Rheumatoid Arthritis: Larsson P

Larsson P, Bratt J, Harju A, van Vollenhoven R, Klareskog L. · Reumatologiska kliniken, Karolinska sjukhuset, Stockholm. · Lakartidningen. · Pubmed #11265568 No free full text.

Abstract: TNF-alpha is a proinflammatory cytokine. It has a key function in the inflammatory cascade both systemically and locally in the inflamed joints of patients affected by rheumatoid arthritis (RA). Treatment with two different "biological" drugs that block the proinflammatory capacity of TNF-alpha has recently been approved by the European drug authorities. This paper discusses experience gained in clinical trials and during the first year of treatment in Sweden using infliximab (anti-TNF-alpha monoclonal antibodies) and etanercept (recombinant TNF-alpha receptor fusion protein).

Baslund B, Tvede N, Danneskiold-Samsoe B, Larsson P, Panayi G, Petersen J, Petersen LJ, Beurskens FJ, Schuurman J, van de Winkel JG, Parren PW, Gracie JA, Jongbloed S, Liew FY, McInnes IB. · Rigshospitalet, Copenhagen, Denmark. · Arthritis Rheum. · Pubmed #16142748 links to  free full text

Abstract: OBJECTIVE: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA. METHODS: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study. RESULTS: In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%). CONCLUSION: These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.

Ohrbach R, Larsson P, List T. · Department of Oral Diagnostic Sciences, University at Buffalo, Buffalo, NY 14214, USA. · J Orofac Pain. · Pubmed #18780535 No free full text.

Abstract: AIMS: To develop the Jaw Functional Limitation Scale (JFLS), comprising 3 constructs and a global scale, based on a preliminary instrument, and to investigate content validity of the overall functional limitation construct, reliability, and generalizability. A temporomandibular disorders (TMD) patient group, compared to other diagnostic groups, was hypothesized to report further limitation in each of the 3 new proposed constructs. METHODS: One hundred thirty-two consecutive patients from 5 diagnostic groups (TMD, primary Sjogren syndrome, burning mouth syndrome, skeletal malocclusion, and healthy controls) participated in a known-groups validity design. Fifty-two jaw functional limitation items were identified by an expert panel for content validity. Rasch methodology was used for item reduction and assessment of model fit. The instrument was retested 1 to 2 weeks later. RESULTS: Three constructs (mastication, vertical jaw mobility, and emotional and verbal expression) comprising a total of 20 items were identified along with a global scale (the JFLS-20), and each exhibited excellent psychometric properties with respect to modeled variance, item fit, reliability, and internal consistency. The psychometric properties of each construct remained satisfactory when analyzed separately among the 5 diagnostic groups. Temporal stability was satisfactory. A shorter 8-item form (JFLS-8) also proved useful for assessing global functional jaw limitation. CONCLUSION: The JFLS-20 is an organ-specific instrument comprising 3 constructs for assessing functional status of the masticatory system; the 3 scales exhibit properties that are ideal for both research and patient evaluation in patient groups with a range of functional limitations of the jaw. The JFLS-8 emerged as a short form for measuring global functional limitation of the jaw.

Weiss RJ, Wretenberg P, Stark A, Palmblad K, Larsson P, Gröndal L, Broström E. · Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska Institutet, Stockholm, Sweden. · Gait Posture. · Pubmed #18226528 No free full text.

Abstract: The purpose of this study was to analyse kinematic and kinetic gait changes in rheumatoid arthritis (RA) patients in comparison to healthy controls and to examine whether levels of functional disability (Health Assessment Questionnaire (HAQ)-scores) were associated with gait parameters. Using a three-dimensional motion analysis system, kinematic and kinetic gait parameters were measured in 50 RA patients and 37 healthy controls. There was a significant reduction in joint motions, joint moments and work in the RA cohort compared with healthy controls. The following joint motions were decreased: hip flexion-extension range (Delta6 degrees ), hip abduction (Delta4 degrees ), knee flexion-extension range (Delta8 degrees ) and ankle plantarflexion (Delta10 degrees ). The following joint moments were reduced: hip extensor (Delta0.30Nm/kg) and flexor (Delta0.20Nm/kg), knee extensor (Delta0.11Nm/kg) and flexor (Delta0.13Nm/kg), and ankle plantarflexor (Delta0.44Nm/kg). Work was lower in hip positive work (Delta0.07J/kg), knee negative work (Delta0.08J/kg) and ankle positive work (Delta0.15J/kg). Correlations were fair although significant between HAQ and hip flexion-extension range, hip abduction, knee flexion-extension range, hip abductor moment, stride length, step length and single support (r=-0.30 to -0.38, p<0.05). Our findings suggest that RA patients have overall less joint movement and specifically restricted joint moments and work across the large joints of the lower limbs during walking than healthy controls. There were only fair associations between levels of functional disability and gait parameters. The findings of this study help to improve the understanding how RA affects gait changes in the lower limbs.

