Prospective multicenter evaluation of the morphometric D-score for prediction of the outcome of endometrial hyperplasias.

Prospective multicenter evaluation of the WHO classification and the morphometric D-score to predict endometrial hyperplasia cancer progression. In 132 endometrial hyperplasias WHO classification was performed by two experienced gynecologic pathologists. The D-score was assessed blindly by technicians in a routine diagnostic setting. Development of endometrial carcinoma during a 1-10-year follow-up was used as the end point. Eleven of 132 patients (8%), 10 of 61 (16%) atypical hyperplasias, and 1 of 71 (1%) nonatypical hyperplasias developed cancer. Twenty-six curettings had a D-score < or = 0 ("unfavorable" or endometrial intraepithelial neoplasia) of which 10 (38%) developed cancer. None of the 86 cases with a D-score > 1 ("favorable") and one of the 20 (5%) cases with 0 < D-score < or = 1 ("uncertain") developed cancer. Sensitivity of the D-score was 100%, specificity 82%, the positive and negative predictive values were 38% and 100%, respectively. These values are similar to those in three prior retrospective D-score studies but higher than the WHO values (which are 91%, 58%, 16%, and 99%, respectively). The D-score in endometrial hyperplasias is a more sensitive and specific marker for cancer prediction than the WHO classification, can be assessed in a routine clinical setting on standard hematoxylin and eosin sections (15-30 minutes per case), and is highly reproducible and cost-effective (U.S. $50 per case).

Raised serum IgA to common cell envelope antigens supports enterobacterial inductive contribution to pathogenesis of secondary ankylosing spondylitis.

Ankylosing spondylitis (AS) is closely associated with the histocompatibility antigen HLA-B27. Pathogenesis of AS is thought to involve interactions between B27 and certain enterobacterial antigens. However, enterobacterial involvement is uncertain and contested by some. The present paper demonstrates raised serum IgA to a common enterobacterial heat modifiable major outer membrane protein (h-momp; Mr 35,000) in active AS (N = 25; IgA = 1485 +/- 20) compared with controls, who were hospital patients without known arthropathies or gastro-intestinal disease (N = 12; IgA = 548 +/- 59). Serum IgG and IgM did not differ statistically. Raised serum IgA to h-momp might indicate enterobacterial antigenic stimulation from the gastro-intestinal tract and thus support an inductive contribution of enterobacterial antigens to the pathogenesis of secondary AS. It does not necessarily imply direct involvement in the pathogenesis of primary AS. H-momp appears to be a convenient tool for serological studies of AS and at present is likely to be more suitable than other bacterial antigens.

Cyclosporine in rheumatoid arthritis.

The efficacy and toxicity of cyclosporine in the treatment of patients with rheumatoid arthritis (RA) are reviewed. Most of the early trials were restricted to patients with intractable RA. The initial daily dose of cyclosporine was 5 to 10 mg/kg, which is now considered high. Of 283 cyclosporine-treated patients in nine studies, 8% discontinued the drug prematurely because of inefficacy and 17% because of adverse reactions. Cyclosporine improves clinical parameters but does not influence the erythrocyte sedimentation rate. The most important side effects are gastrointestinal intolerance and nephrotoxicity. The former is of minor importance with the present dosage schedule (starting daily dose, 2.5 mg/kg), and increments should follow the principle "go low, go slow." Guidelines are given to avoid or reduce nephrotoxicity. It may be beneficial to administer cyclosporine early in the course of RA.

Ankylosing spondylitis and peripheral joint disease.

We reviewed 13 patients with Ankylosing Spondylitis and radiologically demonstrated peripheral arthritis. Due to seriousness and extensiveness, we could distinguish three subgroups.

Plasma viscosity and erythrocyte sedimentation rate in inflammatory and non-inflammatory rheumatic disorders.

