women; mean age at disease onset 34.0 yr, mean disease duration 8.9 yr) who were followed up in the Rheumatology Clinic at Keio University Hospital (Tokyo, Japan) between 1974 and 1995 and fulfilled the preliminary criteria for classification proposed by Yamaguchi et al. [14]. Briefly, five or more criteria are required for diagnosis, including two or more of the major criteria, which include fever (39°C or higher), arthralgia (lasting more than 2 weeks), typical rash, and leucocytosis with granulocytosis. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative results of tests for rheumatoid factor and antinuclear antibodies. Patients with infection, cancer or other rheumatic diseases were excluded. In 35 patients, the frequency of arthritis of 12 areas [cervical spine, temporomandibular, shoulder, elbow, wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP), hip, knee, ankle and metatarsophalangeal (MTP)] and their durations were examined retrospectively. Arthritis in peripheral joints was defined as tenderness or swelling, and cervical, temporomandibular or root joint arthritis was defined as the presence of pain on passive motion. All individuals were classified as having either (i) chronic articular ASD—individuals with chronic arthritis involving at least one joint area, lasting longer than 6 months; or (ii) systemic ASD—individuals without chronic arthritis. Patients with arthritis occurring intermittently over a 6-month period were classed as having chronic articular ASD if they had arthritis lasting more than 6 months, and as having systemic ASD if the disease duration was shorter.

Disease flare-up was defined as two or more of the following, in the absence of other evident causes: fever of 39°C; arthralgia; a rash with features typically seen in juvenile RA; and leucocytosis (10000/mm³) including at least 80% granulocytes. The following extra-articular findings of ASD, observed by rheumatologists, were compared between patients with systematic and chronic articular ASD: typical skin eruption; sore throat; liver dysfunction (abnormality of liver function tests); hepatomegaly; splenomegaly; lymphadenopathy; serositis; and myalgia. ASD-related laboratory parameters [white blood cell counts (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), total IgG and serum ferritin] were compared between the two types of ASD in the active phase.

Serum cytokine and soluble cytokine receptor determinations
Sera were collected from both types of patients in the active phase and in remission. The active phase and remission were defined respectively as the presence and absence of otherwise unexplained high fever. Control sera were collected from Japanese individuals who had no symptoms related to rheumatic disease. Sera were stored at -70°C. Enzyme-linked immunosorbent assay (ELISA) kits were used according to the manufacturer's instructions (Medical Biological Laboratories, Nagoya, Japan) for the detection of the following cytokines or cytokine receptors: interleukin (IL)-4, IL-6, IL-8, IL-18, interferon (IFN)-, tumour necrosis factor (TNF)-, soluble IL-2 receptor (sIL-2R), soluble TNF receptor 1 (sTNF-R1) and soluble TNF receptor 2 (sTNF-R2). Samples were assayed in duplicate wells, and the mean values of absorbance were used for data analysis. In addition, CRP values and cytokine concentrations in one or two serum samples selected randomly from each patient were plotted, and correlation diagrams were made.

Determination of MHC class II alleles
Genomic DNA extracted from peripheral blood granulocytes was amplified by the polymerase chain reaction (PCR) using primers specific for the second exon of the DRB1, DQB1 or DPB1 gene [15]. MHC class II alleles were determined on the basis of restriction fragment length polymorphisms of PCR-amplified products (Shionogi Biomedical Laboratories, Tokyo, Japan). Healthy controls, who had no symptoms related to rheumatic disease, served as controls; these were Japanese individuals living in the Tokyo area.

Statistical analyses
The ² test was used for comparison of non-parametric data and Fisher's exact test was used when numbers were small. For comparison of parametric data, Student's t-test for independent samples was employed. Correlations were examined using the Spearman rank correlation test.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Clinical pictures, joint manifestations and laboratory findings in ASD
All ASD patients were assigned to either the systemic or the chronic articular ASD group (Table 1); 18 patients (51%) had systemic and 17 (49%) had chronic articular ASD. No significant differences in mean age at onset and number of flare-ups were observed. In the chronic articular ASD group, most patients were women (14 patients, 82%). Liver dysfunction and myalgia were rare in patients with chronic articular ASD.