Cao D, Börjesson O, Larsson P, Rudin A, Gunnarsson I, Klareskog L, Malmström V, Trollmo C. · Rheumatology Unit, Department of Medicine at Karolinska University Hospital Solna, Karolinska Institutet, Stockholm. · Scand J Immunol. · Pubmed #16764698 No free full text.

Abstract: Regulatory T cells have recently been implicated in a number of human diseases, including rheumatoid arthritis. To investigate whether the presence of CD25+CD4+ regulatory T cells is a general finding in arthritic joints, synovial fluid of patients with different rheumatic diseases such as undifferentiated arthritides, systemic rheumatic diseases and reactive arthritis were investigated for the presence of such cells. In 95% of the patients, a higher frequency of CD25(bright)CD4+ T cells was found in synovial fluid as compared with peripheral blood. Both in vitro suppression experiments and FOXP3 mRNA analysis confirmed these cells to be natural regulatory T cells. Together with our previous data, we conclude that arthritic joints, irrespective of precise diagnosis and disease duration, are enriched with natural regulatory T cells. These results suggest that suppressor cells migrate to and/or multiply at the sites of inflammation as part of the immune responses' effort to combat injurious inflammation.

Larsson P, List T, Lundström I, Marcusson A, Ohrbach R. · Specialistcentrum Oral Rehabilitering, Linköping, Sweden. · Acta Odontol Scand. · Pubmed #15370634 No free full text.

Abstract: The aim of this study was to translate the Oral Health Impact Profile (OHIP) into Swedish and evaluate the reliability and validity of the Swedish version (OHIP-S). The OHIP is a 49-item, self-administered questionnaire divided into 7 different subscales. The original version in English was translated into Swedish, accompanied by back-translation into English, after which the Swedish version was revised. A total of 145 consecutive patients participated and answered a questionnaire. The patients comprised five clinically separate groups: temporomandibular dysfunction (TMD) (n = 30), Primary Sjögren's Syndrome (SS) (n = 30), burning sensation and pain in the oral mucosa (oral mucosal pain, OMP) (n = 28), skeletal malocclusion (malocclusion) (n = 27), and healthy dental recall patients (controls) (n = 30). The TMD group and the control group participated in a test-retest procedure. The internal reliability of each subscale was calculated with Cronbach's alpha and found to be high and to range from 0.83-0.91. The stability (test-retest) of the instrument, calculated using the intraclass correlation coefficient, ranged from 0.87 to 0.98. The construct validity of OHIP-S was compared with subscales of the Symptom Check List (SCL-90) (rho 0.65) and the Jaw Function Limitation Scale (FLS) (rho 0.76) and analyzed with Spearman's correlation coefficient. Convergent validity was evaluated by comparing OHIP with self-reported health using Spearman's correlation coefficient and was found to be acceptable (rho 0.61). In the evaluation of the discriminative ability of the instrument, significant differences were found in the total OHIP-S score between the controls and the other four groups (P < 0.001). We conclude that the reliability and validity of OHIP-S is excellent. The instrument can be recommended for assessing the impact of oral health on masticatory ability and psychosocial function.

Salomonsson S, Larsson P, Tengnér P, Mellquist E, Hjelmström P, Wahren-Herlenius M. · Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden. · Scand J Immunol. · Pubmed #11967114 No free full text.

