Laura Pirilä

Expression of laminins and their integrin receptors in different conditions of synovial membrane and synovial membrane-like interface tissue

OBJECTIVE To demonstrate the expression of laminins (Lns) and their integrin (Int) receptors in different synovial samples and synovial membrane-like interface tissues from well fixed and aseptically loosened total hip replacement (THR), and the potential role of Ln-Int interaction in the production of collagenases and cytokines. METHODS Immunohistochemical staining was done to detect the distribution of EHS Ln, Ln α2, α3, α5, β1, β2 chains and Int α1, α2, α3, α6, β1, β4 subunits in different samples. Double immunofluorescence labelling was used to find colocalisation of Int α6 subunit and collagenase-1/collagenase-3/TNFα/IL6. RESULTS General Ln immunoreactivity was detected in all specimens. Ln α5, β1 and β2, but not α2 and α3 chains were seen in the synovial lining and the basement membrane of blood vessels with the intensity/extent of labelling in the following rank order: rheumatoid arthritis (RA) loosened prostheses, osteoarthritis, well fixed prostheses, traumatic knees. Among Int subunits, staining for β1 was usually the strongest, followed by staining for Int α6, α1, α3, and α2 subunits, with the same rank order for overall expression of Lns. Int β4 subunit was not detectable in most of the specimens. Double labelling focused on Int α6 subunit disclosed its frequent colocalisation with collagenases 1 and 3 and with tumour necrosis factor α and interleukin 6 in synovial lining. CONCLUSION Synovial lining contains Ln-10, Ln-11, and Int α6β1 and α1β1 receptors. In aseptic loosening of THR, interface tissue has a similar Ln subtype and Int receptor composition as RA synovium, which confirms its “lining-like” phenotype. Synovial lining does not contain Ln-5 (α3β3γ2) or Int α6β4, which are components of epithelial hemidesmosomes. The expression of Lns and their Int receptors is upregulated in inflammation. The close spatial relation between Ln and its Int receptors in synovial lining cells containing proteinases and cytokines suggests a potential role in joint destruction and prosthetic loosening.

Rates of Serious Infections and Malignancies Among Patients with Rheumatoid Arthritis Receiving Either Tumor Necrosis Factor Inhibitor or Rituximab Therapy

Objective. Because of the role of tumor necrosis factor (TNF) in host defense, it was hypothesized that its inhibition might lead to an increased risk of malignancies and infections. The objective of our study was to assess the incidence of serious infections leading to hospitalization and malignancies among patients with rheumatoid arthritis (RA) receiving either TNF inhibitor or rituximab (RTX) therapy. Methods. The study population was identified from the National Register for Biologic Treatment in Finland and the hospital records of Central Finland Central Hospital for conventional disease-modifying antirheumatic drug (cDMARD) users. Data on infections and malignancies were acquired from national healthcare registers. A Poisson model was used to calculate the adjusted incidence rate ratios (aIRR) and was composed of age, sex, time from diagnosis, year of the beginning of the followup, rheumatoid factor status, Disease Activity Score at 28 joints, Health Assessment Questionnaire, prior malignancy, prior serious infection, prior biologic use, and time-updated use of methotrexate, sulfasalazine, hydroxychloroquine, and oral corticosteroids as confounders. Results. In total, during the followup of 10,994 patient-years, 92 malignancies and 341 serious infections were included in the analyses. The aIRR of infections compared to cDMARD users were 1.2 (95% CI 0.63–2.3), 0.84 (95% CI 0.53–1.3), 0.98 (95% CI 0.60–1.6), and 1.1 (95% CI 0.59–1.9) for the patients treated with infliximab (IFX), etanercept, adalimumab, and RTX, respectively. The crude rates of malignancies were highest among the users of cDMARD and RTX, and lowest among patients treated with IFX with no differences in aIRR. Conclusion. Our results provide some reassurance of the safety of biologic treatments in the treatment of RA.

18 F-FDG positron emission tomography/computed tomography in infective endocarditis

BackgroundThe diagnosis of infective endocarditis (IE), especially the diagnosis of prosthetic valve endocarditis (PVE) is challenging since echocardiographic findings are often scarce in the early phase of the disease. We studied the use of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in IE.MethodsSixteen patients with suspected PVE and 7 patients with NVE underwent visual evaluation of 18F-FDG-PET/CT. 18F-FDG uptake was measured also semiquantitatively as maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR). The modified Duke criteria were used as a reference.ResultsThere was strong, focal 18F-FDG uptake in the area of the affected valve in all 6 cases of definite PVE, in 3 of 5 possible PVE cases, and in 2 of 5 rejected cases. In all patients with definite PVE, SUVmax of the affected valve was higher than 4 and TBR higher than 1.8. In contrast to PVE, only 1 of 7 patients with NVE had uptake of 18F-FDG by PET/CT in the valve area. Embolic infectious foci were detected in 58% of the patients with definite IE.Conclusions18F-FDG-PET/CT appears to be a sensitive method for the detection of paravalvular infection associated with PVE. Instead, the sensitivity of PET/CT is limited in NVE.

