Tiina Levälampi

Markku Korpela

Katriina Vuolteenaho

Professor Eeva Moilanen
email: eeva.moilanen@uta.fi

Infliximab treatment in patients with rheumatoid arthritis and spondyloarthropathies in one rheumatological centre; two years' drug survival

Keywords: infliximab, rheumatoid arthritis, spondyloarthropathies, adverse events

Infliximab treatment in patients with rheumatoid

arthritis and spondyloarthropathies in one rheumatological center: two years' drug survival

Introduction

Tumor necrosis factor alpha (TNFα) modulator infliximab has been shown to be effective, antierosive and well tolerated in the tre atment of rheumatoid arthritis (RA) [START_REF] Maini | Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group[END_REF][START_REF] Lipsky | Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study,Group (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group[END_REF][START_REF] St Clair | Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial[END_REF][START_REF] Goekoop-Ruiterman | Clinical and radiographic outcomes of four different treatment strategies in 10[END_REF] and spondyloarthropathies (SpA) [5,6] in clinical trials. It is routinely used in the everyday practice when traditional DMARDs are not sufficiently effective. Although infliximab is generally safe and well tolerated, sometimes the treatment must be discontinued due to adverse events [START_REF] Maini | Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group[END_REF][START_REF] Lipsky | Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study,Group (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group[END_REF][START_REF] St Clair | Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial[END_REF][6][7][8][9][10], mainly infections [START_REF] Listing | Infections in patients with rheumatoid arthritis treated with biologic agents[END_REF][START_REF] Dixon | Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register[END_REF][START_REF] Salliot | Infections during tumour necrosis factor-{alpha} blocker therapy for rheumatic diseases in daily practice: a systematic retrospective stud y of 709 patients[END_REF][START_REF] Buch | Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders[END_REF] and hypersensitivity reactions [START_REF] Buch | Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders[END_REF][START_REF] Wasserman | Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number[END_REF]. In addition, inadequate or waning efficacy complicates drug survival in infliximab-treated patients [8,10,[START_REF] Buch | Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders[END_REF][START_REF] Figueiredo | Maintenance and tolerability of infliximab in a cohort of 152 patients with rheumatoid arthritis[END_REF].

Many clinical trials use ACR20 as the criteria for continuation of infliximab treatment, while in Finland the criteria for continuation has been set as ACR50 or a better response [START_REF]Finnish Medical Society Duodecim[END_REF]. According to the national guidelines [START_REF]Finnish Medical Society Duodecim[END_REF], TNFα antagonist treatment is indicated if the patient is suffering from continuously active disease despite the treatment with combinations of traditional disease modifying antirheumatic drugs (DMARD), including methotrexate. In addition, a TNFα antagonist is usually added to the treatment with one or more DMARDs (see section "Patients and methods"). In the present study, our interest was to analyse data from patients with active and refractory RA or SpA in a single rheumatological centre, who received infliximab as their first biological treatment in combination with DMARDs on clinical grounds according to the national guidelines. We have recently published a six months' follow-up data, on RA and SpA patients receiving infliximab as their first biological drug, focusing on adverse events and other reasons for discontinuation of the treatment [START_REF] Levalampi | Infliximab treatment in patients with rheumatoid arthritis and spondyloarthropathies in clinical practice: adverse events and other reasons for discontinuation of treatment[END_REF]. In the present study, we wanted to extend our analysis to drug survival up to two years in the same cohort. We defined the number of patients who achieved at least 50% response and continued the treatment with infliximab, the number of patients who discontinued the treatment, and the reason for the discontinuation, and listed the adverse events leading to discontinuation of the treatment.

Patients and methods

In the present study, 104 patients with active rheumatoid arthritis or spondyloarthropathy were treated with infliximab as their first biological treatment in the Department of Internal Medicine, Center for Rheumatic Diseases of the Tampere University Hospital, Finland. Indication commencement of infliximab treatment was based on the national recommendations [START_REF]Finnish Medical Society Duodecim[END_REF]. The criteria to start infliximab treatment for RA was that the patient was suffering from continuously active RA [at least six swollen and tender joints, and additionally the duration of morning stiffness at least 45 min and / or erythrocyte sedimentation rate (ESR) ≥ 30 mmHg and / or serum C-reactive protein (CRP) ≥ 28 mg/l] despite treatment with combinations of traditional DMARDs including methotrexate and glucocorticoids [START_REF]Finnish Medical Society Duodecim[END_REF]. In patients with ankylosing spondylitis (AS), the criteria to start infliximab treatment were: 1) inefficiency of at least two nonsteroidal anti-inflammatory drugs (NSAIDs) over at least three months, 2) sulphasalazine (methotrexate if sulphasalazine contraindicated) or possibly other DMARDs had been ineffective, and 3) the patient had an active disease based on BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) (≥ 4 cm) and on clinical grounds [acute sacroiliitis, elevated acute phase reactants, magnetic resonance imaging (MRI) findings]. In the other spondyloarthropathies like psoriatic arthritis (PsA) or inflammatory bowel disease (IBD) associated arthritis, there were no defined criteria to start treatment with biologicals, but the decision was made on clinical grounds by an experienced rheumatologist based on the severity of arthritis and the inflammatory axial disease, and on criteria available for RA and SpA.

Infliximab was given intravenously at a dose of 3 mg/kg in weeks 0, 2, 6 and in every 8 weeks thereafter. The response determined whether the dose was elevated or lowered, or the infusion intervals shortened or lengthened. Infliximab was combined usually with methotrexate and in many cases with other DMARDs (mostly sulphasalazine or hydroxychloroquine) and low-dose prednisolone. The clinical response was carefully followed and registered by an experienced rheumatologist at each visit. In RA, the evaluation included ACR (American College of Rheumatology) response criteria [START_REF] Felson | American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis[END_REF] containing number of swollen and tender joints, the physician's assessment of disease activity (VAS, Visual Analog Scale, 0-10 cm), patient's assessment of general health (VAS), pain (VAS) and HAQ (Health Assessment Questionnaire), and markers of acute phase activity (ESR and CRP). A treatment response lower than ACR50 was regarded ineffective. In SpA, the clinical response included BASDAI and BASFI (Bath Ankylosing Spondylitis Functional Index) indexes, and the treatment was re garded ineffective if the reduction of BASDAI index was lower than 50% or less than 2 cm.

The drug treatment in addition to infliximab i.e. glucocorticoids, DMARDs and NSAIDs, was documented. In the case of withdrawal, the reason (adverse event, inefficiency, remission or other reasons) was registered, and cases in which a severe adverse event caused the discontinuation of the treatment were reported to National Agency of Medicines (NAM).

Results

Patients

In the present study, we analyzed drug survival in patients with active and refractory RA or SpA (n=104) treated with infliximab as their first biologic drug in the Center for Rheumatic Diseases, Tampere University Hospital during years 1999-2005. The mean age was 45 years (range 18-75), 64 patients (62%) were female and the mean disease duration was 12 years (range 0.8-52) (Table 1). One or more concomitant DMARDs in addition to infliximab were being used in 95% of the patients and 91% were receiving glucocorticoids in accordance to the national recommendations for infliximab treatment (Table 1). Sixty-two (60%) patients had RA, including seropositive disease in 37, seronegative in 15 and juvenile idiopathic arthritis (JIA) in 10 patients (Table 2). Fortytwo (40%) patients had SpA with ankylosing spondylitis in 18, psoriatic arthritis in 8, seronegative oligoarthritis in 5, enteropathic arthritis in 4, reactive arthritis in 4 and sacroiliitis in 3 patients (Table 2).

Drug survival in infliximab treated RA and SpA patients

At the two years' time point, forty-one (40%) patients had achieved at least a 50% treatment response and the treatment was still on-go ing (Table 1). In nine of them, the infliximab treatment was, however, transiently halted during the two years' follow-up due to a specific reason (1 infection, 5 remissions, 1 migraine, 1 loss of efficacy, and 1 adverse event from another drug). During two years of follow-up, the infliximab treatment had been discontinued in 62 patients (60%) (Table 1). One patient moved to another district and was lost from the follow-up. After two years, 23 (37%) RA patients and 18 (44%) SpA patients were still continuing the infliximab treatment (Table 2). In those patients in this group, the number receiving glucocorticoid treatment had declined from 93% to 78% and the mean equivalent dose of prednisolone from 10.2 ± 1.1 to 4.7 ± 0.54 mg/day (mean ± SEM p<0.0001) during two years of infliximab treatment.

The reasons for discontinuation of infliximab treatment during two years of follow-up are shown in Table 3. During two years' follow-up, 14 patients achieved remission lasting at least six months. However, seven out of the 14 patients re-initiated infliximab treatment during the follow-up due to disease activation, and thus seven patients were still in remission without infliximab treatment at the two years' time point.

The treatment was withdrawn from 23 (22%) patients due to poor efficacy. Six patients discontinued the treatment already during the first seven months because an adequate response was not attained. Seventeen patients, who initially exhibited an appropriate response, were forced to discontinue due to reducing efficacy.

In twenty-five (24%) patients, infliximab was discontinued due to an adverse event (Table 4). Nine of the adverse events were infections and 14 were hypersensitivity reactions. Two patients discontinued infliximab treatment due to leukopenia. In five patients, infliximab was discontinued for other reasons, i.e. intention to conceive (n=2), technical difficulties in vein cannulation (n=2), and maxillary sinus operation (n=1). Two patients died during the follow-up, one after cerebral infarction and one after myocardial infarction

Infections

We defined nine patients with infections that compelled discontinuation of the infliximab treatment during two years' follow-up. Most of these infections appeared during the first year, only one after 22 months of infliximab treatment. Five of the nine infections were pneumonias. One pneumonia patient suffered for several months from fluctuating fever and dyspnoea, and she was eventually diagnosed to have mediastinal tuberculosis.

