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Objective: To evaluate the 2-year efficacy and safety of etanercept in patients with ankylosing spondylitis (AS)., Methods: A 96-week open-label extension study, which followed a 12-week double-blind placebo-controlled trial, was designed to provide longterm efficacy and safety data, including radiographic outcomes, for patients treated with etanercept 25 mg twice weekly (NCT00421980). In all, 81 patients were enrolled (96% of the participants from the double-blind study). Key efficacy measures included improvement using the Assessment in Ankylosing Spondylitis 20% (ASAS20) criteria, the Bath Ankylosing Spondylitis Functional Index (BASFI), and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Radiographic progression was evaluated using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) method. Paired t tests were used to test within-group changes from baseline., Results: The percentage of responders, by ASAS20 criteria, remained relatively constant in patients who received etanercept during the 12-week double-blind study (60% at Week 0 and 83% at Week 96 of the open-label extension); more patients from the placebo group became responders after being switched to etanercept (23% and 74%, respectively). A similar trend was also observed using the ASAS40 and ASAS5/6 criteria, the BASFI, and the BASDAI. Most patients had no change from baseline in mSASSS values. Etanercept was well tolerated; the most frequent adverse events were injection site reactions (n=30; 37.0%) and headache (n=18; 22.2%), and the most frequent infections were upper respiratory tract infections (n=43; 53.1%) and flu syndrome (n=22; 27.2%)., Conclusion: For 2 years, etanercept was clinically effective and well tolerated, with no unexpected safety findings.

Objective: To assess the incidence and outcome of renal replacement therapy (RRT) among patients with amyloidosis associated with inflammatory rheumatic diseases., Methods: Patients with amyloidosis entering RRT from 1987 to 2002 were identified from the Finnish Registry for Kidney Diseases. Five hundred two patients were identified, 80% of whom had amyloidosis associated with an underlying rheumatic disease. They were followed from the time of entering RRT until death or until the end of 2003 using the Finnish national mortality files., Results: During the study period, there was no decline in the number of patients with amyloidosis entering RRT. Mean age of patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) increased significantly from 1987 to 2002 (p < 0.001). Male sex and a diagnosis of JIA indicated an increased risk of mortality. The median survival time after entering RRT was 2.11 years for RA (95% CI 1.93 to 2.69), 2.37 years for ankylosing spondylitis (95% CI 1.11 to 4.31), and 3.05 years for JIA (95% CI 2.19 to 4.23). The 5-year survival rates among patients with the corresponding diagnoses were 18% (95% CI 14% to 23%), 30% (95% CI 14% to 48%), and 27% (95% CI 14% to 41%), respectively., Conclusion: No decline was seen in the number of patients with amyloidosis associated with inflammatory rheumatic diseases accepted for RRT, but over the years, the age of patients with RA or JIA entering RRT was seen to increase. The outcome of patients with amyloidosis and endstage renal disease associated with rheumatic diseases remains poor.

Objective: To measure the presence of autoantibodies binding to intact human recombinant collagen IX and assess their usefulness as a diagnostic marker and an indicator of disease activity in rheumatoid arthritis (RA)., Methods: Recombinant human full-length collagen IX (rCIX) was produced in a baculovirus expression system and purified for use in ELISA developed to detect antibodies to native and denatured collagen IX. Fifty-three patients with recent-onset rheumatoid factor-seropositive RA were analyzed for the presence of rCIX antibodies of the IgG type at the time of initial diagnosis and after 3, 6, 12, and 24 months of followup. The RA sera were accompanied by 30 controls. Associations were determined between patients' antibody titers, development of erosions in the hands and feet, and various clinical and laboratory markers., Results: Serum antibody levels among patients with RA at time of diagnosis were 1.78 times higher against native rCIX (p < 0.001) and 1.71 times higher against denatured rCIX (p < 0.001) than in the controls, and they remained high during the followup. No correlation was seen between antibody levels and clinical and laboratory findings., Conclusion: Our data show that patients with recent-onset RA have significantly elevated levels of autoantibodies to human rCIX. These autoantibodies were observed already at the early stages of the disease, which may reflect their diagnostic potential in RA.