View this table: [in this window] [in a new window]   TABLE 1. Clinical and laboratory findings in patients with systemic and chronic articular ASD

 
Polyarthritis, oligoarthritis or arthralgia at disease onset was not an indicator of chronic articular disease. In chronic articular ASD, however, 10 patients (59%) subsequently developed narrowing of intercarpal joint spaces or carpal ankylosis. All the patients with carpal ankylosis belonged to the chronic articular ASD group. Nine of 10 patients (90%) with carpal ankylosis had the polycyclic chronic articular pattern, and five of seven patients (71%) without carpal ankylosis had the monocyclic chronic articular pattern. The association of carpal joint damage with cytokines was not observed. In our series, root joint arthritis at disease onset was more frequently observed in the systemic ASD group (50%) than in the chronic articular ASD group (24%), and no significant difference was found. While the WBC was greater in systemic ASD, the elevated level of total IgG was greater in chronic articular ASD.

Methotrexate (MTX) was used to treat 10 patients (56%) with systemic ASD and 12 (71%) with chronic articular ASD (not significant). The doses of MTX, corticosteroid therapy, and non-steroidal anti-inflammatory drugs were not significantly different between the two groups (data not shown).

Cytokine levels in ASD
Cytokine profiles are shown in Table 2. Unfortunately, paired sera obtained in both the active phase and remission were limited to 31 pairs (systemic ASD, 16; chronic articular ASD, 15). In systemic ASD, serum concentrations of IL-6, sTNF-R1, sTNF-R2 and IFN- were increased in association with signs of systemic disease activity, including elevated CRP; even in remission, sTNF-R2 still was higher than in healthy control subjects. IL-18 also remained increased even in remission. In chronic articular ASD, IL-6, sTNF-R1, sIL-2R, IL-4 and IL-18 were increased in association with disease activity, while sTNF-R1 and IL-18 in remission were still higher than in controls. sTNF-R2 showed a similar trend to sTNF-R1 in chronic articular ASD.

View this table: [in this window] [in a new window]   TABLE 2. Cytokine and cytokine receptor profiles in patients with systemic or chronic articular ASD

 
Although IFN- and IL-8 concentrations were not significantly different between the active phase and remission, both were increased compared with controls, even in remission. On the other hand, the concentration of IL-4 in remission was significantly less in the group with chronic articular ASD than in controls. In both types of ASD, the concentration of TNF-, which was not associated with disease activity, was always higher than in controls. When compared in patients with the same disease activity, in the group with chronic articular ASD sIL-2R was significantly higher in the active phase and IFN- and IL-8 were higher in remission.

No significant correlations between increases in cytokines and extra-articular manifestations were observed in the present study.

Correlation between serum cytokine levels and acute-phase reactants
To evaluate the direct correlation of cytokine levels with CRP values, correlation diagrams were made for each cytokine. In both types of ASD, there were positive correlations between IL-6, sTNF-R1 or R2 and CRP (Fig. 1a). In patients with systemic ASD, sIL-2R, IL-4 and IL-18 were not correlated with CRP, whereas they were correlated in patients with chronic articular ASD (). IFN-, TNF- and IL-8 were not correlated with CRP in either type of ASD (data not shown). Serum ferritin and ESR were not correlated with any cytokine (data not shown).

View larger version (26K): [in this window] [in a new window]   FIG. 1. (a) In both types of ASD, statistically significant correlations of IL-6 and sTNF-R1/R2 with CRP were observed. (b) On the other hand, sIL-2R, IL-4 and IL-18 were correlated with CRP in patients with chronic articular ASD but not in those with systemic ASD.

 
The longitudinal associations of clinical manifestations, CRP, serum ferritin level and cytokines in a patient with chronic articular ASD are shown in Fig. 2. This patient developed bilateral intercarpal joint-space narrowing and functional deterioration, even though she was taking prednisolone (PSL) and MTX or azathioprine. At the last time point shown in Fig. 2, IL-6 and sIL-2R had decreased to within the normal range, while sTNF-R1, sTNF-R2, IL-18, IFN- and IL-8 had not, although administration of azathioprine and PSL continued.

