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  • 1.
    Aili, Katarina
    et al.
    Halmstad University, School of Health and Welfare, Centre of Research on Welfare, Health and Sport (CVHI), Health and Sport. Spenshult Research and Development Center, Halmstad, Sweden | Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden.
    Campbell, Paul
    Keele University, School for Primary, Community and Social Care, Keele, United Kingdom | Midlands Partnership NHS Foundation Trust, Stafford, United Kingdom.
    Michaleff, Zoe A.
    Keele University, School for Primary, Community and Social Care, Keele, United Kingdom.
    Strauss, Vicky Y.
    University of Oxford, CSM, NDORMS, Oxford, United Kingdom.
    Jordan, Kelvin P.
    Keele University, School for Primary, Community and Social Care, Keele, United Kingdom | Keele University, Centre for Prognosis Research, Keele, United Kingdom.
    Bremander, Ann
    Spenshult Research and Development Center, Halmstad, Sweden | Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
    Croft, Peter
    Keele University, School for Primary, Community and Social Care, Keele, United Kingdom | Keele University, Centre for Prognosis Research, Keele, United Kingdom.
    Bergman, Stefan
    Spenshult Research and Development Center, Halmstad, Sweden | University of Gothenburg, Institute of Medicine, Gothenburg, Sweden.
    Long-term trajectories of chronic musculoskeletal pain: a 21-year prospective cohort latent class analysis2021In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 162, no 5, p. 1511-1520Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: Our knowledge of the prevalence, impact, and outcomes of chronic pain in the general population is predominantly based on studies over relatively short periods of time. The aim of this study was to identify and describe trajectories of the chronic pain status over a period of 21 years. Self-reported population data (n = 1858) from 5 timepoints were analyzed. Pain was categorized by: no chronic pain (NCP), chronic regional pain (CRP), and chronic widespread pain (CWP). Latent class growth analysis was performed for identification of trajectories and logistic regression analysis for identification of predictors for pain prognosis. Five trajectories were identified: (1) persistent NCP (57%), (2) migrating from NCP to CRP or CWP (5%), (3) persistent CRP or migration between CRP and NCP (22%), (4) migration from CRP to CWP (10%), and (5) persistent CWP (6%). Age, sleeping problems, poor vitality, and physical function at baseline were associated with pain progression from NCP. Female gender, seeking care for pain, lack of social support, poor physical function, vitality, and mental health predicted poor pain prognosis among those with CRP. In conclusion, chronic pain was common in the population including 6% reporting persistent CWP, although the majority persistently reported NCP. Most people had stable pain status, but some had ongoing change in pain status over time including people who improved from chronic pain. It was possible to identify clinically relevant factors, characterizing trajectories of chronic pain development, that can be useful for identifying individuals at risk and potential targets for intervention. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

  • 2.
    Amirahmadi, S. F.
    et al.
    Monash University, Clayton, Victoria, Australia.
    Whittingham, S.
    Monash University, Clayton, Victoria, Australia.
    Crombie, D. E.
    Monash University, Clayton, Victoria, Australia.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Mackay, I. R.
    Monash University, Clayton, Victoria, Australia.
    van Damme, M. P.
    Monash University, Clayton, Victoria, Australia.
    Rowley, M. J.
    Monash University, Clayton, Victoria, Australia.
    Arthritogenic anti-type II collagen antibodies are pathogenic for cartilage-derived chondrocytes independent of inflammatory cells2005In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 6, p. 1897-1906Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Some monoclonal antibodies (mAb) to type II collagen (CII) are arthritogenic upon passive transfer to mice. We undertook this study to investigate whether such mAb are pathogenic in the absence of mediators of inflammation. METHODS: The arthritogenic mAb CIIC1 and M2139, and the nonarthritogenic mAb CIIF4, each reactive with a distinct and well-defined conformational epitope on CII, were compared with control mAb GAD6. Bovine chondrocytes were cultured with one of the mAb, and on days 3, 6, and 9, antibody binding by chondrocytes and newly synthesized extracellular matrix (ECM) was examined by immunofluorescence, morphologic effects were studied by electron microscopy, and synthesis of matrix components was determined by metabolic labeling with (3)H-proline for collagen and (35)S-sulfate for proteoglycans. RESULTS: All 3 mAb to CII bound to the matrix. CIIC1 and M2139 adversely affected the cultures, whereas CIIF4 did not. CIIC1 caused disorganization of CII fibrils in the ECM without affecting chondrocyte morphology, and increased matrix synthesis. M2139 caused thickening and aggregation of CII fibrils in the ECM and abnormal chondrocyte morphology but matrix synthesis was unaffected. CONCLUSION: The unique arthritogenic capacity of particular anti-CII mAb upon passive transfer could be explained by their adverse, albeit differing, effects in primary cultures of chondrocytes. Such effects occur independent of inflammation mediators and are related to the epitope specificity of the mAb. Interference with the structural integrity of CII could precede, and even initiate, the inflammatory expression of disease.

  • 3.
    Andersson, M.
    et al.
    Lund University, Lund, Sweden; Spenshult Research & Development Centre, Halmstad, Sweden.
    Bremander, Ann
    Lund University, Lund, Sweden; Spenshult Research & Development Centre, Halmstad, Sweden; University of Southern Denmark, Odense, Denmark; University Hospital of Southern Denmark, Sonderborg, Denmark.
    Larsson, Ingrid
    Halmstad University, School of Health and Welfare. Spenshult Research & Development Centre, Halmstad, Sweden.
    Empowerment and Associations to Disease Activity and Pain in Patients with Rheumatoid Arthritis2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no Supplement 1, p. 197-197Article in journal (Refereed)
  • 4.
    Andersson, Maria L E
    et al.
    Lund University, Lund, Sweden; Spenshult Research and Development Centre, Halmstad, Sweden.
    Haglund, Emma
    Halmstad University, School of Business, Innovation and Sustainability. Lund University, Lund, Sweden.
    Aili, Katarina
    Halmstad University, School of Health and Welfare. Karolinska Institute, Stockholm, Sweden.
    Bremander, Ann
    University of Southern Denmark, Odense, Denmark; University Hospital of Southern Denmark, Sonderborg, Denmark.
    Bergman, Stefan
    Spenshult Research and Development Centre, Halmstad, Sweden; University of Gothenburg, Gothenburg, Sweden.
    Cohort profile: the Halland osteoarthritis (HALLOA) cohort–from knee pain to osteoarthritis: a longitudinal observational study in Sweden2022In: BMJ Open, E-ISSN 2044-6055, Vol. 12, no 7, article id e057086Article in journal (Refereed)
    Abstract [en]

    Purpose: The overall objective in this study is to investigate the early development of radiographic knee osteoarthritis (OA) and its association with hand or/and knee OA, metabolic diseases, biomarkers, chronic pain, physical function and daily physical activity types.

    Participants: The Halland osteoarthritis (HALLOA) cohort is a longitudinal cohort study that includes individuals with knee pain in the southwest of Sweden. Enrolment took place from 2017 to 2019. The inclusion criteria were current knee pain, with no former known radiographic knee OA and no cruciate ligament rupture or rheumatological disorder. The participants were recruited: (1) when seeking care for knee pain in primary healthcare or (2) by advertisements in local newspapers. There are 306 individuals included in the study, mean age (SD) 51.7 (8.7) years and 69% are women. The baseline and follow-ups include clinical tests, radiographical examinations, blood samples, metabolic measures, pain pressure thresholds, tests of physical functions, daily physical activity types and patient-reported outcomes.

    Findings to date: There were associations between metabolic factors and radiographic knee OA, even in those with normal body mass index at baseline. In addition, clinical hand OA was positively associated with fasting plasma glucose. We also found that modifiable factors as increased visceral fat and total body fat were associated with increased pain sensitivity among individuals with knee pain.

    Future plans: By studying possible pathophysiological mechanisms of OA over time, we aim to provide new insights on OA progression, identify usable preventive measures helping the clinicians in the management of the disease and improve health for the patients. It is also important to study the development of chronic pain in OA, to get tools to identify individuals at risk and to be able to offer them treatment.

     © Author(s) (or their employer(s)) 2022. 

  • 5.
    Andersson, Maria L.E.
    et al.
    Lund University, Department of Clinical Sciences, Rheumatology, Lund, Sweden | Spenshult research and development centre, Halmstad, Sweden.
    Haglund, Emma
    Halmstad University, School of Business, Innovation and Sustainability, The Rydberg Laboratory for Applied Sciences (RLAS). Spenshult research and development centre, Halmstad, Sweden | Lund University, Department of Clinical Sciences, Rheumatology, Lund, Sweden.
    Aili, Katarina
    Halmstad University, School of Health and Welfare, Centre of Research on Welfare, Health and Sport (CVHI), Health and Sport. Spenshult research and development centre, Halmstad, Sweden.
    Bremander, Ann
    Lund University, Department of Clinical Sciences, Rheumatology, Lund, Sweden | Spenshult research and development centre, Halmstad, Sweden | University of Southern Denmark, Department of Regional Health Research, Odense, Denmark.
    Bergman, Stefan
    Spenshult research and development centre, Halmstad, Sweden | Lund University, Department of Clinical Sciences, Rheumatology, Lund, Sweden | The Sahlgrenska Academy, University of Gothenburg, Primary Health Care Unit, Department of Public Health and Community Medicine, Institute of Medicine, Gothenburg, Sweden.
    Metabolic factors associated to clinical hand osteoarthritis in individuals with knee pain2020In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 79, no Suppl. 1, p. 1734-1734Article in journal (Refereed)
    Abstract [en]

    Background: There is some evidence supporting associations between metabolic factors, clinical hand osteoarthritis (OA) and radiographic knee OA. However, more studies are needed regarding early knee OA.

    Objectives: The aim was to study associations between metabolic factors and clinical hand OA at baseline in a cohort of individuals with knee pain, with and without radiographic knee OA.

    Methods: In an ongoing five-year longitudinal study of knee pain, hand OA was assessed by clinical examinations in 296 of the included individuals at baseline [1]. BMI, waist circumference (WC) and blood pressure was measured. Body composition was assessed with Inbody 770. Fasting plasma glucose, triglycerides, cholesterol, HDL-and LDL-cholesterol and HbA1c was analysed. Metabolic syndrome (MetS)was present if central obesity (WC ≥94 cm in men and ≥80cm in women) plus any two of the following factors: raised blood pressure (systolic blood pressure ≥ 130 or diastolic blood pressure ≥ 85 mm Hg or treatment of hypertension), raised triglycerides (≥ 1.7 mmol/L or specific treatment), reduced HDL-cholesterol (men < 1.03 mmol/L and women < 1.29 mmol/L or specific treatment), raised glucose (glucose ≥ 5.6 mmol/L, or type 2 diabetes). Hand strength and self-reported disability of the arm, shoulder and hand (quickDASH) was assessed.

    The individuals were divided according to having clinical hand OA or not, according to Altman [1]. The associations between background factors and clinical hand OA were calculated by crude logistic regression analyses, adjusting for age and sex.

    Results: Fifty-five percent of the individuals in the study was overweight or obese, 40% had MetS and 23% had radiographic knee OA. In total 34% of the individuals had clinical hand OA. The group with hand OA were older, had higher proportion of body fat, fasting plasma glucose, HbA1C, worse quickDASH score and lower hand strength, table 1. Clinical hand OA was significantly associated to higher age (OR 1.04, 95%CI 1.01-1.07), higher fasting plasma glucose (1.56, 1.05-2.30), worse quickDASH (1.04, 1.02-1.06) and lower hand strength (0.99, 0.99 -0.998), but not to proportion of body fat and HbA1c.

    Conclusion: In this cross-sectional study, the only metabolic factor associated with clinical hand OA was fasting plasma glucose. Contrary to other studies, there were no gender differences found. The association between development of clinical hand OA and metabolic factors in individuals with knee pain need to be further assessed in longitudinal studies.

