Pretreatment resistin levels are associated with erosive disease in early rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs and infliximab.

OBJECTIVE: Resistin is an adipocytokine related to insulin resistance and inflammation. We investigated whether resistin is associated with disease activity and inflammation in disease-modifying anti-rheumatic drug (DMARD)-naïve rheumatoid arthritis (RA) patients, whether it has predictive value for radiological disease progression, and whether tumour necrosis factor-α (TNF-α) is involved in these effects. METHOD: Ninety-nine patients with early, DMARD-naïve RA participated in the NEO-RACo study. Patients were treated for the first 4 weeks with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone (FIN-RACo treatment). Thereafter, they were randomized to receive either infliximab or placebo added to the combination for 6 months. Patients were followed for 5 years. Disease activity was evaluated using the Disease Activity Score based on 28-joint count-erythrocyte sedimentation rate, radiographs were scored with the modified Sharp-van der Heijde method, and plasma resistin concentrations were measured by immunoassay. Human THP-1 macrophages were used in the in vitro studies. RESULTS: A high resistin level at baseline was associated with active inflammatory disease and predicted more rapid radiological progression during 5 year follow-up. Adding infliximab to the DMARD combination delayed radiological progression and overcame the poor predictive value of resistin. Resistin increased TNF-α production in human macrophages, indicating a possible connection between resistin and TNF-α. CONCLUSION: The results suggest that high resistin concentration may be a useful marker to distinguish patients with an increased risk of erosive disease in early active RA, and that adding TNF-α antagonist to the traditional DMARD combination may delay radiological progression of the disease in these patients. The study has been registered at https://www.clinicaltrials.gov(NCT00908089).

Disease activity in and quality of life of patients with psoriatic arthritis mutilans: the Nordic PAM Study.

OBJECTIVE: To describe the social status and health-related quality of life of patients with psoriatic arthritis mutilans (PAM) in the Nordic countries. METHOD: Patients with at least one mutilated joint confirmed by radiology were studied. Disease activity involving joints and skin, physician-assessed disease activity, and patient's education and work status were recorded. Data from the 36-item Short Form Health Survey, Health Assessment Questionnaire and Dermatology Life Quality Index questionnaire were gathered and correlated with disease duration, pain, and general well-being (visual analogue scale). The controls were 58 Swedish patients with long-standing psoriatic arthritis sine PAM. RESULTS: Sixty-seven patients were included. Patients with PAM had a protracted disease history (33 ± 14 years) and disease onset at a relatively early age (30 ± 12 years). Overall inflammatory activity at inclusion was mild to moderate. The mean number of mutilated joints was 8.2 and gross deformity was found in 16% of patients. Forty per cent were treated with biological and 32% with conventional synthetic disease-modifying anti-rheumatic drugs. Forty-two per cent had retired early or were on sick leave. Impaired functional capacity with little or no ability to perform self-care or everyday tasks was reported by 21% of the patients. Patients between 45 and 60 years of age reported the most impaired quality of life in comparison to the control group. CONCLUSION: PAM seriously affects social functioning. Whether early recognition of PAM and new forms of therapy can improve disease outcome and quality of life remains to be studied.

Effect of oral clodronate on structural damage and bone turnover in rheumatoid arthritis.

OBJECTIVES: To study the effect of oral clodronate on structural damage and bone metabolism in rheumatoid arthritis (RA). METHODS: In this 2-year proof-of-concept study, sixty patients with at least moderately active RA were randomised to receive anti-rheumatic therapy alone or together with oral clodronate 1600 mg daily. Radiographs of hands and feet and serum samples for bone biomarkers were studied at baseline and at 24 months. RESULTS: At 24 months, progression of radiographic joint damage was similar in the 2 groups. Clodronate suppressed carboxyterminal cross-linked peptide of type I collagen (p=0.03) and aminoterminal propeptide of type I procollagen (p=0.01). Eight patients (27%) withdrew from clodronate therapy due to adverse drug reactions. CONCLUSIONS: Oral clodronate did not retard the focal bone damage in RA despite its beneficial effect on overall bone metabolism, as judged by the decrease in the reference bone biomarkers.

