Browsing by Subject "ARTHRITIS"

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  • Kroger, Liisa; Löppönen, Tuija; Ala-Kokko, Leena; Kröger, Heikki; Jauhonen, Hanna-Mari; Lehti, Kaisa; Jaaskelainen, Jarmo (2019)
    Background MONA, which stands for a spectrum of Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia, is an ultra rare autosomal recessive disorder caused by mutations in the matrix metallopeptidase 2 (MMP2) gene. To date only 44 individuals, carrying 22 different mutations have been reported. Here we report on two brothers with identical homozygous MMP2 gene mutations, but with clearly different phenotypes. Methods Genomic DNA was isolated from the affected brothers and the parents. An iliac crest bone biopsy was taken from the younger patient (index case). The level of matrix metallopeptidase 2 enzyme (MMP2) in serum and synovial fluid of the younger patient was analyzed using gelatin zymography. Results The DNA analysis revealed a homozygous c.1188C>A transversion on exon 8 of the gene. The affected brothers had the same homozygous variant and the parents were heterozygous to this variant. This variant has been reported as a compound heterozygous mutation on one individual resulting in scleroderma like skin thickening. Bone histomorphometry indicated increased trabecular bone remodeling and turnover. The zymography revealed that the level of MMP2 was completely nonmeasurable in the serum and only a minor gelatinolytic protein band of about similar molecular weight as MMP2 was found in the synovial fluid. Conclusions Both the age at the onset and the phenotypic severity of the syndrome in these two brothers were different despite identical genotypes. The younger patients had corneal opacities leading to deteriorating visual acuity. For the first time in this disease, opacities were successfully treated with corneal transplantations.
  • Sillanpaa, Heidi; Skogman, Barbro H.; Sarvas, Heikki; Seppala, Ilkka J. T.; Lahdenne, Pekka (2014)
  • Lei, Jing; Ye, Gang; Pertovaara, Antti; You, Hao-Jun (2020)
    Here we investigated effects of intramuscular (i.m.) heating-needle stimulation on persistent muscle nociception evoked by i.m. injection of different doses (50-200 mu l) of complete Freund's adjuvant (CFA) in rats. Paw withdrawal reflexes evoked by noxious mechanical and heat stimulation as well as hind limb swelling were determined prior to and two weeks after the CFA injection. The unilateral injection of CFA induced a dose-related and long-lasting (5-14 d), bilateral secondary mechanical hyperalgesia and heat hypoalgesia associated with long-term limb swelling. A period of 30-45 min 43 degrees C heating-needle stimulation significantly enhanced the i.m. CFA-induced bilateral heat hypoalgesia and alleviated hind limb swelling. In contrast, 30-45 min 46 degrees C heatingneedle stimulation markedly enhanced both mechanical hyperalgesia and heat hypoalgesia, but failed to influence the CFA-induced hind limb swelling. Microinjection of P2X3 receptor antagonist A-317491 (0.5-4.5 nmol/0.5 mu l) into the thalamic ventromedial (VM) nucleus dose-dependently inhibited the 43 degrees C and 46 degrees C heating-needle stimulation-induced heat hypoalgesia, whereas the 46 degrees C heating-needle stimulation-induced mechanical hyperalgesia was significantly prevented by microinjection of A-317491 into the thalamic mediodorsal (MD) nucleus. In contrast, the hind limb swelling was not affected by the microinjection of A-317491 into the thalamic VM or MD nucleus. The present study indicates that in the CFA-induced persistent muscle nociception condition, 43 degrees C heating-needle stimulation selectively increases descending inhibition, which effect is modulated by the thalamic VM nucleus. In addition to the antinociceptive role of P2X3 receptors in the thalamic VM nucleus, P2X3 receptors within the thalamic MD nucleus participate in the descending facilitation evoked by i.m. 46 degrees C heating-needle stimulation. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Tormalehto, Soili; Aarnio, Emma; Mononen, Mika E.; Arokoski, Jari P. A.; Korhonen, Rami K.; Martikainen, Janne A. (2019)
    Background Knee osteoarthritis (OA) worsens health-related quality of life (HRQoL) but the symptom pathway varies from person to person. We aimed to identify groups of people with knee OA or at its increased risk whose HRQoL changed similarly. Our secondary aim was to evaluate if patient-related characteristics, incidence of knee replacement (KR) and prevalence of pain medication use differed between the identified HRQoL trajectory groups. Methods Eight-year follow-up data of 3053 persons with mild knee OA or at increased risk were obtained from the public Osteoarthritis Initiative (OAI) database. Group-based trajectory modeling was used to identify patterns of experiencing a decrease of >= 10 points (Minimal Important Change, MIC) in the Quality of Life subscale of the Knee injury and Osteoarthritis Outcome Score compared to baseline. Multinomial logistic regression, Cox regression and generalized estimating equation models were used to study secondary aims. Results Four HRQoL trajectory groups were identified. Persons in the 'no change' group (62.9%) experienced no worsening in HRQoL. 'Rapidly' (9.5%) and 'slowly' worsening (17.1%) groups displayed an increasing probability of experiencing the MIC in HRQoL. The fourth group (10.4%) had 'improving' HRQoL. Female gender, higher body mass index, smoking, knee pain, and lower income at baseline were associated with belonging to the 'rapidly worsening' group. People in 'rapidly' (hazard ratio (HR) 6.2, 95% confidence interval (CI) 3.6-10.7) and 'slowly' worsening (HR 3.4, 95% CI 2.0-5.9) groups had an increased risk of requiring knee replacement. Pain medication was more rarely used in the 'no change' than in the other groups. Conclusions HRQoL worsening was associated with several risk factors; surgical and pharmacological interventions were more common in the poorer HRQoL trajectory groups indicating that HRQoL does reflect the need for OA treatment. These findings may have implications for targeting interventions to specific knee OA patient groups.