View larger version (27K): [in this window] [in a new window]   FIG. 2. Clinical course and cytokine concentrations in patient NY, who had chronic articular ASD. IL-6, sTNF-R1 and 2, sIL-2R and IL-18 were correlated with disease activity markers including CRP and serum ferritin. IL-8 appeared to be associated with articular manifestations. Correlations of IFN-, TNF- (not shown) and IL-4 (not shown) with disease activity were not clear in this case. MTX was discontinued because of severe stomatitis. The patient developed bilateral intercarpal joint-space narrowing, but no erosive changes were observed in other joints. DS, diclofenac sodium (mg/day); PSL, prednisolone (mg/day); MTX, methotrexate (mg/week).

 

MHC class II alleles associated with ASD
Thirty of the samples were tested. While four patients with chronic articular ASD had DRB1*1501 (DR2)/1201 (DR5), three others had DRB1*04051 (DR4)/0901(DR9) (data not shown). On the other hand, all patients with systemic ASD different from each other in their DRB1 alleles. Statistical analysis showed that DRB1*1501 or DRB1*1201 was more frequent in patients with ASD overall and in chronic articular ASD than in controls (Table 3). DQB1*0602 (DQ1) was more frequent in both types of ASD than in controls. As DRB1*1201 was not detected in patients with systemic ASD, the allele was more frequent in chronic articular than in systemic ASD. No significant difference was observed for other alleles. On the other hand, the other clinical or laboratory findings were not significantly correlated with these MHC class II alleles. No significant association of an increased cytokine concentration with a particular MHC class II was found in the present study.

View this table: [in this window] [in a new window]   TABLE 3. Predominant MHC class II alleles in patients with ASD

 

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

 
In the present study, we determined the association between cytokine and immunogenetic profiles and chronic articular disease in Japanese patients with ASD. Several reports regarding clinical manifestations in ASD have been published [2–7]. In several reports [3, 6, 7], the criteria of Medsger and Christy [4] were used. We used the criteria of Yamaguchi et al. [14], which were considered the most sensitive [16]; had we used Medsger's criteria [4] in our series, five patients (two with systemic and three with chronic articular ASD) would not been diagnosed with ASD because they had either demonstrable rheumatoid factor or no articular symptoms. These patients, however, had no evidence of other diseases capable of causing high spiking fever and showed no erosive articular changes similar to those seen in RA, and had no evidence of a malignancy as a cause of fever.

Here, because we defined chronic arthritis as the existence of arthritis for >6 months, a relatively high percentage of patients may have been allocated to the chronic articular disease group in comparison with previous reports from Southern China (27% [6]), Canada (36% [3]) and France (38.5% [5]). In these reports, patients whose disease course was dominated by articular disease were considered to have chronic articular ASD. Because arthritis is recognized in more than 70% of cases of ASD, the high rate of chronic articular disease depends on the criteria used to define chronic arthritis.

Masson et al. [5] reported that polyarticular onset or root joint arthritis at disease onset is one of the indicators of chronic articular disease. On the other hand, Pouchot et al. [3] comment that root joint arthritis or oligoarthritis is the important prognostic indicator. These articular manifestations, however, were not the prognostic factor for chronic articular disease in our series. As we reported previously [17], chronic arthritis of the shoulder or hip joint is rare in Japan. We do not speculate about this discrepancy in the frequency of root joint destruction between Japanese and French patients. Wouters et al. have reported that HLA-DR6, which is rare in our series, may be associated with root joint arthritis [18]. Comparison of MHC class II alleles in French and Japanese patients with severe hip joint damage should be helpful, although there may be racial differences in the clinical manifestations of ASD.

Our results indicate that IL-6 is a useful marker of disease activity, as previously reported in ASD [10, 11]. IL-6 participates in the systemic inflammation of both types of ASD but may not be involved in chronic articular damage. Similarly, sTNF-Rs appeared to be associated with activity in both types of ASD, whereas the level of TNF- remained high irrespective of activity. While elevated TNF- has been described [10], elevations of TNF receptors have not been reported in patients with ASD. These results suggest that TNF-–TNF receptor systems might be involved in ASD; additionally, macrophages, which produce TNF-, are activated independently of disease activity. Interestingly, serum concentration of macrophage-colony stimulating factor was reported to be significantly increased in ASD [19], and macrophage activation syndrome (MAS) has sometimes been observed together with systemic juvenile RA (JRA) [20]. Because both sTNF-Rs are related to the coagulation abnormality induced by MAS in systemic juvenile systemic arthritis [21], determination of sTNF-Rs may be particularly important in the laboratory monitoring of ASD patients.