Biological Therapy for Psoriatic Arthritis in Clinical Practice: Outcomes Up to 2 Years

Objective. To evaluate the performance of biological drugs in psoriatic arthritis (PsA) in a routine care setting, using the Finnish national register of biological treatment (ROB-FIN). Methods. Patients with PsA who started therapy with infliximab or etanercept between June 2000 and February 2006 (n = 127) were followed for up to 24 months. Response was evaluated using American College of Rheumatology response criteria including individual measures. Results. Significantly diminished values for swollen and tender joints, patient’s global and pain assessments, doctor’s global assessment of disease activity, erythrocyte sedimentation rate, C-reactive protein, and Health Assessment Questionnaire score were observed within 3 months after commencement of both infliximab and etanercept. Values remained significantly lower throughout the 24 months of followup. ACR20 response at 3 months was 79% (n = 22/28) for infliximab and 76% (n = 34/45) for etanercept. The first biological drug was discontinued in 16% due to lack of effectiveness and in 6% due to adverse events. Conclusion. Anti-tumor necrosis factor-α therapy, often combined with conventional disease-modifying antirheumatic drugs, appeared to have limited toxicity and persistent effectiveness for up to 2 years in a cohort of Finnish patients with severe peripheral PsA.

Syndecan-1 expression is upregulated in degenerating articular cartilage in a transgenic mouse model for osteoarthritis.

Objective: Mice heterozygous for the Del1 transgene locus with a short deletion mutation in the type II collagen gene develop early‐onset degenerative changes in the knee joints that progress to end‐stage osteoarthritis by the age of 12–15 months. This study focuses on the expression and distribution of syndecan‐1, a cell‐surface heparan sulfate proteoglycan, during the development of osteoarthritic cartilage degeneration, to better understand its role in this disease. Methods: Northern analyses of total RNA extracted from knee joints of transgenic Del1 mice and their nontransgenic controls were used to monitor changes in syndecan‐1 mRNA levels during development, growth, ageing, and cartilage degeneration. Immunohistochemistry was used to study the distribution of syndecan‐1 in the knee joints at different stages of cartilage degeneration. Results: Syndecan‐1 mRNA was present in knee joints throughout life, with the highest mRNA levels in ageing knee joints. In Del1 mice, a transient upregulation of syndecan‐1 mRNA synthesis was observed at the age of 6 months coinciding with early stages of cartilage degeneration and a period of attempted repair. Immunostaining for syndecan‐1 was most intense in chondrocytes of superficial and intermediate zones of articular cartilage adjacent to defect areas. Chondrocyte clusters also stained strongly for syndecan‐1. Conclusion: The present temporospatial expression data on upregulation of syndecan‐1 in articular cartilage during early stages of cartilage degeneration suggest that this molecule is involved in the attempted repair of cartilage fibrillations. Combined with the known role of syndecan‐1 during skeletal development and wound healing, this interesting finding warrants further validation.

Fatal Myocardial Necrosis Caused by Staphylococcus lugdunensis and Cytomegalovirus in a Patient with Scleroderma

ABSTRACT A 42-year-old woman developed a rapidly progressing fatal heart failure. At the autopsy extensive necrosis of the myocardium was seen, with an almost complete absence of inflammatory cells and the presence of bacterial structures identified as Staphylococcus lugdunensis by PCR. In addition, the cytomegalovirus genome was found to be located inside the cardiomyocytes.

Expression of the myc-family proto-oncogenes and related genes max and mad in synovial tissue

OBJECTIVE To examine the expression of myc proto-oncogenes; c-myc, L-myc, and N-myc, and their related genes max and mad, in the arthritic synovium. METHODS Using reverse transcription-polymerase chain reaction (RT-PCR), Northern and Southern hybridizations, the expression of these genes in the synovial tissue from rheumatoid arthritis (RA) and osteoarthritis (OA) was analyzed. Synovial specimens from cadavers without any joint disease and peripheral blood mononuclear cells (PBMC) from healthy individuals served as controls. RESULTS As a novel finding, synovial cells were observed to express L-myc, N-myc as well as their related genes max and mad, in addition to the previously described presence of c-myc proto-oncogene in synovium. c-myc, L-myc, N-myc, and mad were expressed in all patient samples studied, including the controls. Instead, max was detected in only 10/12 of RA patients, in 11/13 of OA patients, and in all controls (4/4 cadavers, 5/5 blood donors). Six patients with RA revealed positive signals for max only after hybridization. The same was also true of two patients with OA and of one healthy individual donating blood. CONCLUSIONS The L-myc, N-myc, max, and mad genes are expressed in synovial cells, in addition to c-myc proto-oncogene. However, expression of these genes is not disease-specific, since they were equally expressed in synovial samples from patients with RA or OA as well as from cadavers representing controls without any joint disease.