  • 6.
    Andersson, Maria L.E.
    et al.
    Spenshult Research and Development Center, Halmstad, Sweden; Lund University, Lund, Sweden.
    Thoren, Emelie
    Spenshult Research and Development Center, Halmstad, Sweden.
    Sylwander, Charlotte
    Halmstad University, School of Health and Welfare. Spenshult Research and Development Center, Halmstad, Sweden.
    Bergman, Stefan
    Spenshult Research and Development Center, Halmstad, Sweden; University of Gothenburg, The Sahlgrenska Academy, Gothenburg, Sweden.
    Associations Between Chronic Widespread Pain, Pressure Pain Thresholds and Leptin in Individuals with Knee Pain2022Conference paper (Other academic)
  • 7.
    Andersson, Maria L.E.
    et al.
    Halmstad University, School of Business, Innovation and Sustainability. Spenshult Research and Development Centre, Halmstad, Sweden; Lund University, Lund, Sweden.
    Thorén, Emelie
    Spenshult Research and Development Centre, Halmstad, Sweden.
    Sylwander, Charlotte
    Halmstad University, School of Health and Welfare. Spenshult Research and Development Centre, Halmstad, Sweden.
    Bergman, Stefan
    Spenshult Research and Development Centre, Halmstad, Sweden; University of Gothenburg, Gothenburg, Sweden.
    Associations between chronic widespread pain, pressure pain thresholds, leptin, and metabolic factors in individuals with knee pain2023In: BMC Musculoskeletal Disorders, E-ISSN 1471-2474, Vol. 24, no 1, article id 639Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim was to study associations between chronic widespread pain, widespread pain sensitivity, leptin, and metabolic factors in individuals with knee pain. A secondary aim was to study these associations in a subgroup of individuals with normal BMI.

    METHOD: This cross-sectional study included 265 individuals. The participants were categorised into three different pain groups: Chronic widespread pain (CWP), chronic regional pain (ChRP), or no chronic pain (NCP). The pressure pain thresholds (PPTs) were assessed using computerised pressure algometry. Low PPTs were defined as having PPTs in the lowest third of all tender points. Leptin and metabolic factors such as BMI, visceral fat area (VFA), lipids, and glucose were also assessed.

    RESULT: Sixteen per cent reported CWP, 15% had low PPTs, and 4% fulfilled both criteria. Those who fulfilled the criteria for CWP were more often women, more obese, and had increased leptin levels. In logistic regression, adjusted for age and gender, leptin was associated with fulfilling criteria for CWP, OR 1.015 (95% CI 1.004-1.027, p = 0.008). In logistic regression, adjusted for age and gender, leptin was associated with low PPTs, OR 1.016 (95% CI 1.004-1.029, p = 0.012). Leptin was also associated with fulfilling both criteria, adjusted for age, sex, and visceral fat area (VFA), OR 1.030 (95% CI 1.001-1.060), p = 0.040.

    CONCLUSION: Leptin was associated with fulfilling the combined criteria for chronic widespread pain and low PPTs, even after adjusting for the visceral fat area (VFA). Longitudinal studies are needed to study the causal relationships between leptin and the development of widespread pain.

  • 8.
    Andersson, Åsa
    et al.
    Halmstad University, School of Business, Innovation and Sustainability.
    Haglund, Emma
    Halmstad University, School of Business, Innovation and Sustainability. FoU Spenshult Spenshult Research and Development Centre, Spenshult Research and Development Centre, Halmstad, Sweden; Lund University, Dept. of Clinical Sciences, Section of Rheumatology, Lund, Sweden.
    Berthold, Emma
    Halmstad University, School of Business, Innovation and Sustainability.
    Mogard, Elisabeth
    Lund University, Lund, Sweden.
    Torell, Anna
    Ängelholm Hospital, Ängelholm, Sweden.
    Olsson, M. Charlotte
    Halmstad University, School of Business, Innovation and Sustainability.
    Serum Protein Response To A Single High-Intensity Interval Training Bout – Comparison Between Individuals With Spondyloarthritis And Healthy Controls2022In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 81, no Suppl 1, p. 780-781Article in journal (Refereed)
  • 9.
    Andersson, Åsa
    et al.
    Halmstad University, School of Business, Innovation and Sustainability.
    Olsson, M. Charlotte
    Halmstad University, School of Business, Innovation and Sustainability.
    Torell, Anna
    Halmstad University, School of Business, Innovation and Sustainability. Ängelholm hospital, Dept. of Rehabilitation.
    Mogard, Elisabeth
    Rheumatology, Dept. of Clinical Sciences, Lund University, Skåne University Hospital.
    Haglund, Emma
    Halmstad University, School of Business, Innovation and Sustainability. Spenshult Research and Development Centre, Halmstad.
    Effects on serum protein levels from one bout of high intensity interval training in individuals with axial spondyloarthritis and controlsManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease primarily affecting the axial skeleton causing pain, inflammation, and stiffness. Individuals with axSpA are at greater risk of developing cardiovascular disease, which can be counteracted by physical activity. High-intensity interval training (HIIT) has been shown to improve cardiovascular health, but the effect on disease activity and the level of inflammation in axSpA has been less studied. With the aim of investigating how levels of inflammatory cytokines, myokines, and protein markers for bone metabolism are acutely affected by one bout of HIIT, we studied serum from individuals with axSpA and healthy controls (HC). Methods: Ten participants with axSpA and 11 age- and sex-matched HC performed a single HIIT bout on a cycle ergometer: 4x4 minutes intervals with three minutes active rest in between. Blood samples were taken before and one hour after the HIIT bout. Serum proteins (IL-6, IL-17, IL-18, TNFa, CXCL-10, VEGF-A, BDNF, DKK-1, osteoprotegerin, osteocalcin, osteopontin, BMP-7, CRP) were analyzed with a Luminex system or ELISA. Descriptive data are presented as mean with standard deviation. A two-way ANOVA was used for comparisons. Results: A main effect from baseline to one hour post HIIT showed that both groups had a significant increase in serum levels (pg/ml) of IL-6: axSpA 2.2 (3.0) to 3.2 (1.8) and HC 0.4 (0.4) to 1.9 (2.0), p=0.03. VEGF-A (pg/ml) was significantly lower in the axSpA group: 159 (138) vs. HC 326 (184), p=0.03, but was not affected by the HIIT bout. BMP-7 (ng/ml) increased in both groups after the HIIT: axSpA 61.6 (13.1) to 75.2 (20.0) and HC 64.6 (20.8 to 75.0 (17.8), p<0.001. For the other proteins analyzed, there were no significant differences in serum concentrations between individuals with axSpA and HC, or within the two groups before and after one bout of HIIT. Conclusions: One acute bout of HIIT significantly increases the serum concentrations of IL-6 and BMP-7 after 1 hour in both individuals with axSpA and HC. 

  • 10.
    Backlund, J.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Li, C.
    Karolinska Institute, Stockholm, Sweden.
    Jansson, E.
    Karolinska Institute, Stockholm, Sweden.
    Carlsen, S.
    Karolinska Institute, Stockholm, Sweden.
    Merky, P.
    Karolinska Institute, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden.
    Haag, S.
    Karolinska Institute, Stockholm, Sweden.
    Ytterberg, J.
    Karolinska University Hospital, Stockholm, Sweden.
    Zubarev, R. A.
    Karolinska Institute, Stockholm, Sweden.
    Holmdahl, R.
    Karolinska Institute, Stockholm, Sweden.
    C57BL/6 mice need MHC class II Aq to develop collagen-induced arthritis dependent on autoreactive T cells2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no 7, p. 1225-1232Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Collagen-induced arthritis (CIA) has traditionally been performed in MHC class II A(q)-expressing mice, whereas most genetically modified mice are on the C57BL/6 background (expressing the b haplotype of the major histocompatibility complex (MHC) class II region). However, C57BL/6 mice develop arthritis after immunisation with chicken-derived collagen type II (CII), but arthritis susceptibility has been variable, and the immune specificity has not been clarified. OBJECTIVE: To establish a CIA model on the C57BL/6 background with a more predictable and defined immune response to CII. RESULTS: Both chicken and rat CII were arthritogenic in C57BL/6 mice provided they were introduced with high doses of Mycobacterium tuberculosis adjuvant. However, contaminating pepsin was strongly immunogenic and was essential for arthritis development. H-2(b)-restricted T cell epitopes on chicken or rat CII could not be identified, but expression of A(q) on the C57BL/6 background induced T cell response to the CII260-270 epitope, and also prolonged the arthritis to be more chronic. CONCLUSIONS: The putative (auto)antigen and its arthritogenic determinants in C57BL/6 mice remains undisclosed, questioning the value of the model for addressing T cell-driven pathological pathways in arthritis. To circumvent this impediment, we recommend MHC class II congenic C57BL/6N.Q mice, expressing A(q), with which T cell determinants have been thoroughly characterised.

  • 11.
    Backlund, J.
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Bockermann, R.
    Lund University, Lund, Sweden.
    Mori, L.
    University Hospital, Basel, Switzerland.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Genetic control of tolerance to type II collagen and development of arthritis in an autologous collagen-induced arthritis model2003In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 171, no 7, p. 3493-3499Article in journal (Refereed)
    Abstract [en]

    T cell recognition of the type II collagen (CII) 260-270 peptide is a bottleneck for the development of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. We have earlier made C3H.Q mice expressing CII with glutamic acid instead of aspartic acid at position 266 (the MMC-C3H.Q mouse), similar to the rat and human CII epitope, which increases binding to MHC class II and leads to effective presentation of the peptide in vivo. These mice show T cell tolerance to CII, but also develop severe arthritis. The present investigation shows that non-MHC genes play a decisive role in determining tolerance and arthritis susceptibility. We bred MMC into B10.Q mice, which display similar susceptibility to CIA induced with rat CII as the C3H.Q mice. In contrast to MMC-C3H.Q mice, MMC-B10.Q mice were completely resistant to arthritis. Nontransgenic (B10.Q x C3H.Q)F(1) mice were more susceptible to CIA than either of the parental strains, but introduction of the MMC transgene leads to CIA resistance, showing that the protection is dominantly inherited from B10.Q. In an attempt to break the B10-mediated CIA protection in MMC-transgenic mice, we introduced a transgenic, CII-specific, TCR beta-chain specific for the CII(260-270) glycopeptide, in the highly CIA-susceptible (B10.Q x DBA/1)F(1) mice. The magnification of the autoreactive CII-specific T cell repertoire led to increased CIA susceptibility, but the disease was less severe than in mice lacking the MMC transgene. This finding is important for understanding CIA and perhaps also rheumatoid arthritis, as in both diseases MHC class II-restricted T cell recognition of the glycosylated CII peptide occurs.

  • 12.
    Bajtner, E.
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Engström, Å.
    Uppsala Biomedical Center, IMBIM, Uppsala, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen2005In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 7, p. R1148-R1157Article in journal (Refereed)
    Abstract [en]

    Antibodies against type II collagen (CII) are important in the development of collagen-induced arthritis (CIA) and possibly also in rheumatoid arthritis. We have determined the fine specificity and arthritogenicity of the antibody response to CII in chronic relapsing variants of CIA. Immunization with rat CII in B10.Q or B10.Q(BALB/cxB10.Q)F2 mice induces a chronic relapsing CIA. The antibody response to CII was determined by using triple-helical peptides of the major B cell epitopes. Each individual mouse had a unique epitope-specific response and this epitope predominance shifted distinctly during the course of the disease. In the B10.Q mice the antibodies specific for C1 and U1, and in the B10.Q(BALB/cxB10.Q)F2 mice the antibodies specific for C1, U1 and J1, correlated with the development of chronic arthritis. Injection of monoclonal antibodies against these epitopes induced relapses in chronic arthritic mice. The development of chronic relapsing arthritis, initially induced by CII immunization, is associated with an arthritogenic antibody response to certain CII epitopes.

  • 13.
    Bas, D. B.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Su, J.
    Karolinska Institutet, Stockholm, Sweden.
    Sandor, K.
    Karolinska Institutet, Stockholm, Sweden.
    Agalave, N. M.
    Karolinska Institutet, Stockholm, Sweden.
    Lundberg, J.
    Karolinska Institutet, Stockholm, Sweden.
    Codeluppi, S.
    Karolinska Institutet, Stockholm, Sweden.
    Baharpoor, A.
    Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institutet, Stockholm, Sweden.
    Holmdahl, R.
    Karolinska Institutet, Stockholm, Sweden.
    Svensson, C. I.
    Karolinska Institutet, Stockholm, Sweden.
    Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency2012In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 64, no 12, p. 3886-3896Article in journal (Refereed)
    Abstract [en]

    Objective

    Pain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the collagen antibody–induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain-like behavior induced by anticollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in antibody-induced pain was explored.

    Methods

    CAIA was induced in mice by intravenous injection of a collagen antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain-like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK-interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real-time polymerase chain reaction and immunohistochemistry.

    Results

    Following the induction of CAIA, mice developed transient joint inflammation. In contrast, pain-like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time-dependent signs of activation, and inhibition of glial activity reversed CAIA-induced mechanical hypersensitivity.

    Conclusion

    CAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time-dependent prostaglandin and spinal glial contribution to antibody-induced pain highlight the importance of using appropriate disease models to assess joint-related pain.