Anti-citrullinated peptide antibodies and the progression of radiographic joint erosions in patients with early rheumatoid arthritis treated with FIN-RACo combination and single disease-modifying antirheumatic drug strategies.

OBJECTIVES: To evaluate the impact of antibodies to cyclic citrullinated peptide (ACPAs) on radiographic progression in patients with early rheumatoid arthritis (RA) initially treated either with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD. METHODS: This study included 129 patients with early active RA initially randomised to treatment either with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone (FIN-RACo) (n=69) or with a single DMARD (initially sulfalasalazine) with or without prednisolone (SINGLE) (n=60). After 2 years, the use of DMARDs and prednisolone became unrestricted. Radiographic progression in hands and feet was assessed at baseline and at 1, 2, 3, 4 and 5 years. ACPAs at baseline were determined with enzyme immunoassay. RESULTS: ACPAs were positive in 92 (71%) patients. ACPA-positive vs. negative patients were more frequently rheumatoid factor (RF) positive (83% vs. 22%, p<0.001) and had an erosive disease (54% vs. 22%, p<0.001) at baseline. The presence of ACPA was associated with radiographic progression in FIN-RACo group even when the impact of RF was controlled; the radiographic progression was remarkably slower in ACPA-negative than in ACPA-positive cases (RF adjusted change over time between groups p=0.034). In the SINGLE group, the radiographic changes progressed parallel in ACPA-negative and positive patients. CONCLUSIONS: Most ACPA-positive RA patients have joint erosions already at diagnosis. ACPA positivity in early RA was related to radiographic progression even in patients treated initially with the FIN-RACo regimen. The initial FIN-RACo therapy seems to slow down the progression of joint damage in ACPA-negative patients.

Impact of early radiographic remission on the 15-year radiographic outcome in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the 15-year radiographic outcome in patients with rheumatoid arthritis (RA) in relation to early radiographic remission. METHODS: A cohort of 87 patients with RA, treated with early-initiated disease-modifying anti-rheumatic drug (DMARD) therapy, was followed up prospectively for 15 years. Radiographs of hands and feet were taken at baseline and at 1, 2, 3, 5, 7, 10, and 15 years, and radiographs of large joints at 15 years. Radiographic outcome was assessed by the Larsen score (LS). Early radiographic remission was defined as a change of ≤ 1 Larsen unit in a year, during the first 2 years. RESULTS: A complete set of radiographs for evaluation was available from 69 patients. Outcome was evaluated in three groups: group A comprised 18 (26%) patients with sustained early radiographic remission (at both year 1 and year 2); group B comprised 20 (29%) patients with temporary early radiographic remission (at either year 1 or year 2); and group C comprised 31 (45%) patients with no early radiographic remission. Radiographic outcome was most favourable in patients with sustained early radiographic remission. The mean change in LS over 15 years was 11 [95% confidence interval (CI) 0-22] in group A, 30 (95% CI 12-51) in group B, and 62 (95% CI 45-81) in group C (p < 0.001). A similar relationship to large joint damage (Larsen large joint score) was seen. CONCLUSIONS: Compared with patients with progressive erosions, our results indicate that early radiographic remission relates to a better long-term radiographic outcome in RA regarding both small joint and large joint changes.

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors.

Eighteen patients with refractory and progressive solid tumors were treated with a single round of triple modified oncolytic adenovirus (Ad5/3-Cox2L-D24). Ad5/3-Cox2L-D24 is the first non-Coxsackie-adenovirus receptor-binding oncolytic adenovirus used in humans. Grades 1-2 flu-like symptoms, fever, and fatigue were seen in most patients, whereas transaminitis or thrombocytopenia were seen in some. Non-hematological grades 3-5 side effects were seen in one patient with grade 3 ileus. Treatment resulted in high neutralizing antibody titers within 3 weeks. Virus appeared in serum 2-4 days after treatment in 83% of patients and persisted for up to 5 weeks. One out of five radiologically evaluable patients had partial response (PR), one had minor response (MR), and three had progressive disease (PD). Two patients scored as PD had a decrease in tumor density. Tumor reductions not measurable with Response Evaluation Criteria In Solid Tumors (RECIST) were seen in a further four patients. PR, MR, stable disease, and PD were seen in 12, 23.5, 35, and 29.5% of tumor markers analyzed, respectively (N=17). Ad5/3-Cox2L-D24 appears safe for treatment of cancer in humans and extended virus circulation results from a single treatment. Objective evidence of anti-tumor activity was seen in 11/18 (61%) of patients. Clinical trials are needed to extend these findings.