Two cases of septic arthritis appeared during the follow-up, one patient with arthritis in the ankle joint caused by Staphylococcus aureus and another with arthritis in the knee caused by Staphylococcus species. One patient had a generalized infection with elevated CRP (145 mg/l) with no clinically evident infection focus being detected (Table 4). One 75-year-old female patient suffered from an asymptomatic recurrent urinary tract infection and infliximab treatment was discontinued.

Hypersensitivity reactions

Fourteen of the 25 adverse events that required the discontinuation of the infliximab treatment were hypersensitivity reactions (Table 4), including acute infusion reactions like urticaria, rash, itching or oedema in eleven patients, and delayed hypersensitivity reactions in three patients. All hypersensitivity reactions were reduced after discontinuation of the infliximab infusions and glucocorticoid treatment. Three patients were not receiving ongoing glucocorticoid treatment at the time of the hypersensitivity reaction.

Other adverse events

Two patients developed leukopenia related to infliximab, and the treatment was discontinued. In one 58-year-old patient, with neutrophils 1.4 x 10 9 /l, conventional DMARD's (sulphasalazine and methotrexate) were first discontinued without improvement. Discontinuation of infliximab infusions resulted in a favourable response and leukocyte levels became normalized. Another patient experienced recurrent leukopenia (neutrophils 1.1 x 10 9/l). Discontinuation of conventional DMARDs had no effect, and leukopenia was only relieved after discontinuation of the infliximab treatment.

Discussion

The treatment of rheumatic diseases with biologicals in Pirkanmaa Health Care District including city of Tampere (serving a population of about 500.000) is concentrated in the Center for Rheumatic Diseases, Tampere University Hospital. In the present study, all the patients (n=104) treated with infliximab as their first biological treatment for active RA or SpA according to the national guidelines during 1999-2005 in the Center for Rheumatic Diseases, were analyzed. Infliximab treatment was started for patients with active disease according to the discretion of an experienced rheumatologist, not as a randomized enrolment in a clinical trial. Thus this analysis of the patient records analyses data of the outcomes of infliximab treatment in everyday practice in one rheumatological centre.

The main goal in the treatment of active RA can be set to achieve and maintain remission with a combination of anti-rheumatic drugs [START_REF] Mottonen | Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group[END_REF][START_REF] Makinen | Sustained remissio n and reduced spondyloarthropathies in clinical practice: adverse events and other reasons leading to discontinuation of the treatment[END_REF]. According to the national guidelines, infliximab treatment is added to combination DMARD therapy when patients have severe and refractory RA despite active treatment with traditional DMARDs.

Contrary to the situation in randomized clinical trials, the patients in the present survey had severe and aggressive disease despite ongoing treatment with combinations of two or more DMARDs, not only MTX which is the case in most randomized clinical trials with TNFα inhibitors. In addition, the doses and numbers of glucocorticoids and NSAIDs were adjusted by the treating rheumatologist.

In the present study, we were able to retrieve patient records during the two years followup from all patients who started the treatment with infliximab except for one subject who moved to another district. A significant loss of patients during follow-up is quite a common phenomenon in many, especially observational, studies [22][23][24]. Concomitant DMARDs, especially methotrexate, when combined with biological treatment enhance compliance to the treatment [25] and this may have influenced the very good adherence to the treatment also in the present survey. Combination therapy with methotrexate and infliximab achieved a better response than methotrexate or infliximab as monotherapy [START_REF] Lipsky | Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study,Group (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group[END_REF][START_REF] St Clair | Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial[END_REF][START_REF] Goekoop-Ruiterman | Clinical and radiographic outcomes of four different treatment strategies in 10[END_REF]. As mentioned previously, combination therapy with two or more DMARDs is widely used in Finland [START_REF] Mottonen | Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group[END_REF][START_REF] Makinen | Sustained remissio n and reduced spondyloarthropathies in clinical practice: adverse events and other reasons leading to discontinuation of the treatment[END_REF] and a biological drug is frequently to supplement combination DMARD therapy. In our previous study, we have shown that in patients with refractory RA or SpA, the addition of etanercept or adalimumab to a combination of traditional DMARDs, resulted in good compliance as well as a favourable treatment response during 12 months' follow-up [26].

In the initial clinical randomized studies, Maini et al reported continuation rates up to 91% with ACR20 criteria after 30 weeks' infliximab treatment depending on the dose and infusion intervals [START_REF] Maini | Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group[END_REF], and in the study of Lipsky et al. a continuation rate of 79% was reported after 54 weeks' treatment [START_REF] Lipsky | Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study,Group (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group[END_REF]. In observational studies, continuation rates are usually lower than in clinical randomized trials, 66% of the patients continued infliximab infusions after one year [8] and after two years' intervention 67% [9] and 73% [10] drug survival rates were reported. In the study of Buch et al., only 27 out of 174 patients (16%) continued infliximab treatment at the 24 months' time-point [START_REF] Buch | Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders[END_REF]. In the present study, 40% of the patients continued with infliximab treatment after the two years' follow-up since they had achieved at least a 50% response without any severe adverse event or other reason requiring discontinuation of the treatment. In addition, seven (7%) of 104 patients had discontinued infliximab treatment due to remission.

In the present study, the continuation rate was 35% in RA patients and 44% in SpA patients. Although the difference was small, it confirms the results obtained in previous studies. In a Spanish study, SpA patients had a 33% lower probability to discontinue the biologicals than RA patients [START_REF] Carmona | Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER[END_REF] and recently also Heiberg et al. reported a higher continuation rate among patients with AS or PsA versus RA patients [START_REF] Heiberg | The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study[END_REF]. In some clinical trials, infliximab has been given at higher doses and/or shorter inter vals to patients with SpA than in patients with RA [6, 7]. In the present study, infliximab treatment was started at a dose 3 mg/kg also in SpA patients and if needed, the dose was increased and/or the infusion interval was adjusted in conjunction with the response.

Accordingly, Braun and co-workers concluded in their review that often a dose of 3 mg/kg is adequate also in SpA patients [7]. However, there is data showing that increasing the infliximab dose in SpA patients after 36 weeks of treatment from 5 mg/kg to 7,5 mg/kg achieved no better efficacy [6].

The response to infliximab treatment is evident already after two weeks of treatment, when over 50% of the RA patients have been reported to achieve ACR20 response [START_REF] Maini | Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group[END_REF].

There is probably some variation in the onset time of the response, and the effect of the drug treatment can also wane with time. It was recently reported that in RA an increase in frequency of infusions may contribute to more a constant effect than an increase in the dose [START_REF] Van Vollenhoven | Infliximab dosage and infusion frequency in clinical practice: experiences in the Stockholm biologics registry STURE[END_REF]. In the study of Figueiredo et al., nearly 40% of the RA patients required an increase of the dose or a shortening of the interval between the infliximab infusions or both to maintain relief of symptoms [START_REF] Figueiredo | Maintenance and tolerability of infliximab in a cohort of 152 patients with rheumatoid arthritis[END_REF]. In the present study, the average discontinuation time among the 23 patients with an inadequate response was 11 months after treatment initiation. According to the patients' records, 6 / 23 patients discontinued the treatment due to inadequate response during the first seven months, and 17 / 23 patients had an appropriate response at the beginning but discontinued the treatment later because of waning efficacy. Buch et al. reported also that some patients could not maintain an already achieved response at later time points [START_REF] Buch | Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders[END_REF]. In observational studies, the rate of discontinuation due to inefficacy varies between 9. 2-11% [8, 10, 16]. In clinical studies, discontinuation rates due to inefficacy are around 10 % [START_REF] Maini | Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group[END_REF][START_REF] Lipsky | Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study,Group (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group[END_REF]. It is worth noticing the continuation criteria in those studies have been mostly set as ACR20 and not ACR50 as in the present study which is the clinical practice in Finland.

The formation of antibodies against infliximab has been reported in clinical trials [START_REF] Maini | Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group[END_REF][START_REF] St Clair | Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial[END_REF] and anti-infliximab antibodies are more often found in patients with reduced response [START_REF] Wolbink | Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis[END_REF]. In addition, there is also evidence about the association between antibody formation and increased infliximab clearance [START_REF] Lobuglio | Mouse/human chimeric monoclonal antibody in man: kinetics and immune response[END_REF][START_REF] Xu | Population pharmacokinetics of infliximab in patients with ankylosing spondylitis[END_REF]. In the present study, antibodies against infliximab were not measured. It is possible that the dissipating efficacy was due to decreased concentrations of active infliximab as a result of the formation of infliximabantibody-complex or to differences in the metabolism of infliximab in individual patients [START_REF] St Clair | The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial[END_REF].