  • Törmälehto, Soili; Mononen, Mika E.; Aarnio, Emma; Arokoski, Jari P. A.; Korhonen, Rami K.; Martikainen, Janne (2018)
    Background: The purpose was to quantify the decrement in health utility (referred as disutility) associated with knee osteoarthritis (OA) and different symptomatic and radiographic uni- and bilateral definitions of knee OA in a repeated measures design of persons with knee OA or at increased risk of developing knee OA. Methods: Data were obtained from the Osteoarthritis Initiative database. SF-12 health-related quality of life was converted into SF-6D utilities, and were then handled as the health utility loss by subtracting 1.000 from the utility score, yielding a negative value (disutility). Symptomatic OA was defined by radiographic findings (Kellgren-Lawrence, K-L, grade >= 2) and frequent knee pain in the same knee. Radiographic OA was defined by five different definitions (K-L >= 2 unilaterally / bilaterally, or the highest / mean / combination of K-L grades of both knees). Repeated measures generalized estimating equation (GEE) models were used to investigate disutility in relation to these different definitions. Results: Utility decreased with worsening of symptomatic or radiographic status of knee OA. The participants with bilateral and unilateral symptomatic knee OA had 0.03 (p <0.001) and 0.02 (p <0.001) points lower utility scores, respectively, compared with the reference group. The radiographic K-L grade 4 defined as the mean or the highest grade of both knees was related to a decrease of 0.04 (p <0.001) and 0.03 (p <0.001) points in utility scores, respectively, compared to the reference group. Conclusions: Knee OA is associated with diminished health-related quality of life. Health utility can be quantified in relation to both symptomatic and radiographic uni- and bilateral definitions of knee OA, and these definitions are associated with differing disutilities. The performance of symptomatic definition was better, indicating that pain experience is an important factor in knee OA related quality of life.
  • Perelygina, Ludmila; Hautala, Timo; Seppänen, Mikko; Adebayo, Adebola; Sullivan, Kathleen E.; Icenogle, Joseph (2017)
    Persistent rubella virus (RV) infection has been associated with various pathologies such as congenital rubella syndrome, Fuchs's uveitis, and cutaneous granulomas in patients with primary immune deficiencies (PID). Currently there are no drugs to treat RV infections. Nitazoxanide (NTZ) is an FDA-approved drug for parasitic infections, and has been recently shown to have broad-spectrum antiviral activities. Here we found that empiric 2-month therapy with oral NTZ was associated in the decline/elimination of RV antigen from lesions in a PID patient with RV positive granulomas, while peginterferon treatment had no effect. In addition, we characterized the effects of NTZ on cell culture models of persistent RV infection. NTZ significantly inhibited RV replication in a primary culture of human umbilical vein endothelial cells (HUVEC) and Vero and A549 epithelial cell lines in a dose dependent manner with an average 50% inhibitory concentration of 0.35 mu g/ml (1.1 mu M). RV strains representing currently circulating genotypes were inhibited to a similar extent. NTZ affected early and late stages of infection by inhibiting synthesis of cellular and RV RNA and interfering with intracellular trafficking of the RV surface glycoproteins, E1 and E2. These results suggest a potential application of NTZ for the treatment of persistent rubella infections, but more studies are required.