Can disease-modifying anti-rheumatic drugs be discontinued in long-standing rheumatoid arthritis? A 15-year follow-up.

OBJECTIVE: To investigate the 15-year outcome of patients with early rheumatoid arthritis (ERA) with respect to the continuity of treatment. METHODS: We conducted a 15-year follow-up study of 87 patients with ERA treated since diagnosis with disease-modifying anti-rheumatic drugs (DMARDs) according to the 'sawtooth' strategy. The patients were divided into groups according to the continuity of treatment: (A) 'continuous DMARDs', (B) 'discontinued and restarted DMARDs', and (C) 'permanently discontinued DMARDs'. The main outcome measurements included the Health Assessment Questionnaire (HAQ), the Larsen score, and clinical remission according to the American Rheumatism Association (ARA) criteria. RESULTS: Seventy (80%) patients participated in the 15-year follow-up. DMARDs were discontinued in 20 (29%) patients due either to remission or to a symptom-free period of the disease. The disease flared up in nine (45%) of these patients, in some patients several years after the discontinuation. At the 15-year follow-up, 59 (84%) patients were on DMARDs; only three (4%) were using biologicals. Functional capacity remained good in all groups (mean HAQ score 0.52). The mean Larsen score was higher (54) in group A than in groups B (25) and C (12) (p =0.001). The remission rate was 64% in group C and considerably lower in groups A (6%) and B (0%) (p<0.001). CONCLUSIONS: Our results indicate that most of the patients with long-standing RA require continuous DMARD treatment. If the treatment is discontinued, patients should be followed-up closely and DMARDs readministered without delay if the disease flares up.

Combination drug strategy in recent-onset rheumatoid arthritis suppresses collagen I degradation and is associated with retardation of radiological progression.

OBJECTIVE: To assess whether serum C-terminal cross-linking telopeptide of type I collagen (ICTP), a marker of type I collagen degradation, has any additional value in the assessment of treatment effect in patients with early rheumatoid arthritis (RA). METHODS: A total of 182 patients were randomized to treatment either with three disease-modifying anti-rheumatic drugs (DMARDs) and low-dose prednisolone (COMBI) or with a single DMARD with or without low-dose prednisolone (SINGLE). We investigated the prognostic value of serum ICTP level for the progression of joint destruction in X-rays (Larsen's score) from baseline to 2 years. RESULTS: There was a statistically significant decrease in serum ICTP levels from baseline to 1 year. At 6 months, the serum ICTP level was lower in the COMBI patients compared to that of the SINGLE cases (p = 0.008, after adjustment for baseline ICTP). When grouping the patients according to serum ICTP tertiles at 6 months, there was a statistically significant trend for increasing median change in Larsen score from baseline to 2 years from lowest to highest ICTP tertile in the SINGLE patients [p = 0.008, after adjustment for 28-joint Disease Activity Score (DAS28) score and RF status at baseline], while in the COMBI, the change remained low in all ICTP tertiles. CONCLUSIONS: The COMBI strategy for recent-onset RA results in early suppression of type I collagen degradation, which is reflected in radiological joint damage at 2 years. Serum ICTP at 6 months may be useful for identifying those RA patients whose treatment should be intensified to prevent further joint damage.

Preoperative assessment of focal liver lesions: multidetector computed tomography challenges magnetic resonance imaging.