In the present study, only those adverse events that led to discontinuation of infliximab treatment were registered. Those were serious and often required either medical treatment or hospitalization. During the two years follow-up, 24% of all patients were compelled to discontinue the medication due to adverse events. Infection were responsible for discontinuation of the treatment in 9% of the patients. In RA, there is an increased risk for infections [START_REF] Mutru | Ten year mortality and causes of death in patients with rheumatoid arthritis[END_REF][START_REF] Doran | Predictors of infection in rheumatoid arthritis[END_REF]. Traditional DMARDs have been reported to further elevate the risk [START_REF] Smitten | The risk of hospitalized infection in patients with rheumatoid arthritis[END_REF][START_REF] Caporali | DMARDS and infections in rheumatoid arthritis[END_REF][START_REF] Bernatsky | Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis[END_REF], but there are also contradictory findings [START_REF] Lacaille | Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis[END_REF]. Biologicals have also a tendency to increase the risk of infections [START_REF] Listing | Infections in patients with rheumatoid arthritis treated with biologic agents[END_REF][START_REF] Curtis | Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists[END_REF][START_REF] Favalli | Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients[END_REF] in RA patients. We observed in the present study a higher number of infections which caused discontinuation of treatment during the first year of the treatment than in the second year. These data are in agreement with the results of Curtis et al. who reported a 4-fold greater risk of infections during the first 6 months of infliximab treatment [START_REF] Curtis | Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists[END_REF]. The most frequently occurring severe infections during infliximab treatment are pulmonary, skin, soft tissue, joint and bone infections, and also septic infections are slightly more probable in RA patients treated with biological agents than in those treated with conventional DMARDs [START_REF] Listing | Infections in patients with rheumatoid arthritis treated with biologic agents[END_REF][START_REF] Dixon | Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register[END_REF][START_REF] Salliot | Infections during tumour necrosis factor-{alpha} blocker therapy for rheumatic diseases in daily practice: a systematic retrospective stud y of 709 patients[END_REF][START_REF] Favalli | Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients[END_REF]. Oral glucocorticoids ha ve also been reported to elevate the risk of infections in patients with RA even at a dose under 5 mg/day [START_REF] Smitten | The risk of hospitalized infection in patients with rheumatoid arthritis[END_REF][START_REF] Bernatsky | Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis[END_REF][START_REF] Lacaille | Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis[END_REF]. In active and severe RA or SpA, the use of biologicals in addition to combinations of DMARDs and oral glucocorticoidsis is probably associated with a high risk for infections and this should be taken into account clinically, and when interpreting the results of the present study.

Hypersensitivity reactions appear to be related to infliximab infusions quite often, but these are usually benign. In previous reports, hypersensitivity reactions have been a notable reason for discontinuation of infliximab treatment, and they have most frequently occurred during the second to fourth infusion [START_REF] Buch | Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders[END_REF][START_REF] Wasserman | Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number[END_REF] manifesting as urticaria, rash, itching and dyspnoea. In the clinical study of Maini et al. [START_REF] Maini | Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group[END_REF], hypersensitivity reactions appeared most commonly during the first infusion. In our study, 13% of the patients had to discontinue infliximab treatment due to a hypersensitivity reaction and half of these reactions occurred during the first six months. In the present study, three patients with a hypersensitivity reaction were not receiving glucocorticoid treatment in addition to the infliximab and DMARDs. Augustsson et al. [START_REF] Augustsson | Lowdose glucocorticoid therapy decreases risk for treatment-limiting infusion reaction to infliximab in patients with rheumatoid arthritis[END_REF] reported that daily low-dose glucocorticoids lowered the risk of treatment-limiting infusion reactions to infliximab.

In previous studies, only a few cases of leukopenias have been reported [9, [START_REF] Vidal | Severe neutropenia and thrombocytopenia associated with infliximab[END_REF][START_REF] Favalli | Drug-induced agranulocytosis during treatment with infliximab in enteropathic spondyloarthropathy[END_REF][START_REF] Montane | Antitumor necrosis factor-induced neutropenia: a case report with double positive rechallenges[END_REF]. In the present study, two patients developed leukopenia during two years of follow-up. In a recent analysis of 1440 patients with rheumatic disease who were treated with a biological drug, four patients with leukopenias were reported [START_REF] Konttinen | Biological treatment in rheumatic diseases: results from a longitudinal surveillance: adverse events[END_REF].

In the present study, RA and SpA patients with active disease despite ongoing treatment with combinations of DMARDs were treated with infliximab as their first biological drug. Drug survival after two years of follow-up was 40%, when ACR50 (or 50% reduction in BASDAI) was set as the response criteria. As compared to our previous results with six months' follow-up [START_REF] Levalampi | Infliximab treatment in patients with rheumatoid arthritis and spondyloarthropathies in clinical practice: adverse events and other reasons for discontinuation of treatment[END_REF], drug survival decreased, mainly due waning efficacy and an increasing number of adverse events. Infections and hypersensitivity reactions were the most common adverse events which were responsible for the discontinuation of treatment. In addition, two patients with drug related leukopenia were diagnosed.

  patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52: 3381-90 5. van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Willia mson P, Braun J, Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group (2005) Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 52: 582-91 6. Braun J, Deodhar A, Dijkmans B, Geusens P, Sieper J, Williamson P, Xu W, Visvanathan S, Baker D, Goldstein N, van der Heijde D, Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group (2008) Efficacy and safety of infliximab in patients with ankylosing spondylitis over a twoyear period. Arthritis Rheum 59: 1270-8 7. Braun J, Baraliakos X, Brandt J, Sieper J (2005) Therapy of ankylosing spondylitis. Part II: biological therapies in the spondyloarthritides. Scand J Rheumatol 34: 178-90 8. Flendrie M, Creemers MC, Welsing PM, den Broeder AA, van Riel PL (2003) Survival during treatment with tumour necrosis factor blocking agents in rheumatoid arthritis. Ann Rheum Dis 62 Suppl 2: ii30-3 9. Wendling D, Materne GE, Michel F, Lohse A, Lehuede G, Toussirot E, Massol J, Woronoff-Lemsi MC (2005) Infliximab continuation rates in patients with rheumatoid arthritis in everyday practice. Joint Bone Spine 72: 309-12

Table 2 .

 2 Infliximab treated patients according to the diagnosis.

			Continuing after
			two years,
	Diagnosis	n =41 (40%)
	RA, rheumatoid arthritis; SpA, spondyloarthrotpathy;
	*Arthritis associated with Crohn's disease or ulserative colitis.
	Reason	Number	%*
	Remission	7	11
	Lack of efficacy	23	37
	Adverse event	25	40
	Other reason	7	11
	Total	62	100
	* % of patients who discontinued
	the medication

Table 3 .

 3 Reasons to discontinue infliximab treatment.

							Time of
					Disease		adverse
			Age		duration		event
	Classification	Nr Diagnosis	(years) Sex	(years)	DMARD's	(months)	Adverse event
	Infection	1 Seronegative	43	F	19	PRED 5 mg/day	11	Septic arthritis of right knee joint
		oligoarthritis				MTX 25 mg/wk
						HCQ 257 mg/day
		2 Seropositive	49	F	6	MTX 10 mg/wk	1,5	Pulmonary tuberculosis with
		rheumatoid				CyA 200 mg/day		mediastinum lymph nodes,
		arthritis				SSZ 2000 mg/day		diagnosed by biopsy
		3 Seronegative	51	F	7	PRED 10 mg/day	5	Infection (CRP 145 mg/ml)
		rheumatoid				MTX 25 mg/wk		with unknown focus
		arthritis
		4 Ankylosing	54	M	7	PRED 15 mg/day	11	Pneumonia
		spondylitis				MTX 25 mg/wk
						SSZ 2000 mg/day
		5 Ankylosing	57	M	15	PRED 7,5 mg/day	22	Pneumonia
		spondylitis				SSZ 2000 mg/day
						HCQ 300mg/day
		6 Seropositive	58	F	26	PRED 15 mg/day	3	Septic arthritis of right ancle joint
		rheumatoid				ATM 50 mg/6wk
		arthritis				HCQ 300mg/day
		7 Ankylosing	60	M	12	SSZ 2000 mg/day	3	Pneumopericarditis
		spondylitis
		8 Seropositive	71	F	12	PRED 10 mg/day	2	Pneumonia
		rheumatoid				AF 9 mg / day
		arthritis
		9 Seropositive	75	F	16	PRED 5 mg/day	9	Recurrent urinary tract infections
		rheumatoid				LEF 20 mg/every
		arthritis				other day
	Hypersensitivity	1 Seropositive	23	F	2	PRED 5 mg/day	22	Infusion reaction (pain and swelling
	reaction	rheumatoid						of throat)
		arthritis
		2 Seronegative	28	F	15		6	Infusion reaction (rash), DMARDs
		rheumatoid						stopped previously because of mild
		arthritis						pharyngitis
		3 Juvenile	31	F	30	PRED 5 mg/day	3	Infusion reaction
		idiopathic				CyA 100 mg/day		(dyspnea, rash and itching)
		arthritis				SSZ 2000 mg/day
						AF 3 mg/day
		4 Enteropathic	31	M	6	PRED 7,5 mg/day	18	Infusion reaction (headache,
		arthropathy				CyA 300 mg/day		dyspnea and rash)
						SSZ 3000 mg/day
		5 Ankylosing	35	M	7	MTX 5 mg/wk	13	Infusion reaction (dyspnea, swelling
		spondylitis						of throat and erythema of face)
		6 Seropositive	37	F	21	PRED 7,5 mg/day	23	Delayd infusion reaction (itching
		rheumatoid				MTX 22,5 mg/wk		and rash), developed four days after
		arthritis						infusion
		7 Seronegative	40	M	2	PRED 5 mg/day	3	Infusion reaction
		rheumatoid				MTX 10 mg/wk		(rash in upper-body)
		arthritis				SSZ 2000 mg/day
		8 Seronegative	47	F	15	PRED 15 mg/day	15	Infusion reaction
		rheumatoid				MTX 20 mg/wk		(rash and itching)
		arthritis				SSZ 2000 mg/day
		9 Seropositive	50	F	7	PRED 10 mg/day	20	Delayd infusion reaction (rash,
		rheumatoid				AZA 50 mg/day		itching and edema of face),
		arthritis						developed few days after infusion
						PRED 5 mg/day
		10 Seropositive	52	F	6	CyA 150 mg/day	5	Infusion reaction (dyspnea, rash and
		rheumatoid				SSZ 3000 mg/day		cough)
		arthritis				HCQ 214 mg/day
		11 Seropositive	54	F	11	PRED 10 mg/day	1,5	Infusion reaction (sickliness, chills
		rheumatoid				MTX 20 mg/wk		and rash)
		arthritis
		12 Seropositive	73	F	25	MTX 5 mg/wk	15,5 Infusion reaction (rash and itching
		rheumatoid						in the hand)
		arthritis
		13 Psoriatic	73	F	15	PRED 10 mg/day	5,5	Delayd infusion reaction
		arthropathy						(rash, dyspnea), developed two
								days after infusion
		14 Seropositive	75	F	53	PRED 5 mg/day	6	Infusion reaction
		rheumatoid				CyA 100 mg/day		(hoarseness, dyspnoea, rash)
		arthritis				SSZ 2000 mg/day
	Other reason	1 Seropositive	44	F	15	PRED 10 mg/day	24	Recurrent cytopenia/neutropenia
		rheumatoid				CyA 150 mg/day		(0.85-l.1 x 10 9/l)
		arthritis				HCQ 214 mg/day
		2 Enteropathic	58	F	22	PRED 5 mg/day	5	Cytopenia/neutropenia
		arthropathy				SSZ 1000 mg/day		(1.4 x 10 9/l)

Table 4 .