In the two types of ASD that we compared, sIL-2R, IL-4 and IL-18 showed different profiles in correlation diagrams. These cytokines may be involved in the pathogenesis of chronic articular ASD. sIL-2R cleaved from the surfaces of active T lymphocytes may be a useful marker in autoimmune diseases such as RA, systemic lupus erythematosus, Sjögren's syndrome [22] and systemic JRA [23]. Schwarz-Eywill et al. reported a patient with ASD whose sIL-2R concentration was correlated with disease activity [24]. This result, along with the proliferation of T cells bearing the V9/V2 receptor in active ASD [12], strongly suggests that abnormal T-cell activation occurs in active chronic articular ASD, whereas T cells are not always pathogenic but rather perform a suppressive function in autoimmune disorders [25]. We do not speculate about the mechanisms involved in the decreased level of IL-4 in remission in chronic articular ASD. Together with the increased level of IFN- in remission, the Th1/Th2 balance, in association with ASD activity, should be elucidated, as discussed in relation to the other autoimmune disorders. Finally, IL-18 was markedly increased in the active phase. Administration of IL-18 has been found to facilitate the development of erosive arthritis in DBA/1 mice [26], suggesting that it may induce articular damage in patients with RA. Both IL-8 and IFN- are induced by IL-18 [27], which indicates the participation of Th1-related pathways in chronic articular damage in ASD. Of note, IL-18, as well as sTNF-R2, was increased in remission even in systemic ASD. Recent reports indicate that IL-18 is markedly increased in sera from patients with ASD [28], suggesting that IL-18 has a central role in the clinical manifestations of ASD.

IL-8, a chemokine derived from macrophages, is involved in the recruitment of neutrophils in RA synovial tissue [29]. Notably, in chronic articular ASD, IFN- and IL-8 remained increased in serum even during remission. Anti-IFN- monoclonal antibody therapy sometimes ameliorates articular damage [30], suggesting that IFN- may have regulatory effects on joint damage. On the other hand, IL-8 may stimulate the migration of T cells or monocytes from the circulation into synovial tissues through epithelium [31]. To begin to elucidate these mechanisms, we are planning to examine local mRNA expression and the concentrations of IFN- and IL-8 in carpal lesions of patients with chronic articular ASD. As articular damage occurs independently of systemic activity, these cytokines may be candidate markers of chronic articular ASD and chronic articular damage.

Although MTX was used to similar extents in patients with systemic and chronic articular ASD and had little effect on cytokine profiles, we could not exclude the possibility that anti-rheumatic drugs affect the levels of these cytokines. Comparison between sera from patients who received the same doses of anti-rheumatic drugs may be informative.

The immunogenetic associations of ASD have been controversial. A few studies concerning MHC class II in ASD have been reported [3, 5, 18, 32]. While DR2 was observed frequently in our patients with ASD (53%), as previously reported [3], DR6, which has been associated with root joint involvement [24], was rare in our series. HLA-DRB1 alleles related to RA among Japanese (DRB1*0101 and 0405 [33]) were equally frequent in both types of ASD and in normal controls, arguing against a link between chronic articular ASD and RA. We strongly suggest that chronic articular disease is associated with certain immunogenetic backgrounds, although both genetic and environmental factors may be involved in ASD [34, 35].

We conclude that chronic articular ASD has immunogenetic and cytokine profiles distinct from those of systemic ASD. These laboratory findings should be useful markers of articular damage in ASD. Combination treatment with immunosuppressive agents such as cyclosporin A [36] or MTX [37] and biological agents such as TNF- antagonists may be effective against chronic articular ASD.

	Notes

 
Correspondence to: T. Fujii, Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.

