Ingemar F. Petersson

Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas

Objective: To determine whether TNF blockers increase tumour risk in patients with RA. Material and methods: The South Swedish Arthritis Treatment Group register (SSATG) comprises over 90% of anti-TNF treated patients with RA in the area. 757 patients treated with etanercept or infliximab included between 1 February 1999 and 31 December 2002 were identified. 800 patients with conventional antirheumatic treatment in a community based cohort served as a comparison cohort. Tumours and deaths were identified in the cancer registry and population census registers. Patients were followed up from initiation of anti-TNF treatment or 1 July 1997 for the comparison group, until death or 31 December 2002. Results: In the anti-TNF group, 16 tumours (5 lymphomas) were identified in 1603 person-years at risk, and in the comparison group 69 tumours (2 lymphomas) in 3948 person-years. Standardised incidence ratios (SIRs) for total tumour relative risk for the anti-TNF group and the comparison group were 1.1 (95% confidence interval (CI) 0.6 to 1.8) and 1.4 (95% CI 1.1 to 1.8), respectively. The lymphoma relative risk (RR) was 11.5 (95% CI 3.7 to 26.9) and 1.3 (95% CI 0.2 to 4.5), respectively The total tumour RR excluding lymphoma was 0.79 (95% CI 0.4 to 1.42) and 1.39 (95% CI 1.08 to 1.76), respectively. Proportional hazard analysis for lymphomas yielded RR 4.9 (95% CI 0.9 to 26.2) in anti-TNF treated versus untreated patients. Conclusion: Community based patients with RA treated conventionally had an increased overall tumour risk compared with the background population. A possible additional increased risk for lymphoma associated with TNF blockers was based on few cases and needs confirmation.

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial

BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly. We aimed to compare addition of conventional disease-modifying antirheumatic drugs (sulfasalazine and hydroxychloroquine) with addition of a tumour necrosis factor antagonist (infliximab) to methotrexate in patients with early rheumatoid arthritis. METHODS We undertook a randomised trial in 15 rheumatology units in Sweden. We enrolled patients with early rheumatoid arthritis (symptom duration <1 year) and administered methotrexate (up to 20 mg per week). After 3-4 months, those who had not achieved low disease activity but who could tolerate methotrexate were randomly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab. Primary outcome was achievement of a good response according to European League Against Rheumatism (EULAR) criteria at 12 months. Patients were followed up to 24 months; here, we present findings at 12 months. Analysis was by intention to treat and we used non-responder imputation. The Swefot (Swedish Pharmacotherapy) study is registered in the WHO database at the Karolinska University Hospital, number CT20080004. FINDINGS 487 patients were initially enrolled. Of 258 who had not achieved low disease activity with methotrexate, 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab. 32 of 130 (25%) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 (39%) assigned infliximab (risk ratio 1.59 [95% CI 1.10-2.30], p=0.0160). Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used. No deaths occurred in either group. INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed, addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinically superior to addition of conventional disease-modifying antirheumatic drugs. FUNDING Swedish Rheumatism Association, Schering-Plough.

Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden

Objective: To explore the feasibility of prospectively monitoring treatment efficacy and tolerability of infliximab, etanercept, and leflunomide over a two year period in patients with established rheumatoid arthritis (RA) in clinical practice using a structured protocol. Methods: All patients with RA at seven centres in southern Sweden, for whom at least two disease modifying antirheumatic drugs, including methotrexate, had failed or not been tolerated, who started treatment with either infliximab, etanercept, or leflunomide were included. They were evaluated at predefined times using a standardised protocol including items required for evaluating response to the American College of Rheumatology (ACR) or EULAR criteria. All adverse events were recorded using World Health Organisation terminology. Concomitant treatment and survival while receiving a drug were recorded. Results: During the study 166 patients were treated with etanercept, 135 with infliximab, and 103 with leflunomide. Treatment response as determined by the ACR and EULAR response criteria was similar for the tumour necrosis factor (TNF) blockers. The TNF blockers performed significantly better than leflunomide both as determined by the response criteria and by survival on drug analysis. Thus 79% and 75% continued to receive etanercept or infliximab compared with 22% of patients who started leflunomide after 20 months. The spectrum of side effects did not differ from those previously reported in the clinical trials. The initial two year experience of a protocol for postmarketing surveillance of etanercept, infliximab, and leflunomide shows that a structured protocol with central data handling can be used in clinical practice for documenting the performance of newly introduced drugs. Conclusions: Efficacy data for the TNF blockers comply with results in clinical trials, whereas leflunomide appeared to perform worse than in clinical trials. Prolonged monitoring is required to identify possible rare side effects.