 4 Adverse events which led to discontinuation of infliximab treatment.

DMARD, disease modifying antirheumatic drug; AF, auranofin; ATM, aurothiomalate; AZA, azathioprine; CyA, cyclosporin A; HCQ, hydroxychloroquine; MTX, methotrexate; PRED, prednisolone; SSZ, sulfasalazine

Acknowledge ments

We thank Mrs. Heli Määttä and Mrs. Heli Pikkuharju for excellent secretarial help. The study was supported by Clinical Drug Research Graduate School, Finland and The the Competitive Research Funding of the Pirkanmaa Hospital District.

radiographic progression with combination disease modifying antirheumatic drugs in early rheumatoid arthritis. J Rheumatol 34: 316-21 22. Feltelius N, Fored CM, Blomqvist P, Bertilsson L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapaa-Dahlqvist S, Saxne T, Klareskog L, ARTIS Group


PhD Tuominen Risto
email: risto.tuominen@utu.fi

MCand Azbel Michael

MCand Hemmilä Joonas

MD Möttönen Timo

Professor Risto Tuominen

Willingness to pay for improvement 1 Willingness to pay for improvement of physical function among rheumatoid arthritis patients as measured by Health Assessment Queationnaire

Keywords: Rheumatoid arthritis, willingness to pay, function, disability

Objectives: To assess the symptoms and functional difficulties caused by rheumatoid arthritis through application of the willingness-to-pay (WTP) method.

Methods : Structured questionnaire study was conducted among 242 RA patients. The subjects were asked to evaluate their functional capacity using VAS for all the 20 questions in the Health Assessment Questionnaire (HAQ). Each VAS was followed by a question asking how much the respondent would be willing to pay on a monthly basis for a 50 % improvement with the function in question. These were combied with later collected data on clinical status and use of RA related health services.

Results : The average WTP varied greatly in the examined 20 different functions. The total WTP average on a 50 % improved functional capacity amounted to € 567.05 per month. Patients with lower functional capacity (HAQ 1.2 or more) were ready to contribute significantly (p<0.001) more (705 euros/month) than those with better functional status (199 euros/month). Subjects, whose financial standing was better, reported a higher total WTP (r=0.218, p<0.01). On average the total WTP of the respondents equaled 18.44 % of the disposable net monthly income per person of the household. However, the variation was quite substantial. WTP among patients with rheumatoid arthritis was best depicted through the functional capacity of the patient, the possible time the patient had retired, and the global feeling of pain.

Conclusions : Monetary value is a concrete way of portraying subjective valuation. WTP method is suitable for assessing functional deficits of rheumatoid arthritis.

Introduction

The prevalence of rheumatoid arthritis is 0.8 % among the adult population of Finland, and the annual incidence is approximately 40 per 100,000 adults. The prevalence increases with age [START_REF] Aho | Epidemiology of rheumatoid arthritis in Finland[END_REF].

Thus, rheumatoid arthritis causes considerable costs. According to an international comparative survey the overall costs per person caused by rheumatoid arthritis varied among the OECD countries from an annual € 2,825 in Bulgaria to € 24,688 in Iceland, while the annual costs in Finland were € 19,099 [START_REF] Lundkvist | The burden of rheumatoid arthritis and access to treatment: health burden and costs[END_REF]. The severity of the disease greatly affects the costs of rheumatoid arthritis. In Germany the average yearly costs for rhematoid arthritis were nearly double in patient group with low functional capacity compared to those with less functional disabilities [START_REF] Huscher | Cost of illness in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and systemic lupus erythematosus in Germany[END_REF].

The functional capacity of patients with rheumatoid arthritis is described with different indicators, of which the Health Assessment Questionnaire (HAQ) is widely used and generally approved [START_REF] Fries | Measurement of patient outcome in arthritis[END_REF][START_REF] Bruce | The Health Assessment Questionnaire (HAQ)[END_REF].

Several different indicators have been developed in order to measure valuation of the state of health and of the health care services among patients and population groups [START_REF] Drummnd | Methods for the Evaluation of Health Care Programmes[END_REF][START_REF] Haas | The economic evaluation of health care[END_REF]. In addition to the costs caused by the disease, the disease causes inconvenience and difficulties for the patient, such as pain, anxiety and discomfort, which cannot directly be measured in money. The so called willingness-topay (WTP) method has been introduced as a method to measure the overall evaluation by the patient. With this method a person is asked the largest sum he/she would be willing to pay, within his/her solvency range, in order to attain a given health gain, such as alleviation in, or recovery from, the disease. Thus the effect of the disease can be measured monetarily in a more holistic fashion than solely through the loss of income and the direct expenses inflicted by the disease [START_REF] Fautrel | Costs of rheumatoid arthritis: new estimates from the human capital method and comparison to the willingness-to-pay method[END_REF].

The aim of this study was to assess the symptoms and functional difficulties caused by rheumatoid arthritis through application of the WTP method.

Material and methods

The material of the study consisted of patients with rheumatoid arthritis at Turku University In April-May 2007 new questionnaires were sent to those who had not replied. They were also contacted by telephone and motivated to fill the questionnaire. Of those subjects who were reached by telephone 73.1 % (68/93) returned the new questionnaire. However, 46.3 % (19/41) of the subjects who were not reached by telephone responded to the questionnaire. Part of the subjects in the sample did not wish to, or were not able to, participate. Fourteen of those who did not reply were unable to answer due to disease, 6 did not consider themselves to suffer from rheumatoid arthritis, 14 reported unwillingness to reply to a questionnaire related to money and 26 people were not reached. A total of 182 responded, of these 179 had filled the questionnaire satisfactorily, giving us the final participation rate of 74.0 % (179/242).

At the beginning of the questionnaire there was an account of the implementing instances, the aim, the sampling method, as well as an account in accordance with the Declaration of Helsinki of the voluntary nature of the study and the rights of the study subject. In addition, the subjects were asked for their consent for collecting their patient information from the patient register of the Hospital District of Southwest Finland.

As demographic information the subjects were asked about, for instance their age, gender, if they were retired or working, the number of family members and the net monthly income of the household. The disposable net monthly income per family member was calculated in order to describe the financial state. Replying was facilitated through example questions, and ways of answering through given examples at the beginning of the questionnaire. Global well-being and global feeling of pain from the previous week were asked using Visual Analogue Scales (VAS). The segment extremes were "Worst possible condition" (0) and "Best possible condition" (100), as well as "Most intense pain possible" (0) and "No pain at all" (100). Adverse figure was used to describe pain intensity, where a larger number would represent a more intense pain.

Functional capacity was measured using all the 20 questions in the HAQ. The respondent was asked to indicate his/her functional capacity of the previous week in a VAS where the extremes were "I was entirely unable to" (0) and "I was effortlessly able to" (100). Each VAS was followed by a question asking how much the respondent would be willing to pay on a monthly basis for a medicinal treatment enabling him/her to cope 50 % better with the function in question than the week before. Some of the respondents were unable to or did not wish to estimate their willingness to pay in all functions. Unanswered questions were not used in the final WTP analyses. In addition, a sum total variable was calculated, showing the total sum that the respondent would have been prepared to pay in order to attain an improvement of 50 % of the functional capacity in all 20 investigated functions.

In addition, a value describing the personal deficit was specified for eight domains, in accordance with the calculation principle of the HAQ, i.e. the function with greatest disability of each functional domain of HAQ was recorded. Correspondingly, the highest WTP value was also specified for each domain.

Altogether 177 respondents gave their consent for collection of their patient information. The following information, collected from the patient register, was used in the study: duration of the disease in years, counted from the confirmation of the rheumatoid arthritis diagnosis, as well as other diagnoses, of which a sum variable was formed, (0) no other coinciding systemic diseases, and (1) one or more coinciding systemic diseases. The rheumatoid arthritis was considered to be seropositive if the rheumatoid factor in the plasma had been found to be elevated at any stage of the disease. The numbers of prosthetic joint surgeries and joint fusions were registered, and these were used in the analyses in their original form, and furthermore, classified variables were also formed:

(0) no joint prosthetics and (1) one or more joint prosthetics, as well as (0) no joint fusions and (1) one or more joint fusions.

We ascertained the number of outpatient ward visits and days of hospital stay related to the treatment of rheumatoid arthritis for the years 2005 -2006, as well as the latest available index values for DAS28 illustrating the activity of the disease [START_REF] Prevoo | Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis[END_REF] and HAQ for overall functional status [START_REF] Fries | Measurement of patient outcome in arthritis[END_REF]. The HAQ index was used both in its original form and categorized in classes; (0), less than 1.2, depicting a good or only slightly deteriorated functional level, and (1), in excess or equal to 1.2, depicting a low functional level.