  • 14.
    Bergman, Stefan
    Spenshult Hospital, Oskarström, Sweden.
    Management of musculoskeletal pain2007In: Baillière's Best Practice & Research: Clinical Rheumatology, ISSN 1521-6942, E-ISSN 1532-1770, Vol. 21, no 1, p. 153-166Article in journal (Refereed)
    Abstract [en]

    Chronic musculoskeletal pain is a major public health problem affecting about one third of the adult population. Pain is often present without any specific findings in the musculoskeletal system and a strictly biomedical approach could be inadequate. A biopsychosocial model could give a better understanding of symptoms and new targets for management. Identification of risk factors for chronicity is important for prevention and early intervention. The cornerstones in management of chronic non-specific, and often widespread, musculoskeletal pain are non-pharmacological. Physical exercise and cognitive behavioral therapy, ideally in combination, are first line treatments in e.g. chronic low back pain and fibromyalgia. Analgesics are useful when there is a specific nociceptive component, but are often of limited usefulness in non-specific or chronic widespread pain (including fibromyalgia). Antidepressants and anticonvulsants could be of value in some patients but there is a need for more knowledge in order to give general recommendations.

  • 15.
    Bergman, Stefan
    Spenshult Hospital, Oskarström, Sweden.
    Public health perspective - how to improve the musculoskeletal health of the population2007In: Baillière's Best Practice & Research: Clinical Rheumatology, ISSN 1521-6942, E-ISSN 1532-1770, Vol. 21, no 1, p. 191-204Article in journal (Refereed)
    Abstract [en]

    Musculoskeletal disorders are the most common cause of long-term sick leave in several western countries and individuals with chronic musculoskeletal pain score very low on health status measurements. Musculoskeletal health is multidimensional and is best understood from a biopsychosocial perspective. Body structure and function interacts with personal and environmental factors, affecting the ability to perform activities and participate in society. Interventions aimed at the whole population must attend to the underlying causes of musculoskeletal disorders and promote a healthy lifestyle. Safe environments and activities could reduce the risk of traumatic events and also make participation possible for those with a disability. Public beliefs about musculoskeletal symptoms and consequences need to be changed in order to minimise fear and avoidance, which, together with other psychosocial factors, could lead to chronicity. Public awareness and identification of those at risk for the development of musculoskeletal problems could lead to early and properly timed management.

  • 16.
    Bergman, Stefan
    et al.
    Primary Care Centre Hertig Knut, Halmstad, Sweden.
    Herrström, Per
    Jacobsson, Lennart T
    Petersson, Ingemar F
    Chronic widespread pain: a three year followup of pain distribution and risk factors2002In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 29, no 4, p. 818-825Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe the change of pain reports over time in 3 cohorts derived from the general population: (1) no chronic pain (NCP; n = 1156); (2) chronic regional pain (CRP; n = 502); and (3) chronic widespread pain (CWP; n = 242). To identify risk factors that predict the development or persistence of chronic widespread pain.

    METHODS: A 3-year followup from 1995 to 1998 with postal questionnaire to 2425 subjects of both sexes aged 20-74 years on the west coast of Sweden.

    RESULTS: At followup, a larger proportion of subjects with initial CRP compared to initial NCP reported CWP (16.4 and 2.2%, respectively; p < 0.001). The majority of subjects (56.9%) who primarily reported CWP remained in that group at followup, but 26.8% had changed status to CRP and 16.3% to NCP. The number of painful regions (7-12 vs 0 regions) reported at baseline was the strongest predictor for the development of CWP with an odds ratio (OR) of 12.13 (95% CI 4.47-32.88). The development of CWP was also predicted by higher age (OR = 3.13, 95% CI 1.47-6.69, age-group 59-74 years vs age-group 20-34 years), and a family history of chronic pain (OR = 1.87, 95% CI 1.14-3.07). A habit of drinking alcohol weekly (OR = 0.42, 95% CI 0.21-0.85) compared to the habit of never or seldom drinking alcohol was protective, as well as having personal social support (OR = 0.49, 95% CI 0.28-0.85). The persistence of CWP was predicted by the number of painful regions (13-18 vs 1-6 regions) at baseline (OR = 7.56, 95% CI 2.17-26.30), and being an immigrant (OR = 3.22, 95% CI 1.33-7.77).

    CONCLUSION: Although the overall prevalence of CWP was stable over a 3-year period there was a considerable variation on an individual basis. This variability in expressing CWP was moderately predicted by a combination of risk factors, the most important being the number of painful regions at baseline. Future research will need to show how useful the identified factors are in clinical practice and whether intervention aimed at changing these factors will improve pain outcome. 

  • 17.
    Bergsten, Ulrika
    et al.
    Jonkoping Univ, Sch Hlth Sci, Jonkoping.
    Bergman, Stefan
    Spenshult Hosp, Ctr Res & Dev, Oskarstrom.
    Fridlund, Bengt
    Jonkoping Univ, Sch Hlth Sci, Jonkoping.
    Alfredsson, Lars
    Karolinska Inst, Inst Environm Med, S-10401 Stockholm.
    Berglund, Anita
    Karolinska Inst, Inst Environm Med, S-10401 Stockholm.
    Arvidsson, Barbro
    Halmstad University, School of Health and Welfare, Centre of Research on Welfare, Health and Sport (CVHI).
    Petersson, Ingemar
    Univ Lund Hosp, Dept Rheumatol, S-22185 Lund.
    Patterns of background factors related to early RA patients conceptions of the cause of their disease2011In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 30, no 3, p. 347-352Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to identify patterns of background factors related to the early RA patients' conceptions of the cause of the disease. Conceptions from a qualitative study formed the basis for the stratification of 785 patients from the Swedish EIRA study answering a question about their own thoughts about the cause to RA. Logistic regression analyses were used to explore the associations between patients' conceptions and relevant background factors: sex, age, civil status, educational level, anti-cyclic citrullinated peptide antibody (anti-CCP) and smoking habits. The results were presented as odds ratios (OR) with 95% confidence intervals (CI). A conception of family-related strain was strongly associated with being young (OR 0.50; 95% CI 0.33-0.78 for age 58-70 vs. 17-46), female (OR 0.38; 95% CI 0.25-0.60 for male vs. female) and having a high level of education (OR 2.15; 95% CI 1.54-3.01 for university degree vs. no degree). A conception of being exposed to climate changes was associated with being male (OR 1.99; 95% CI 1.24-3.22 for male vs. female), having a low level of education (OR 0.33; 95% CI 0.18-0.58 for university degree vs. no degree) and positive Anti-CCP (OR 1.72; 95% CI 1.03-2.87 for positive vs. negative Anti-CCP). Linking patients' conceptions of the cause of their RA to background factors potentially could create new opportunities for understanding the complexity of the aetiology in RA. Furthermore, this information is important and relevant in the care of patients with early RA.

  • 18.
    Bersellini Farinotti, Alex
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institutet, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons2019In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 216, no 8, p. 1904-1924Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.

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  • 19.
    Bremander, Ann
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS). FoU Spenshult & Lunds universitet, Lund, Sverige.
    Reumatoid artrit2015In: Fysisk aktivitet vid reumatisk sjukdom / [ed] Christina H. Opava, Lund: Studentlitteratur AB, 2015, 1:1, p. 129-139Chapter in book (Other academic)
    Abstract [sv]

    Reumatoid artiri (RA) medför ofta konsekvenser för en persons funktionstillstånd, upplevda hälsa och livskvalitet. Att främja förmågan till fysisk aktivitet är en viktig uppgift för hälso- och sjukvården och ger stora vinster för den enskildes hälsa. Rekommendationer för om fysisk aktivitet och träning har gått från vila och passiv rörelseträning till att idag kunna jämställas med aktiv träning på samma nivå som finns i rekommendationer till befolkningen i allmänhet. Naturligtvis måste träningen anpassas till individens behov, förutsättningar och önskemål.

  • 20.
    Bremander, Ann
    et al.
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). Lund University, Lund, Sweden & Spenshult Research and Development Center, Halmstad, Sweden.
    Forslind, K.
    Lund University, Lund and Helsingborg, Sweden & Helsingborg's hospital, Helsingborg, Sweden.
    Eberhardt, K.
    Lund University, Lund, Sweden.
    Andersson, M.
    Lund University, Lund, Sweden & Spenshult Research and Devlopment Centre, Halmstad, Sweden.
    Functional Impairment in Patients with RA in an Eight Year Perspective2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no Suppl. 2, p. 1513-1514Article in journal (Refereed)
    Abstract [en]

    Background: In people with Rheumatoid arthritis (RA) impaired physical functioning is an acute as well as long term effect of the disease. Observational performance tests reflecting range of motion in upper as well as in lower extremities should be easy to perform in the clinic as well as in research as a complement to self-reported measures of physical functioning. The Signal Of Functional Impairment (SOFI)1 is a performance test which so far has been applied only in Sweden but commonly used in the clinic and in long term follow-up clinical studies.

    Objectives: The aim was to study performance-based function assessed with SOFI over 8 years and, secondly, to study which items included in SOFI that were associated with change in functioning over time.

    Methods: An inception cohort of 1 052 patients with early RA, from the BARFOT-study, recruited 1992–2006 was investigated, mean (SD) age was 54 years (14), 70% were women. The patients were followed by a structured protocol at baseline, 3 and 6 months and at 1, 2, 5, and 8 years. SOFI consists of 3 parts measuring hand, arm (upper), and leg (lower) function (1). Hand function is tested by 4 movements; cylinder grip (H1), pen grip (H2), pincer grip (H3) and opposition of the thumb (H4). Arm function is assessed by 3 movements; hand behind the head and the ability to touch the cervical spine processes with fingers (A1), elbow supination (A2) and elbow extension (A3). Leg function is tested by 4 movements; the ability to touch the opposite knee with the heel while sitting (L1), knee extension in supine position (L2), dorsiflexion of the foot standing on a balance board (L3), and the ability to stand on tip toes without shoes (L4). An assessor scores the patient's ability to perform the different tests on an ordinal scale (0=normal, 1= partly impaired and 2= unable to perform). The range of SOFI scores is 0–44 (best to worst).

    Results: At baseline the mean (SD) SOFI was 7.2 (5.8), and at 1 year follow-up the improvement was 2.75 (5.65), p<0.001. From 1 year to 8 year follow-up the deterioration was 1.5 (4.6), p<0.001. When studying hand, upper and lower function separately, the pen grip and the ability to stand on tip toes improves most during the first year. From 1 to 8 year the pincer grip and the ability to stand on tip toes are the items that deteriorate most (Figure). Assessment of the pen grip, the pincer grip and the ability to stand on tip toes explain 58% to 70% of the SOFI score over time, with the highest rate at 5 (65%) and 8 years follow-up (70%).

    Conclusions: Functioning as assessed by SOFI improved during the first year in patients with early RA and then deteriorated slowly. Over a longer period, pincer grip and the ability to stand on tip toes seemed to be the two most important items to measure when assessing functional impairment over time. © 2017, BMJ Publishing Group Limited

  • 21.
    Bremander, Ann
    et al.
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). Department of Clinical Sciences, Section of Rheumatology, Lund, Sweden & R&D centre, Spenshult, Halmstad, Sweden.
    Haglund, Emma
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). R&D centre, Spenshult, Halmstad, Sweden.
    Bergman, Stefan
    Department of Clinical Sciences, Section of Rheumatology, Lund, Sweden & R&D centre, Spenshult, Halmstad, Sweden & Primary Health Care Unit, Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Measures of Physical Activity and Fear Avoidance in People with Chronic Pain2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no Suppl. 2, p. 1829-1830, article id SAT0737-HPRArticle in journal (Refereed)
    Abstract [en]

    Background Lifestyle factors such as physical activity (PA) has the possibility to contribute to improved health and quality of life in the population as well as in chronic diseases. Most often PA is self-reported while measures of the aerobic capacity are more seldom measured in subjects with chronic pain.

    Objectives To describe physical activity levels (self-reported and aerobic capacity) in people with chronic pain classified as regional or widespread and to compare the findings with a group that report no pain.

    Methods From the 2016 follow-up of the Swedish population based Epipain cohort (n 1321), 146 subjects were invited to a clinical assessment where the aerobic capacity was assessed by using a submaximal bicycle test, the Ekblom-Bak test, together with assessment of the Borg scale for perceived exertion (RPE). Aerobic capacity was also classified as low, average or high according to data from the general population. Self-reported physical activity was coded as MVPArec if recommended levels of PA was reported (physically active on a moderate level ≥150 min/week (MPA) or on an vigorous level ≥75 min/week (VPA) or not). The Fear Avoidance Beliefs Questionnaire for PA (FABQ-PA, 0–24 best to worst) and for work (FABQ-W, 0–48 best to worst) were also assessed. The participants were classified as having chronic widespread pain (CWP), chronic regional pain (CRP) or no chronic pain (NCP) based on a pain mannequin presenting 0–18 pain regions and if pain had lasted for 3 months or more. Chi2 and Kruskal-Wallis tests were performed to study differences between the three pain groups.

