Radiographic remission in seropositive rheumatoid arthritis. A 20-year follow-up study.

OBJECTIVE: Rheumatoid arthritis (RA) is in most instances a progressive disease. Very little information is available on halting of the radiographic damage, particularly in later phases of the disease. We studied radiographic remission of RA lasting to the end of follow-up, covering the period 1973-96. METHODS: Radiographs of hands and feet were taken at onset and at 1, 3, 8, 15 and 20 years from entry in 102 cases of recent onset (< 6 months) seropositive and erosive RA. A Larsen score of 0-100 was formed for 20 joints of hands and feet. If the score did not worsen by more than one point between one of the above time points and the end of the study, the patient was considered to be in remission. RESULTS: Remission was confirmed in 27 (26%) of the patients. In 3 cases the remission was from the 1-year check-up, in 5 from the 3-year check-up, in 6 from the 8-year check-up and in 13 cases from the 15-year check-up. Some of the remission cases had a mild disease from the outset, but there were cases in which the disease process had led to marked joint destruction before slowing down. CONCLUSION: This data may serve as a basis for comparison with subsequent cohort studies on new treatments-of-choice.

Secondary amyloidosis has decreased in patients with inflammatory joint disease in Finland.

We studied whether the high incidence of secondary amyloidosis (SA) is a consistent finding in patients with inflammatory joint disease. A total of 4508 biopsies of patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis were studied at the Rheumatism Foundation Hospital during 1987-1997. The results show that the annual number of findings of SA was reduced from 68 to less than 10. We suggest that a change in medication towards more frequent use of cytostatic agents is the reason for the reduction in incidence of SA.

Antifilaggrin antibodies in recent-onset arthritis.

We evaluated the sensitivity and prognostic value of an enzyme-linked immunosorbent assay (ELISA) for the measurement of antifilaggrin antibodies (AFA), using filaggrin purified from human skin as an antigen. The AFA test was applied to a series of 306 patients with various recent-onset inflammatory joint diseases. The results were compared to those of the conventional immunofluorescence tests for antikeratin antibody (AKA) and antiperinuclear factor (APF) and of the rheumatoid factor (RF) tests from a previous study. There was a very good agreement between the results of the tests for APF and AFA (kappa-value 0.79 in patients with peripheral poly/oligoarthritis). The agreement between the tests for AKA and AFA was significant but less pronounced (kappa-value 0.50). The AFA test detected 10/22 of the RF-negative erosive cases, particularly those with a large number of erosive joints. Thus, the test for AFA supplements RF in the prediction of erosiveness.

Weight-bearing physical activity, calcium intake, systemic glucocorticoids, chronic inflammation, and body constitution as determinants of lumbar and femoral bone mineral in juvenile chronic arthritis.

The associations between the lumbar and femoral bone mineral and several body constitutional, lifestyle, and disease related variables were studied in 111 children with juvenile chronic arthritis (JCA) by factor and multiple linear regression analyses. In addition to the measurement of bone mineral density (BMD), bone width and bone mineral volumetric density (BMDvol) were determined by dual-x-ray absorptiometry (DXA). Factor analysis of 13 explanatory variables yielded six non-correlating factors, named as body size, physical activity, calcium intake, glucocorticoids, disease duration, and disease activity. These six factors were used as new variables to explain BMD, BMDvol, and bone width by multiple linear regression analyses. These showed body size, physical activity, and calcium intake as significant positive and disease activity and glucocorticoids as significant negative determinants of BMD in JCA. The analyses revealed also considerable differences in the relationships between factors and BM Dvol or bone width.

Development of bone mineral density at the lumbar spine and femoral neck in juvenile chronic arthritis--a prospective one year followup study.