Drug survival on tumour necrosis factor inhibitors in patients with rheumatoid arthritis in Finland.

Objective: A systematic review found that an average of 27% of rheumatoid arthritis (RA) patients using tumour necrosis factor (TNF) inhibitors discontinue their treatment within 1 year. The aim of this study was to assess drug survival on TNF inhibitors among patients with RA. Methods: Patients were identified from the National Register for Biologic Treatment in Finland (ROB-FIN), which is a longitudinal cohort study established to monitor the effectiveness and safety of biologic drugs in rheumatic diseases. Inclusion was limited to TNF-inhibitor treatments started as the patient’s first, second, or third biologic treatment between 2004 and 2014. Follow-up was truncated at 36 months. The results of a time-dependent Cox proportional hazards model were reported as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Of the 4200 TNF-inhibitor treatment periods identified from ROB-FIN, 3443 periods from 2687 patients met the inclusion criteria. Twenty-seven per cent of the patients discontinued their treatment within 12 months. Infliximab (HR 1.8, 95% CI 1.3–2.5) and certolizumab pegol (HR 1.7, 95% CI 1.2–2.3) had lower drug survival compared to golimumab. A similar trend was seen with adalimumab (HR 1.2, 95% CI 0.90–1.7) and etanercept (HR 1.2, 95% CI 0.87–1.6). Concomitant use of methotrexate (MTX) was associated with improved drug survival (HR 0.76, 95% CI 0.64–0.90) in comparison with TNF-inhibitor monotherapy. Conclusions: Golimumab was better in terms of drug survival than infliximab or certolizumab pegol and at least as good as adalimumab and etanercept. Concomitant use of MTX improved drug survival on TNF inhibitors.

Visualization of pericarditis by fluorodeoxyglucose PET.

We describe a case of postpericardiotomy syndrome imaged by positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) and computed tomography (CT). A 53-year-old woman had surgical aortic valve replacement with mechanical prosthesis due to severe aortic valve regurgitation. Within 1 month of surgery, she was diagnosed inflammatory pericarditis with …

Influence of triple disease modifying anti-rheumatic drug therapy on carotid artery inflammation in drug-naive patients with recent onset of rheumatoid arthritis

OBJECTIVE Increased atherosclerosis in RA is not fully explained by the ordinary risk factors, but it may be related to vascular inflammation. The aim of this study was to investigate the degree of carotid artery inflammation in drug-naive patients with early RA before and after DMARD triple therapy. METHODS Fifteen non-diabetic patients with recently diagnosed RA [age 51 (16) years, 6 males] were examined before and at 2 and 4 weeks after the initiation of combination therapy with MTX, SSZ, HCQ and ⩽10 mg/day oral prednisolone. Eight healthy males aged 49 (6) years were examined once as controls. Inflammation in the carotid artery was quantified, using [(18)F]fluorodeoxyglucose ((18)F-FDG)-PET/CT, as the maximum standardized uptake value (SUVmax) and the maximum target-to-background ratio (TBRmax). RESULTS Before the treatment, patients with RA had significantly higher carotid artery (18)F-FDG uptake, as compared with healthy controls [TBRmax 1.78 (0.07) vs 1.51 (0.08), P = 0.03]. The 4-week DMARD therapy reduced the TBRmax to the level of healthy controls [1.53 (0.05), P = 0.84]. Compared with the baseline, the TBRmax decreased by 12.4 (16.8)% (P = 0.01) during 4-week DMARD therapy. At baseline, the SUVmax correlated with ESR (r = 0.52, P = 0.02) and CRP (r = 0.65, P = 0.01). Change in SUVmax correlated with changes in ESR and CRP after 4 weeks of treatment, as did the changes in TBRmax and SUVmax with DAS at 12 weeks of treatment. CONCLUSION (18)F-FDG-PET/CT revealed that drug-naive patients with early RA show carotid artery inflammation that can be efficiently reduced by 1-month DMARD triple therapy.