Objective: To determine the outcome of amyloidosis associated with juvenile idiopathic arthritis (JIA) in a hospital-based series., Methods: Patient registers and amyloidosis biopsy files of the Department of Pediatrics of Rheumatism Foundation Hospital, the main tertiary center for inflammatory joint disorders in children in Finland, were scrutinized from 1976 to the end of 2003 to look for amyloidosis in patients under age 19 years. Medical records were reviewed and patients were interviewed by telephone. The causes of any deaths were obtained from death certificates., Results: Twenty-four patients under age 19 years with biopsy-proven amyloidosis were found. As a sign of renal disease at the time of diagnosis of amyloidosis, 16 patients (67%) had proteinuria, but none had renal insufficiency. The 5-year survival rate of the series was 87.5% (95% CI 75% to 100%), and 10-year survival was 75% (54% to 92%). Ten patients (42%) out of the 24 died during a mean followup of 15.4 (range 1.5-27.6) years. The main cause of death was related to JIA in all patients but one. Patients treated with prednisolone alone from the diagnosis of amyloidosis onward had a mortality rate significantly higher than those taking disease modifying antirheumatic drugs and/or cytostatics (p = 0.001). At the end of followup, 14 patients (58%) were alive, 12 with normal renal function (3 of them had undergone renal transplantation), one had renal insufficiency, and one proteinuria. Proteinuria disappeared in 4 patients who were proteinuric (2 with nephrotic syndrome) at baseline, and their renal function remained normal. All the live patients had completed at least the 9 years of compulsory education, and 4 had academic degrees. Two female patients had delivered healthy children., Conclusion: The outcome of JIA-associated amyloidosis is poor. However, renal disease regressed in some patients under vigorous treatment. Successful treatment makes an active life possible for these patients.

Objective: To study the characteristics of the Multidimensional Health Assessment Questionnaire (MDHAQ) in Finnish patients with rheumatoid arthritis., Methods: The reliability of the questionnaire was tested by test-retest procedure. Construct validity was studied by factor analysis and convergent validity by calculating correlations between the Finnish MDHAQ (Finn-MDHAQ) scales and the Finnish Health Assessment Questionnaire (HAQ) and the Finnish Arthritis Impact Measurement Scales (Finn-AIMS2). Correlations between Finn-MDHAQ and measures of clinical characteristics, disease activity, and functional class were also measured. An item analysis was made of the Finn-MDHAQ scales Function (FN) and Psychological (PS)., Results: Internal consistency on the FN scale was 0.92 (95% lower limit 0.89) and 0.66 (0.56) on the PS scale. Reproducibility (95% CI) on FN was 0.93 (0.82 to 0.97) and on PS 0.84 (0.70 to 0.92). Factor analysis identified 2 factors, mobility of upper extremities and trunk, and mobility of lower extremities. Strong correlations were found between the FN scale and HAQ and physical subscales of Finn-AIMS2 and between PS and the psychological subscales of Finn-AIMS2. In item analysis corrected item correlation was high on the Finn-MDHAQ scales, except in one item on the PS scale., Conclusion: The Finn-MDHAQ is an applicable, reliable, and valid instrument for the part of the FN scale measuring functional ability in Finnish rheumatic patients. The incongruity in the PS scale structure that produced moderate internal consistency can be overcome with minor modifications.

Objective: To assess the costs of adding etanercept to the prevailing drug therapy for a one-year period in a group of 31 children with juvenile idiopathic arthritis (JIA) whose disease was refractory to conventional disease modifying antirheumatic drugs., Methods: The changes in total costs were retrospectively collected from medical records and by interviewing parents 6 months before the initiation of etanercept treatment and during a 12-month followup divided into 3-month periods., Results: Direct median costs increased during the first 3 months after the introduction of etanercept, but decreased later during the followup. The estimated median direct costs per patient increased by 4200 US dollars per year, and the indirect costs were reduced by 50%, i.e., 1700 US dollars . The estimated median total cost per patient was increased by about 2700 US dollars per year (10%)., Conclusion: After combining etanercept with the prevailing treatment, the total costs of refractory JIA calculated per year were only slightly higher than those of traditional therapy. This finding must be evaluated in light of the reduced inflammatory activity of the joint disease and the probable reduction of lifetime pain and disability produced by the disease.

Objective: Autonomic neuropathy is associated with increased mortality. Autonomic nervous system disorders have been described in patients with primary Sjögren's syndrome (SS), but the results in controlled studies have been contradictory, varying from normal to sympathetic or parasympathetic dysfunction. Since the earlier studies employed varying methodologies, which may have led to the discrepancy, we conducted a comprehensive study on autonomic function in patients with primary SS and compared our findings to healthy, carefully matched population based controls., Methods: A conventional cardiovascular reflex test battery (Valsalva maneuver, deep breathing test, active orthostatic test) and measurements of baroreflex sensitivity with phenylephrine and 24 hour heart rate variability were performed on 30 patients with primary SS and 30 healthy age and sex matched population based controls., Results: There were no significant differences between the SS patients and the healthy controls in any of the tests., Conclusions: The prevalence of autonomic dysfunction is not increased in patients with primary SS compared to the general population.