Predictors of patient relevant outcome after total hip replacement for osteoarthritis: a prospective study

Objectives: To investigate prospectively long term patient relevant outcomes after unilateral total hip replacement (THR) for osteoarthritis (OA). To identify non-responders to this intervention and patient related predictors of unsatisfactory outcome. Methods: A case-control study comparing health related quality of life of 219 patients (mean age 71) after THR with that of a matched reference group of 117 subjects without hip complaints recruited from the community. Patients and reference group answered SF-36 and WOMAC questionnaires preoperatively, at 3, 6, 12 months, and at 3.6 years (range 26–65 months) postoperatively. Supplementary questions were asked at the final follow up. Results: 198/211 (94%) of the patients and 83/109 (76%) of the reference group participated at the final follow up. At follow up, the only difference between the two groups in the SF-36 was physical function, where patients scored worse. Patients also reported worse WOMAC function. 31% of the patients had improved by <10/100 WOMAC score points for pain and/or function at final follow up, compared with preoperatively. More pain preoperatively and higher age and postoperative low back pain predicted a worse outcome in WOMAC function. Conclusion: 3.6 years after THR for OA, health related quality of life was similar for patients and reference group except for function, where patients had worse function. Higher age and more pain preoperatively predicted a poor outcome. Patients with hip OA with musculoskeletal comorbidities, such as low back pain and OA of the non-operated hip, have less long term functional improvement after THR.

Radiographic osteoarthritis of the knee classified by the Ahlbäck and Kellgren & Lawrence systems for the tibiofemoral joint in people aged 35-54 years with chronic knee pain

OBJECTIVES To determine the prevalence of tibiofemoral radiographic knee osteoarthritis (OA) in people aged 35–54 years associated with chronic (> 3 months) knee pain using two different radiographic grading systems. METHODS Population based postal survey in a random sample of inhabitants in a district in southern Sweden followed by clinical examination and plain posteroanterior, weight bearing radiographical examination. The Ahlbäck criteria (focusing on joint space narrowing) and the Kell- gren & Lawrence classification for knee OA were used for diagnosing tibiofemoral OA. RESULTS A questionnaire was sent to 2000 randomly selected people aged 35–54 years. The response rate was 92.6%. Fifteen per cent of these people reported chronic knee pain. This group (n=279) was offered a clinical and radiographic examination of the knee joint and 204 persons agreed to participate. According to the Kellgren & Lawrence classification 28 subjects had OA of the knee grade 2 or more and 16 grade 3 or more. Radiographically detected OA of the knee according to Ahlbäck was found in 20 cases. The minimum prevalence of radiological tibiofemoral knee OA with knee pain was thus 1.5% for Kellgren & Lawrence grade 2 or more, 0.9% for grade 3 or more, and 1.1% according to the Ahlbäck classification. The agreement between the Kellgren & Lawrence grades 2–3 versus Ahlbäck grade I as well as grade 3–4 versus Ahlbäck grade I–II was good (κ 0.76 and 0.78 respectively). CONCLUSION The prevalence of radiographic tibiofemoral OA combined with chronic knee pain in people aged 35–54 years was around 1% as estimated by either the Kellgren & Lawrence or the Ahlbäck classifications systems. Prospective follow up of this cohort should elucidate the significance of knee pain as a sign of developing OA.

Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis

Objective: To assess mortality in patients with rheumatoid arthritis (RA) treated with tumour necrosis factor (TNF) inhibitors, compared with a standard RA population. Methods: Patients were recruited from a regional register, which includes over 90% of patients with RA treated with TNF blockers in the area in 1999 or later, and a local community-based cohort of patients with RA, established in 1997. Of a total of 1430 patients in the combined cohort <80 years old, 921 received treatment with TNF inhibitors during the study period. The total cohort was linked with the national register for cause of death. Overall mortality in those treated versus those not treated with TNF blockers was estimated using standardised mortality ratios and time-dependent Cox proportional hazards. Results: There were 188 deaths per 7077 person-years at risk in the total cohort. Controlling for age, sex, disability and baseline comorbidity, the adjusted HR for death was 0.65 (95% CI 0.46 to 0.93) in those treated with anti-TNF versus those not treated. The effect was significant in women (HR = 0.52, 95% CI 0.33 to 0.82) but not in men (HR = 0.95, 95% CI 0.52 to 1.71). Conclusion: After adjusting for disease severity, treatment with TNF inhibitors was found to be associated with a reduced mortality in women but not men with RA. These findings are compatible with a critical role for inflammation in RA-associated premature mortality.

