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.

Background/Purpose: Chronic widespread pain (CWP), one of the hallmarks of fibromyalgia, is not uncommon in adolescents and it has previously been shown that adolescents with pain often become young adults with pain. CWP often co-varies with anxiety, depression, and stress symptoms in adults, but the knowledge regarding this is small in youth and young adults.

The aim was to study the associations between CWP, anxiety, depression and stress in adolescents attending first year of high school.

Methods: A computerized questionnaire to 296 adolescents attending Swedish high school, with validated questions regarding presence and distribution of pain (Epipain mannequin), stress symptoms (ELO question), anxiety and depression (Hospital Anxiety and Depression Scale – HADS), and health related quality of life (HRQL as measured by EQ5D). Pain was considered chronic when persistent for more than three months, and the subgroup CWP was defined according to the 1990 ACR criteria for fibromyalgia. Statistical analyses in SPSS v21 with comparison of means by Student’s t-test and proportions by chi2-test or Fischer’s exact test.

Results: 257 (87%) out of 296 eligible students, mean (SD) age 16.1 (0.7) and 65.8% girls, responded to the questionnaire.  Prevalence of chronic pain was 20.8% and that of the subgroup CWP was 4.7%, without any gender differences (boys 18.2% vs girls 22.2%; p=0.224, and 3.4% vs 5.4%; p=0.692). High level (4 or 5 on a 5 point scale) of stress symptoms were less common in boys (16.0% vs 28.2%; p=0.015), as was possible or probable anxiety (17.1% vs 44.4%; p<0.001), but not depression (10.3% vs 12.5%; p=0.764). Students with high level of stress reported CWP five times more often than those with less stress (30.4% vs 5.8%; p=0.001). Students with probable anxiety reported CWP ten times more often than students with no anxiety (17.6% vs 1.8%; p=0.001), and CWP was also more common, but not statistically significant, in students with probable depression (20.0% vs 3.1%; p=0.163). Those reporting CWP had significantly lower HRQL (0.58 vs 0.87; p=0.038) than students with no chronic pain.

Conclusion: The high prevalence of chronic pain and the strong associations between CWP and reports of stress and anxiety in adolescents highlights that a multifactorial background to chronic pain must be considered early in life. An apparent lower score in EQ5D also indicates that the presence of CWP has an marked impact on HRQL also in adolescents.

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.

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.

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

OBJECTIVE: In rheumatoid arthritis, joint inflammation and cartilage destruction are mediated by autoantibodies directed to various self antigens. Type II collagen (CII)-specific antibodies are likely to play a role in this process and have been shown to induce experimental arthritis in susceptible animals. The purpose of this study was to reveal how arthritogenic autoantibodies recognize native CII in its triple-helical conformation. METHODS: Site-directed mutagenesis and crystallographic studies were performed to reveal crucial contact points between the CII antibody and the triple-helical CII peptide. RESULTS: The crystal structure of a pathogenic autoantibody bound to a major triple-helical epitope present on CII was determined, allowing a first and detailed description of the interactions within an arthritogenic complex that is frequently occurring in both mice and humans with autoimmune arthritis. The crystal structure emphasizes the role of arginine residues located in a commonly recognized motif on CII and reveals that germline-encoded elements are involved in the interaction with the epitope. CONCLUSION: The crystal structure of an arthritogenic antibody binding a triple-helical epitope on CII indicates a crucial role of germline-encoded and arginine residues as the target structures.

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.

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.

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.

Background/Purpose:

The treatment target for axial spondyloarthritis (SpA) is to maximize health-related quality of life (HRQoL) by controlling disease activity and improving functioning. The treatment cornerstones are a combination of patient education, pharmacological and non-pharmacological treatment. Health professionals are familiar with providing patient education but the knowledge is scarce concerning how this education is experienced by the patients.

The aim was to describe patients’ experiences of education in SpA management.

Methods:

The study had a descriptive design with a qualitative conventional content analysis approach performed in seven steps in accordance with Graneheim & Lundman (1). The analysis aimed to describe and preserve contextual meanings. After coding and subgrouping meaningful parts of the text were merged into categories. Eleven interviews were conducted between 2014-2015 in patients with SpA based on a strategic sampling in order to achieve variation with regard to sex (7 men, 4 women), age (38-66 years), subdiagnoses (5 patients with AS, 6 with USpA), quality of life (EQ5D 0.29-1.0), disease activity (BASDAI 1-6), physical function (BASFI 0-5), and global health (BASG 0-7) .