Willingness to pay for improvement 7

The statistical evaluation was based on a chi-square test for proportions and on the Student's t-test for means. Correlation coefficients were used to assess the relationships of the continuous variables.

Both fixed and stepwise linear regression models were used to study the effects of used background factors on WTP. The distribution of total WTP was skewed to the left, wherefore also a logarithmic transformation of it, giving close to normal distribution, was used in separate models. In these models the individual effect of each underlying factor was determined while the effects of the other underlying factors of the model were simultaneously controlled.

Results

The majority of the respondents were women. The gender-specific differences in the underlying factors were minute, except that the women had undergone more joint surgeries, especially prosthetic surgeries. Measured with the DAS28 index the activity of the rheumatoid arthritis was relatively low, although on average 5 -6 instances of both swollen and tender joints were found.

The last measured HAQ index value of the patients also indicated on average a good functional capacity (Table 1).

The average WTP varied greatly in the examined 20 different functions. The gender-specific variations in the different functions were minor and not statistically significant. Both the men and the women reported the highest WTP for a possible improvement in walking outdoor on flat ground. The most significant differences between genders could be discerned in a possible improvement of functional capacity in washing the hair and turning the faucets on and off (Table 2).

The total WTP average on a 50 % improved functional capacity amounted to € 567.05 per month.

Patients with lower functional capacity (HAQ 1.2 or more) were ready to contribute significantly (p<0.001) more (705 euros/month) than those with better functional status (199 euros/month).

The patients who had experienced a lower functional capacity reported a higher WTP in each of the eight domains of the HAQ index (Table 3). Subjects, whose financial standing was better, reported a higher total WTP. This positive correlation (r=0.218) was statistically significant (p<0.01). On average the total WTP of the respondents equaled 18.44 % (median value 8.44 %) of the disposable net monthly income per person of the household. However, the variation between the income level and the WTP was quite substantial.

WTP among patients with rheumatoid arthritis was best depicted through the functional capacity of the patient (indicated with the HAQ index), the possible time the patient had retired, and the global feeling of pain. Although, in logarithmic models the effect of pain was statistically non-significant.

In the linear regression model these three factors alone explained 59.2 % of the variation in the WTP (and 39.8 % of its logarithmic transformation). The effects of the other explanatory factors were minor and not statistically significant. All the 14 background variables, used in the study, together explained 60.7 % of the variation in the WTP (and 41.2 % of its logarithmic transformation). The effect of income was not statistically significant in the multivariate models (Table 4).

Discussion

Our material consisted of patients whose follow-ups were within the sphere of the specialized health care. Some of the patients underwent hospital care periods in connection with treatment of Willingness to pay for improvement 9 rheumatoid arthritis during the follow-up period. As the patients were systematically sampled over a period of ten months, there is reason to assume that the patient group is not selective but represents the patient group in question well. Our material consisted of patients suffering from moderately severe rheumatoid arthritis, as the care of patients in the calm stage of the disease is carried out by the primary health care. Therefore, the results should not be directly generalized to all patients suffering from rheumatoid arthritis.

The response rate was high in our study, and it was significantly improved when such patients who had not responded to the first mailed questionnaire were contacted by telephone. Only very few of the respondents who were reached by telephone refused to participate in the study, by referring to its monetary character. The WTP assessments, which were acquired through the questionnaire, complemented with the clinical information collected from the patient register, enabled holistic examination where medical assessment of patients with rheumatoid arthritis was combined with the subjective evaluation by the patients of their functional capacity. The results of the questions evaluating the functional capacity of a patient were consistent with earlier studies. In these it has been found that patients with rheumatoid arthritis consider the ability to move to be important [START_REF] Verhoeven | Validity of the MACTAR questionnaire as a functional index in a rheumatoid arthritis clinical trial[END_REF][START_REF] Hewlett | Outcomes generated by patients with rheumatoid arthritis: how important are they?[END_REF]. The patients in this study were also willing to pay the highest sum of money for a possible improvement of functional capacity of walking outdoors on flat ground.

The total WTP was in our study calculated through adding up the WTPs awarded to the 20 different functions. The total sum specified in such a fashion may overestimate the factual WTP among the patients, as the individual patient may not necessarily perceive the total sum when pondering the values of the specific functions. Then again the logarithmic transformation of the total WTP used in the regression models describes accurately the relative change in WTP and the effects of various background factors thereon.

Willingness to pay for improvement 10

There is a publically financed health care in Finland, but the costs of the private health care are also partially financed with public funds. As the patient out-of-pocket costs do not correspond with the factual costs to the society, it is possible that the patients do not necessarily perceive the total costs inflected on society. Thus the acquired WTPs should not be directly related to factual societal costs.

However, in earlier studies on WTP among patients with rheumatoid arthritis, carried out in countries where health care is funded to a considerable extent publically, the assessments of WTP have been considered reliable [START_REF] Slothuus | Willingness to pay in arthritis: a Danish contribution[END_REF][START_REF] Fautrel | Valuing a hypothetical cure for rheumatoid arthritis using the contingent valuation methodology: the patient perspective[END_REF].

When comparing assessments of WTP in different studies one has to observe caution and be critical.

In order for the assessments of WTP to be mutually comparable they should be implemented in societies with sufficiently similar provision of health services, as well as similar cost structures, within the health care systems. In addition, the purchasing power of the currencies used, and the financial base of the health care, should be similar. The questions in the questionnaires should also be standardized. Despite differences in societal factors the WTP method can be applied to measure differences in relative importance of the studied values, not only in placing them in order of importance.

Our results corroborate earlier findings, suggesting that the WTP method is suitable for assessing functional deficits of rheumatoid arthritis [START_REF] Slothuus | Willingness to pay in arthritis: a Danish contribution[END_REF][START_REF] Fautrel | Valuing a hypothetical cure for rheumatoid arthritis using the contingent valuation methodology: the patient perspective[END_REF]. All HAQ domains displayed statistically significant correlations between the functional level and the WTP. There were apparent differences in WTP between the different functions in the HAQ. The reliability of the results is further supported by the direction of differences in WTP between genders, although statistically nonsignificant. It is more difficult for women to wash their hair, and indeed their WTP was higher in improving this function than in that shown by the men. Corresponding differences could also be seen especially in functions related to cleaning and cooking. WTP was increased by a higher HAQ index value and an increased feeling of pain, and it was reduced by a longer retirement. One explanation for the reductive effect of longer retirement could be that patients such as these have been on disability pension due to rheumatoid arthritis for a longer period of time. In their case the degree of the disease has been severe for a longer time, and their expectations for improvement of the functional capacity is apparently lower than among those who have suffered shorter period of time and suffer from a less severe disease. The level of income among the respondents had an effect on the WTP. However, it was interrelated with other examined background factors, such as age and retirement and it had statistically non-significant effect in the multivariate models when the effects of other factors were controlled. In our sample the income level of the respondents did not significantly vary, thus the measurement of WTP likely yielded fairly reliable assessments also in absolute monetary amounts.

Measured with the DAS28 index, the disease was under good control among our study subjects, even though they have suffered from the disease for a relatively long time and a considerate part of them had undergone articular surgeries. This might be considered to indicate that the treatment strategies have been adequate and that they have improved over time. However, the DAS28 index does have its limitations in assessing rheumatoid arthritis activity, as it does not include the condition of all joints, for example ankles and feet. At least an indirect indication on the success of the surgical treatment can be perceived in that the WTP among patients that had undergone surgery was not higher than among those patients that had not undergone surgery.

WTPs related to e.g. driving cars or using bathtubs were not reported by such respondents that did not have them at their disposal. Thus the WTP assessment of some functions was emphasized by the evaluations of such respondents that had experience in a particular function. Only a part of the respondents reported functional deficit or WTP in the improvement thereof as regarding use of a bathtub. However, they did convey relatively high evaluations of WTP. Contrary to earlier decades, the bathtub no longer is a standard piece of equipment in most Finnish homes. The respondents, who had replied to the question on bathtub use, were those who still have a bathtub in their residences, and who probably hold them in high esteem as they have retained one as part of their domestic equipment.

The strength of the WTP method is its ability to separately emphasize the different functions in the HAQ. It has been found in earlier studies that health care professionals and RA patients emphasize different issues in the treatment outcomes [START_REF] Hewlett | Outcomes generated by patients with rheumatoid arthritis: how important are they?[END_REF][START_REF] Hewlett | Values for function in rheumatoid arthritis: patients, professionals, and public[END_REF]. The significance of, for instance, pain and functional deficits also differ among the patients during the different stages of the disease [START_REF] Carr | Rheumatology outcomes: the patient's perspective[END_REF]. In addition, the function with worst functional capacity in each domain is used in forming the HAQ index, which may distort the actual functional capacity. It has been suggested that a tool parallel to HAQ would be developed, which would measure how the patients value different functions and would provide weighted values for the different functional deficits [START_REF] Hewlett | Outcomes generated by patients with rheumatoid arthritis: how important are they?[END_REF][START_REF] Hewlett | Values for function in rheumatoid arthritis: patients, professionals, and public[END_REF]. Monetary value is a concrete way of portraying subjective valuation and could be a starting point for the creation of such a tool.

8 (

 8 Hospital's Paimio Hospital. The systematic sampling was obtained from the patient register of the Hospital District of Southwest Finland. The first 20 patients treated with the diagnosis M05.seropositive rheumatoid arthritis) and the 10 first patients treated with the diagnosis M06.0 (seronegative rheumatoid arthritis) of each calendar month during March -December of 2006 were sampled. Full amount of patients with the diagnose number in question was not available every calendar month and thus the final sample amounted to 242 patients. The Ethics Committee of the Hospital District of Southwest Finland had given its consent for implementation of the study. A questionnaire and a postpaid return envelope were sent to the patients chosen for the sample in March 2007. A completed questionnaire was returned by 95 people (39.2 %) within the month.