    Results 141/146 (97%) subjects (mean (SD) age 59.4 (8.2) years) whereof 61% were women, could be classified into pain groups; 43 as CWP (84% women), 43 as CRP (42% women) and 55 as NCP (58% women). The group with CWP was slightly older than those with CRP (mean (SD) age 57.0 (7.6) years vs. 61.9 (6.9) years, p 0.02). The CWP group also had lower aerobic capacity (mean (SD) 2.2 (0.5) l/min vs. 2.6 (0.6) l/min, p 0.03), and a larger proportion was classified as having low aerobic capacity (CWP 21%, CRP 7% and NCP 10%, p 0.04). The proportion of MVPArec did not differ between the groups; CWP 70%, CRP 81% and NCP 74% (p 0.5). There was neither a difference between the groups in BMI, RPE or in sitting hours/week (p>0.6). However, differences were found in the FABQ where in the PA scale those with CRP had worse scores compared with NCP (mean (SD) 11.2 (7.3) vs. 6.0 (6.0), p<0.001), the difference between CWP (mean (SD) 8.9 (6.7)) and NCP was p 0.06. In the work subscale of FABQ, CWP had worse scores compared with CRP (mean (SD) 18.9 (15.7) vs. 10.0 (12.5), p 0.002) and CRP had worse scores compared to those with NCP (mean (SD) 10.0 (12.5) vs. 6.5 (9.1), p<0.001).

    Conclusions In this sample of subjects with chronic pain or no pain, having widespread pain tended to affect the aerobic capacity negatively while self-reports of reaching recommended levels of physical activity did not differ between groups. Fear avoidance in relation to physical activity and especially in relation to work was more noticeable in subjects with chronic pain compared to those with no pain. Measures of aerobic capacity and information of fear avoidance beliefs might help health professionals to better tailor the non-pharmacological treatment for subjects with chronic pain.

    Disclosure of Interest None declared

    © 2018, Published by the BMJ Publishing Group Limited.

  • 22.
    Bremander, Ann
    et al.
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS).
    Jacobsson, Lennart T. H.
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bergman, Stefan
    Research and Development Centre Spenshult, Halmstad, Sweden.
    Haglund, Emma
    Research and Development Centre Spenshult, Halmstad, Sweden.
    Petersson, Ingemar
    Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden.
    Smoking is Associated with Worse and More Widespread Pain, Worse Fatigue, General Health and Quality of Life in a Swedish population Based Cohort of Patients with Psoriatic Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S777-S778, article id 1828Article in journal (Refereed)
    Abstract [en]

    Background/Purpose: Smoking has been found to be associated with an increased risk of developing psoriatic arthritis (PsA)1. The purpose of this study was analyse possible associations of smoking habits with self-reported clinical features in a large population based cohort of patients with a diagnosis of PsA.

    Methods: All health care seeking subjects with a diagnose of PsA according to ICD 10 codes (given at least once by a rheumatologist/internist or twice by any other physician) were identified by a regional health care register during 2003-20072. In 2009 all identified subjects aged 18 years or older (n=2003) were invited to participate in a cross sectional questionnaire survey. The questionnaire included self-reported data on smoking (never smokers or ever smokers), age at disease onset, physical function (HAQ, 0-3 best to worst), pain, fatigue and global health (numerical rating scales 0-10 best to worst) health related quality of life (EQ-5D, 0-1 worst to best), and number of painful regions noted on a pain mannequin (0-16, best to worst). Linear regression analysis was performed and all data were controlled for sex and age.

    Results: Response rate was 77% whereof 369 patients (18%) declined participation and 1185 (59%) returned the questionnaire,  mean age 57.5 (SD 13.5) years and 58% were women. 1173 subjects responded to the smoking question whereof 448 (38%) were never smokers and 725 (62%) were ever smokers.

    Mean age at disease onset was 42.3 (SD 13.4) years in never smokers vs. 46.0 (SD 13.2) in ever smokers. Never smokers vs. ever smokers had mean HAQ 0.59 (SD 0.6) vs. 0.71 (SD 0.6),  mean pain 3.9 (SD 2.4) vs.4.4 (SD 2.5),  mean fatigue 4.4 (SD 2.8) vs. 5.0 (SD 2.7),  mean global health 3.9 (SD 2.4) vs. 4.4 (SD 2.3), mean EQ-5D 0.68 (SD 0.23) vs. 0.63 (SD 0.26) and mean no of painful regions were 7.2 (SD 4.0) vs. 7.9 (SD 4.3).

    The regression analysis showed that ever smokers had worse pain with age-sex adjusted parameter estimates (B) = 0.38 (95% CI 0.09 ; 0.67), worse fatigue B = 0.34 (95% CI 0.02 ; 0.66), worse global health B = 0.36 (95% CI 0.09 ; 0.64), worse EQ-5D B = -0.04 (95% CI -0.07 ; -0.01) and an increased no of painful regions B = 0.54 (95% CI 0.02 ; 1.07) compared with never smokers.

    Conclusion: In this population based PsA cohort, patients who were ever smokers reported worse clinical features compared with never smokers. Further longitudinal studies are needed to better understand cause and effect. However, smoking cessation should be recommended due to general health perspectives and also due to disease specific issues.

  • 23.
    Bremander, Ann
    et al.
    Department of Clinical Sciences, Lund, Section of Rheumatology, Lund, Sweden & R&D Centre, Spenshult, Halmstad, Sweden.
    Malm, K.
    R&D Centre, Spenshult, Halmstad, Sweden.
    Andersson, M. L.
    Department of Clinical Sciences, Lund, Section of Rheumatology, Lund, Sweden & R&D Centre, Spenshult, Halmstad, Sweden.
    Physical Activity in Established RA and Variables Associated with Physical Activity Maintenance Over a Seven Year Period2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no Suppl. 2, p. 188-188, article id OP0280-HPRArticle in journal (Refereed)
    Abstract [en]

    Background: Interventions to promote a healthy lifestyle also in patients with rheumatoid arthritis (RA) have been in focus over the last years. Physical activity (PA) defined as moderate-to-vigorous physical activity (MVPA) has the possibility to reduce disease burden in RA and may contribute to improved quality of life (QoL). It is well known that a large number of patients with RA have a sedentary life style and are less active than their healthy peers. However, less information is known about the long term change of MVPA and possible associated variables.

    Objectives: To study self-reported change of MVPA over seven years in a well-defined RA cohort.

    Methods: A lifestyle questionnaire was sent twice to patients in the BARFOT cohort, in 2010 (n 1525) and in 2017 (n 1046) with a response rate of 73% and 68% respectively and 950 patients responded to both questionnaires. All patients fulfilled the ACR criteria for classification of RA and had a disease duration at inclusion (1992 to 2006) of ≤12 months. Patients were dichotomized as being active on recommended levels of MVPA (MVPArec ;physically active on a moderate level ≥150 min/week (MPA) or on an intense level ≥75 min/week (VPA)) or not (sedentary). The patients reported body mass index, smoking habits, tender (TJC) and swollen joint count (SJC, 28-joints), patient global assessment (PatGA), pain intensity (NRS) and distribution (pain mannequin), fatigue (NRS), physical function (HAQ), health related QoL (EQ5D), comorbidities and medical treatment. Possible associated variables with meeting MVPArec at both time points or not (dependent variable) was studied by using a logistic regression analysis. All variables were adjusted for age, gender and smoking habits.

    Results: Forty-one percent (n 389) of the patients met MVPArec at both occasions, and they reported better EQ5D scores compared with the sedentary group (mean 0.77 (SD 0.18) vs 0.68 (0.27). The patients who met MVPArec were younger, (mean age (SD) 5913 years vs 6213 years, p<0.001) and were to higher extent never smokers 46% vs 38%, p=0.021. There was a negative association with meeting MVPArec and being overweight (OR 0.58, 95% CI: 0.43 to 0.96) or obese (OR 0.38, 95% CI: 0.25 to 0.59), the presence of cardiovascular (OR 0.56, 95% CI: 0.41 to 0.75) and pulmonary diseases (OR 0.51, 95% CI: 0.31 to 0.85), TJC (OR 0.98, 95% CI: 0.95 to 0.995), high pain intensity (OR 0.99, 95% CI: 0.987 to 0.998), and pain distribution (OR 0.93, 95% CI: 0.90 to 0.96), worse fatigue (OR 0.99, 95% CI: 0.998 to 0.997) and a worse physical function (HAQ, OR 0.58, 95% CI: 0.45 to 0.76). Patients with higher values in QoL (EQ5D, OR 3.1, 95% CI: 1.52 to 6.2) were positively associated with meeting MVPArec. In 2010 there were no differences in medical treatment between the groups, p=0.377. In 2017 the group meeting MVPArec included a lower number of untreated patients compared to 2010 (25% vs 34%, p=0.017).

    Conclusions: Only four out of ten patients with established RA reported to maintain recommended levels of PA over a seven year period. Experiencing high quality of life seems to be important for PA maintenance together with lower levels of pain, fatigue and better physical function. Health care professionals need to take the patient perspective into account andsupport maintenance of physical activities accordingly.

    Disclosure of Interest: None declared

  • 24.
    Bremander, Ann
    et al.
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS), Biomechanics and Biomedicine. Research and Development Centre, Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden.
    Petersson, Ingemar F.
    Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden.
    Haglund, Emma
    Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden.
    Bergman, Stefan
    Research and Development Centre, Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden.
    Jacobsson, Lennart T.H.
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Smoking Is Associated with Worse and More Widespread Pain, Worse Disease Activity, Function, Fatigue and Health Related Quality of Life in Patients with Axial Spondyloarthritis: Results From a Population Based Cohort2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S43-S43, article id 95Article in journal (Refereed)
    Abstract [en]

    Background: In subjects with early axial Spondyloarthritis (SpA) smoking has recently been associated with earlier onset of disease, worse lesions of the sacroiliac joints and in later stages syndesmophyte progression. The aim was to study associations of smoking habits with self-reported information in a large population based cohort of patients with axial SpA.

    Methods: A cross-sectional questionnaire survey performed in 2009 included all health care seeking subjects aged >18 years with a diagnosis of SpA according to ICD 10 codes identified by a regional health care register (n=3711). Smoking habits were studied in patients with ankylosing spondylitis (AS, ICD M45) and in patients who fulfilled criteria for “non AS axial SpA” (without having one of AS). Criteria for non AS axial SpA were based on data from the questionnaire: pain for 3 months or more during the last 12 months together with 2 or more features out of 5 (inflammatory back pain, history of psoriasis, uveitis/tendinitis, inflammatory bowel disease or heredity). The questionnaire included data on smoking (never smokers vs. ever smokers), disease activity (BASDAI) physical function (BASFI), general health (BAS-G) all measured with numerical rating scales 0-10 (best to worst), health related quality of life (EQ-5D, 0-1 worst to best), pain, fatigue (numerical rating scales 0-10 best to worst) and number of painful regions noted on a pain mannequin (0-16 best to worst). Linear regression analysis was performed and all data were controlled for sex and age.

    Results:

    Response rate was 76% whereof 2167 (58%) returned the questionnaire and 18% declined participation in the study. 598 subjects had an AS diagnose and 572 fulfilled the criteria for non AS axial SpA.

    The AS group had a mean age of 54 (SD14) years and 35% were women. Never smokers constituted 48% of the AS group. Ever smokers had worse scores in all studied variables compared with never smokers.

    The linear regression analysis showed that ever smokers in the AS group had worse self-reported scores in BASDAI with age-sex adjusted parameter estimate (B) = 0.60 (95% CI 0.21 ; 1.00), BASFI B = 0.51 (95% CI 0.11 ; 0.91) and fatigue B = 0.51 (95% CI  0.06 ; 1.00) . There was a tendency to worse scores for ever smokers also in EQ-5D B = -0.04 (95% CI -0.09 ; 0.001)

    Mean age in the non AS axial SpA group was 55 (SD 14) years and 68% were women. Never smokers constituted 38% of this group. Also in the non AS axial SpA group the linear regression analysis showed that ever smokers had worse self-reported scores in BASDAI with age-sex adjusted parameter estimate (B) = 0.59 (95% CI 0.23 ; 0.94), BASFI B = 0.59 (95% CI 0.17 ; 1.00), pain B = 0.45 (95% CI 0.08 ; 0.82) and fatigue B = 0.43 (95% CI  0.03 ; 0.83), no of painful areas B = 0.73 (95% CI  0.06 ; 1.46) and also in EQ-5D B = -0.06 (95% CI -0.11 ; -0.002).                                                                                                                                                

    Conclusion: In a large population based axial SpA cohort, both patients with AS and non AS axial SpA who were ever smokers reported worse clinical features compared with never smokers. Further longitudinal studies are needed to better understand cause and effect. However, smoking cessation should be recommended not only due to general health perspectives but also due to disease specific issues.