OBJECTIVE: To determine the magnitude of lumbar and femoral bone mineral gain in patients with juvenile chronic arthritis (JCA) using dual X-ray absorptiometry. METHODS: Bone mineral density (BMD) was measured at entry and again after 12 months at the lumbar spine and femoral neck in healthy children (n = 65) and children with oligoarticular (n = 36) and polyarticular (n = 69) JCA. Five of the oligoarticular and 38 polyarticular patients were treated with systemic glucocorticoids. In addition to the changes in BMD, the annual changes in calculated bone mineral volumetric density (BMDvol) and bone size were determined simultaneously. RESULTS: In polyarticular JCA, the acquisition of BMD was decreased at the femoral neck (2.2 vs 4.8%; p < 0.05), but remained the same at the spine compared with healthy children; in oligoarticular JCA, the increase in BMD at the femoral neck was similar to that in controls, but significantly increased at the spine compared with the change in the control group (7.4 vs 4.9%; p < 0.05). The detected annual changes in BMD were associated with the changes in BMDvol. Bone mineral gain was significantly delayed at the lumbar spine in children treated with glucocorticoids. CONCLUSION: In children with JCA, the development of bone mineral is different at the lumbar spine and at the femoral neck, but it also depends on the subtype of JCA and on the use of systemic glucocorticoids.

Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment.

Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19%; P < 0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P < 0.001), nausea and vomiting (P < 0.05), abdominal pain (P < 0.001) and diarrhoea (P < 0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P < 0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P < 0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.01% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P < 0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may in part reflect the preferential COX-2 selectivity of meloxicam, although the dose and other aspects of tolerability may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.

Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis.

SELECT is a large-scale, prospective, international, multicentre, double-blind, double-dummy, randomized, parallel-group trial. Patients with exacerbation of osteoarthritis were treated with the recommended dose of meloxicam (7.5 mg) or piroxicam (20 mg) once daily for 28 days; 4320 patients were administered meloxicam and 4336 piroxicam. The incidence of adverse events was significantly lower in the meloxicam group (22.5%) compared with the piroxicam group (27.9%; P < 0.001), mainly due to the significantly lower incidence of gastrointestinal (GI) adverse events in the meloxicam than in the piroxicam group (10.3% vs 15.4%,; P < 0.001), while the efficacy of both drugs was equivalent. Individual GI events occurred significantly less often with meloxicam than piroxicam: dyspepsia (3.4% vs 5.8%; P < 0.001), nausea/vomiting (2.5% vs 3.4%; P < 0.05) and abdominal pain (2.1% vs 3.6%; P < 0.001). There were 16 patients with perforations, ulcerations or bleeding (PUBs) of the upper GI tract in the piroxicam group compared with seven in the meloxicam group (relative risk piroxicam:meloxicam = 1.4). Four PUBs were complicated (perforations or bleedings); none of these occurred in the meloxicam group (relative risk piroxicam:meloxicam = 1.9). The outcome of SELECT is consistent with that of the large-scale clinical trial of similar design and size which compared 7.5 mg meloxicam with 100 mg diclofenac in patients with osteoarthritis, and with a previous global analysis of the safety of meloxicam. It adds further data to the proposed relationship between selective inhibition of cyclooxygenase-2 and improved GI tolerability of non-steroidal anti-inflammatory drugs.

IgM, IgG and IgA class enterobacterial antibodies in serum and synovial fluid in patients with ankylosing spondylitis and rheumatoid arthritis.

IgM, IgG and IgA class antibodies against three Klebsiella pneumoniae capsular types, Escherichia coli and Proteus mirabilis, as well as total immunoglobulin concentrations, were measured by enzyme immunoassay and radial immunodiffusion technique, respectively, in paired serum and synovial fluid samples from eight patients with ankylosing spondylitis and 10 with rheumatoid arthritis. No clear evidence for intra-articular antibody production against any of the studied microbes was found.

Elevated incidence of hematologic malignancies in patients with Sjögren's syndrome compared with patients with rheumatoid arthritis (Finland).