Prevalence of fibromyalgia and chronic widespread pain

Objective - To explore the prevalence of fibromyalgia and chronic widespread musculoskeletal pain in a general population using the criteria of the American College of Rheumatology from 1990. Design - Structured interview and clinical examination, including tender-point count and pain threshold measured with a dolorimeter, of subjects with suspected chronic widespread musculoskeletal pain. Setting - The general population in south-west Sweden 1995-1996. Subjects - 303 individuals with suspected chronic widespread pain were identified in a previously defined cohort containing 2425 men and women aged 20-74 years. 202 individuals were invited and 147 agreed to participate. Main outcome measures - Tenderpoint count, pain threshold and prevalence of chronic widespread pain and fibromyalgia. Results - The prevalence of fibromyalgia was estimated to 1.3% (95% CI 0.8-1.7; n=2425) and that of all chronic widespread pain to 4.2% (95% CI 3.4-5.0; n=2425). The mean pain threshold measured with a dolorimeter was lower in subjects with chronic widespread pain (p<0.01) and correlated with the number of tender points (r= -0.59, p<0.01) but could not be used to distinguish the subjects with fibromyalgia. Conclusion - Compared to other studies, fibromyalgia and chronic widespread musculoskeletal pain seemed to be relatively rare conditions in the south-west of Sweden.OBJECTIVE To explore the prevalence of fibromyalgia and chronic widespread musculoskeletal pain in a general population using the criteria of the American College of Rheumatology from 1990. DESIGN Structured interview and clinical examination, including tender-point count and pain threshold measured with a dolorimeter, of subjects with suspected chronic widespread musculoskeletal pain. SETTING The general population in south-west Sweden 1995-1996. SUBJECTS 303 individuals with suspected chronic widespread pain were identified in a previously defined cohort containing 2425 men and women aged 20-74 years. 202 individuals were invited and 147 agreed to participate. MAIN OUTCOME MEASURES Tenderpoint count, pain threshold and prevalence of chronic widespread pain and fibromyalgia. RESULTS The prevalence of fibromyalgia was estimated to 1.3% (95% CI 0.8-1.7; n = 2425) and that of all chronic widespread pain to 4.2% (95% CI 3.4-5.0; n = 2425). The mean pain threshold measured with a dolorimeter was lower in subjects with chronic widespread pain (p < 0.01) and correlated with the number of tender points (r = -0.59, p < 0.01) but could not be used to distinguish the subjects with fibromyalgia. CONCLUSION Compared to other studies, fibromyalgia and chronic widespread musculoskeletal pain seemed to be relatively rare conditions in the south-west of Sweden.

Correlation between radiographically diagnosed osteophytes and magnetic resonance detected cartilage defects in the tibiofemoral joint

OBJECTIVE To assess the correlation between radiographically diagnosed osteophytes in the axial and lateral view of the patellofemoral joint (PFJ) and (1) magnetic resonance (MR) detected cartilage defects in the same joint and (2) knee pain. METHODS Fifty seven pepole with chronic knee pain, (aged 41–58 years, mean 50 years) were examined with axial and lateral radiograms when standing of the right and the left PFJ. The presence and grade of osteophytes was assessed. On the same day, a MR examination was performed of the signal knee with proton density and T2 weighted turbo spin-echo sequences in the sagittal and axial view on a 1.0 T imager. Cartilage defects in the PFJ were noted. The subjects were questioned for current knee pain for each knee. RESULTS Osteophytes at the PFJ had a specificity varying between 59 and 100% and a positive predictive value between 74 and 100% for MR detected cartilage defects. The corresponding values for osteophytes at the lateral aspect of the femoral trochlea were both 100%. In PFJ with narrowing (<5 mm) osteophytes had a sensitivity and a positive predictive value of 90 and 95% respectively for MR detected cartilage defects, while in PFJ with non-narrowing (⩾5 mm) the corresponding values were 75 and 65% and the specificity was 50%. A correlation (p<0.05) between osteophytes at the inferior pole of the patella and knee pain was found. CONCLUSIONS Osteophytes at the PFJ are associated with MR detected cartilage defects in the same joint. The relation was strong for osteophytes at the lateral femoral trochlea and in the PFJ with narrowing (<5 mm), but weak in the PFJ with non-narrowing (⩾5 mm).

The prevalence of rheumatoid arthritis in Sweden.

The aim of this study was to ascertain the prevalence of rheumatoid arthritis (RA) in a Swedish general adult population. A questionnaire about chronic pain was mailed to a total of 3928 subjects who were chosen as a random sample of the population in two communities in the county of Halland. All persons answering affirmatively to questions intended to identify patients with RA were invited to a clinical examination. X-rays of hands and feet, and analyses of rheumatoid factor and C reactive protein were performed provided that the patients fulfilled two or more of the five clinical items of the 1987 ARA criteria. Furthermore, non-participants were searched for in a patient register and in medical records from the local rheumatology unit in an attempt to identify further cases. Using the modified 1987 ARA criteria for population studies the prevalence rate of RA was calculated to 0.51% (95%, CI = 0.31-0.79).

Population-based estimates of common comorbidities and cardiovascular disease in ankylosing spondylitis.

To study the rate of common comorbidities and cardiovascular disease in patients with ankylosing spondylitis (AS) compared with the general population seeking health care.