Results:

Three categories representing patients’ experiences of patient education in disease management emerged; guiding education, reliable education and available education. Guiding education comprised SpA management including disease knowledge such as symptoms, prognosis, treatment, self-management, climate impact, heredity, and assisting devices. Reliable education meant how and by whom the education was communicated and was considered reliable if it was based on science and communicated by specialists, for example by physician, nurse, PT, dietician and senior patients with experience of rheumatic diseases. The patients experienced difficulties in assessing the large flow of education coming from various sources. Individualized education also increased the reliability. Available education meant that the education can and should be presented in varied formats, and that the amount of information could be chosen. The education could be given orally (through meetings, videos, lectures), in writing (by pamphlets, e-mails, journals, webpages) or obtained through own personal experiences. There were requests to utilize newer media like skype, video and chat forums. Furthermore, individual contacts with healthcare professionals when needed were of importance.

Conclusion:

This study highlights the importance of obtaining a guiding, reliable and available patient education for management of SpA. Health care professionals need to consider the importance of presenting varied formats of education based on patients’ experiences and expectations.

References:

1.Graneheim UH, Lundman B. Qualitative content analysis in nursing research: concepts, procedures and measures to achieve trustworthiness. Nurse education today 2004;24(2):105-12.

OBJECTIVE: A deficiency in C5 protects against arthritis development. However, there is currently no approach successfully translating these findings into arthritis therapy, as by targeting the key component, C5a. The aim of this study was to develop a vaccination strategy targeting C5a as therapy for patients with rheumatoid arthritis. METHODS: An anti-C5a vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (4NPA) into selected sites in the murine C5a molecule. C5a-4NPA variants were screened for their immunogenicity in mice on different arthritis-susceptible class II major histocompatibility complex (MHC) backgrounds. A candidate vaccine was tested for its impact on disease in a murine model of collagen-induced arthritis (CIA). Immunity toward endogenous C5a as well as type II collagen was monitored and characterized. RESULTS: Replacing a single tyrosine residue in position 35 (Y(35) ) with 4NPA allowed the generation of an anti-C5a vaccine, which partly protected mice against the development of CIA while strongly ameliorating the severity of clinical disease. Although differing in just 3 atoms from wild-type C5a (wtC5a), C5aY(35) 4NPA induced loss of T cell and B cell tolerance toward the endogenous protein in mice expressing class II MHC H-2(q) molecules. Despite differential B cell epitope recognition, antibodies induced by both wtC5a and C5aY(35) 4NPA neutralized C5a. Thus, anti-wtC5a IgG titers during arthritis priming were potentially of critical importance for disease protection, because high titers of C5a-neutralizing antibodies after disease onset were unable to reverse the course of arthritis. CONCLUSION: The results of this study suggest that the most effective anti-C5a treatment in arthritis can be accomplished using a preventive vaccination strategy, and that treatment using conventional biologic or small molecule strategies targeting the C5a/C5aR axis may miss the optimal window for therapeutic intervention during the subclinical priming phase of the disease.

Background/Purpose:

Person-centred care (PCC) is a holistic approach with respectful and individualized care allowing negotiation of care where persons with health problems are empowered to be involved in health decisions. Patients’ illness narratives constitute a starting point for building a collaboration with health care professionals and to empower them to play an active role in their health care. Little is known of the impact of PCC vs. regular care on patients’ skills as health care consumers. The aim was to study the impact on effective consumers’ skills over 6 and 12 months as measured by the Effective Consumer Scale (EC17) in patients undergoing biological therapy and randomly assigned to either a nurse-led rheumatology clinic (NLC) based on PCC or to a rheumatologist-led clinic (RLC) based on regular care.

Methods:

A 12 month RCT in 107 patients with chronic inflammatory arthritis¹. Inclusion criteria were ongoing biological therapy and a DAS28 ≤3.2. All patients met a rheumatologist at inclusion and after 12 months, while the 6 month follow-up was randomized to either at an NLC (PCC) or at an RLC (regular care). Outcome measure was the EC17, developed and endorsed by the OMERACT, including five subscales; 1. Use of health information, 2. Clarifying personal priorities, 3. Communicating with others, 4. Negotiating roles and 5. Deciding and taking action. EC17 total score ranges from 0-100, worse to best. Differences between and within NLC and RLC were analyzed with Friedmans’ test or Mann Whitney U-test.