Table 1 .

 1 Background and health information of the sample as percentages and mean values with

	standard deviations.
		Women (n=122)	Men (n=52)
	Percentage of respondents	70.1	29.9
	Age in years	63.0 (13.6)	60.0 (11.7)
	Disposable family income per person 921.9 (351.0)	900.8 (311.3)
	Retired	59.8	61.5
	Years of retirement	8.9 (9.7)	7.9 (10.0)
	Years with RA	12.4 (13.9)	10.8 (11.4)
	One or more coinciding diseases	54.9	46.2
	Seropositivity	53.3	55.8
	One or more joint prostheses	49.2	30.8
	One or more joint fusions	27.9	19.2
	Number of outpatient ward visits	5.0 (4.0)	5.4 (4.1)
	Days at inpatient wards	7.2 (14.9)	5.0 (7.1)
	DAS28	2.9 (1.2)	3.3 (1.2)
	HAQ	0.7 (0.6)	0.7 (0.7)
	Global well-being VAS	59.9 (23.0)	60.9 (18.7)
	Global feeling of pain VAS	59.4 (25.8)	60.9 (21.3)
	Number of swollen joints	4.9 (6.2)	4.9 (5.0)
	Number of tender joints	5.8 (7.8)	6.2 (6.3)

Table 2 .

 2 Willingness to pay per month for 50 % improvement in the 20 functions used in the HAQ

	index by sex
	Function	Willingness to pay (€ / month)
		All	Women	Men
	Dress yourself	25.63	25.63	25.63
	Wash your hair	24.61	28.84	14.87
	Stand up from a chair	24.38	25.57	21.55
	Get in and out of bed	26.26	28.12	22.17
	Cut your meat	24.39	25.26	22.58
	Lift a full glass to your mouth	20.22	20.87	18.69
	Prepare your own food	23.72	26.47	17.50
	Walk outdoors on flat ground	40.95	44.37	33.82
	Climb up five steps	31.60	34.69	25.24
	Wash and dry your body	27.89	31.25	20.97
	Take a tub bath	31.58	31.62	31.52
	Get on and off the toilet	22.78	24.30	19.40
	Reach and get down
	a 2 kg flourbag	26.24	27.86	22.33
	Bend down and pick up
	clothing from the floor	26.39	26.29	26.61
	Open car doors	17.52	17.70	17.11
	Open jars which have been
	previously opened	23.02	23.54	21.84

Table 3 .

 3 Correlations between the functional levels (VAS) and the willingness to pay in the eight domains used in the HAQ index

	Domain

Table 4 .

 4 Effects of studied underlying factors on the logarithmic transformation of willingness to

	pay
	Explanatory factor	Beta	p value
	Constant term	6.890	0.000
	HAQ index 1.2 or more	1.719	0.005
	Age	-0.024	0.150
	Seropositivity	-0.197	0.541
	One or more coinciding diseases	0.326	0.329
	One or more joint fusions	-0.018	0.970
	One or more joint prostheses	0.227	0.606
	Years with RA	-0.016	0.366
	Days at inpatient wards	-0.009	0.785
	Number of outpatient ward visits	0.006	0.902
	Disposable family income per person	0.000	0.585
	Years of retirement	-0.071	0.012
	Male sex	-0.218	0.546
	DAS28	0.249	0.091
	Global feeling of pain	-0.014	0.119
	R² 0.412

Ackowledgements

This study has been supported by grants from the research funds of The Hospital District of Southwest Finland and from Wyeth AB.

Willingness to pay for improvement


MD Valentina Bagnari
email: valentina7@libero.it

Matteo Colina

Giovanni Ciancio

Marcello Govoni

Francesco Trotta

"Adult-onset Still's disease: a review"

Keywords: Adult-onset Still's disease, FUO, systemic diseases, autoinflammatory syndromes

teaching and research institutions in France or abroad, or from public or private research centers.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown aetiology, characterised by spiking fever, usually exceeding 39° C, an evanescent salmon-pink rash, arthritis and multiorgan involvement [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF][START_REF] Pouchot | Manifestations cliniques et biologiques de la maladie de Still de l'adulte[END_REF]. The disorder owes its name to Sir George Frederick Still, who, in 1897, described twenty-two children with symptoms consistent with what is currently known as systemic onset juvenile idiopathic arthritis [START_REF] Still | On a form of chronic joint disease in children[END_REF]. AOSD was established as an autonomous disease entity almost a century later, when Eric Bywaters described 14 adults patients presenting symptoms similar to those seen in paediatric Still's disease [START_REF] Bywaters | Still's disease in the adult[END_REF].

Epidemiology

Nowadays there is no agreement on the incidence and prevalence of the disease in different populations: AOSD occurs worldwide and women barely seem to be affected more often than men.

AOSD usually affects young people, with 75% of the cases reporting disease onset between 16 and 35 years of age [START_REF] Ohta | Adult Still's disease: review of 228 cases from the literature[END_REF]. Nevertheless, onset of AOSD after the age of 60 has been described in some cases [START_REF] Wouters | Adult onset Still's disease in the elderly: a report of two cases[END_REF]. The incidence in the Brittany and Loire regions of France has been assessed at 0.16 per 100,000 persons. The mean age of the study population was 36 years, with two peaks of distribution respectively at 15-25 and 36-45 years [START_REF] Magadur-Joly | Epidemiology of adult disease: estimate of the incidence by a retrospectie study in West France[END_REF]. In a Dutch study of 45 patients, women were 60% and the median age of presentation was 25 years (range 16 to 65 years), with 27% of the patients showing onset of symptoms after the age of 35 [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF]. An epidemiologic analysis from Japan evaluated the incidence amongst men at 0.22 per 100,000 inhabitants and at 0.34 per 100,000 amongst women [START_REF] Wakai | Estimated prevalence and incidence of adult Still's disease: findings by a nationwide epidemiological survey in Japan[END_REF].

Etiopathogenesis

More than a century ago, Sir George Still reported that the aetiology of the disease he had described was "very uncertain" [START_REF] Still | On a form of chronic joint disease in children[END_REF]. Uncertainty remains, but some progress has been made. Ma ny studies evaluated a genetic predisposition, linking the disease with HLA antigens. In a retrospective survey of 62 patients from Canada, immunogenetic studies were executed on 55 of them, and HLA B17, B18, B35, and DR2 were significantly associated with AOSD [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF]. However, other studies failed to confirm these claims and reported other associations, including HLA-B14 and DR7, or Bw35 and Cw4, or DR4 and Dw6 [START_REF] Van De Putte | Adult-onset Still's disease[END_REF]. In summary, no consistent results have been obtained from association studies between AOSD and HLA loci. This may result from a real absence of an association or from heterogeneity of the disease. Besides, a familial tendency has not been reported.

A Japanese study evaluated polymorphisms of the IL-18 gene and discovered that the frequency of the diplotype configuration of S01/S01 was significantly higher in AOSD patients than in healthy control subjects [START_REF] Sugiura | A promoter haplotype of the interleukin-18 gene is associated with juvenile idiopathic arthritis in the Japanese population[END_REF].

The constellation of abrupt onset, high fever, generalized adenopathy and leukocytosis suggest that AOSD may be a reactive syndrome, where a range of infectious agents trigger the disease in genetically predisposed hosts. These include viruses, such as rubella, CMV, EBV, human herpes virus 6, mumps, echovirus 7, parainfluenza, Coxsackievirus B4, adenovirus, influenza A, HBV, HCV and parvovirus B19, and others microbial agents like Mycoplasma pneumoniae, Chlamydia pneumoniae, Yersinia enterocolitica, Brucella abortus, and Borrelia burgdoferi [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF][START_REF] Wouters | Adult onset Still's disease and viral infections[END_REF].

Even abnormalities in cytokines production may play a pathophysiological role in AOSD. Patients with active, untreated AOSD seem to have a prevalence of Th1 cytokines in peripheral blood and tissues. The Th1 immune response increases production of interleukin (IL)-2, interferon (IFN) γ, and tumour necrosis factor (TNF) α, cytokines that concur in activating macrophages and natural killer (NK) cells, leading B lymphocyte to the production of IgG2a subtype and promoting cell mediated immunity [START_REF] Chen | Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onse t Still's disease[END_REF].

Serum levels of IL-1, IL-6, IL-18, TNFα, and IFNγ are considerably higher if compared with controls [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Hoshino | Elevated serum interleukin 6, interferon-gamma, and tumor necrosis factor-alpha levels in patients with adult Still's disease[END_REF][START_REF] Kawashima | Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease[END_REF]. High levels of IL-18 are observed in the acute phase of AOSD and this cytokine is considered to be the initiating factor for the inflammatory cascade that includes IFNγ, IL-6, and TNFα. Over production of IL-1, TNF and IL-6 may account for symptoms observed in the disease and may provide possible therapeutic targets (Table 1).

Unlike rheumatoid arthritis and systemic lupus erythematosus, hormonal influences do not seem to be considered important in AOSD. Pregnancy does not appear to be a risk factor for the development of the disease and does not increase the risk of relapses. Fetal outcomes are also normal in AOSD.

Clinical features

AOSD may affect several organs and it is worth recalling that the full constellation of symptoms may not be present at onset, and that the evolution to a "typical" case of AOSD may take several weeks or even months.

Fever, usually more than 39°C, is typically quotidian or double quotidian in pattern, with the highest temperatures seen in the late afternoon or early evening, and it is transient [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF]. In particular, incidence of fever was estimated at about 95.7% according to five of the largest retrospective studies [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF][START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Ohta | Adult Still's disease: a multicenter survey of Japanese patients[END_REF][START_REF] Masson | Adult Still's disease: part I. Manifestations and complications in sixty-five cases in France[END_REF][START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF]. Fever usually precedes the onset of other manifestations and, in the majority of the cases, it represents the reason for which the patient addresses the physician.