    References

    1Smokers in early axial spondyloarthritis have earlier disease onset, more disease activity, inflammation and damage, and poorer function and health-related quality of life: results from the DESIR cohort. Chung HY, Machado P, van der Heijde D, D'Agostino MA, Dougados M. Ann Rheum Dis. 2012 Jun;71(6):809-16.

  • 25.
    Brorsson, Sofia
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS).
    Biomechanical studies on hand function in rehabilitation2012In: Human Musculoskeletal Biomechanics / [ed] Tarun Goswami, New York: InTech, 2012, p. 87-106Chapter in book (Other academic)
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  • 26.
    Brorsson, Sofia
    et al.
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS).
    Hilliges, Marita
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS).
    Sollerman, Christer
    R & D centre Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden.
    Nilsdotter, Anna
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS).
    6 weeks of hand exercise significantly improved the hand-strength and -function in Rheumatoid Arthritis patients2008Conference paper (Refereed)
  • 27.
    Brorsson, Sofia
    et al.
    Halmstad University, School of Business and Engineering (SET), Biological and Environmental Systems (BLESS), Biomechanics and Biomedicine.
    Pedersen, Eja
    Halmstad University, School of Business and Engineering (SET), Biological and Environmental Systems (BLESS).
    12-weeks of hand exercise provides better hand function, muscle balance and muscle strength in the rheumatoid arthritis hand2010In: Abstract Archive Sessions Index 2010, EULAR , 2010Conference paper (Refereed)
    Abstract [en]

    Background:

    Impaired grip ability in RA is due to reduced strength in the flexor muscles as well as by dysfunctional extensor muscles leading to inability to open the hand. Furthermore the extensor muscles are important for stabilization during flexion force production and active for developing a controlled grip force. There is today scientific evidence showing that various forms of hand exercise are beneficial for improving hand function and strength in RA patients (Ronningen and Kjeken 2008; Brorsson, Hilliges et al. 2009). However, comparatively little research has evaluated and specific designed hand exercise program for the extensor muscles controlling the hand and fingers (Weiss, Moore et al. 2004; O'Brien, Jones et al. 2006).

    Objectives:

    The objectives for this study were to evaluate the effect of an exercise program on hand strength, hand function and perceived function of daily life activities among RA patients and to explore the possibility to improve the balance between the extensor and flexor muscle forces in the hand.

    Methods:

    The study group comprised of 20 patients with RA (median disease duration 20 years) that performed a hand exercise program for twelve weeks. The finger extension force was measured with a newly developed device (EX-it), finger flexion force was measured with the Grippit. Hand function was evaluated with the Grip Ability Test (GAT) and self reported questionnaire Disability Arm Shoulder and Hand (DASH).

    Results:

    Hand strength (both extension and flexion force) and hand function improved significantly after twelve weeks. The RA group showed improvement in the results of the DASH questionnaire (p < 0.05), but on individual level, the result was partly significant. The relation between extension and flexion force in the hand was not correlated, however, after the exercise there was a strong association between flexion and extension force (p < 0.001). The result on individual level is related to age and duration time.

    Conclusion:

    Twelve weeks of hand exercise significantly improved hand strength, hand function and perceived function for RA patients. Furthermore, exercise improved the relation between the finger extension and flexion force. Hand exercise is thus an effective intervention for RA patients, providing better strength and function.

    References:

    1. Brorsson, S., M. Hilliges, et al. (2009). A six-week hand exercise programme improves strength and hand function in patients with rheumatoid arthritis. J Rehabil Med 41(5): 338-42.
    2. O'Brien, A.V., P. Jones, et al. (2006). Conservative hand therapy treatments in rheumatoid arthritis–a randomized controlled trial. Rheumatology (Oxford) 45(5): 577-83.
    3. Ronningen, A. and I. Kjeken (2008). ffect of an intensive hand exercise programme in patients with rheumatoid arthritis. Scand J Occup Ther: 1-11.
    4. Weiss, A. P., D. C. Moore, et al. (2004). Metacarpophalangeal joint mechanics after 3 different silicone arthroplasties. J Hand Surg [Am] 29(5): 796-803.
  • 28.
    Burkhardt, H.
    et al.
    Friedrich-Alexander-University of Erlangen–Nuremberg, Erlangen, Germany.
    Koller, T.
    Friedrich-Alexander-University of Erlangen–Nuremberg, Erlangen, Germany.
    Engström, Å.
    Uppsala University, Uppsala, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Turnay, J.
    Universidad Complutense, Madrid, Spain.
    Kraetsch, H. G.
    Friedrich-Alexander-University of Erlangen–Nuremberg, Erlangen, Germany.
    Kalden, J. R.
    Friedrich-Alexander-University of Erlangen–Nuremberg, Erlangen, Germany.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse2002In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 46, no 9, p. 2339-2348Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To analyze the fine specificity of IgG autoantibodies in sera from rheumatoid arthritis (RA) patients for type II collagen (CII) epitopes that are arthritogenic in collagen-induced arthritis (CIA), a relevant murine model of RA. METHODS: For enzyme-linked immunosorbent assay (ELISA) analysis of conformation-dependent autoantibody binding, recombinant chimeric collagens that harbor the respective CII epitopes as an insertion within the frame of a constant type X collagen triple helix were constructed. In addition, synthetic peptides mimicking the native collagen structures were applied for the first time in the ELISA assessment of humoral CII autoimmunity. RESULTS: The pathogenicity of IgG responses to certain CII determinants in CIA was demonstrated by arthritis development in BALB/c mice upon the combined transfer of 2 mouse monoclonal antibodies specific for precisely mapped conformational CII epitopes (amino acid residues 359-369 [C1(III)] and 551-564 [J1]), whereas antibodies to another epitope (F4) were not arthritogenic. To test whether human autoimmune responses are similarly directed to these conserved CII determinants, serum IgG was analyzed. The prevalence of sera with increased IgG binding to the C1(III) epitope was significantly higher in RA compared with sera from healthy donors or from patients with other rheumatic conditions, e.g., osteoarthritis (OA), systemic lupus erythematosus (SLE), or relapsing polychondritis (RP), whereas levels of antibodies specific for the nonarthritogenic F4 epitope were associated with OA rather than RA. CONCLUSION: Autoimmunity to CII, although detectable in different rheumatic conditions, differs in fine specificity between distinct disease entities. In RA, in contrast to degenerative joint disease, RP, and SLE, autoantibody responses are directed to an evolutionary conserved CII structure that is also targeted by pathogenic autoimmune responses in murine models of arthritis.

  • 29.
    Bäcklund, A.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Holmdahl, M.
    Karolinska Institute, Stockholm, Sweden.
    Mattsson, R.
    Lund University, Lund, Sweden.
    Håkansson, K.
    Lund University, Lund, Sweden; Novo Nordisk A/S, Novo Nordisk Park, Måløv, Sweden.
    Lindström, V.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden.
    Grubb, A.
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Karolinska Institute, Stockholm, Sweden.
    Cystatin C influences the autoimmune but not inflammatory response to cartilage type II collagen leading to chronic arthritis development2011In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, article id R54Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis (RA) and is induced after immunization with type II collagen (CII). CIA, like RA, is an autoimmune disease leading to destruction of cartilage and joints, and both the priming and inflammatory phases have been suggested to be dependent on proteases. In particular, the cysteine proteases have been proposed to be detrimental to the arthritic process and even immunomodulatory. A natural inhibitor of cysteine proteases is cystatin C. METHODS: Cystatin C-deficient, sufficient and heterozygous mice were tested for onset, incidence and severity of CIA. The effect of cystatin C-deficiency was further dissected by testing the inflammatory effector phase of CIA; that is, collagen antibody-induced arthritis model and priming phase, that is, T cell response both in vivo and in vitro. In addition, in order to determine the importance of T cells and antigen-presenting cells (APCs), these cell populations were separated and in vitro T cell responses determined in a mixed co-culture system. Finally, flow cytometry was used in order to further characterize cell populations in cystatin C-deficient mice. RESULTS: Here, we show that mice lacking cystatin C, develop arthritis at a higher incidence and an earlier onset than wild-type controls. Interestingly, when the inflammatory phase of CIA was examined independently from immune priming then cystatin C-deficiency did not enhance the arthritis profile. However, in line with the enhanced CIA, there was an increased T cell and B cell response as delayed-type hypersensitivity reaction and anti-CII antibody titers were elevated in the cystatin C-deficient mice after immunization. In addition, the ex vivo naive APCs from cystatin C-deficient mice had a greater capacity to stimulate T cells. Interestingly, dendritic cells had a more activated phenotype in naive cystatin C-deficient mice. CONCLUSIONS: The lack of cystatin C enhances CIA and primarily affects in vivo priming of the immune system. Although the mechanism of this is still unknown, we show evidence for a more activated APC compartment, which would elevate the autoimmune response towards CII, thus resulting in an enhanced development of chronic arthritis.

  • 30.
    Carlsen, S.
    et al.
    Lund University, Lund; Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund; Karolinska Institutet, Stockholm, Sweden.
    Backlund, J.
    Lund University, Lund; Karolinska Institutet, Stockholm, Sweden.
    Holmberg, J.
    Lund University, Lund; Karolinska Institutet, Stockholm, Sweden.
    Hultqvist, M.
    Lund University, Lund; Karolinska Institutet, Stockholm, Sweden.
    Vestberg, M.
    Lund University, Lund; Karolinska Institutet, Stockholm, Sweden.
    Holmdahl, R.
    Lund University, Lund; Karolinska Institutet, Stockholm, Sweden.
    Cartilage oligomeric matrix protein induction of chronic arthritis in mice2008In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 7, p. 2000-2011Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop a new mouse model for arthritis using cartilage oligomeric matrix protein (COMP) and to study the role of major histocompatibility complex (MHC) and Ncf1 genes in COMP-induced arthritis (COMPIA). METHODS: Native (pentameric) and denatured (monomeric) COMP purified from a rat chondrosarcoma was injected into mice with Freund's adjuvant to induce arthritis. C3H.NB, C3H.Q, B10.P, B10.Q, (B10.Q x DBA/1)F1, (BALB/c x B10.Q)F1, Ncf1 mutated, H-2Aq, H-2Ap, and human DR4+-transgenic mice were used. Anti-COMP antibodies and COMP levels in the immune sera were analyzed, and passive transfer of arthritis with purified immune sera was tested. RESULTS: Immunization with rat COMP induced a severe, chronic, relapsing arthritis, with a female preponderance, in the mice. The disease developed in C3H.NB mice, but not in B10.P mice, although they share the same MHC haplotype. Both H-2q and H-2p MHC haplotypes allowed the initiation of COMPIA. Using H-2Aq-transgenic and H-2Ap-transgenic mice, we demonstrated a role of both the Aq and Ep class II molecules in this model. Interestingly, the introduction of a mutation in the Ncf1 gene, which is responsible for the reduced oxidative burst phenotype, into the COMPIA-resistant B10.Q mouse strain rendered them highly susceptible to arthritis. In addition, the transfer of anti-COMP serum was found to induce arthritis in naive mice. Mice transgenic for the rheumatoid arthritis (RA)-associated DR4 molecule were found to be highly susceptible to COMPIA. CONCLUSION: Using rat COMP, we have developed a new and unique mouse model of chronic arthritis that resembles RA. This model will be useful as an appropriate and alternative model for studying the pathogenesis of RA.

  • 31.
    Carlsen, S.
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Type IX collagen deficiency enhances the binding of cartilage-specific antibodies and arthritis severity2006In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, no 4, article id R102Article in journal (Refereed)
    Abstract [en]

    Joint cartilage is attacked in both autoimmune inflammatory and osteoarthritic processes. Type IX collagen (CIX) is a protein of importance for cartilage integrity and stability. In this study we have backcrossed a transgenic disruption of the col9a1 gene, which leads to an absence of CIX, into two different inbred mouse strains, DBA/1 and B10.Q. None of the CIX-deficient mice developed observable clinical or microscopic osteoarthritis, but DBA/1 male mice had more pronounced enthesopathic arthritis, the so-called stress-induced arthritis. Both DBA/1 and B10.Q strains are susceptible to the induction of collagen-induced arthritis, and CIX deficiency in both strains led to the development of a more severe arthritis than in the controls. Induction of arthritis with monoclonal antibodies against type II collagen (CII) led to an earlier arthritis in the paws that also involved the knee joints. The antibodies used, which were specific for the J1 and the C1I epitopes of CII, initiate their arthritogenic attack by binding to cartilage. The C1I-specific antibodies bound to cartilage better in CIX-deficient mice than in wild-type animals, demonstrating that the lack of CIX in cartilage leads to an increased accessibility of structures for antibody binding and thus making the joints more vulnerable to inflammatory attack. These findings accentuate the importance of cartilage stability; cartilage disrupted as a result of genetic disorders could be more accessible and vulnerable to an autoimmune attack by pathogenic antibodies.