  • Helminen, Eeva-Eerika; Arokoski, Jari P. A.; Selander, Tuomas A.; Sinikallio, Sanna H. (2020)
    Objective: To identify predictors of long-term pain and disability in knee osteoarthritis. Design: A longitudinal cohort study of five years. Setting: Primary care providers. Subjects: In all, 108 patients (mean age = 63.6 years, standard deviation (SD) = 7.2 years) with knee pain (> 40 mm on a 100 mm visual analogue scale in the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain scale) and radiographic grading (Kellgren-Lawrence: 2-4) of knee osteoarthritis who participated in a randomized controlled trial. Main measures: Disease-specific pain and functioning were assessed using the corresponding WOMAC subscales. Generic functioning was assessed by the RAND-36 subscales for function and physical and mental component summary scores. Possible baseline predictors for these outcomes were (1) demographic and disease-related variables and (2) psychological variables of mood (anxiety, depression), pain-related cognitions (pain self-efficacy, pain catastrophizing, kinesiophobia), and positive resource factors (life satisfaction, sense of coherence). Results: Multivariate linear mixed model analyses revealed that minimal anxiety at baseline predicted significantly better results for pain (WOMAC, P = 0.019) and function (WOMAC, P = 0.001, RAND-36 function P = 0.001). High pain self-efficacy predicted significantly better scores in RAND-36 function (P = 0.006), physical (P = 0.004) and mental (P = 0.001) component summaries. Pain catastrophizing predicted higher pain (P = 0.015), whereas fear of movement predicted poorer functioning in RAND-36 physical (P = 0.016) and mental (P = 0.009) component summaries. Those satisfied with life reported higher scores in RAND-36 function (P = 0.002) and mental component summary (P = 0.041). A low number of comorbidities predicted significantly better results in pain (WOMAC P = 0.019) and function (WOMAC P = 0.033, RAND-36 P = 0.009). Conclusion: Anxiety, pain-related cognitions, and psychological resources predict symptoms in knee osteoarthritis in the long term.
  • Heikkilä, Helka M.; Hielm-Björkman, Anna K.; Innes, John F.; Laitinen-Vapaavuori, Outi M. (2017)
    Background: Recently, intra-articular botulinum toxin A (IA BoNT A) has been shown to reduce joint pain in osteoarthritic dogs. Similar results have been reported in human patients with arthritis. However, the mechanism of the antinociceptive action of IA BoNT A is currently not known. The aim of this study was to explore this mechanism of action by investigating the effect of IA BoNT A on synovial fluid (SF) and serum substance P (SP), prostaglandin E-2 (PGE(2)), and tumor necrosis factor alpha (TNF-alpha) in osteoarthritic dogs. Additionally, the aim was to compare SF SP and PGE(2) between osteoarthritic and non-osteoarthritic joints, and investigate associations between SP, PGE(2), osteoarthritic pain, and the signalment of dogs. Thirty-five dogs with chronic naturally occurring osteoarthritis and 13 non-osteoarthritic control dogs were included in the study. Osteoarthritic dogs received either IA BoNT A (n = 19) or IA placebo (n = 16). Serum and SF samples were collected and osteoarthritic pain was evaluated before (baseline) and 2 and 8 weeks after treatment. Osteoarthritic pain was assessed with force platform, Helsinki Chronic Pain Index, and joint palpation. Synovial fluid samples were obtained from control dogs after euthanasia. The change from baseline in SP and PGE(2) concentration was compared between the IA BoNT A and placebo groups. The synovial fluid SP and PGE(2) concentration was compared between osteoarthritic and control joints. Associations between SP, PGE(2), osteoarthritic pain, and the signalment of dogs were evaluated. Results: There was no significant change from baseline in SP or PGE(2) after IA BoNT A. Synovial fluid PGE(2) was significantly higher in osteoarthritic compared to control joints. Synovial fluid PGE(2) correlated with osteoarthritic pain. No associations were found between SP or PGE2 and the signalment of dogs. The concentration of TNF-alpha remained under the detection limit of the assay in all samples. Conclusions: The results suggest that the antinociceptive effect of IA BoNT A in the joint might not be related to the inhibition of SP nor PGE(2). Synovial fluid PGE(2,) but not SP, could be a marker for chronic osteoarthritis and pain in dogs.
  • Molloy, O. E.; Malara, A.; Hassan, J.; Lynch, M.; Clowry, J.; Hedman, K.; De Gascun, C. F.; Kirby, B. (2020)
  • Ruan, Merry Z. C.; Cerullo, Vincenzo; Cela, Racel; Clarke, Chris; Lundgren-Akerlund, Evy; Barry, Michael A.; Lee, Brendan H. L. (2016)
    Osteoarthritis (OA) is a joint disease characterized by degeneration of the articular cartilage, subchondral bone remodeling, and secondary inflammation. It is among the top three causes of chronic disability, and currently there are no treatment options to prevent disease progression. The localized nature of OA makes it an ideal candidate for gene and cell therapy. However, gene and cell therapy of OA is impeded by inefficient gene transduction of chondrocytes. In this study, we developed a broadly applicable system that retargets cell surface receptors by conjugating antibodies to the capsid of helper-dependent adenoviral vectors (HDVs). Specifically, we applied this system to retarget chondrocytes by conjugating an HDV to an alpha-10 integrin monoclonal antibody (a10mab). We show that a10mab-conjugated HDV (a10mabHDV)-infected chondrocytes efficiently in vitro and in vivo while detargeting other cell types. The therapeutic index of an intra-articular injection of 10mabHDV-expressing proteoglycan 4 (PRG4) into a murine model of post-traumatic OA was 10-fold higher than with standard HDV. Moreover, we show that PRG4 overexpression from articular, superficial zone chondrocytes is effective for chondroprotection in postinjury OA and that a-10 integrin is an effective protein for chondrocyte targeting.