Objective: Autonomic neuropathy is associated with increased mortality. In patients with primary Sjögren's syndrome (SS), disturbances in the autonomic nervous system have been described using conventional cardiovascular reflex tests. Heart rate variability (HRV) measured from Holter recording has proved to be a reliable and sensitive method in assessing autonomic function and prognosis. We evaluated cardiovascular autonomic function based on HRV in patients with primary SS compared to the general population., Methods: We analyzed HRV from 24 h electrocardiography recordings in 28 patients with primary SS and 28 healthy age and sex-matched population-based controls., Results: There were no significant differences in time or frequency domains or nonlinear measures of HRV between the groups., Conclusion: The prevalence of autonomic disturbances is not increased in patients with primary SS compared to the general population.

Objective: To assess mortality, causes of death, and patient and disease characteristics predicting survival in a 5 year followup of a community based population of 103 patients with rheumatoid arthritis (RA) in the Kuusamo community in Northern Finland., Methods: Mortality and causes of death were assessed on the basis of official data registers and death certificates. The relation of different baseline patient demographics and disease characteristics to mortality was evaluated., Results: Functional status, measured by the lower extremity component of the Keitel function test, emerged as the most powerful factor predicting mortality. A poor lower extremity function (score > or = 13) increased the relative risk of death (hazard ratio 9.1) compared to well preserved lower extremity function. If the Keitel function test was omitted from the survival analysis, the best predictor of mortality was the Health Assessment Questionnaire. Twenty-one percent of the patients had died during the followup, the most usual cause of death being cardiovascular disease., Conclusion: Poor functional status, measured in this series by the Keitel function test, is a powerful predictor of mortality in RA. Our results confirm the importance of measurement of functional status in rheumatology care.

Objective: To study the pathogenetic mechanisms responsible for and prevalence of stable atlantoaxial subluxation (AAS)., Methods: Lateral view cervical spine radiographs during flexion and extension were studied in 262 patients with rheumatoid arthritis (RA)., Results: AAS was found in 130 patients, 42 (32%) of whom had a stable deformity; in a population based subseries, stable AAS was seen in 16% of the patients with ASS. Atlantoaxial impaction (AAI) was diagnosed in 98 cases and in 37 (88%) of the 42 patients with stable AAS., Conclusion: The main cause of the spontaneous stabilization and occasional ankylosis of the atlantoaxial area is the development of erosions and collapse in the lateral facet joints leading to AAI.

Objectives: To determine the severity of impairment due to rheumatoid arthritis (RA) in a community based population., Methods: The level of impairment in the study group, which represented 88% of the subjects known to have RA in a rural community in Finland, was assessed using the Keitel function test (KFT), a series of 23 range of motion tasks, with score ranging from 96 (worst) to 0., Results: According to the KFT results, 10% of the subjects had severe impairment with a KFT score of 65-96. As to the different Keitel components, the mean hand function index was 22.6 from a possible score of 42, and the mean lower limb function 8.9 out of 44., Conclusions: Our results showed that severely incapacitated patients with RA are rare in the community. The reasons remain speculative. Multidisciplinary care, including early and active treatment with disease modifying antirheumatic drugs and a high number of orthopedic operations may be an explanatory factor. Total joint replacement surgery of the large joints, performed in 19% of patients, may explain the absence of marked restriction in mobility and the divergence between the limitations in the upper and lower limb functions in this series.

Objective: To evaluate the serum concentration of the mature, crosslinked carboxy terminal telopeptide of type I collagen (ICTP) in patients with early onset rheumatoid arthritis (RA) and to assess its correlation with clinically relevant features of the disease., Methods: The serum ICTP concentration was measured in 99 adult patients with RA with a duration of disease less than one year. The main clinical outcome measures were joint count, modified Lansbury index, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Larsen index and number of erosions in peripheral joints., Results: There was a strong positive correlation (p < 0.001) between the serum ICTP concentration and the Lansbury joint index and a weaker but still significant correlation (p < 0.01) between the serum ICTP concentration and the number of eroded hand and foot joints., Conclusion: Serum ICTP may have value as a marker of tissue destruction in patients with early RA.