PURPOSE: To investigate prospectively multidetector computed tomography (CT) (MDCT) and magnetic resonance (MR) imaging (MRI) in the preoperative assessment of focal liver lesions. MATERIAL AND METHODS: Multiphasic MDCT and conventional gadolinium-enhanced MRI were performed on 31 consecutive patients prior to hepatic surgery. All images were blindly analyzed as consensus reading. Lesion counts and their relation to vascular structures and possible extrahepatic disease were determined. The data from the MDCT and MRI were compared with the results obtained by intraoperative ultrasound (IOUS) and palpation. Histopathologic verification was available. RESULTS: At surgery, IOUS and palpation revealed 45 solid liver lesions. From these, preoperative MDCT detected 43 (96%) and MRI 35 (78%) deposits. MDCT performed statistically better than MRI in lesion detection (P=0.008). Assessment of lesion vascular proximity was correctly determined by MDCT in 98% of patients and by MRI in 87%. Statistical difference was found (P=0.002). IOUS and palpation changed the preoperative surgical plan as a result of extrahepatic disease in 8/31 (26%) cases. In MDCT as well in MRI extrahepatic involvement was suspected in two cases. CONCLUSION: MDCT was superior to MRI and nearly equal to IOUS in liver lesion detection and in the determination of lesion vascular proximity. However, both techniques fail to reliably detect extrahepatic disease.

Lumbosacral radiographic signs in patients with previous enteroarthritis or uroarthritis.

OBJECTIVE: To investigate if there are differences in radiological findings in lumbosacral spine radiographs between different subgroups of patients with previous reactive arthritis. METHODS: 95 patients with previous enteroarthritis (n = 53), uroarthritis (n = 37), or Reiter's syndrome, aetiology unknown (n = 5) were included in the study. Lumbosacral radiographs were taken 7 to 38 years after the initial arthritis. Three independent observers read the radiographs. Spinal changes included squaring of vertebrae, Romanus lesions, syndesmophytes, and osteophytes. Sacroiliitis was recorded according to the New York and Stoke methods. Signs of enthesitis in the iliac crest and disc space narrowing were recorded. Interobserver reliability and intraobserver reproducibility were determined. RESULTS: 23% of patients had grade 2-4 sacroiliitis (New York criteria) and 14% had syndesmophytes. There was more frequent sacroiliitis (32% v 13%) in uroarthritis than in enteroarthritis, and more syndesmophytes (mean 0.54 v 0.15 per patient; prevalence 24% v 6%, respectively). In other radiological features, no significant differences were present between the groups. In the material as a whole, patients with sacroiliitis of grade 2 or more had significantly less disc space narrowing both in patient comparisons (chi(2) test) and in numbers of spaces involved (Mann-Whitney test). Interobserver and intraobserver agreement, calculated using Cohen's kappa method, varied from 0.2 to 1. CONCLUSIONS: Syndesmophytes and sacroiliitis are more common in patients with previous uroarthritis than in those with previous enteroarthritis, but radiological findings in lumbosacral spine radiographs are characteristically similar.

Antibiotic treatment and long term prognosis of reactive arthritis.

OBJECTIVE: To evaluate whether a three month course of lymecycline has an effect on the long term prognosis of reactive arthritis (ReA). METHODS: In 1987-88 a double-blind controlled study with three month course of lymecycline/placebo was conducted. 17 of 23 patients treated at the outpatient department of Helsinki University Central Hospital volunteered to take part in a follow up study, where a physical examination were performed, and erythrocyte sedimentation rate, C reactive protein, rheumatoid factor, and radiographs of the lumbosacral spine and sacroiliac joints and of symptomatic peripheral joints were examined. RESULTS: 16/17 (94%) patients reported some kind of back pain and 10/17 (59%) peripheral joint symptoms during the follow up. Two patients had unilateral grade 1 sacroiliitis, one patient grade 4 sacroiliitis, and one patient bilateral grade 2 sacroiliitis. In one patient the disease had progressed to ankylosing spondylitis (AS), and in another to chronic spondyloarthropathy. In addition, two patients had small erosions in radiocarpal joints. No statistically significant differences were found between placebo and lymecycline groups in the development of chronic arthritis, sacroiliitis, or AS. CONCLUSION: The results of the initial study showed that long term treatment with lymecycline in patients with acute ReA decreased the duration of arthritis in those with Chlamydia trachomatis triggered ReA, but not in other patients with ReA. Ten years after the acute arthritis one patient had developed AS, and three had radiological sacroiliitis, three patients had radiological changes at peripheral joints. Long term lymecycline treatment did not change the natural history of the disease.

Infectious background of patients with a history of acute anterior uveitis.