The classic rash is an evanescent, salmon-pink, macular or maculopapular eruption, which usually appears with the fever spike. The rash occurs in about 73% of patients, and it is predominantly found on the proximal limbs and trunk: it can be mildly pruritic (32% of the patients according to a Dutch study), and may be mistaken for a drug allergy. Histological findings show mild perivascular inflammation of the superficial dermis with infiltration of lymphocytes and histiocytes [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Masson | Adult Still's disease: part I. Manifestations and complications in sixty-five cases in France[END_REF]. The typical Still's rash has only rarely been seen in other diseases, namely ulcerative colitis, vasculitis and leukemia. However, the presence of atypical cutaneous manifestations does not have to exclude the suspicion of AOSD because several cases with atypical cutaneous manifestations have been described as well (Table 2).

Arthralgia and arthritis occur in the majority of patients with AOSD, with incidences ranging from 64% to 100%. Arthritis may initially be mild, oligoarticular and transient, but it may evolve into a more severe, destructive, symmetrical and polyarticular form [START_REF] Masson | Adult Still's disease: part I. Manifestations and complications in sixty-five cases in France[END_REF] over a period of several months., Joints usually involved are knees, wrists, and ankles, even though elbows, hips, shoulders, metacarpo-phalangeal and metatarso-phalangeal joints, proximal and distal interphalangeal joints and temporo-ma ndibular joints may be involved too [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Masson | Adult Still's disease: part I. Manifestations and complications in sixty-five cases in France[END_REF].

Useful signs for the differential diagnosis with rheumatoid arthritis, typically more frequent in cases of AOSD, are carpal and pericapitate abnormalities: changes in the wrist were described 6 months after disease onset with progressive joint space narrowing, especially in pericapitate or carpometacarpal regions: ankylosis may develop after 1.5-3 years [START_REF] Bywaters | Still's disease in the adult[END_REF]. During the initial acute phase of the disease, imaging is not helpful in establishing the diagnosis, but up to 41% of patients show a non erosive intercarpal and carpometacarpal joint space narrowing of the wrist. Joint fluid aspiration often reveals leucocytosis with a predominance of granulocyte polymorphonucleate [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Masson | Adult Still's disease: part I. Manifestations and complications in sixty-five cases in France[END_REF].

Generalised myalgias, often rising with fever spikes, are usually found in the majority of patients with incidence ranging from 56% to 84% [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF][START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Ohta | Adult Still's disease: a multicenter survey of Japanese patients[END_REF][START_REF] Masson | Adult Still's disease: part I. Manifestations and complications in sixty-five cases in France[END_REF].

Liver abnormalities, such as hepatomegaly, and slight alterations in liver enzymes, are found in approximately 50-75% of patients: it is not possible to exclude that non-steroidal anti-inflammatory drugs (NSAIDs) may play a significant role in these variations [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF][START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF][START_REF] Andres | Retrospective monocentric study of 17 patients with adult Still's disease, with special focus on liver abnormalities[END_REF].

Splenomegaly has been found in about 44% of patients [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF][START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Ohta | Adult Still's disease: a multicenter survey of Japanese patients[END_REF][START_REF] Masson | Adult Still's disease: part I. Manifestations and complications in sixty-five cases in France[END_REF][START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF]: lymphadenopathies also occur frequently, and lymph node biopsies demonstrate benign polyclonal B cells hyperplasia [START_REF] Quaini | Immunohistological characterization of lymph nodes in two cases of adult onset Still's disease[END_REF].

Sore throat is a typical sign that can precede fever and other symptoms: it seems to occur early in the disease course in 69% of the patients and it is particularly common in the first month of the disease. Its pathogenesis is still unclear, being attributed both to an inflammation of crico-aritenoid joints and an aseptic non-exudative pharyngitis [START_REF] Nguyen | Severe sore throat as a presenting symptom of adult onset Still's disease: a case series and review of the literature[END_REF].

Cardiopulmonary involvement like pleuritis (26.4%) or pericarditis (23.8%) have been observed [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF][START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Ohta | Adult Still's disease: a multicenter survey of Japanese patients[END_REF][START_REF] Masson | Adult Still's disease: part I. Manifestations and complications in sixty-five cases in France[END_REF][START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF]. Tamponade, myocarditis [START_REF] Sachs | Myocarditis in adult Still's disease[END_REF][START_REF] Colina | Fatal myocarditis in adult-onset Still disease with diffuse intravascular coagulation[END_REF], pulmonary fibrosis, pleural effusions and adult respiratory distress syndrome have also been described [START_REF] Stoica | Adult Still's disease and respiratory failure in a 74 year old woman[END_REF].

Haematological complications, like pure red cell aplasia, thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, have rarely been described : pancytopenia may be due to the haemophagocytic syndrome (HS). It is important to bear in mind that AOSD may begin with an HS [START_REF] Dhote | Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review[END_REF]. Furthermore, malignant lymphoma should not only be excluded for diagnosis, but they may be added to the large variety of complications associated with this disease [START_REF] Trotta | Immunoblastic malignant lymphoma in adult onset Still's disease[END_REF]. Finally, cases of disseminated intravascular coagulation that have led to death have rarely been described [START_REF] Colina | Fatal myocarditis in adult-onset Still disease with diffuse intravascular coagulation[END_REF].

The clinical course may be divided into three main patterns, with different prognostic implications: 1. Self limiting or monophasic pattern is characterised by a single disease episode with systemic symptoms like fever, rash, serositis, and organomegaly. Median time to remission is 9 months, and most patients get remission within 1 year [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF]. This clinical pattern has a favourable prognosis and serious complications from disease or therapy are uncommon [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF].

2. Intermittent or polycyclic systemic pattern is marked by recurrent disease flares, with or without articular symptomatology, interspersed by complete remissions. Subsequent flares become less severe and can occur many years after the first one [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF].

3. Chronic articular pattern is characterised by a persistent active disease, dominated by the articular manifestations. Arthritis can be severe and lead to joint destruction [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF].

Laboratory

Laboratory test results largely reflect the systemic inflammatory nature of the disease process and none of the findings is specific for AOSD [START_REF] Saito | Two cases of adult-onset Still's disease with atypical rash[END_REF]. An increased sedimentation rate is universal and there is no association with rheumatoid factor (RF) or antinuclear antibody (ANA) [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF].

Serum ferritin and its glycosylated fraction are currently assessed as a useful diagnostic and disease activity markers. Ferritin is an acute phase protein closely associated with inflammatory processes, inclusive of the mechanisms underlying oxidative stress. Inflammation is linked with increased discharge of ferritin by the histiocyte-macrophage system and from damaged hepatocytes. IL-1β, IL-18, TNFα and IL-6 are cytokines that induce the greatest production of ferritin [START_REF] Fautrel | Ferritin levels in adult Still's disease: any sugar?[END_REF]. Serum ferritin levels in AOSD are usually higher than in other autoimmune or inflammatory diseases, and very high levels, between 3,000 ng/ml and 30,000 ng/ml, are not uncommon (normal range ng/ml): even levels higher then 250,000 ng/ml have been reported. A cut off for ferritin levels of 1,000 ng/ml (fivefold the upper normal limit) has been used in many studies to be indicative of AOSD [START_REF] Fautrel | Ferritin levels in adult Still's disease: any sugar?[END_REF]. Besides, disease activity seems to be correlated with serum ferritin levels: these ones often normalise during remission, so that they may also be used as a tool to evaluate response to therapy. A retrospective French study with 49 patients employed a threshold of 1000 ng/ml in serum ferritin as diagnostic marker: a fivefold increase had 80% sensitivity and 41% specificity [START_REF] Fautrel | Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease[END_REF] while, in a Japanese study, sensitivity was 82% and specificity 46% [START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF]. However, elevated levels of serum ferritin can also be detected in other diseases, such as infections, malignancies, haemophagocytic syndrome and liver diseases like haemochromatosis or Gaucher's disease, so that the usefulness of this marker is limited in clinical practice [START_REF] Fautrel | Ferritin levels in adult Still's disease: any sugar?[END_REF].

A more specific diagnostic tool may be ferritin glycosylated fraction. Glycosylation is a process that protects serum ferritin from proteolytic enzymes. Healthy subjects have 50-80% of serum ferritin glycosylated, whereas this fraction falls to 20-50% in patients with inflammatory diseases. This can be explained both by saturation of glycosylation mechanisms that occurs in inflammatory diseases, and by lower clearance of non-glycosylated proteins by the histiocyte-macrophage system that occurs specifically in AOSD [START_REF] Fautrel | Ferritin levels in adult Still's disease: any sugar?[END_REF]. Glycosylated ferritin persists to low levels in both active phases of disease and in remission, so that it cannot be useful in monitoring the response to treatment.

Combining a fivefold elevation of the serum ferritin concentration with a glycosyla te fraction ≤20%, diagnostic specificity enhances to 93%, while sensitivity drops to 43% [START_REF] Fautrel | Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease[END_REF].

Patients frequently have a marked leukocytosis, that is the result of a remarkable neutrophilia, probably secondary to bone marrow granulocyte hyperplasia [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Min | Bone marrow findings in patients with adult Still's disease[END_REF]. Fewer than 2% of cases present a diminished white blood cell count, with obvious diagnostic difficulties.