Objective: To examine the severity of rheumatoid arthritis (RA), as defined by the American Rheumatism Association (ARA) 1987 revised criteria, at the population level., Methods: The level of functional disability of the 103 patients with RA who represented practically all subjects with RA in a rural community of 13,000 adult inhabitants was assessed by the ARA Functional Classification and the Health Assessment Questionnaire (HAQ)., Results: Only one of the 103 patients was bedridden (ARA Class IV). According to the HAQ Functional Disability Index (FDI) two thirds of the patients had mild or at most moderate disability. Overall, less than 10% of the patients in the community were severely disabled., Conclusion: The level of disability in our series is lower than that reported earlier in populations with RA. These patients were treated aggressively with a median interval of one year from the first joint symptoms to the start of disease modifying antirheumatic drugs and had a median number of 2 orthopedic operations. How these interventions influenced the result cannot be accurately assessed on the basis of our cross sectional study protocol. However, high grade impairment due to destruction of large joints of lower limbs was in most instances compensated by total joint replacement surgery, performed in 20% of the cases in the series. This may partly explain the low prevalence of totally disabled patients with severe restriction in mobility in this population.

Objective: To determine how well self-report functional ability reflects the impairment due to the arthritic process in rheumatoid arthritis (RA) and how much it is affected by other factors of health status., Methods: We examined the relationships between self-report measures such as the Health Assessment Questionnaire (HAQ) and Arthritis Impact Measurement Scales (AIMS) and measures of impairment such as the Keitel function test (KFT), which is intended to reflect the degree of functional limitation of the joints, grip strength and radiological destruction as well as anxiety and depression in a population-based series of RA., Results: First, the HAQ and AIMS had a high correlation coefficient (r = 0.89, p < 0.0001). Second, the above measures of impairment were more significant predictors of self-report functional measures than, for example, mental health perceptions. The AIMS scales also correlated well with the corresponding physical function of the KFT., Conclusion: Patients' self-report functional ability in RA reflects their physical impairment due to the arthritic joint disease and is less influenced by other factors such as emotional adjustment.

We tested the traditional format of the American Rheumatism Association (ARA) 1987 revised criteria for the classification of rheumatoid arthritis (RA) in a cohort of 220 subjects with drug reimbursement for chronic rheumatic diseases extracted from the National Sickness Insurance Register, in a community of 18,000 people in Finland. One hundred and nine of the 193 who consented to the study both met the new ARA criteria for RA and had disease onset after 16 years of age, giving a cumulative prevalence of 0.8% in the population of 13,300 over 16 years. The disease of 6 of them, however, fulfilled the criteria and clinical picture of some other rheumatic disease. Thus 103 patients had RA as the only diagnosis. The female:male ratio in the 103 patients was 1.7:1. Ninety-one (88%) had seropositivity at some time in their disease and 99 (96%) had erosive joint disease. In most instances the 12 seronegatives had either mild or nontypical RA and only one of them was male. The 103 patients who met the new ARA criteria had significantly more interventions, such as hospitalization, drug treatment and orthopedic surgery, than the subjects (n = 42) who despite a clinician's primary diagnosis of RA did not fulfill the criteria. Thus the new ARA criteria distinguish clinical and severe cases of RA from nonclinical or non-RA cases when applied to a population based cohort of subjects with chronic rheumatic diseases registered for drug reimbursement.

To acquire more information on the controversial question of a possible association between rheumatoid arthritis (RA) and insulin dependent diabetes mellitus we searched for insulin dependent diabetes mellitus among patients hospitalized due to RA in 2 rheumatism hospitals in Finland. Nine subjects with insulin dependent diabetes mellitus were found among an annual number of 1460 patients admitted to one of the hospitals due to RA. These figures give a frequency of insulin dependent diabetes mellitus in patients with RA of 0.6% (95% confidence interval 0.2-1.0%), which does not exceed the prevalence of insulin dependent diabetes mellitus among the middle aged population of Finland in general (0.5-0.6%). Accordingly, no overrepresentation of homozygosity for HLA-DR4 was found among the total number of 25 patients with RA as well as insulin dependent diabetes mellitus, though the opposite might be expected as these diseases have a common DR4 association--RA with DR4 and DR1 and insulin dependent diabetes mellitus with DR4 and DR3. Instead, an increased frequency of DR1 (p less than 0.0002) and the antigen combination DR1/4 (p less than 0.01) was found in the subjects with both RA and insulin dependent diabetes mellitus compared with the subjects with insulin dependent diabetes mellitus alone.