The risk of hematologic malignancies was studied in Finnish patients with rheumatoid arthritis or Sjögren's syndrome, and the difference in the risk between those diseases was evaluated. The study cohorts comprised 676 patients with primary Sjögren's syndrome, 709 with secondary Sjögren's syndrome, and 9,469 with rheumatoid arthritis identified from the Finnish hospitals' national discharge register. The follow-up times were 5,336, 4,254 and 65,391 person-years, respectively. Data on the incidence of malignancies were collected from the files of the Finnish Cancer Registry. The incidence of hematologic malignancies was elevated in the study cohorts. The standardized incidence ratio (SIR) of non-Hodgkin's lymphoma was: 2.2 (95 percent confidence interval [CI] 1.5-3.1) for rheumatoid arthritis; 4.5 (CI = 1.5-11) for secondary Sjögren's syndrome; and 8.7 (CI = 4.3-16) for primary Sjögren's syndrome. The ratio of the SIR of primary Sjögren's syndrome cf rheumatoid arthritis alone was 3.9 (CI = 1.8-8.0) in non-Hodgkin's lymphoma, and 3.4 (CI = 1.2-8.1) in other hematologic cancers. The incidence of hematologic malignancies, especially that of non-Hodgkin's lymphoma, is elevated in patients with rheumatoid arthritis. It is higher in patients with secondary Sjögren's syndrome and highest in patients with primary Sjögren's syndrome. Differences in the immunologic aberration influence oncogenesis.

Antibody to stratum corneum (antikeratin antibody) and antiperinuclear factor: markers for progressive rheumatoid arthritis.

The purpose of this study was to examine the relationship between circulating antibodies to stratum corneum (AKA) and antiperinuclear factors (APF) on one hand, and the x-ray progression of joint damage in chronic poly/oligoarthritis on the other hand. The analysis involved 133 patients with either rheumatoid or nonspecific arthritis derived from a cohort of 442 patients with recent onset arthritis. The patients were followed up for eight years with regular clinical, laboratory, and radiological evaluations. Radiographic evidence of joint destruction was quantitated by a radiographic index based on the Larsen grading. AKA and APF were detected, either at entry or at follow-up, in 26 and 54 patients, respectively. Seventy-six of the 133 patients had developed erosions. All AKA-positive patients had a rheumatoid factor-positive erosive poly-arthritis. The presence of APF was also associated with a progressive arthritis although four APF-positive patients had a non-erosive disease. Neither AKA nor APF were able to distinguish a particularly severe form of progressive RA.

Azathioprine in patients with juvenile chronic arthritis: a longterm followup study.

OBJECTIVE: To evaluate drug survival, efficacy, side effects, and longterm toxicity of azathioprine treatment in patients with juvenile chronic arthritis (JCA). METHODS: In an uncontrolled, prospective study we evaluated 129 consecutive patients with JCA refractory to therapy in whom azathioprine treatment was begun during 1980-1989. In the first 29 patients, a 2 year trial was planned, while for the remaining 100 patients the protocol was to continue until remission or dropout. The median treatment period was 13 months (range 3 days-8.5 yrs). Patients were assessed every 2 months for 2 years for efficacy, side effects, growth and need for glucocorticoids, and outcome evaluated in late 1996. RESULTS: Remission without drugs was attained in 19 patients (15%); in addition, temporary remission in patients continuing treatment was attained in 18 cases (14%). Treatment was discontinued due to side effects in 18 cases (14%); in two-thirds of these cases side effects occurred during the first 2 months. Of the total number of patients, 49 (38%) completed 2 years of treatment, with significant improvement in both clinical and laboratory indices of disease activity. Treatment had no noticeable effect on iridocyclitis. One patient died of cytomegalovirus infection during azathioprine treatment. CONCLUSION: Azathioprine is a useful drug in severe JCA, with a sustained effect and acceptable side effects. Even in cases of incomplete remission, its glucocorticoid sparing effect was noteworthy.

Peripheral blood neutrophil leukotriene B4 release and migration in rheumatoid arthritis.