OBJECTIVE: To study the infectious background of patients with a history of acute anterior uveitis (AAU) and healthy control subjects. METHODS: Sixty four patients with previous AAU and 64 sex and age matched controls were studied. Serum antibodies to Salmonellae, Yersiniae, Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, Campylobacter jejuni, and Borrelia burgdorferi were measured using enzyme linked immunosorbent assay (ELISA), and antibodies to Chlamydia trachomatis and Chlamydia pneumoniae by microimmunofluorescence test. Peripheral blood mononuclear cells (PBMCs), separated by density gradient centrifugation, were studied for Salmonella and Yersinia antigens by means of an immunofluorescence test, and for C pneumoniae DNA with a polymerase chain reaction (PCR). RESULTS: Neither prevalence nor levels of single microbial antibodies studied differed between the patients and control subjects, or between subgroups of patients created on the basis of clinical characteristics. In logistic regression analysis, the high number of recurrences (>10) of AAU was independently related to the presence of single or multiple bacterial antibodies (p=0.04). None of the PBMC samples of the patients were positive for Yersinia or Salmonella antigens. C pneumoniae PCR was positive in a patient who was negative for C pneumoniae antibodies. CONCLUSION: Although neither the prevalence nor the levels of single microbial antibodies studied differed between the patients and the controls, current data suggest that the presence of single or multiple antibodies in patients with many recurrences of AAU compared with patients with none or few recurrences may be a sign of repeated infections, antigen persistence, or raised innate immune responsiveness.

Long term efficacy and safety of cyclosporin versus parenteral gold in early rheumatoid arthritis: a three year study of radiographic progression, renal function, and arterial hypertension.

OBJECTIVE: To compare the three year safety and efficacy of cyclosporin and parenteral gold in the treatment of early, active, severe rheumatoid arthritis (RA), and to study the reversibility of cyclosporin associated renal dysfunction in patients who discontinued cyclosporin treatment. METHODS: The patients continued to receive cyclosporin or parenteral gold in an 18 month open extension to an 18 month randomised, parallel group study. The main efficacy variable was blinded evaluation of radiographic progression of joint damage. Safety variables included serum creatinine, calculated creatinine clearance, and blood pressure. RESULTS: Radiographic progression during follow up was similar in both groups. About 60% of the patients in the intention to treat groups (n=272) and about half of the patients in the completer groups (n=114) had definite radiographic progression in joint damage (increases >6 in the Larsen-Dale score), and about one in three also had substantial progression (>18 increase in Larsen-Dale score). Both systolic and diastolic blood pressure were significantly increased in the cyclosporin group compared with the gold group, and 12/139 (9%) versus 3/139 (2%) (p=0.03) had notably raised blood pressure. The mean serum creatinine increased by 28% at the treatment end point in the cyclosporin group as compared with 7% in the gold group. The mean calculated creatinine clearance was reduced by 16% and increased by 1% in the cyclosporin and gold groups, respectively, at the end of the study. At the final follow up visit after discontinuation of cyclosporin (at least three months after treatment was stopped) the mean serum creatinine was increased by 15% and creatinine clearance reduced by 16%. Sustained increases in serum creatinine at this post-treatment end point were mostly seen in patients with a raised serum creatinine during treatment of at least 50%. CONCLUSION: Three year changes in radiographic damage during cyclosporin and parenteral gold were similar in patients with early, active RA. Abnormal renal function and raised blood pressure were often seen in the cyclosporin treated patients.

A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens.

OBJECTIVE: Whether food intake can modify the course of rheumatoid arthritis (RA) is an issue of continued scientific and public interest. However, data from controlled clinical trials are sparse. We thus decided to study the clinical effects of a vegan diet free of gluten in RA and to quantify the levels of antibodies to key food antigens not present in the vegan diet. METHODS: Sixty-six patients with active RA were randomized to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 yr. All patients were instructed and followed-up in the same manner. They were analysed at baseline and after 3, 6 and 12 months, according to the response criteria of the American College of Rheumatology (ACR). Furthermore, levels of antibodies against gliadin and beta-lactoglobulin were assessed and radiographs of the hands and feet were performed. RESULTS: Twenty-two patients in the vegan group and 25 patients in the non-vegan diet group completed 9 months or more on the diet regimens. Of these diet completers, 40.5% (nine patients) in the vegan group fulfilled the ACR20 improvement criteria compared with 4% (one patient) in the non-vegan group. Corresponding figures for the intention to treat populations were 34.3 and 3.8%, respectively. The immunoglobulin G (IgG) antibody levels against gliadin and beta-lactoglobulin decreased in the responder subgroup in the vegan diet-treated patients, but not in the other analysed groups. No retardation of radiological destruction was apparent in any of the groups. CONCLUSION: The data provide evidence that dietary modification may be of clinical benefit for certain RA patients, and that this benefit may be related to a reduction in immunoreactivity to food antigens eliminated by the change in diet.