  • 32.
    Crombie, D. E.
    et al.
    Monash University, Clayton, Victoria, Australia.
    Turer, M.
    Monash University, Clayton, Victoria, Australia.
    Zuasti, B. B.
    Monash University, Clayton, Victoria, Australia.
    Wood, B.
    Monash University, Clayton, Victoria, Australia.
    McNaughton, D.
    Monash University, Clayton, Victoria, Australia.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Van Damme, M. P.
    Monash University, Clayton, Victoria, Australia.
    Rowley, M. J.
    Monash University, Clayton, Victoria, Australia.
    Destructive effects of murine arthritogenic antibodies to type II collagen on cartilage explants in vitro2005In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 7, no 5, article id R927Article in journal (Refereed)
    Abstract [en]

    Certain monoclonal antibodies (mAbs) to type II collagen (CII) induce arthritis in vivo after passive transfer and have adverse effects on chondrocyte cultures and inhibit self assembly of collagen fibrils in vitro. We have examined whether such mAbs have detrimental effects on pre-existing cartilage. Bovine cartilage explants were cultured over 21 days in the presence of two arthritogenic mAbs to CII (CIIC1 or M2139), a non-arthritogenic mAb to CII (CIIF4) or a control mAb (GAD6). Penetration of cartilage by mAb was determined by immunofluorescence on frozen sections and correlated with changes to the extracellular matrix and chondrocytes by morphometric analysis of sections stained with toluidine blue. The effects of mAbs on matrix components were examined by Fourier transform infrared microspectroscopy (FTIRM). A possible role of Fc-binding was investigated using F(ab)2 from CIIC1. All three mAbs to CII penetrated the cartilage explants and CIIC1 and M2139, but not CIIF4, had adverse effects that included proteoglycan loss correlating with mAb penetration, the later development in cultures of an abnormal superficial cellular layer, and an increased proportion of empty chondrons. FTIRM showed depletion and denaturation of CII at the explant surface in the presence of CIIC1 or M2139, which paralleled proteoglycan loss. The effects of F(ab)2 were greater than those of intact CIIC1. Our results indicate that mAbs to CII can adversely affect preformed cartilage, and that the specific epitope on CII recognised by the mAb determines both arthritogenicity in vivo and adverse effects in vitro. We conclude that antibodies to CII can have pathogenic effects that are independent of inflammatory mediators or Fc-binding.

  • 33.
    Croxford, Allyson M.
    et al.
    Monash University, Clayton, Australia.
    Crombie, Duncan
    Monash University, Clayton, Australia.
    McNaughton, Donald
    Monash University, Clayton, Australia.
    Holmdahl, Rikard
    Karolinska Institute, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden.
    Rowley, Merrill J.
    Monash University, Clayton, Australia.
    Specific antibody protection of the extracellular cartilage matrix against collagen antibody-induced damage2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 11, p. 3374-3384Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The type II collagen (CII)-specific monoclonal antibodies (mAb) M2139 and CIIC1 induce arthritis in vivo and degrade bovine cartilage explants in vitro, whereas mAb CIIF4 is nonarthritogenic and prevents arthritis development when given in combination with M2139 and CIIC1. To determine the nature of the protective capacity of CIIF4 antibody, we examined the effects of adding CIIF4 to cartilage explants cultured in vitro with M2139 and CIIC1. METHODS: Bovine cartilage explants were cultured in the presence of M2139 and CIIC1, with or without CIIF4. Histologic changes were examined, and chemical changes to collagens and proteoglycans were assessed by Fourier transform infrared microspectroscopy (FTIRM). Fresh cartilage and cartilage that had been freeze-thawed to kill chondrocytes cultured with or without the addition of GM6001, a broad-spectrum inhibitor of matrix metalloproteinases (MMPs), were compared using FTIRM analysis. RESULTS: M2139 and CIIC1 caused progressive degradation of the cartilage surface and loss of CII, even in the absence of viable chondrocytes. CIIF4 did not cause cartilage damage, and when given with the arthritogenic mAb, it prevented their damage and permitted matrix regeneration, a process that required viable chondrocytes. Inhibition of MMP activity reduced cartilage damage but did not mimic the effects of CIIF4. CONCLUSION: CII-reactive antibodies can cause cartilage damage or can be protective in vivo and in vitro, depending on their epitope specificity. Since CII antibodies of similar specificity also occur in rheumatoid arthritis in humans, more detailed studies should unravel the regulatory mechanisms operating at the effector level of arthritis pathogenesis. © 2010 by the American College of Rheumatology.

  • 34.
    Croxford, Allyson M.
    et al.
    Monash University, Clayton, Australia.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden.
    Holmdahl, Rikard
    Karolinska Institute, Stockholm, Sweden.
    Tobin, Mark J.
    Australian Synchrotron, Clayton, Australia.
    McNaughton, Don
    Monash University, Clayton, Australia.
    Rowley, Merrill J.
    Monash University, Clayton, Australia.
    Chemical changes demonstrated in cartilage by synchrotron infrared microspectroscopy in an antibody-induced murine model of rheumatoid arthritis2011In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 16, no 6, article id 066004Article in journal (Refereed)
    Abstract [en]

    Collagen antibody-induced arthritis develops in mice following passive transfer of monoclonal antibodies (mAbs) to type II collagen (CII) and is attributed to effects of proinflammatory immune complexes, but transferred mAbs may react directly and damagingly with CII. To determine whether such mAbs cause cartilage damage in vivo in the absence of inflammation, mice lacking complement factor 5 that do not develop joint inflammation were injected intravenously with two arthritogenic mAbs to CII, M2139 and CIIC1. Paws were collected at day 3, decalcified, paraffin embedded, and 5-mum sections were examined using standard histology and synchrotron Fourier-transform infrared microspectroscopy (FTIRM). None of the mice injected with mAb showed visual or histological evidence of inflammation but there were histological changes in the articular cartilage including loss of proteoglycan and altered chondrocyte morphology. Findings using FTIRM at high lateral resolution revealed loss of collagen and the appearance of a new peak at 1635 cm(-1) at the surface of the cartilage interpreted as cellular activation. Thus, we demonstrate the utility of synchrotron FTIRM for examining chemical changes in diseased cartilage at the microscopic level and establish that arthritogenic mAbs to CII do cause cartilage damage in vivo in the absence of inflammation. © 2011 Society of Photo-Optical Instrumentation Engineers (SPIE).

  • 35.
    Croxford, Allyson M.
    et al.
    Monash University, Clayton, Australia.
    Whittingham, Senga
    Monash University, Clayton, Australia.
    McNaughton, Donald
    Monash University, Clayton, Australia.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden.
    Holmdahl, Rikard
    Karolinska Institute, Stockholm, Sweden.
    Rowley, Merrill J.
    Monash University, Clayton, Australia.
    Type II collagen-specific antibodies induce cartilage damage in mice independent of inflammation2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 3, p. 650-659Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Murine collagen antibody-induced arthritis (CAIA), like collagen-induced arthritis, has clinical and immunopathologic features that parallel those in human rheumatoid arthritis (RA). This study was undertaken to examine the effects of autoantibodies to type II collagen (CII) on articular cartilage in the paws of mice, under conditions in which other factors that may influence joint pathology could be excluded. METHODS: Mice of 2 different strains, B10.QC5delta and the parental strain B10.Q, were injected intravenously with either saline or arthritogenic monoclonal antibodies (mAb) to CII. B10.QC5delta mice lack complement factor C5 and do not develop CAIA when injected with arthritogenic mAb, whereas B10.Q mice have C5 and develop CAIA when administered the mAb and a subsequent injection of lipopolysaccharide. Three days after injection the paws of the mice were examined by standard histologic methods to assess morphologic appearance and proteoglycan loss, and by synchrotron-enhanced Fourier transform infrared microspectroscopy to assess chemical evidence of structural change. RESULTS: No macroscopic or microscopic signs of inflammation were evident in the mice. However, in contrast to the saline-injected controls, all mAb-injected mice exhibited cartilage damage in all joints, with loss of proteoglycans and collagen, chondrocyte hyperplasia and/or loss, and surface damage in the interphalangeal joints. CONCLUSION: The implication of these findings is that an autoimmune response to CII can disrupt articular cartilage, particularly that of the small joints, and the subsequent integrity of the cartilage depends on a balance between breakdown and repair. This has relevance with regard to RA, in which such autoantibodies occur but the inflammatory response may dominate clinically and mask underlying features of the autoimmune response. © 2013 by the American College of Rheumatology

  • 36.
    Dahdah, Albert
    et al.
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Habir, Katrin
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Saxena, Amit
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Xu, Bingze
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Holmdahl, Rikard
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Malin, Stephen
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Germinal Center B Cells Are Essential for Collagen-Induced Arthritis2018In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 2, p. 193-203Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disorder. Several mechanisms have been proposed for the known pathologic function of B cells in RA, including antigen presentation, cytokine secretion, and humoral immunity. The aim of this study was to address the function of B lymphocytes in experimental arthritis.

    METHODS: We mapped the adaptive immune response following collagen-induced arthritis (CIA). We subsequently monitored these responses and disease outcomes in genetically modified mouse strains that lack mature B cell or germinal center (GC) functionality in a B cell-intrinsic manner.

    RESULTS: Following primary immunization, the draining lymph nodes broadly reacted against type II collagen (CII) with the formation of GCs and T cell activation. Mice that lacked mature B cell function were fully protected against CIA and had a severely attenuated ability to mount isotype-switched humoral immune responses against CII. Almost identical results were observed in mice that were selectively deficient in GC responses. Importantly, GC-deficient mice were fully susceptible to collagen antibody-induced arthritis.

    CONCLUSION: We identified GC formation and anticollagen antibody production as the key pathogenic functions of B cells in CIA. The role of B cells in RA is likely to be more complex. However, targeting the GC reaction could allow for therapeutic interventions that are more refined than general B cell depletion.

  • 37.
    Dahdah, Albert
    et al.
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Habir, Katrin
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Saxena, Amit
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Xu, Bingze
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Holmdahl, Rikard
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Malin, Stephen
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Germinal Center B Cells Are Essential for Collagen-Induced Arthritis2018In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 2, p. 193-203Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disorder. Several mechanisms have been proposed for the known pathologic function of B cells in RA, including antigen presentation, cytokine secretion, and humoral immunity. The aim of this study was to address the function of B lymphocytes in experimental arthritis. METHODS: We mapped the adaptive immune response following collagen-induced arthritis (CIA). We subsequently monitored these responses and disease outcomes in genetically modified mouse strains that lack mature B cell or germinal center (GC) functionality in a B cell-intrinsic manner. RESULTS: Following primary immunization, the draining lymph nodes broadly reacted against type II collagen (CII) with the formation of GCs and T cell activation. Mice that lacked mature B cell function were fully protected against CIA and had a severely attenuated ability to mount isotype-switched humoral immune responses against CII. Almost identical results were observed in mice that were selectively deficient in GC responses. Importantly, GC-deficient mice were fully susceptible to collagen antibody-induced arthritis. CONCLUSION: We identified GC formation and anticollagen antibody production as the key pathogenic functions of B cells in CIA. The role of B cells in RA is likely to be more complex. However, targeting the GC reaction could allow for therapeutic interventions that are more refined than general B cell depletion. © 2017, American College of Rheumatology

  • 38.
    Dobrydnjov, Igor
    et al.
    Department of Rheumasurgery, Spenshult Hospital, Oskarström, Sweden.
    Anderberg, Christian
    Department of Rheumasurgery, Spenshult Hospital, Oskarström, Sweden.
    Olsson, Christer
    Department of Rheumasurgery, Spenshult Hospital, Oskarström, Sweden.
    Shapurova, Olga
    Department of Rheumasurgery, Spenshult Hospital, Oskarström, Sweden.
    Angel, Krister
    Department of Rheumasurgery, Spenshult Hospital, Oskarström, Sweden.
    Bergman, Stefan
    Spenshult Hospital, Oskarström, Sweden.
    Intraarticular vs. extraarticular ropivacaine infusion following high-dose local infiltration analgesia after total knee arthroplasty: a randomized double-blind study2011In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 82, no 6, p. 692-698Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Ropivacaine infusion following high-volume local infiltration analgesia has been shown to be effective after total knee arthroplasty, but the optimum site of administration of ropivacaine has not been evaluated. We compared the effects of intraarticular and extraarticular adminstration of the local anesthetic for postoperative supplementation of high-volume local infiltration analgesia.

    PATIENTS AND METHODS: In this double-blind study, 36 rheumatic patients aged 51-78 years with physical status ASA 2-3 who were scheduled for total knee arthroplasty were randomized into 2 groups. All patients received wound infiltration at the end of surgery with 300 mg ropivacaine, 30 mg ketorolac, and 0.5 mg epinephrine (total volume 156 mL). A tunneled catheter was randomly placed either extraarticularly or intraarticularly. Continuous infusion of ropivacain (0.5%, 2 mL/h) was started immediately and was maintained during the next 48 h. Pain intensity at rest, on movement, and with mobilization was estimated by the patients and the physiotherapist; rescue morphine consumption was recorded.

    RESULTS: As estimated by the patients, ropivacaine administered intraarticularly did not improve analgesia relative to extraarticular infusion, but improved the first mobilization. The incidence of high intensity of pain (VAS 7-10) was less in the group with intraarticular infusion. Analgesic requirements were similar in the 2 groups (47 mg and 49 mg morphine). No complications of postoperative wound healing were seen and there were no toxic side effects.

    INTERPRETATION: Continuous infusion of ropivacaine intraarticulary did not improve postoperative analgesia at rest relative to extraarticular administration, but it appeared to reduce the incidence of high pain intensity during first exercises, and could therefore be expected to improve mobilization up to 24 h after total knee arthroplasty.

  • 39.
    Drake af Hagelsrum, Klara
    et al.
    Halmstad University, School of Health and Welfare. Skåne University Hospital, Lund, Sweden.
    Mogard, Elisabeth
    Skåne University Hospital, Lund, Sweden; Lund University, Lund, Sweden.
    Bremander, Ann
    Lund University, Lund, Sweden; Spenshult Research and Development Centre, Halmstad, Sweden; University of Southern Denmark, Odense, Denmark; University Hospital of Southern Denmark, Sonderborg, Denmark.
    Lindqvist, Elisabet
    Skåne University Hospital, Lund, Sweden; Lund University, Lund, Sweden.
    Larsson, Ingrid
    Halmstad University, School of Health and Welfare. Lund University, Lund, Sweden; Spenshult Research and Development Centre, Halmstad, Sweden.
    Healthcare professionals' perceptions of working on lifestyle management for patients with early rheumatoid arthritis – a qualitative study2023In: International Journal of Qualitative Studies on Health and Well-being, ISSN 1748-2623, E-ISSN 1748-2631, Vol. 18, no 1, article id 2241225Article in journal (Refereed)
    Abstract [en]

    AIM: To explore HPs' perceptions of working on lifestyle management for patients with early rheumatoid arthritis (RA). METHODS: In this qualitative study, individual interviews were conducted with 20 HPs. Qualitative content analysis was used, and three categories and six subcategories were identified. RESULTS: HPs' perceptions of working on lifestyle management for patients with early RA revealed a need for commitment from different levels. This included commitment from healthcare managers and organizations prioritizing work on lifestyle management and providing competence development for HPs. Commitment within the team regarding coordination of interdisciplinary teamwork and development of a structured lifestyle management approach, and commitment to involving patients in lifestyle management, by facilitating patient engagement and a person-centred approach. CONCLUSIONS: HPs' perceptions of working on lifestyle management for patients with early RA revealed that commitment from healthcare managers, organizations, and the interdisciplinary team was essential to facilitate collaboration, patient involvement, and a person-centred approach. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

  • 40.
    Dzhambazov, Balik
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Kihlberg, Jan
    Umeå University, Umeå, Sweden.
    Fugger, Lars
    University of Oxford, Oxford, United Kingdom.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Vestberg, Mikael
    Lund University, Lund, Sweden.
    Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide in complex with MHC class II molecules2006In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 176, no 3, p. 1525-1533Article in journal (Refereed)
    Abstract [en]

    In both collagen-induced arthritis (CIA) and rheumatoid arthritis, T cells recognize a galactosylated peptide from type II collagen (CII). In this study, we demonstrate that the CII259-273 peptide, galactosylated at lysine 264, in complex with Aq molecules prevented development of CIA in mice and ameliorated chronic relapsing disease. In contrast, nonglycosylated CII259-273/Aq complexes had no such effect. CIA dependent on other MHC class II molecules (Ar/Er) was also down-regulated, indicating a bystander vaccination effect. T cells could transfer the amelioration of CIA, showing that the protection is an active process. Thus, a complex between MHC class II molecules and a posttranslationally modified peptide offers a new possibility for treatment of chronically active autoimmune inflammation such as rheumatoid arthritis. © 2006 by The American Association of Immunologists, Inc.

  • 41.
    Folkhammar Andersson, Siv
    et al.
    Unit of Rehabilitation, Kalmar County Council, Samrehab, Oskarshamn, Sweden.
    Bergman, Stefan
    The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Lund University, Lund, Sweden & FoU Spenshult, Halmstad, Sweden.
    Bremander, Ann
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS), Biomechanics and Biomedicine. Lund University, Lund, Sweden & FoU Spenshult, Halmstad, Sweden.
    Arthritis Management in Primary Care and Adherence to National Guidelines – a Swedish Survey Based on the Canadian Physiotherapists Arthritis Care Questionnaire2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no Suppl. S10, article id 2385Article in journal (Refereed)
    Abstract [en]

    Background/Purpose:

    For patients with osteoarthritis (OA) physical therapy is recommended first line treatment and performed in primary care while patients with rheumatoid arthritis (RA) may be treated in primary care at disease onset and during stable phases of the disease. This requires updated skills and evidence based knowledge of the physical therapists (PTs) in arthritis treatment. The aim of this study was to explore physical therapy arthritis practice in primary care and to study the application of evidence based care given to patients with OA or RA.

    Methods:

    All PTs working in primary care in one health care region in Sweden (n=70) were e-mailed a questionnaire (the Canadian Physiotherapists Arthritis Care Survey1) to assess the frequency of current practice, feeling of confidence, educational needs and adherence to national guidelines in managing patients with OA or RA.  The questionnaire was translated and culturally adapted into Swedish according to international recommendations. Interventions supported by national guidelines were compared with reports of treatment modalities in the questionnaire. Mann-Whitney U test, Chi-square test or Fishers Exact test, were used where appropriate, to analyze differences between groups (PT management of patients with OA vs. RA).

    Results:

    Sixty-four PTs responded (91%), reporting a higher feeling of confidence in assessment, treatment and education for patients with OA than for RA (p<0.001). The total numbers of roles assumed by the PTs were higher in management of OA compared to RA (p<0.001). PTs who assumed a large numbers of roles also reported a higher feeling of confident in assessing OA (p=0.036). PTs who assumed a lower numbers of roles also reported a lower feeling of confidence in RA treatment (p=0.045). The recommendations in the guidelines were reported to be followed by almost all PTs in managing patients with RA and for eight out of eleven treatment modalities for patients with OA. Most PTs did provide joint mobilization and education of proper footwear for patients with OA even though Swedish national guidelines did not recommend this as treatment until further research has proven its effectiveness.

    Conclusion:

    PTs reported a lower feeling of confidence and to have assumed a lower numbers of roles in managing patients with RA than OA. There was a good adherence to the national guidelines for almost all listed treatment modalities. However, experienced evidence care and national guidelines did not totally agree. The results indicate a need for education in arthritis care, especially in RA.

    References:

    Li CL, Hurkmans EJ, Sayre EC, Vliet Vlieland TPM (2010). Continuing professional development is associated with increasing physical therapists´ roles in arthritis management in Canada and the Netherlands. Physical Therapy 90:629-42.

  • 42.
    Forster, M.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Raposo, B.
    Karolinska Institutet, Stockholm, Sweden.
    Ekman, D.
    Karolinska Institutet, Stockholm, Sweden.
    Klaczkowska, D.
    Karolinska Institutet, Stockholm, Sweden.
    Popovic, M.
    Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institutet, Stockholm, Sweden.
    Lindvall, T.
    Lund University, Lund, Sweden.
    Hultqvist, M.
    Lund University, Lund, Sweden.
    Teneva, I.
    Lund University, Lund, Sweden.
    Johannesson, M.
    Karolinska Institutet, Stockholm, Sweden.
    Ahlqvist, E.
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Karolinska Institutet, Stockholm, Sweden.
    Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 11, p. 3594-3603Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To identify genetic factors driving pathogenic autoantibody formation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), in order to better understand the etiology of RA and identify possible new avenues for therapeutic intervention. METHODS: We performed a genome-wide analysis of quantitative trait loci controlling autoantibody to type II collagen (anti-CII), anti-citrullinated protein antibody (ACPA), and rheumatoid factor (RF). To identify loci controlling autoantibody production, we induced CIA in a heterogeneous stock-derived mouse cohort, with contribution of 8 inbred mouse strains backcrossed to C57BL/10.Q. Serum samples were collected from 1,640 mice before arthritis onset and at the peak of the disease. Antibody concentrations were measured by standard enzyme-linked immunosorbent assay, and linkage analysis was performed using a linear regression-based method. RESULTS: We identified loci controlling formation of anti-CII of different IgG isotypes (IgG1, IgG3), antibodies to major CII epitopes (C1, J1, U1), antibodies to a citrullinated CII peptide (citC1), and RF. The anti-CII, ACPA, and RF responses were all found to be controlled by distinct genes, one of the most important loci being the immunoglobulin heavy chain locus. CONCLUSION: This comprehensive genetic analysis of autoantibody formation in CIA demonstrates an association not only of anti-CII, but interestingly also of ACPA and RF, with arthritis development in mice. These results underscore the importance of non-major histocompatibility complex genes in controlling the formation of clinically relevant autoantibodies.

  • 43.
    Geng, H.
    et al.
    Central China Normal University, Wuhan, China; Karolinska Institute, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden.
    Xiong, L.
    Central China Normal University, Wuhan, China.
    Jie, R.
    Central China Normal University, Wuhan, China.
    Dong, J.
    Central China Normal University, Wuhan, China.
    Holmdahl, R.
    Karolinska Institute, Stockholm, Sweden.
    Incomplete B cell tolerance to cartilage oligomeric matrix protein in mice2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 9, p. 2301-2309Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Cartilage oligomeric matrix protein (COMP) is a major noncollagenous component of cartilage and is used as a biomarker in rheumatoid arthritis and experimental arthritis. Injection of COMP leads to severe inflammatory joint disease, and antibodies play a critical role in mediating arthritis. The arthritogenicity of COMP might be due to the lack of self tolerance. This study was undertaken to determine the status of COMP-specific B cell tolerance using COMP-deficient mice. METHODS: Arthritis development and antibody responses were compared between COMP-sufficient and COMP-deficient littermates after immunization with rat COMP. Serum anti-COMP antibody levels were measured using a panel of recombinant mouse COMP proteins, and antibody-secreting cells were enumerated by enzyme-linked immunospot assays. A novel sandwich enzyme-linked immunosorbent assay was developed to assess COMP molecules in serum. RESULTS: COMP-sufficient mice, but not COMP-deficient mice, developed severe arthritis following immunization with rat COMP. However, anti-COMP antibody titers to native COMP and recombinant protein domains covering the entire mouse COMP sequence, except the less immunodominant type 3 repeat domains, were decreased in COMP-sufficient mice compared to COMP-deficient mice. In addition, COMP-sufficient mice had fewer B cells secreting COMP-reactive antibodies. Detectable levels of full-length COMP in arthritic COMP-sufficient B10.Q NCF-1(*/*) and healthy mice suggested systemic availability of COMP to the immune system. CONCLUSION: The lack of arthritis, together with high levels of COMP-specific antibodies, in COMP-deficient mice indicates that susceptibility to arthritis is COMP specific and that endogenous expression of COMP in wild-type mice tolerizes B cells in vivo.