	References

Top Abstract Introduction Patients and methods Results Discussion References

 

1. Bywaters EGL. Still's disease in the adult. Ann Rheum Dis1971;30:121–33.[Free Full Text]
2. Ohta A, Yamaguchi M, Kaneoka H, Nagayoshi T, Hiida M. Adult Still's disease: Review of 228 cases from the literature. J Rheumatol1987;14:1139–46.[Web of Science][Medline]
3. Pouchot J, Sampalis JS, Beaudet F et al. Adult Still's disease: Manifestations, disease course, and outcome in 62 patients. Medicine1991;70:118–36.[Medline]
4. Masson C, Le Loët X, Lioté F et al. Adult Still's disease. Part I. Manifestations and complications in sixty-five cases in France. Rev Rhum1995;62:748–57.
5. Masson C, Le Loët X, Lioté F et al. Adult Still's disease. Part II. Management, outcome, and prognostic factors. Rev Rhum1995;62:758–65.
6. Mok CC, Lau CS, Wong RWS. Clinical characteristics, treatment, and outcome of adult onset Still's disease in southern Chinese. J Rheumatol1998;25:2345–51.[Medline]
7. Bambery P, Thomas RJ, Malhotra HS et al. Adult onset Still's disease: clinical experience with 18 patients over 15 years in northern India. Ann Rheum Dis1992;51:529–32.[Abstract/Free Full Text]
8. Medsger TA Jr, Christy WC. Carpal arthritis with ankylosis in late onset Still's disease. Arthritis Rheum1976;19:232–42.[Medline]
9. Cabane J, Michon A, Ziza J-M et al. Comparison of long term evolution of adult onset and juvenile onset Still's disease, both followed up for more than 10 years. Ann Rheum Dis1990;49:283–5.[Abstract/Free Full Text]
10. Hoshino T, Ohta A, Yang D et al. Elevated serum interleukin 6, interferon-, and tumor necrosis factor- levels in patients with adult Still's disease. J Rheumatol1998;25:396–8.[Medline]
11. Scheinberg MA, Chapira E, Fernandes ML, Hubscher O. Interleukin 6: A possible marker of disease activity in adult Still's disease. Clin Exp Rheumatol1996;14:653–5.[Medline]
12. Hoshino T, Ohta A, Nakao M et al. TCR+ T cells in peripheral blood of patients with adult Still's disease. J Rheumatol1996;23:124–9.[Medline]
13. Cush JJ, Medsger TA Jr, Christy WC, Herbert DC, Cooperstein LA. Adult-onset Still's disease. Clinical course and outcome. Arthritis Rheum1987;30:186–94.[Web of Science][Medline]
14. Yamaguchi M, Ohta A, Tsunematsu T et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol1992;19:424–30.[Web of Science][Medline]
15. Uryu N, Maeda M, Ota M, Tsuji K, Inoko H. A simple and rapid method for HLA-DRB and -DQB typing by digestion of PCR-amplified DNA with allele specific restriction endonucleases. Tissue Antigens1990;35:20–31.[Medline]
16. Masson C, Loët XL, Lioté F et al. Comparative study of 6 types of criteria in adult Still's disease. J Rheumatol1996;23:495–7.
17. Fujii T, Suwa A, Mimori T, Akizuki M. Chronic arthritis and carpo:metacarpal ratio in Japanese patients with adult Still's disease. J Rheumatol1998;25:2402–7.[Medline]
18. Wouters JMGW, Reekers P, van de Putte LBA. Adult-onset Still's disease. Disease course and HLA associations. Arthritis Rheum1986;29:415–8.[Web of Science][Medline]
19. Matsui K, Tsuchida T, Hiroishi K et al. High serum level of macrophage-colony stimulating factor (M-CSF) in adult-onset Still's disease. Rheumatology1999;38:447–8.
20. Grom AA, Passo M. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis. J Pediatr1996;129:630–2.[Web of Science][Medline]
21. De Benedetti F, Pignatti P, Massa M et al. Soluble tumour necrosis factor receptor levels reflect coagulation abnormalities in systemic juvenile chronic arthritis. Br J Rheumatol1997;36:581–8.[Abstract/Free Full Text]
22. Manoussakis MN, Papadopoulos GK, Drosos AA, Moutsopoulos HM. Soluble Interleukin 2 receptor molecules in serum of patients with autoimmune diseases. Clin Immunol Immunopathol1989;50:321–32.[Web of Science][Medline]
23. Madson KL, Moore TL, Lawrence III JM, Osborn TG. Cytokine levels in serum and synovial fluid of patients with juvenile rheumatoid arthritis. J Rheumatol1994;21:2359–63.[Web of Science][Medline]
24. Schwarz-Eywill M, Heilig B, Bauer H, Breitbart A, Pezzutto A. Evaluation of serum ferritin as a marker for adult Still's disease activity. Ann Rheum Dis1992;51:683–5.[Abstract/Free Full Text]
25. Hayday A, Geng L. T cells regulate autoimmunity. Curr Opin Immunol1997;9:884–9.[Web of Science][Medline]
26. Gracie JA, Forsey RJ, Chan WL et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest1999;104:1393–401.[Web of Science][Medline]
27. Dayer J-M. Interleukin-18, rheumatoid arthritis, and tissue destruction. J Clin Invest1999;104:1337–9.[Web of Science][Medline]
28. Kawashima M, Yamamura M, Morita Y et al. Highly elevated levels of serum interleukin-18 in adult onset Still's disease. Arthritis Rheum1998;41:S39.
29. Koch AE, Kunkel SL, Burrows JC et al. Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol1991;147:2187–95.[Abstract]
30. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol1996;14:397–440.[Web of Science][Medline]
31. Koch AE, Kunkel SL, Burrows JC et al. Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol1991;147:2187–95.
32. Terkeltaub R, Esdaile JM, Decary F, Harth M, Lister J, Lapointe N and Cooperating Centers. HLA-Bw35 and prognosis in adult Still's disease. Arthritis Rheum1981;24:1469–72.[Medline]
33. Wakitani S, Murata N, Toda Y et al. The relationship between HLA-DRB1 alleles and disease subsets of rheumatoid arthritis in Japanese. Br J Rheumatol1997;36:630–6.[Abstract/Free Full Text]
34. Sampalis JS, Medsger TA Jr, Fries JF et al. Risk factors for adult Still's disease. J Rheumatol1996;23:2049–54.[Medline]
35. Brandwein SR, Salusinsky-Sternbach M. Adult Still's disease in only one of identical twins. J Rheumatol1989;16:1599–601.[Medline]
36. Marchesoni A, Ceravolo GP, Battafarano N et al. Cyclosporin A in the treatment of adult Still's disease. J Rheumatol1997;24:1582–7.[Medline]
37. Fujii T, Akizuki M, Kameda H et al. Methotrexate treatment in patients with adult onset Still's disease—retrospective study of 13 Japanese cases. Ann Rheum Dis1997;56:144–8.[Abstract/Free Full Text]