Effects of low-dose, noncytotoxic, intraarticular liposomal clodronate on development of erosions and proteoglycan loss in established antigen-induced arthritis in rabbits.

OBJECTIVE: To assess the clinical and histologic effects of an intraarticular application of low-dose (non-cytotoxic) liposomal clodronate in established antigen-induced monarthritis (AIA) in rabbits. METHODS: AIA was monitored by assessments of joint swelling, C-reactive protein levels, and radiographic changes in 17 NZW rabbits for 8 weeks during the course of weekly intraarticular injections of liposomal clodronate (0.145 mg/injection, low dose) or "empty" liposomes. The contralateral knee was injected with liposome buffer alone as the control. End-point analyses included macroscopic joint examination, immuno- and TUNEL staining, Safranin O staining/microspectrophotometry, and tumor necrosis factor alpha (TNFalpha) convertase enzyme (TACE) inhibition assay. RESULTS: Liposomal clodronate-treated rabbits showed a reduction and delay in joint swelling during the first 3 injections. Expression of matrix-bound (solubilized) TNFalpha, lining cell hyperplasia, and levels of RAM-11+ macrophages were low in the synovium of the liposomal clodronate treatment group, but the proportion of apoptotic lining cells was not affected. The radiologic score was low at the end of weeks 2 and 4, but at 8 weeks, no difference, compared with controls, was found in pannus formation or in the extent of joint erosion; also, joint swelling was higher than before initiation of treatment. Injections of liposomal clodronate prevented cartilage proteoglycan loss, which was significant in the superficial zone only. TACE activity was not inhibited by clodronate. CONCLUSION: Liposomal clodronate had temporary antiinflammatory and antierosive effects on established AIA in rabbits. Over the long-term, the loss of cartilage proteoglycans was halted. This observed treatment effect may be related to the inhibition of TNFalpha production and processing in the synovium.

Automated stereotactic core needle biopsy of microcalcifications with correlation to surgical biopsy.

PURPOSE: To compare pathologic findings from stereotactic core and excisional biopsies in patients with microcalcifications in the breast. MATERIAL AND METHODS: Stereotactic core needle biopsies of 101 lesions with mammographic evidence of microcalcifications were performed with long-throw (2.2 cm) automated core biopsy devices fitted with 2.1-mm needles. The core specimens were placed on microscope slides and radiographed. The pathologic features of core and excisional specimens were compared. RESULTS: In 100 of the 101 breast lesions, a correct choice for an additional diagnostic procedure or definitive treatment could have been made upon histopathologic findings of the core needle biopsy. CONCLUSION: Stereotactic core needle biopsy is a reliable alternative to surgical biopsy of breast lesions with microcalcifications provided that specimen radiography has been performed to ensure that appropriate tissue has been obtained. Excisional biopsy may be avoided if microcalcifications are visible in radiographs of core biopsy specimen with benign histology.

Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group.

BACKGROUND: The treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis. METHODS: 199 patients were randomly assigned to two treatment groups. 195 started the treatment (97 received combination and 98 single drug therapy). Single-drug therapy in all patients started with sulphasalazine; in 51 patients methotrexate was later substituted. Oral prednisolone was required by 63 patients. The primary outcome measure was induction of remission. Analyses were intention to treat. FINDINGS: 87 patients in the combination group and 91 in the single-therapy group completed the trial. After a year, remission was achieved in 24 of 97 patients with combination therapy, and 11 of 98 with single-drug therapy (p=0.011). The remission frequencies at 2 years were 36 of 97 and 18 of 98 (p=0.003). Clinical improvement (American College of Rheumatology criteria of 50% clinical response) was achieved after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using single-drug therapy (p=0.028), while at the 2-year visit 69 and 57 respectively (71% vs 58%, p=0.058) had clinically improved. The frequencies of adverse events were similar in both treatment groups. INTERPRETATION: Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis. The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis.

Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4.

To test the hypothesis that interaction between genetic, immunological, clinical and metabolic risk factors influences the outcome of Type II (non-insulin-dependent) diabetes mellitus, we examined which of the above factors present at baseline were associated with mortality in 134 Type II diabetic patients followed for 9 years. Thirty-eight patients (29%) died during the follow-up period; the majority of whom (68%) died from cardiovascular disease. At baseline, the deceased patients had higher HbA1c values (p = 0.002), higher LDL-triglycerides (p = 0.007), lower HDL-cholesterol (p = 0.007), higher non-esterified fatty acid (NEFA) concentrations (p = 0.014), and higher albumin excretion rate (p < 0.0001) than the patients who survived. In addition, the frequency of HLA-DR4 (21 vs 39%, p = 0.048) and of parietal cell antibodies (5 vs 14%, p = 0.016) were decreased in the deceased as compared to the living patients. Patients who died during follow-up also had more retinopathy (42 vs 16%, p = 0.002), neuropathy (57 vs 23%, p < 0.001), microalbuminuria (45 vs 6%, p < 0.0001), coronary heart disease (50 vs 13%, p < 0.0001), and peripheral vascular disease (27 vs 9%, p = 0.005) at baseline than patients who survived. In a multiple logistic regression analysis macroangiopathy (p = 0.004), neuropathy (p = 0.007), HbA1c (p = 0.018) and albumin excretion rate (p = 0.016) were independent risk factors for death. In patients free of cardiovascular disease at baseline, conventional risk factors such as LDL-cholesterol (p = 0.005) and age (p = 0.003) were associated with subsequent development of cardiovascular disease. In conclusion, in addition to coexisting macroangiopathy, increased albumin excretion rate, poor glycaemic control and neuropathy are risk factors for cardiovascular mortality in patients with Type II diabetes. The presence of HLA-DR4 and signs of autoimmunity may be associated with decreased risk of cardiovascular disease.

Screening for renovascular hypertension in a population with relatively low prevalence.

OBJECTIVE: To evaluate the accuracy and cost-efficacy of the diagnostic procedure and treatment for renovascular hypertension. SETTING AND PATIENTS: A total of 519 patients referred to the university clinic for hypertension were screened for renovascular hypertension with 405 captopril challenge tests (CCT) and 450 captopril renographies (CRG). INTERVENTIONS: Abdominal angiography was performed on 84 patients for positive screening. Fifteen patients underwent angiography for a sole suspicious clinical presentation. The angiography revealed 17 renal artery stenoses and five occlusions in 20 patients. Fifteen technically successful angioplasties and three nephrectomies were performed. RESULTS: In the patients who underwent angiography, CCT had a specificity of 39% and a sensitivity of 67% for renovascular hypertension. CRG had a sensitivity of 100% and a specificity of 68%. In the whole study population, the estimated specificity of CCT was 88% and that of CRG 95%. Invasive treatment reduced systolic/diastolic blood pressure from 157/99 to 140/87 mmHg and the number of antihypertensive drugs used from 2.6 to 1.4 in 16 patients (mean age 49 years). Angiotensin converting enzyme (ACE) inhibition was effective in four elderly patients. Cost-efficacy analysis Screening with CRG and invasive treatment cost US$15400 per successful invasive treatment Equally effective pharmacological treatment would have cost US$10400. Limiting the screening with CRG to the 173 patients with no obvious renal parenchymal disease and with hypertension at a younger age (< or =30 years) or unresponsive to two antihypertensive drugs (diastolic blood pressure > 90 mmHg) would have yielded a prevalence of 12% and missed only one elderly patient who responded to ACE inhibition. The limited screening, along with invasive treatment, would have cost US$7300 per patient CONCLUSIONS: CRG is superior to CCT for screening of renovascular hypertension. Screening with CRG is cost-effective when limited to patients with no obvious renal parenchymal disease and with hypertension that does not respond to two antihypertensive drugs or is detected in patients no older than 30 years.