Plasma viscosity (PV) and erythrocyte sedimentation rate (ESR) are considered to reflect the complex of acute phase reactants in inflammations. Both tests were studied with regard to their ability to discriminate between inflammatory and non-inflammatory rheumatic diseases. PV and ESR were measured using the Coulter Viscometer II and the Westergren method, respectively. ESR was found to be a better parameter for rheumatoid arthritis and ankylosing spondylitis than PV, independent of the chosen reference values, age, gender and the hemoglobin level. ESR may still be regarded as an acceptable parameter for monitoring inflammatory rheumatic diseases.

Sequential joint scintigraphy in rheumatoid arthritis.

In this sequential study joint scintigraphy was compared with clinical and röntgenological evaluation in 19 patients with rheumatoid arthritis. Scintigraphy sometimes preceded clinical and radiological abnormalities and scan results were independent of radiological findings showing no differences when large and small joints were compared. Scan findings in 2 patients with arthralgias only were negative, suggesting that arthritis was unlikely.

Chloroquine therapy in patients with recent-onset rheumatoid arthritis: the clinical response can be predicted by the low level of acute-phase reaction at baseline.

If rheumatoid arthritis (RA) patients with a mild disease course could be identified early in the phase of the disease, therapy with less aggressive and probably less toxic antirheumatic drugs seems to be rational. The aim of this study was to investigate which factors at baseline could predict a clinical response (American College of Rheumatology preliminary response criteria) after treatment with chloroquine for 16 weeks. Two hundred and three early RA patients with active disease were treated with oral chloroquine sulphate (Nivaquine) at a daily dose of 300 mg during the first 4 weeks, 200 mg during the second 4 weeks and 100 mg thereafter. One hundred and eighty-three patients (90%) completed the study and 20 patients prematurely discontinued treatment. Of all the patients, 43 patients (21%) met the response criteria. A low level of C-reactive protein (CRP) was the only independent predictor for clinical response [relative risk: 0.97 (95% confidence interval: 0.95-0.98)]. It was concluded that a clinical response to chloroquine therapy in early RA patients can be predicted by a low CRP level at baseline.

[No difference in effectiveness measured between treatment in a thermal bath and in an exercise bath in patients with rheumatoid arthritis]. / Geen verschil in effectiviteit gemeten tussen behandeling in een thermaalbad en in een oefenbad bij patiënten met reumatoïde artritis.

OBJECTIVE: To determine whether hydrotherapy in a thermomineral institution is superior to the same hydrotherapy in an ordinary hospital exercise-bath. DESIGN: Controlled therapeutic trial. SETTING: The thermomineral institution at Arcen and the exercise bath at the Maasland Hospital in Sittard, the Netherlands. PATIENTS AND METHODS: 46 patients with rheumatoid arthritis were treated in a by a skilled physiotherapist, according to a standardized exercise-scheme: 27 were treated in the thermomineral institution and 19 (control-group) in the hospital exercise-bath. Each patient received 12 treatments in 12 weeks. ENDPOINTS PARAMETERS: Morning stiffness, erythrocyte sedimentation rate, Ritchie index, amount of pain, answers to 11 questions concerning the activities of daily life, and psychosocial aspects of the disease. The various subjective and objective parameters were scored by the same physician. RESULTS: Statistically significant improvement was observed in both groups concerning morning stiffness. Other subjective parameters improved, but did not reach significance. Objective parameters did not change significantly. Between-group differences were not found. CONCLUSION: Hydrotherapy has a positive effect on some subjective but not on objective parameters in patients with rheumatoid arthritis, whether it is applied in a thermomineral institution or an ordinary hospital exercise bath.

Isolated lesions of the manubriosternal joint in patients with inflammatory back pain and negative sacroiliac and spinal radiographs.

The prevalence of radiological lesions of the manubriosternal joint was assessed in 151 patients with chronic inflammatory back pain and in 31 controls with non-inflammatory back pain. Nineteen out of these 151 patients and none of the controls showed unequivocal lesions of the manubriosternal joint without accompanying radiological lesions of the sacroiliac joints or the lumbar spine. Thoracic pain and stiffness were present in 7 out of the 19 patients and in 3 out of the 31 controls (P less than 0.05); peripheral enthesopathy was present in 10 out of the 19 patients and in 4 out of the 31 controls (P less than 0.01); none of the patients or controls had rheumatoid factor, subcutaneous nodules, or peripheral arthritis. The suggestion of a "manubriosternal joint syndrome" is warranted by these findings.