Abstract: Sjögren's syndrome is an autoimmune disease characterized by lymphocytic infiltrates resembling secondary lymphoid organs in salivary glands. In this study, we demonstrate the expression of the lymphoid tissue homing chemokine CXCL13 (BCA-1/BLC), which has attracting properties for B cells and subsets of activated T cells, in salivary glands of patients with Sjögren's syndrome using immunohistochemistry and in situ hybridization. CXCL13 expression was primarily observed in epithelial cells in acini and ducts of inflamed glands while its receptor, CXCR5 (BLR-1), was expressed on the infiltrating mononuclear cells. In addition, cells producing antibodies against one of the major autoantigens in Sjögren's syndrome, Ro 52, were identified at the periphery of the follicular infiltrates indicating that the ectopic lymphoid tissue is directly involved in the disease process. Identification of CXCL13 and CXCR5 in salivary glands suggests that the target organ plays an essential role in the inflammatory process by recruiting B and T cells. These results also provide a molecular mechanism by which lymphoid neogenesis and ectopic germinal centre formation might occur in the glands of these patients, which may be the key step in the development of the chronic inflammatory process in Sjögren's syndrome.

Mattsson L, Larsson P, Erlandsson-Harris H, Klareskog L, Harris RA. · Division of Rheumatology and Neuroimmunology Unit, Centre for Molecular Medicine L8:04, Karolinska Hospital, Stockholm, Sweden. · Clin Exp Immunol. · Pubmed #11122258 links to  free full text

Abstract: Microbial infection can impact on the course of autoimmune disease, both in disease-inducing and disease-protecting capacities. Here we investigated if infection with Trypanosoma brucei brucei (Tbb), the protozoan causative agent of African Sleeping Sickness, could ameliorate the course of CIA in the Dark Agouti rat, an experimental model which shares many features with human rheumatoid arthritis. Infection of animals with living, but not inoculation with dead Tbb resulted in complete or significant reduction of clinical arthritic symptoms. Infection prior to collagen immunization was more effective than a later treatment, and this effect was related to the level of parasitaemia. Using reverse transcriptase-polymerase chain reaction we detected an increase in interferon-gamma mRNA in the draining lymph nodes of Tbb-treated animals relative to controls at day 28 after disease induction. Transforming growth factor-beta could be detected in the lymph nodes in four out of six animals that had received Tbb. In the joints, immunohistochemistry revealed reduced production of tumour necrosis factor-alpha in Tbb-treated animals relative to controls. The most striking difference between Tbb-infected and control groups, as measured by ELISA, was the down-regulation of anti-collagen II IgG antibody responses in parasite-infected animals. We conclude that live parasites can exert an immunomodulatory and protective effect in CIA in which several mechanisms may work in parallel, although the almost complete down-regulation of the anti-collagen antibody response may alone explain the protective effect in CIA. The described model may be useful in further attempts to use the mechanisms involved in parasite immune defence to prevent and treat certain autoimmune conditions.

Gunnarsson I, Nordmark B, Hassan Bakri A, Gröndal G, Larsson P, Forslid J, Klareskog L, Ringertz B. · Department of Rheumatology and. Department of Clinical Immunology, Karolinska Hospital, Stockholm, Sweden. · Rheumatology (Oxford). · Pubmed #10952745 links to  free full text

Abstract: OBJECTIVE: The development of systemic lupus erythematosus (SLE)-related syndromes during treatment with sulphasalazine has been described and demonstrated to be influenced by genetic factors. The prevalence of this drug-induced condition and the immunological mechanisms involved are less known. The aim of this study was to determine the prevalence of sulphasalazine-induced lupus-like reactions in a well-defined early rheumatoid arthritis (RA) cohort and to analyse the roles of HLA haplotypes, autoantibodies and the B-cell stimulating cytokine interleukin-10 (IL-10) as possible underlying risk factors. Patients and methods. Forty-one consecutive patients with early RA, in whom sulphasalazine was used as the first disease-modifying anti-rheumatic drug in single therapy and was maintained for at least 6 months, were investigated for the occurrence of lupus-related events. Longitudinal analyses of rheumatoid factor (RF), antinuclear antibodies (ANA), anti-double-stranded DNA antibodies and serum IL-10 (ELISA) and the typing of HLA DR and DQ alleles were performed. RESULTS: Four of the 41 patients developed lupus-like disease. Three of four patients who had lupus-related events vs four of 37 patients without side-effects had an HLA DR 0301 haplotype. The patients developing lupus-related side-effects had increased levels of serum IL-10 and a high frequency of ANA in speckled patterns before the onset of therapy. CONCLUSION: The development of SLE-like symptoms and SLE-related autoantibody production was observed more commonly than expected, with an increased risk in patients with SLE-related HLA haplotypes, increased serum IL-10 levels and ANA in speckled patterns. The data suggest that immunomodulation associated with sulphasalazine treatment may contribute to the development of lupus-related reactions in genetically predisposed individuals.