Results:

After 12 months 97 patients completed the RCT (NLC n=47, RLC n=50), mean (SD) age 55.4 (12.7) years, disease duration 16.7 (11.5) years, DAS28 2.1 (0.7), HAQ 0.54 (0.38), global health 20.4 (17.1), pain 21.1 (18.0) and 56% were women. There were no statistically significant differences within or between the two intervention groups at baseline nor in EC17 total score mean (SD) at baseline (NLC 83.5 (9.4) vs. RLC 83.2 (10.8), 6 months (NLC 85.4 (10.4) vs. RLC 82.9 (10.9) and 12 months (NLC 85.3 (11.1) vs. RLC 82.3 (10.9)). However, in NLC there was a statistically significant improvement in EC17 subscale “1. Use of health information” at both 6 and 12 months (p=0.041 and p=0.004 respectively).

Conclusion:

Replacing just one of three visits over 12 months to an NLC based on PCC instead of an RLC based on regular care resulted in more effective consumers concerning the use of health information. Larger studies over longer time frames focusing on PCC are needed to better understand its full impact on effective consumer skills measured by EC17.

References:

1. Larsson I, et al. Randomized controlled trial of a nurse-led rheumatology clinic for monitoring biological therapy. J Adv Nurs 2014;70:164-75.

OBJECTIVE: To investigate the significance and pathogenic potential of a highly conserved major type II collagen triple-helical epitope-specific antibody (U1; amino acids 494-504) in vivo and in vitro in patients with early rheumatoid arthritis (RA) and in experimental animal models of collagen-induced arthritis (CIA). METHODS: U1-specific antibodies in sera from patients with early RA (with or without joint erosions) were analyzed. Disease progression in the CIA models in mice and rats with anti-U1 antibodies was compared. The pathogenicity of binding of monoclonal antibodies (mAb) UL1 and CIIF4 to the U1 epitope and the F4 epitope (aa 926-936), respectively, was compared in vivo and on chondrocyte cultures and preformed cartilage in vitro, using Fourier transform infrared microspectroscopy analysis. In addition, UL1-induced proteoglycan depletion in vivo in the presence and absence of the complement factor C5 was analyzed. RESULTS: Increased levels of U1 antibodies were observed in patients with early RA, especially in association with joint erosions. A significant correlation of U1-specific antibodies with disease progression was found in rats and mice with CIA. UL1 mAb induced, whereas CIIF4 mAb inhibited, the progression of arthritis. Similarly, UL1, but not CIIF4, impaired matrix synthesis on chondrocyte cultures and adversely affected preformed cartilage. Furthermore, UL1 induced significant proteoglycan depletion in vivo 3 days after injection, even in the absence of C5. CONCLUSION: Antibody epitope specificity contributes significantly to the development of arthritis, and the early pathogenic events operate independent of inflammation both in vitro and in vivo.

OBJECTIVE: Antileukoproteinase (ALP) is a physiologic inhibitor of granulocytic serine proteases. The present study was undertaken to investigate its therapeutic benefit in an antibody-transfer model of erosive polyarthritis and to elucidate its potential to interfere with immune complex-dependent inflammatory pathways. METHODS: Arthritis development was induced in male (BALB/c x B10.Q)F(1) mice by intravenous injection of two monoclonal antibodies specific for type II collagen and was quantified by clinical scoring and histopathology. Arthritis severity was assessed in a cohort of mice under systemic treatment with recombinant human ALP (daily doses of 0.1 mg for 5 days starting immediately after disease induction) in comparison with untreated controls. Concomitantly, functional assays (phagocytosis, oxidative burst, fluorescence-activated cell sorting analysis of integrin expression) were performed on neutrophils upon in vitro stimulation by IgG-coated latex beads. RESULTS: ALP treatment reduced arthritis incidence and severity and had a protective effect against cartilage and bone erosion. ALP inhibited the conversion of the leukocyte beta2 integrins into an active conformation upon Fc receptor stimulation of granulocytes. ALP bound to the actin-bundling protein L-plastin and down-modulated filamentous actin assembly in response to stimulation with IgG-coated latex beads in granulocytes. ALP exerted additional inhibitory effects on neutrophil functions associated with cytoskeletal reorganization, such as phagocytosis and oxidative burst. CONCLUSION: In addition to its antiprotease activity, ALP exerts a variety of blocking effects on neutrophil functions, probably due to modulation of cytoskeletal changes, that may contribute to this inhibitor's antiarthritis potential and qualify it as a multifunctional regulator of inflammatory responses.