Submitted 30 November 2000; Accepted 19 June 2001

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				D.-Y. CHEN, Y.-M. CHEN, H.-H. CHEN, C.-W. HSIEH, C.-C. LIN, and J.-L. LAN Functional Association of Interleukin 18 Gene -607 (C/A) Promoter Polymorphisms with Disease Course in Chinese Patients with Adult-onset Still's Disease J Rheumatol, October 1, 2009; 36(10): 2284 - 2289. [Abstract] [Full Text] [PDF]

				H.-T. LEE, W.-S. CHEN, K.-H. SUN, C.-T. CHOU, and C.-Y. TSAI Increased Spontaneous But Decreased Mitogen-stimulated Expression and Excretion of Interleukin 18 by Mononuclear Cells in Patients with Active Systemic Lupus Erythematosus J Rheumatol, September 1, 2009; 36(9): 1910 - 1916. [Abstract] [Full Text] [PDF]

				P. Woo Anakinra treatment for systemic juvenile idiopathic arthritis and adult onset Still disease Ann Rheum Dis, March 1, 2008; 67(3): 281 - 282. [Full Text] [PDF]

				T Lequerre, P Quartier, D Rosellini, F Alaoui, M De Bandt, O Mejjad, I Kone-Paut, M Michel, E Dernis, M Khellaf, et al. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France Ann Rheum Dis, March 1, 2008; 67(3): 302 - 308. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (35) Request Permissions Disclaimer Google Scholar Articles by Fujii, T. Articles by Mimori, T. Search for Related Content PubMed Articles by Fujii, T. Articles by Mimori, T. Related Collections Immunogenetics Systemic Lupus Erythematosus and Autoimmunity Social Bookmarking          What's this?

Online ISSN 1462-0332 - Print ISSN 1462-0324

Copyright © 2009 British Society for Rheumatology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics