Pentraxin 3 in serum and synovial fluid of patients with rheumatoid arthritis with and without autoantibodies.

OBJECTIVES: Pentraxin 3 (PTX3) is a locally produced multifunctional protein involved in inflammation, matrix deposition, and immunity. As patients with seropositive rheumatoid arthritis (RA) have a more severe disease course and higher risk of joint destruction than seronegative patients, the aim of the present study was to examine differences in PTX3 in synovial fluid (SF) (and serum) in seropositive compared to seronegative RA, and other local markers of inflammation and destruction. METHOD: Ninety-seven RA patients with knee effusion were included. Serum and SF levels of PTX3, as well as serum levels of anti-citrullinated protein antibody and rheumatoid factor of immunoglobulin A and M subclasses, and markers of inflammation and potential destruction in SF: white blood cell counts, tumour necrosis factor, interleukin-6, vascular endothelial growth factor, metalloproteinase 3, and cartilage oligomeric matrix protein, were analysed. In addition, a radiographic knee examination was performed. RESULTS: Seropositive patients had significantly higher PTX3 levels in SF than seronegative patients, whereas there was no difference for serum levels. SF-PTX3 levels correlated with disease activity and with local inflammatory markers, especially polymorphonuclear cells, and with autoantibody levels. There was no correlation between PTX3 levels in serum and SF. CONCLUSION: The correlation of disease activity and autoantibody levels with SF-PTX3 levels in antibody-positive patients suggests a role for PTX3 in the inflammatory process specifically in seropositive RA joints, and supports the hypothesis that seropositive and seronegative RA are different disease entities. Polymorphonuclear granulocytes may be an important source of PTX3 in RA SF.

Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register.

BACKGROUND: Tumour necrosis factor (TNF) antagonists have proved effective as treatment against rheumatoid arthritis (RA), but the unresolved issue of whether the use of anti-TNF therapy increases the already elevated risk of lymphoma in RA remains a concern. METHODS: Using the Swedish Biologics Register (ARTIS), the Swedish Cancer Register, pre-existing RA cohorts and cross-linkage with other national health and census registers, a national RA cohort (n = 67,743) was assembled and patients who started anti-TNF therapy between 1998 and July 2006 (n = 6604) were identified. A general population comparator (n = 471,024) was also assembled and the incidence of lymphomas from 1999 to 31 December 2006 was assessed and compared in these individuals. RESULTS: Among the 6604 anti-TNF-treated RA patients, 26 malignant lymphomas were observed during 26,981 person-years of follow-up, which corresponded to a relative risk (RR) of 1.35 (95% CI 0.82 to 2.11) versus anti-TNF-naive RA patients (336 lymphomas during 365,026 person-years) and 2.72 (95% CI 1.82 to 4.08) versus the general population comparator (1568 lymphomas during 3,355,849 person-years). RA patients starting anti-TNF therapy in 1998-2001 accounted for the entire increase in lymphoma risk versus the two comparators. By contrast, RR did not vary significantly by time since start of first treatment or with the accumulated duration of treatment, nor with the type of anti-TNF agent. CONCLUSION: Overall and as used in routine care against RA, TNF antagonists are not associated with any major further increase in the already elevated lymphoma occurrence in RA. Changes in the selection of patients for treatment may influence the observed risk.

Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists.

BACKGROUND: Existing studies of solid cancers in rheumatoid arthritis (RA) reflect cancer morbidity up until the early 1990s in prevalent cohorts admitted to hospital during the 1980s. OBJECTIVE: To depict the cancer pattern of contemporary patients with RA, from updated risk data from prevalent and incident RA populations. To understand the risk of solid cancer after tumour necrosis factor (TNF) treatment by obtaining cancer data from cohorts treated in routine care rather than trials. METHODS: A population based study of three RA cohorts (one prevalent, admitted to hospital 1990-2003 (n = 53,067), one incident, diagnosed 1995-2003 (n = 3703), and one treated with TNF antagonists 1999-2003 (n = 4160)), which were linked with Swedish nationwide cancer and census registers and followed up for cancer occurrence through 2003. RESULTS: With 3379 observed cancers, the prevalent RA cohort was at marginally increased overall risk of solid cancer, with 20-50% increased risks for smoke related cancers and +70% increased risk for non-melanoma skin cancer, but decreased risk for breast (-20%) and colorectal cancer (-25%). With 138 cancers, the incident RA cohort displayed a similar cancer pattern apart from non-decreased risks for colorectal cancer. TNF antagonist treated patients displayed solid cancer (n = 67) risks largely similar to those of other patients with RA. CONCLUSION: The cancer pattern in patients treated with TNF antagonists mirrors those of other contemporary as well as historic RA cohorts. The consistent increase in smoking associated cancers in patients with RA emphasises the potential for smoking cessation as a cancer preventive measure in RA.

Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists.

BACKGROUND: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear. OBJECTIVE: To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA. METHODS: A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53,067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed. RESULTS: Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas. CONCLUSION: Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.

Results from a nationwide postmarketing cohort study of patients in Sweden treated with etanercept.

OBJECTIVES: To describe a nationwide system for postmarketing follow up of new antirheumatic drugs in Sweden, and to analyse safety and effectiveness in an etanercept treated patient cohort. METHODS: Etanercept became available in Sweden for prescribing on a named patient basis in 1999. All patients treated were included in a follow up of intensified adverse event reporting and recording of clinical outcome during 24 months, according to the EULAR core set. RESULTS: The mean (SD) disease activity score (DAS 28) value at inclusion among 820 patients recruited on a named patient basis during year 1 was 5.99 (1.19). After two years, 21% (n = 172) of these patients had discontinued the treatment. Of the remaining 648 patients, 68% (n = 442) responded to the treatment. However, in 55% of the responders, the disease activity was intermediate or high (mean DAS 28, 3.37 (1.20)). In all, 540 adverse events were reported in 421 adverse drug reaction (ADR) reports, in 294 patients. The events in 80 reports (19%) were serious. Twenty two per cent of the events were infections, of which 24% (n = 29) were serious. The incidence of serious adverse events remained constant over time. CONCLUSIONS: At start of etanercept treatment, patients had high disease activity. Activity remained high in a large proportion of the responding patients. Although serious ADRs occurred during late phases of treatment, no unexpected safety problems arose. No specific indicators of ADR risk were found. The monitoring system that was established may be useful in future postmarketing surveillance.

Local anti-type II collagen antibody production in rheumatoid arthritis synovial fluid. Evidence for an HLA-DR4-restricted IgG response.

OBJECTIVE: To investigate the production of type II collagen (CII) antibodies in the synovial fluid (SF) of rheumatoid arthritis (RA) patients, and to examine the HLA dependence of this local production. METHODS: The ELISPOT method was used for enumerating anti-CII-reactive cells. Serologic tissue typing was performed. RESULTS: Anti-CII-reactive cells were found in the SF of 16 of 31 patients, but not in any of the peripheral blood samples obtained in parallel. SF anti-CII antibody production showed no correlation with clinical parameters, but its frequency increased significantly with age. The IgG anti-CII response occurred exclusively in patients who were positive for HLA-DR4 and was significantly associated with DR4. CONCLUSION: Anti-CII production may be important in local immune complex formation. The indirect demonstration of a DR4-restricted T cell response to CII is an indication of a pathogenetic role of collagen autoimmunity in RA.

Results of arthroscopic acromioplasty related to rotator cuff lesions.

Seventy-nine patients with a history of the subacromial impingement syndrome were treated by arthroscopic acromioplasty. The results were evaluated with a new scoring system designed to assess subjective symptoms before and after operation. The outcome was related to the pathological lesions of the rotator cuff seen at arthroscopy and graded by our modification of the Neer classification. The overall results were satisfactory in 67%, with men having better results than women. Those with a history of injury did better than those without, and the results in those with partial or total cuff tears were better than those with intact cuffs. Since the state of the cuff affects the result, arthroscopy should precede acromioplasty.

T-cell receptor V-gene usage in synovial fluid and synovial tissue from RA patients.

The question of whether there is a preferential use of certain V genes in T cells entering an inflamed joint has hitherto been studied mainly using unfractionated cells from synovial fluid and tissue respectively, and no clear answer to the question has yet been provided. Concomitantly, evidence has been provided that the use of V genes may differ considerably between CD4+ and CD8+ T cells, and consequently that detection of biased V-gene expression within an inflammatory lesion may require separate analysis of the two T-cell subsets. In this paper we have therefore studied T-cell receptor V-gene expression in rheumatoid arthritis by means of double stainings of synovial fluid and blood for available anti-TCR monoclonal antibodies and antibodies to CD4 and CD8, respectively. Double stainings were also performed with anti-TCR antibodies and antibodies to activation markers HLA-DR and IL-2R. A certain bias towards the preferential use of certain V genes was seen particularly in the synovial fluid samples within both the CD4+ and CD8+ T-cell populations, but no uniform pattern was evident among the 35 patients investigated.

The late course of acute partial anterior cruciate ligament tears. A nine to 15-year follow-up evaluation.

Twenty-two patients had an acute anterior cruciate ligament (ACL) tear. Nineteen patients were treated conservatively, except for associated injuries. In three patients, a reinsertion of the torn portion of the ACL was done surgically. All patients were reexamined after nine to 15 years with special emphasis on stability testing; this was done manually and with instruments. Knee function score and activity level were also measured. Standing roentgenograms with the knee in slight flexion were taken as well. At follow-up examination, none of the patients had needed ACL reconstruction. Knee function was good, with a mean Lysholm score of 93 points. Patients had changed activities from recreational team sports to light individual sports. Manual laxity values were similar to the values obtained at the time of initial injury. A 1-mm sagittal laxity increase was found on the injured knee with the Stryker laxity tester. Slight signs for osteoarthrosis were found in more than half of the knees, mainly in cases with chondral fractures or meniscectomy. In general, conservative treatment had a good long-term prognosis.

The long-term course after treatment of acute anterior cruciate ligament ruptures. A 9 to 16 year followup.

Acute total ACL (N = 60) and concomitant medial collateral ligament (N = 46) ruptures were repaired in 60 patients (mean age, 28 years) without augmentation. Menisci were removed in 23 knees. Fifty-three (88%) of the patients were reexamined 9 to 16 years later with special emphasis on manual and instrumented stability testing (Stryker, Genucom), knee function score (Lysholm), and activity level (Tegner). Standing roentgenograms (30 degrees of knee flexion) were taken in 69% of the patients. At followup, an ACL reconstruction had been performed in seven patients (12%) due to symptomatic instability. Sixty-four percent of the knees had a positive Lachman sign and 40% a positive pivot shift. Sagittal laxity difference was +3 mm or more in 57%. Knee function score was a mean of 86 +/- 12 points. The mean activity level had changed from recreational team sports (Level 7) to recreational individual sports (Level 5). Only patients with good knee stability were able to perform demanding sports and could continue at their desired activity level. Osteoarthritis of slight to moderate degree (Fairbank I/II) was found in 58% of the patients younger than 35 years of age at the time of trauma and in 87% of the older patients. Knees with intact menisci had less osteoarthritis than knees with removed menisci (P less than 0.05).

Arthroscopy for the diagnosis of shoulder pain.

Arthroscopy under anaesthesia was used to investigate 123 patients with painful shoulders. The clinical diagnosis was compared with the arthroscopic findings. Four types of rotator cuff lesions were found in which there were significant differences between sex and age. Instability detected under anaesthesia was an important cause of pain. These examinations proved valuable in the diagnosis of shoulder pain, particularly when the clinical diagnosis was uncertain.

Arthroscopy and stability testing for anterior shoulder instability.

The extreme manifestation of anterior shoulder instability is anterior dislocation. Minor anterior instability often gives rise to vague symptoms from which a diagnosis is difficult. The use of arthroscopy may increase diagnostic accuracy in cases of anterior shoulder instability. Examinations were performed on 145 patients with shoulder complaints using stability testing under anesthesia and arthroscopy; of these, 62 patients were found to have anterior shoulder instability. The clinical signs were compared with the findings on stability testing and arthroscopy, and the morphological changes noted on arthroscopy were recorded. The combination of arthroscopy and stability testing proved valuable in the diagnosis of minor anterior instability and for the morphological changes and associated injuries in established anterior dislocations.

The effect of derotation braces on knee motion.

Four different types of derotation braces and an elastic knee support were tested on ice-hockey players. The elastic support did not noticeably affect rotation and abduction-adduction of the knee. All four braces reduced rotation and abduction-adduction in test actions simulating sports situations. Flexion-extension was slightly affected by two of the individually made braces in one action. Running a figure eight was slower with two of the individually made braces. The best braces, one individually made and one ready-made, limited rotation and abduction-adduction effectively, but did not affect performance. Minor differences in design may account for differences in effect and may alter the protection afforded by a brace.

Evaluation of cruciate ligament injuries. A review.

A good system for evaluating the degree of impairment, disability, and handicap of the patient with a cruciate ligament injury includes functional score, activity grading, stability testing, and measurements of performance and strength, all of which are relevant to different aspects of knee function. The symptom-related knee score gives a more differentiated picture of the disability than does a binomial rating of symptoms. A way of grading the disability in an objective way is to use a performance test. This test could also be used for monitoring rehabilitation before full activity has been resumed. The activity grading scale is very useful for grading the handicap.

Proresid in the long-term treatment of rheumatoid arthritis.

Drug withdrawal rate and reasons for treatment termination were studied in a retrospective life-table analysis of patients with rheumatoid arthritis prescribed Proresid, a semisynthetic podophyllotoxin derivative. Two years after starting with Proresid medication, half of the patients were still on treatment. After 5 years the termination rate had risen to 71%. Gastrointestinal side effects were the most common reason for abandoning medication. The results are compared with those found in other studies of similar desing. It is concluded that Proresid is a valuable and well-tolerated disease-modifying drug for long-term treatment of rheumatoid Arthritis.

Injuries in runners.

Sixty runners belonging to two clubs were followed for 1 year with regard to training and injury. There were 55 injuries in 39 athletes. The injury rate per 1,000 hours of training was 2.5 in long-distance/marathon runners and 5.6 to 5.8 in sprinters and middle-distance runners. There were significant differences in the injury rate in different periods of the 12 month study, the highest rates occurring in spring and summer. In marathon runners there was a significant correlation between the injury rate during any 1 month and the distance covered during the preceding month (r = 0.59). In a retrospective analysis of the cause of injury, a training error alone or in combination with other factors was the most common injury-provoking factor (72%). The injury pattern varied among the three groups of runners: hamstring strain and tendinitis were most common in sprinters, backache and hip problems were most common in middle-distance runners, and foot problems were most common in marathon runners.