  • Lindström, Ulf; Glintborg, Bente; Di Giuseppe, Daniela; Nordström, Dan; Provan, Sella Aarrestad; Gudbjornsson, Bjorn; Askling, Johan; Hetland, Merete Lund; Aaltonen, Kalle; Krogh, Niels Steen; Geirsson, Arni Jon; Jacobsson, Lennart T. H. (2019)
    Objective Although clinical trials support equivalence of originator products and biosimilars for etanercept and infliximab, real-world studies among biologics-naive patients with spondyloarthritis (SpA) are lacking. The objectives were to compare treatment retention in biologics-naive patients with SpA starting either the originator product or a biosimilar of infliximab and etanercept, and to explore the baseline characteristics of these patients. Methods Patients with SpA (ankylosing spondylitis/non-radiographical axial SpA/undifferentiated SpA), starting infliximab or etanercept as their first-ever biological disease-modifying antirheumatic drug during January 2014-June 2017 were identified in five Nordic biologics-rheumatology registers. Baseline characteristics were retrieved from each registry; comorbidity data were identified through linkage to national health registers. Country-specific data were pooled, and data on infliximab and etanercept were analysed separately. Comparisons of treatment retention between originators and biosimilars were assessed through survival probability curves, retention rates (2 years for infliximab/1 year for etanercept) and Hazard Ratios (HR). Results We included 1319 patients starting infliximab (24% originator/76% biosimilar), and 1015 patients starting etanercept (49% originator/51% biosimilar). Baseline characteristics were largely similar for the patients treated with the originators compared with the corresponding biosimilars. Survival probability curves were highly similar for the originator and its biosimilar, as were retention rates: infliximab 2-year retention originator, 44% (95% CI 38% to 50%)/biosimilar, 46% (95% CI: 42% to 51%); and etanercept 1-year retention originator, 66% (95% CI 61% to 70%)/biosimilar, 73% (95% CI 68% to 78%). HRs were not statistically significant. Conclusion This observational study of biologics-naive patients with SpA from five Nordic countries showed similar baseline characteristics and very similar retention rates in patients treated with originators versus biosimilars, for both infliximab and etanercept, indicating comparable effectiveness in clinical practice.
  • Skarp, Sini; Kämäräinen, Olli-Pekka; Wei, Gong-Hong; Jakkula, Eveliina; Kiviranta, Ilkka; Kröger, Heikki; Auvinen, Juha; Lehenkari, Petri; Ala-Kokko, Leena; Männikkö, Minna (2018)
    Introduction Osteoarthritis (OA) is the most common degenerative joint disease and one of the major causes of disability worldwide. It is a multifactorial disorder with a significant genetic component. The heritability of OA has been estimated to be 60% for hip OA and 39% for knee OA. Genetic factors behind OA are still largely unknown. Studying families with strong history of OA, facilitates examining the co-segregation of genetic variation and OA. The aim of this study was to identify new, rare genetic factors and novel candidate genes for OA. Methods Eight patients from three Finnish families with hip and knee OA were studied using whole exome sequencing. We focused on rare exonic variants with predicted pathogenicity and variants located in active promoter or strong enhancer regions. Expression of identified candidate genes were studied in bone and cartilage tissues and the observed variants were investigated using bioinformatic analyses. Results Two rare variants co-segregated with OA in two families. In Family 8 a missense variant (c.628C>G, p.Arg210Gly) was observed in the OLIG3 gene that encodes a transcription factor known to be associated with rheumatoid arthritis and inflammatory polyarthritis. The Arg210Gly variant was estimated to be pathogenic by Polyphen-2 and Mutation taster and the locus is conserved among mammals. In Family 12 the observed variant (c.-127G>T) was located in the transcription start site of the FIP1L1 gene. FIP1L1 participates in the regulation of polyadenylation. The c.-127G>T is located in the transcription start site and may alter the DNA-binding of transcription factors. Both, OLIG3 and FIP1L1 were observed in human bone and cartilage. Conclusion The identified variants revealed novel candidate genes for OA. OLIG3 and FIP1L1 have specific roles in transcription and may effect expression of other genes. Identified variants in these genes may thus have a role in the regulatory events leading to OA.