A double-blind, randomized trial to compare meloxicam 15 mg with diclofenac 100 mg in the treatment of osteoarthritis of the knee.

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID), which, in animal tests, displays a high potency for anti-inflammatory and analgesic action. The aim of this study was to investigate the efficacy and tolerability of 15 mg meloxicam in comparison with 100 mg slow-release diclofenac in patients with osteoarthritis of the knee. Two hundred and fifty-eight patients were included in the intent-to-treat analysis; these were randomized into two groups to receive either 15 mg meloxicam (N = 128) or 100 mg diclofenac (N = 130) for a period of 6 weeks. The results with respect to efficacy showed a trend in favor of meloxicam regarding pain on movement, global efficacy and paracetamol consumption, although these differences did not reach statistical significance. The most frequently-occurring adverse events in both groups were of a gastrointestinal (GI) nature. However, there was a higher incidence (26 vs 16%) of GI adverse events in the diclofenac group compared with the meloxicam group. Both drugs were well tolerated when assessed by the patients on a visual analog scale (VAS). Thus, 15 mg meloxicam is an effective and well-tolerated therapy for osteoarthritis and compares favorably with diclofenac 100 mg, a well-established treatment for this indication.

Evaluation of diagnostic criteria for ankylosing spondylitis: a comparison of the Rome, New York and modified New York criteria in patients with a positive clinical history screening test for ankylosing spondylitis.

The modified New York criteria for the diagnosis of ankylosing spondylitis were evaluated and compared to the older criteria in 151 patients, referred to hospital because of low back pain and who had a positive clinical history screening test for ankylosing spondylitis and in 31 controls with non-inflammatory back pain. Radiological examination of the sacro-iliac joints showed sacro-iliitis in 124 (82%) from the 151 with inflammatory back pain. In 110 (72%) of those patients a diagnosis of definite ankylosing spondylitis according to the classical New York criteria could be made and they had a prevalence of HLA-B27 of 84%. Application of the modified New York scheme increased the number of patients meeting the criteria for definite ankylosing spondylitis to all 124 patients with sacro-iliitis, and 82% of this group carried HLA-B27. The classical New York criteria of 'limitation of the lumbar spine in three directions' and of 'limitation of chest expansion' appeared to reflect disease duration rather than help in the initial diagnosis.

Longterm cyclosporine therapy in rheumatoid arthritis.

Sixteen patients who had shown a good clinical response to cyclosporine therapy during a randomized 6-month double blind study comparing cyclosporine with D-penicillamine in active rheumatoid arthritis, had an opportunity to participate in an open study with cyclosporine. The initial daily dose of cyclosporine was 5 mg/kg. Before the planned maximal duration of 18 months, there were 6 premature discontinuations, 2 because of inefficacy, 2 because of side effects, and 2 for other reasons. During the study there was an improvement in all clinical variables. Even under the strict conditions of our trial there was an irreversible loss of about 15% of renal function. Suggestions are given to minimize the chance of nephrotoxicity.

Cyclosporin A therapy in rheumatoid arthritis: only strict application of the guidelines for safe use can prevent irreversible renal function loss.