Other haematological alterations include a normocytic normochromic anaemia, with Hb <10 mg/dl, which often associates with increased disease activity, and thrombocytosis [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF][START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Ohta | Adult Still's disease: a multicenter survey of Japanese patients[END_REF]. Liver abnormalities are not uncommon: lactate dehydrogenase, γ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, and bilirubin can increase in 75% of patients with AOSD and frequently rise concomitantly with fever and exacerbations of arthritis [START_REF] Ohta | Adult Still's disease: review of 228 cases from the literature[END_REF].

Diagnosis and classification criteria

Diagnosis is one of exclusion and the differential diagnosis may be lengthy (Table 3). Infectious, neoplastic and autoimmune diseases can mimic the clinical manifestation of AOSD. Cultures and serological tests can be helpful to exclude infections. Moreover, viral syndromes can be excluded if the symptoms remain over 3 months. The clinical and haematological profile are often sufficient in order to distinguish the disease from lymphomas and leukemias, but sometimes it may be necessary to resort to bone marrow or lymph node biopsy.

Other disorders frequently confused with the AOSD include reactive arthritis and the other spondyloarthropathies, vasculitides, dermatomyositis, haemophagocytic syndrome, Kikuchi's syndrome, Sweet's syndrome and granulomatous disorders [START_REF] Esdaile | Adult Still's disease[END_REF].

There are several sets of classification criteria for AOSD, all developed from retrospective studies.

Masson et al. in 1996 published a comparative study about criteria in AOSD: Yamaguchi's criteria [START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF] (Table 4) were shown to be by far the most sensitive (93.5%), followed by Cush's [START_REF] Cush | Adult onset Still's disease. Clinical course and outcome[END_REF] (80.6%) and Calabro's [START_REF] Calabro | Adult onset Still's disease[END_REF] (80.6%). Specificity could not be evaluated due to lack of a control group [START_REF] Masson | Comparative study of 6 types of criteria in adult Still's disease[END_REF].

In 2002, Fautrel et al. proposed a new set of classification criteria that took into consideration glycosylated fraction of serum ferritin and deleted exclusion criteria (Table 5). This set seems to be promising, because it provided a sensitivity of 80.6% and a specificity of 98.5%: however, it has to be validated in different populations before becoming broadly received [START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF].

Management

The management of AOSD is firstly directed at the acute systemic features of the disease.

Therapeutic strategies have been exclusively empirical, with data on treatment efficacy obtained from case reports, retrospective studies and small case series. The therapy of AOSD includes NSAIDs, glucocorticoids, and other disease modifying anti-rheumatic drugs (DMARDs) to control arthritis and systemic disease [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF][START_REF] Bywaters | Still's disease in the adult[END_REF].

NSAIDs are traditionally considered first line therapy for musculoskeletal symptoms and fever, but NSAIDs monotherapy is effective in controlling disease in only 12% of patients [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Ohta | Adult Still's disease: a multicenter survey of Japanese patients[END_REF]. Among NSAIDs, indometacin and naproxen seem to be more effective in controlling the disease compared with salicylates [START_REF] Wouters | Adult-onset Still's disease: clinical and laboratory features, treatment and progress of 45 cases[END_REF].

Most patients with AOSD are treated with steroids in the course of the disease, with responses ranging from 76% to 95% [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF][START_REF] Wouters | Adult onset Still's disease in the elderly: a report of two cases[END_REF][START_REF] Cush | Adult onset Still's disease. Clinical course and outcome[END_REF]. According to the clinical course of AOSD, patients may need increasing steroid treatment: prednisone is required for 57% of patients with the self limited pattern, for 67% with the intermittent and for 77% with the chronic articular one [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF].

There are no prospective, clinically controlled trials about the use of DMARDs in AOSD. In clinical practice, their use should be proposed for cases in which the combination of NSAIDs and steroids fails or in which a tapering of steroid is necessary [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF]. Many drugs have been tried in AOSD, including methotrexate (MTX), ciclosporin A, sulfasalazine, hydroxychloroquine,

immunoglobulins (IVIg), anti TNF agents, anakinra and rituximab with overall response across studies at approximately 40% [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF].

Polyarthritis seems to be particularly susceptible to MTX treatment and it resolves completely in many patients, while the results of MTX on systemic manifestations have not yet been well delineated [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF]. A small case series of six patients treated with ciclosporin A reported remission in 66% of cases, and improvement in the other 33% [START_REF] Marchesoni | Cyclosporin A in the treatment of adult onset Still's disease[END_REF].

Treatment with sulfasalazine has been related with high drug toxicity (60% vs 15% of other drugs) [START_REF] Jung | High toxicity of sulfasalazine in adult-onset Still's disease[END_REF], so this medication should be avoided in AOSD patients.

High dose intravenous immunoglobulin (IVIg) may be employed to achieve remission and control of early disease before the use of steroids [START_REF] Vignes | Intravenous immunoglobulin in adult Still's disease refractory to non-steroidal anti-inflammatory drugs[END_REF].

A prolonged remission of refractory disease was also obtained using CD34-selected autologous peripheral blood stem cell transplantation [START_REF] Lanza | Prolonged remission state of refractory adult onset Still's disease following CD34-selected autologous peripheral blood stem cell transplantation[END_REF].

patients, addition of etanercept to the pre-study regimens of prednisone, MTX and NSAIDs, leads to an improvement in the number of tender and swollen joints count higher than 63% [START_REF] Husni | Etanercept in the treatment of adult patients with Still's disease[END_REF]. Even infliximab, a monoclonal chimeric anti-TNFα antibody, seems to be effective in AOSD: a European study of eight patients attempted to evaluate the long term outcome of patients treated with infliximab after the failure of treatments with corticosteroids and DMARDs: the clinical and serological responses improved rapidly in seven out of eight patients, and five of them went into long term remission even after discontinuation of therapy [START_REF] Efthimiou | Diagnosis and management of adult onset Still's disease[END_REF][START_REF] Dechant | Longterm outcome of TNF blockade in adult-onset Still's disease[END_REF].

IL-1 receptor antagonist anakinra has recently emerged as a possible new therapeutic option [START_REF] Fitzgerald | Rapid responses to anakinra in patients with refractory adult-onset Still's disease[END_REF].

As mentioned above, IL-6 represents an important inflammatory cytokine involved in the pathogenesis of AODS, and it may be a promising target, especially with the development of antihuman IL-6 monoclonal antibody tocilizumab [START_REF] Lequerré | Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France[END_REF]. A case of refractory AOSD successfully treated with rituximab has also been described [START_REF] Ahmadi-Simad | Successful treatment of refractory adult onset Still's disease with rituximab[END_REF]. Acne-like lesions Ohta et al. 18 Cutaneous pain Ohta et al. 18 Eczematous lesions Ohta et al. 18 Toxic eruptions Ohta et al. 18 Alopecia Rowell et al. 22

Angioedema

Soy 23 Erythema chronicum migrans Saito et al. 24 Persistent plaques and linear pigmentation Suzuki et al. 25 Non-caseating dermal granulomas Wissler et al. 26 Fixed plaques

Lubbe et al. 27 -Thien Huong et al. 28 -Kaur et al. 29 Urticaria Setterfield et al. 30 -Salaffi et al. 31 Vesiculopustules on the hands and feet Lee et al. 32

Table 1 Cytokines involved in the pathophysiology of AOSD

 1 [from 17, modified]

	Cytokine	Source	Action

IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; sIL-2R: soluble IL -2 receptor ; M -CSF : macrophagecolony stimulating factor.

Table 2 . Atypical cutaneous manifestations reported in association with AOSD

 2

		[from 21, modified]
	Pruritus	Pouchot et al. 10

  -Bachmeyer et al.33

	Generalized peau d'orange-like skin infiltration (diffuse cutaneous mucinosis)	Philips et al. 34
	Persistent generalized erythema	Fujii et al. 35

Table 3 .

 3 Differential diagnosis of AOSD[from 48, modified]

	Connective tissue diseases
		SLE, mixed connettive tissue disease
	Granulomatous disorders
		Sarcoidosis, idiopathic granulomatous hepatitis,
		Crohn's disease
	Vasculitis
		Polyarteritis nodosa, Takayasu's arteritis, Wegener's
		granulomatosis
	Infections	Viral infection (rubella, parvovirus B19, coxsackie,
		HBV, EBV, CMV, HIV), subacute bacterial
		endocarditis, chronic meningococcemia, tuberculosis,
		syphilis, Lyme disease
	Malignancy
		Leukemia, lymphoma, angioblastic lymphadenopathy
	Other autoinflammatory syndromes
		Familial mediterranean fever, criopirinopathies,
		familial cold autoinflammatory syndrome, hyper-IgD
		syndrome, PAPA syndrome, TRAPS, Schnitzler's
		syndrome, PFAPA syndrome, SAPHO syndrome

Table 4 .

 4 Yamaguchi classification criteria[START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF]

	Major criteria
	Fever of at least 39°C, intermittent, lasting 1 week or longer
	Arthralgias of arthritis, lasting 2 weeks or longer
	Typical rash
	Leucocytosis (≥ 10 000/mm 3 ), with 80 % or more granulocytes
	Minor criteria
	Sore throat
	Recent development of significant lymphadenopathy
	Hepatomegaly or splenomegaly
	Abnormal liver function
	Negative tests for antinuclear antibody and rheumatoid factor
	Exclusion criteria
	Infections
	Malignancies
	Other rheumatic diseases
	Diagnosis requires 5 or more criteria, 2 of which must be major

Table 5 . Classification criteria proposed by Fautrel

 5 [START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF] Diagnosis requires at least 4 or more major criteria or 3 major + 2 minor criteria

	Major criteria
	Spiking fever ≥ 39° C
	Arthralgias
	Transient erythematous rash
	Sore throat
	Polymorphonuclear cells ≥ 80%
	Glycosylated ferritin ≤ 20%
	Minor criteria
	Maculopapular rash
	Leucocytosis ≥ 10000/mm 3