The present study was designed to compare peripheral blood neutrophil migration and leukotriene (LT) release between patients with rheumatoid arthritis (RA) and healthy controls and to correlate the neutrophil functions with clinical disease activity. Nineteen patients with moderately active RA and 19 age and sex matched healthy volunteers participated in this study. Isolated peripheral blood neutrophils from RA patients released equal amounts of LTB4 but their random migration was enhanced as compared with neutrophils from healthy controls. LTB4 release in whole blood was significantly lower in samples from RA patients than in those from the healthy volunteers (13.5 +/- 1.4 and 19.1 +/- 1.4 ng/10(6) neutrophils respectively; P < 0.001). LTB4 release from isolated RA neutrophils correlated with the levels of C-reactive protein, duration of morning stiffness and Ritchie articular swelling index. Concentrations of hyaluronate, cyclic AMP and 13, 14-dihydro-15-keto prostaglandin were not different between patients with RA and healthy volunteers. Neither was there any difference in TXB2 production by platelets during blood clotting. In conclusion, peripheral blood neutrophils of RA patients seem to be primed and/or activated as their random migration is enhanced as compared with those of healthy volunteers. In RA, LTB4 release from peripheral blood neutrophils seems to reflect the clinical activity of the disease. However, RA neutrophils released smaller (in whole blood) or equal (isolated cells) amount of LTB4 as compared with the respective controls. These contradictory findings suggest that LTB4 release from peripheral blood neutrophils has no major role in the regulation of disease activity in rheumatoid arthritis.

Incidence of rheumatoid arthritis in Finland during 1980-1990.

OBJECTIVE: To obtain information on the incidence of rheumatoid arthritis and on its recent trends in Finland. METHODS: The study covered those subjects entitled to receive specially reimbursed medication for rheumatoid arthritis under the nationwide sickness insurance scheme in five out of 21 central hospital districts in Finland (population basis about one million adults) during three years: 1980, 1985, and 1990. RESULTS: The annual incidence of rheumatoid arthritis in 1980 and 1985, satisfying the American Rheumatism Association 1987 classification criteria, was 39/100,000 of the population > or = 16 years of age. The combined incidence of rheumatoid factor (RF) positive arthritis and RF negative polyarthritis was 46/100,000. A decline of approximately 40% occurred in the number of RF negative rheumatoid arthritis cases in 1990 compared with the earlier years. The declining trend was statistically significant (P = 0.008). CONCLUSION: The decline in incidence of RF negative rheumatoid arthritis in Finland may reflect changes in the environment specifically affecting the risk of RF negative disease.

Shift in the incidence of rheumatoid arthritis toward elderly patients in Finland during 1975-1990.

OBJECTIVE: To obtain information on changes in the age distribution of new cases of rheumatoid arthritis (RA) in Finland. METHODS: The present study covered those subjects entitled under the nationwide sickness insurance scheme to receive specially reimbursed medication for RA in 5/21 central hospital districts in Finland (population base about one million adults) in 1975, 1980, 1985, and 1990. RESULTS: During the four study years 1321 incident cases occurred, which satisfied the American Rheumatism Association 1987 classification criteria for RA. The mean age at diagnosis increased by 7.6 years from 1975 (50.2 years) to 1990 (57.8 years). No appreciable differences occurred between men and women. The incidence rates declined in the younger age groups. CONCLUSION: The epidemiology of RA is in a dynamic state. The trends may reflect marked changes in the host-environment relationship.

Low incidence of colorectal cancer in patients with rheumatoid arthritis.

OBJECTIVE: Aspirin (ASA) and also nonsteroidal anti-inflammatory drug (NSAID) use has been associated with a low incidence of colorectal cancer. The incidence of colorectal cancer in a cohort of patients with rheumatoid arthritis (RA) is reported here. METHODS: Cancer incidence was studied in a cohort of 9469 persons hospitalized for RA during 1970-1991 in Finland. The follow-up time was about 65,400 person-years. RESULTS: The incidence of colon cancer was significantly lower than in the general population [standardized incidence ratio (SIR) 0.57; 95% confidence interval (CI) 0.33-0.93], and the combined SIR for colorectal cancer was 0.62 (95% CI 0.42-0.88), while the combined incidence of all malignancies (SIR 1.16; 95% CI 1.07-1.26) was higher in RA patients than in the general population. CONCLUSION: Chronic use of NSAIDs or ASA, including antiinflammatory doses, is probably the main explanation for the low incidence of colorectal cancer in RA patients.