OBJECTIVES: To investigate (1) whether the increase in serum creatinine observed during cyclosporin A (CsA) therapy was reversible in a group of patients with rheumatoid arthritis (RA) treated before the current guidelines for safe use in RA were developed and (2) whether the application of these guidelines prevents serum creatinine increases in the long term. PATIENTS AND METHODS: Eighty-three RA patients who had started low-dose CsA therapy between September 1990 and October 1992, and who were treated according to guidelines that allowed a 50% rise in serum creatinine, were tested for serum creatinine levels in December 1995 if they had discontinued CsA for at least 3 months. Predictors for irreversibility of renal function were determined by using multiple regression analysis. RESULTS: The mean level of serum creatinine gradually increased from 69+/-14 (mean+/-S.D.) micromol/l when starting CsA therapy to 88+/-23 micromol/l (28% above baseline) at the moment of CsA discontinuation, and had decreased to 80+/-17 micromol/l (16% above baseline) at follow-up, 35+/-14 months after drug discontinuation. During CsA therapy, the mean level of serum creatinine had increased to 82+/-19 micromol/l (26% above baseline) at 6 months and to 87+/-22 micromol/1 (39% above baseline) at 42 months. The mean CsA dose had decreased from 3.1+/-0.9 mg/kg/day at 6 months to 1.9+/-0.8 mg/kg/day at 42 months. The absolute number of months that serum creatinine levels were > 30% above baseline was an independent predictor for a persistent increase of the serum creatinine after CsA discontinuation. More than 2 months with a serum creatinine increase of > or = 30% resulted in a higher percentage irreversible increase than for less than 2 months with a > or = 30% increase: 27 and 6%, respectively (P < 0.0001). CONCLUSION: Long-term low-dose CsA administration in RA patients was associated with an increase in serum creatinine which was partially irreversible after drug discontinuation. The increase in serum creatinine was completely reversible in the patient group that was treated according to the current guidelines for safe use of CsA.

Antibodies to Enterobacteriaceae in ankylosing spondylitis.

Serological studies on ankylosing spondylitis (AS; N = 82) show that although statistically more AS patients than controls (N = 24) may possess elevated serum titres to enterobacteria such as Salmonella, Shigella and Yersinia, this does not necessarily imply enterobacterial involvement in AS, as other groups without enteritis or arthropathies that frequent health care facilities (N = 72) may also display this phenomenon, presumably due to increased exposure. Moreover, an inventory of all detectable antibody reactivities to the separated cell envelope antigens of five enterobacterial species suspected of involvement in AS (notably Enterobacter, Klebsiella, Salmonella, Shigella and Yersinia) failed to reveal statistical associations with AS. This might be explained, assuming that the aetiology of AS entails a set of enterobacteria rather than a few individual species. It is proposed that serological studies on AS should be supported by additional information, e.g. that of the faecal carriage, and that these combined studies encompassing other enterobacteria, in addition to Klebsiella, might be fruitful.

A randomized, double-blind, 24-week controlled study of low-dose cyclosporine versus chloroquine for early rheumatoid arthritis.

OBJECTIVE: To investigate whether low-dose cyclosporin A (CSA) is safe and effective in comparison with chloroquine (CQ) in patients with early rheumatoid arthritis (RA). METHODS: We performed a randomized, double-blind study comparing CSA with CQ in patients with early RA (duration < 2 years) who had had active disease for at least 3 months. Forty-four RA patients with a mean disease duration of 6 months were randomly allocated to receive CSA (initial dosage 2.5 mg/kg/day, maintenance dosage 3.6 mg/kg/day) or CQ (initial dosage 300 mg/day, maintenance dosage 100 mg/day) for 24 weeks. RESULTS: Five patients (2 taking CSA and 3 taking CQ) discontinued the study prematurely. Intention-to-treat analysis disclosed a decrease in the swollen joint count by 7 in both groups. The erythrocyte sedimentation rate and C-reactive protein level did not change significantly. CSA and CQ were tolerated equally well, although mild paraesthesia occurred more frequently in the CSA-treated group. The serum creatinine level increased by 13 mumoles/liter (95% confidence interval [95% CI] 4, 22) in the CSA group and by 6 mumoles/liter (95% CI 1, 11) in the CQ group (difference not statistically significant). CONCLUSION: Both CSA and CQ are effective in alleviating the symptoms of active early RA. There is only slightly impaired renal function after 24 weeks of drug administration of either drug in patients with early RA.