  • 44.
    Geng, Hui
    et al.
    Lund University, Lund, Sweden; Huazhong Normal University, Wuhan, China.
    Carlsen, Stefan
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Aspberg, Anders
    Lund University, Lund, Sweden; University of Copenhagen, Copenhagen, Denmark.
    Oldberg, Åke
    Lund University, Lund, Sweden.
    Mattsson, Ragnar
    Lund University, Lund, Sweden.
    Cartilage oligomeric matrix protein deficiency promotes early onset and the chronic development of collagen-induced arthritis2008In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 10, no 6, article id R134Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Cartilage oligomeric matrix protein (COMP) is a homopentameric protein in cartilage. The development of arthritis, like collagen-induced arthritis (CIA), involves cartilage as a target tissue. We have investigated the development of CIA in COMP-deficient mice. METHODS: COMP-deficient mice in the 129/Sv background were backcrossed for 10 generations against B10.Q mice, which are susceptible to chronic CIA. COMP-deficient and wild-type mice were tested for onset, incidence, and severity of arthritis in both the collagen and collagen antibody-induced arthritis models. Serum anti-collagen II and anti-COMP antibodies as well as serum COMP levels in arthritic and wild-type mice were measured by enzyme-linked immunosorbent assay. RESULTS: COMP-deficient mice showed a significant early onset and increase in the severity of CIA in the chronic phase, whereas collagen II-antibody titers were similar in COMP-deficient and wild-type controls. COMP antibodies were not found in wild-type mice. Finally, COMP-deficient and wild-type mice responded similarly to collagen antibody-induced arthritis, indicating no difference in how collagen II antibodies interact with COMP-deficient cartilage during the initial stages of arthritis. CONCLUSIONS: COMP deficiency enhances the early onset and development of chronic arthritis but does not affect collagen II autoimmunity. These findings accentuate the importance of COMP in cartilage stability. © 2008 Geng et al.; licensee BioMed Central Ltd.

  • 45.
    Geng, Hui
    et al.
    Central China Normal University, Wuhan, China.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden.
    Pramhed, Anna
    Lund University, Lund, Sweden.
    Aspberg, Anders
    University of Copenhagen, Copenhagen, Denmark; Lund University, Lund, Sweden.
    Mattsson, Ragnar
    Lund University, Lund, Sweden.
    Holmdahl, Rikard
    Karolinska Institute, Stockholm, Sweden.
    Cartilage oligomeric matrix protein specific antibodies are pathogenic2012In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 14, no 4, article id R191Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Cartilage oligomeric matrix protein (COMP) is a major non-collagenous component of cartilage. Earlier, we developed a new mouse model for rheumatoid arthritis using COMP. This study was undertaken to investigate the epitope specificity and immunopathogenicity of COMP-specific monoclonal antibodies (mAbs). METHODS: B cell immunodominant regions on the COMP molecule were measured with a novel enzyme-linked immunosorbent assay using mammalian expressed full-length mouse COMP as well as a panel of recombinant mouse COMP fragments. 18 mAbs specific to COMP were generated and the pathogenicity of mAbs was investigated by passive transfer experiments. RESULTS: B cell immunodominant epitopes were localized within 4 antigenic domains of the COMP but with preferential response to the epidermal growth factor (EGF)-like domain. Some of our anti-COMP mAbs showed interactions with the native form of COMP, which is present in cartilage and synovium. Passive transfer of COMP-specific mAbs enhanced arthritis when co-administrated with a sub-arthritogenic dose of a mAb specific to collagen type II. Interestingly, we found that a combination of 5 COMP mAbs was capable of inducing arthritis in naive mice. CONCLUSIONS: We have identified the specificities of mAbs to COMP and their contribution to the development of arthritis. These findings will further improve our understanding of the autoantibody mediated immunopathologies occurring widely in rheumatoid arthritis (RA), as well as in other autoimmune disorders.

  • 46.
    Gilljam, Britt-Mari
    et al.
    Halmstad University, School of Health and Welfare, Centre of Research on Welfare, Health and Sport (CVHI).
    Arvidsson, Susann
    Halmstad University, School of Health and Welfare, Centre of Research on Welfare, Health and Sport (CVHI), Health promotion and disease prevention.
    Nygren, Jens
    Halmstad University, School of Health and Welfare, Centre of Research on Welfare, Health and Sport (CVHI), Health promotion and disease prevention.
    Svedberg, Petra
    Halmstad University, School of Health and Welfare, Centre of Research on Welfare, Health and Sport (CVHI), Health promotion and disease prevention.
    Promoting participation in healthcare situations for children with JIA: a grounded theory study2016In: International Journal of Qualitative Studies on Health and Well-being, ISSN 1748-2623, E-ISSN 1748-2631, Vol. 11, article id 30518Article in journal (Refereed)
    Abstract [en]

    Children’s right to participate in their own healthcare has increasingly become highlighted in national and international research as well as in government regulations. Nevertheless, children’s participation in healthcare is unsatisfactorily applied in praxis. There is a growing body of research regarding children’s participation, but research from the children’s own perspective is scarce. The aim of this study was thus to explore the experiences and preferences for participation in healthcare situations among children with juvenile idiopathic arthritis (JIA) as a foundation for creating strategies to promote their participation in pediatric healthcare. Twenty children, aged 8 to 17 years, with JIA were interviewed individually and in focus groups. In order to increase the children’s opportunities to express their own experiences, different interview techniques were used, such as draw-and-tell and role play with dolls. The analysis was conducted with a constructivist grounded theory. The result explores children’s perspective of influencing processes promoting their participation in healthcare situations. The core category that emerged was, “Releasing fear and uncertainty opens up for confidence and participation,” and the categories related to the core category are, “surrounded by a sense of security and comfort,” and “strengthened and supported to become involved.” In conclusion, the knowledge gained in this study offers new insights from the perspective of children themselves, and can constitute a valuable contribution to the understanding of necessary conditions for the development of specific interventions that promote participation among children in healthcare situations.

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  • 47.
    Hagel, Sofia
    et al.
    Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.
    Petersson, Ingemar F
    Department of Orthopedics, Lund University, Lund, Sweden.
    Bremander, Ann
    Halmstad University, School of Business, Engineering and Science, Biological and Environmental Systems (BLESS), Biomechanics and Biomedicine.
    Lindqvist, Elisabet
    Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.
    Bergknut, Charlotte
    Department of Orthopedics, Lund University, Lund, Sweden.
    Englund, Martin
    Department of Orthopedics, Lund University, Lund, Sweden.
    Trends in the first decade of 21st century healthcare utilisation in a rheumatoid arthritis cohort compared with the general population2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no 7, p. 1212-1216Article in journal (Refereed)
    Abstract [en]

    Purpose: To study 21st century trends in healthcare utilisation by patients with rheumatoid arthritis (RA) compared with the general population.

    Methods: Observational cohort study. Using Swedish healthcare register data, we identified 3977 Region Skåne residents (mean age in 2001, 62.7 years; 73% women) presenting with RA (International Classification of Diseases-10 codes M05 or M06) in 1998-2001. We randomly sampled two referents from the general population per RA patient matched for age, sex and area of residence. We calculated the year 2001-2010 trends for the annual ratio (RA cohort/referents) of the mean number of hospitalisations and outpatient clinic visits.

    Results: By the end of the 10-year period, 62% of patients and 74% of referents were still alive and resident in the region. From 2001 to 2010, the ratio (RA cohort/referents) of the mean number of hospitalisations for men and women decreased by 27% (p=0.01) and 28% (p=0.004), respectively. The corresponding decrease was 29% (p=0.005) and 16% (p=0.004) for outpatient physician care, 34% (p=0.009) and 18% (p=0.01) for nurse visits, and 34% (p=0.01) and 28% (p=0.004) for physiotherapy. The absolute reduction in number of hospitalisations was from an annual mean of 0.79 to 0.69 in male patients and from 0.71 to 0.59 in female patients. The corresponding annual mean number of consultations in outpatient physician care by male and female RA patients changed from 9.2 to 7.7 and from 9.9 to 8.7, respectively.

    Conclusions: During the first decade of the 21st century, coinciding with increasing use of earlier and more active RA treatment including biological treatment, overall inpatient and outpatient healthcare utilisation by a cohort of patients with RA decreased relative to the general population. Copyright Article author (or their employer) 2012.

  • 48.
    Hagert, C.
    et al.
    University of Turku, Turku, Finland.
    Sareila, O.
    University of Turku, Turku, Finland; Karolinska Institute, Stockholm, Sweden.
    Kelkka, T.
    The National Doctoral Programme in Informational and Structural Biology, Turku, Finland; University of Turku, Turku, Finland.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Collin, M.
    Lund University, Lund, Sweden.
    Xu, B.
    Karolinska Institute, Stockholm, Sweden.
    Guerard, S.
    Karolinska Institute, Stockholm, Sweden.
    Bäcklund, J.
    Karolinska Institute, Stockholm, Sweden.
    Jalkanen, S.
    University of Turku, Turku, Finland.
    Holmdahl, R.
    Karolinska Institute, Stockholm, Sweden; Southern Medical University, Guangzhou, China; Lund University, Lund, Sweden; University of Turku, Turku, Finland.
    Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells: A Novel Experimental Model of Rheumatoid Arthritis2018In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 8, p. 1343-1353Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system. METHODS: Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains. RESULTS: A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcgamma receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity. CONCLUSION: Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system.

  • 49.
    Hagert, Cecilia
    et al.
    University of Turku, Turku, Finland.
    Sareila, Outi
    University of Turku, Turku, Finland; Karolinska Institute, Stockholm, Sweden.
    Kelkka, Tiina
    University of Turku, Turku, Finland.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Collin, Mattias
    Lund University, Lund, Sweden.
    Xu, Bingze
    Karolinska Institute, Stockholm, Sweden.
    Guérard, Simon
    Karolinska Institute, Stockholm, Sweden.
    Bäcklund, Johan
    Karolinska Institute, Stockholm, Sweden.
    Jalkanen, Sirpa
    University of Turku, Turku, Finland.
    Holmdahl, Rikard
    Karolinska Institute, Stockholm, Sweden; Southern Medical University, Guangzhou, China; Lund University, Lund, Sweden; University of Turku, Turku, Finland.
    Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells: A Novel Experimental Model of Rheumatoid Arthritis2018In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 8, p. 1343-1353Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system.

    METHODS: Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains.

    RESULTS: A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcγ receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity.

    CONCLUSION: Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system. © 2018, American College of Rheumatology.

  • 50.
    Haglund, Emma
    et al.
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). Spenshult Research and Development Center, Halmstad, Sweden.
    Bremander, Ann
    Spenshult Research and Development Center, Halmstad, Sweden & Section of Rheumatology, Lund University, Lund, Sweden & University of Southern Denmark, Odense, Denmark & University Hospital of Southern Denmark, Sønderborg, Denmark.
    Bergman, Stefan
    Spenshult Research and Development Center, Halmstad, Sweden & Section of Rheumatology, Lund University, Lund, Sweden & Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    The StarT back screening tool and a pain mannequin improve triage in individuals with low back pain at risk of a worse prognosis - a population based cohort study2019In: BMC Musculoskeletal Disorders, E-ISSN 1471-2474, Vol. 20, no 1, article id 460Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The STarT Back Screening Tool (SBT) identifies patients with low back pain (LBP) at risk of a worse prognosis of persistent disabling back pain, and thereby facilitates triage to appropriate treatment level. However, the SBT does not consider the pain distribution, which is a known predictor of chronic widespread pain (CWP). The aim of this study was to determine if screening by the SBT and screening of multisite chronic widespread pain (MS-CWP) could identity individuals with a worse prognosis. A secondary aim was to analyze self-reported health in individuals with and without LBP, in relation to the combination of these two screening tools.

    METHODS: One hundred and nineteen individuals (aged 40-71 years, mean (SD) 59 (8) years), 52 with LBP and 67 references, answered two screening tools; the SBT and a pain mannequin - as well as a questionnaire addressing self-reported health. The SBT stratifies into low, medium or high risk of a worse prognosis. The pain mannequin stratifies into either presence or absence of CWP in combination with ≥7 painful areas of pain (0-18), here defined as MS-CWP (high risk of worse prognosis). The two screening tools were studied one-by-one, and as a combined screening. For statistical analyses, independent t-tests and Chi-square tests were used.

    RESULTS: Both the SBT and the pain mannequin identified risk of a worse prognosis in individuals with (p = 0.007) or without (p = 0.001) LBP. We found that the screening tools identified partly different individuals at risk. The SBT identified one individual, while the pain mannequin identified 21 (19%). When combining the two screening methods, 21 individuals (17%) were at high risk of a worse prognosis. When analyzing differences between individuals at high risk (combined SBT and MS-CWP) with those at low risk, individuals at high risk reported worse health (p = 0.013 - < 0.001).

    CONCLUSIONS: Both screening tools identified individuals at risk, but they captured different aspects, and also different number of individuals at high risk of a worse prognosis. Thus, using a combination may improve early detection and facilitate triage to appropriate treatment level with multimodal approach also in those otherwise missed by the SBT. 

    © The Author(s). 2019

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